Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:12]1[CH2:17][CH2:16][CH:15]([C@H:18]([NH2:22])[C:19](O)=[O:20])[CH2:14][CH2:13]1.C1C([C@@H](N)C(O)=O)=CC=C(O)C=1.N[C@@H](C(O)=O)CCSC.N[C@H](C(O)=O)CC1C2C(=CC=CC=2)NC=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:22][C@@H:18]([CH:15]2[CH2:16][CH2:17][CH2:12][CH2:13][CH2:14]2)[CH2:19][OH:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: N[C@H](C(=O)O)C1CCCCC1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Agent: CSCC[C@@H](N)C(=O)O
Agent: N[C@@H](C(=O)O)c1ccc(O)cc1
Agent: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Product: O=S(=O)(N[C@H](CO)C1CCCCC1)c1ccc(Br)cc1

Procedure:
The following compounds (Examples 16-19, Table 3) were prepared using 4-bromobenzensulfonyl chloride with L-cyclohexylglycine, D-4-hydroxyphenylglycine, D-methionine, and L-tryptophan and following the procedure outlined in Example 16.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[CH:23]=[CH:24]/[CH2:25][OH:26])=[CH:17][CH:16]=1>[O-2].[O-2].[Mn+4]>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18](/[CH:21]=[CH:22]/[CH:23]=[CH:24]/[CH:25]=[O:26])=[CH:19][CH:20]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCc1ccc(/C=C/C=C/CO)cc1
Agent: [Mn+4]
Agent: [O-2]
Product: Cc1oc(-c2ccccc2)nc1CCc1ccc(/C=C/C=C/C=O)cc1

Procedure:
(E,E)-5-[4-[2-(5-methyl- 2-phenyl-4-oxazolyl )ethyl]phenyl ]- 2,4-pentadien-1-ol was oxidized with activated manganese dioxide in the same manner as in Reference Example 25 to yield (E,E)-5-[4-[2-(5-methyl-2-phenyl4-oxazolyl)ethyl]phenyl]-2,4-pentadien-1-al, which was then recrystallized from ethyl acetate to yield yellow rods having a melting point of 107°-108° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:19]([O:21]CC)=[O:20])[NH:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>C(O)C.O>[CH2:1]([O:8][C:9]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:19]([OH:21])=[O:20])[NH:13]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc2c(OCc3ccccc3)cc(C)cc2[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cc(OCc2ccccc2)c2cc(C(=O)O)[nH]c2c1
Yield: 95 %

Procedure:
31.0 4-benzyloxy-2-ethoxycarbonyl-6-methyl indole (see preparation of the primary products in connection with Example 1) are heated to boiling in a mixture of 100 ml ethanol and 100 ml water during addition of 7.0 potassium hydroxide, for 2 to 3 hours. The ethanol is then evaporated in vacuum and the remaining, water alkaline solution is acidified with conc. hydrochloric acid. The resulting precipitate is aspirated, thoroughly washed with water and dried. There is obtained 27.6 g (~95% of theory) 4-benzyloxy-2-carboxy-6-methyl indole; m.p. 178°-180° C.
Reaction SMILES: C(N(CC)CC)C.Cl.[F:9][C:10]1([F:16])[CH2:15][CH2:14][CH2:13][NH:12][CH2:11]1.Br[CH2:18][C:19]([O:21]CC1C=CC=CC=1)=[O:20]>C(Cl)Cl>[F:9][C:10]1([F:16])[CH2:15][CH2:14][CH2:13][N:12]([CH2:18][C:19]([OH:21])=[O:20])[CH2:11]1
Reactant: FC1(F)CCCNC1
Reactant: O=C(CBr)OCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)CN1CCCC(F)(F)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.6 %

Procedure:
Triethylamine (0.660 mL, 4.76 mmol) was added to a solution of 3,3-difluoropiperidine-HCl (500 mg, 3.17 mmol) and benzyl 2-bromoacetate (763 mg, 3.33 mmol) in methylene chloride (10 mL). The reaction mixture was stirred at ambient temperature for 2 h. The mixture was washed with 1 N aqueous sodium hydroxide and water, successively. The organic layer was concentrated and the residue was purified by flash column chromatography on silica gel (Hexane/EtOAc=25:1) to afford benzyl ester of 2-(3,3-difluoropiperidin-1-yl)acetic acid (486 mg, 56% yield) as a yellow oil.
Reaction SMILES: [CH3:1][SiH:2]1[O:9][SiH:8]([CH3:10])[O:7][SiH:6]([CH3:11])[O:5][SiH:4]([CH3:12])[O:3]1.[C:13]([O:17][CH2:18][CH2:19][OH:20])(=[O:16])[CH:14]=[CH2:15].C1C=CC=CC=1>[Zn](OC(C)=O)OC(C)=O.O>[C:13]([O:17][CH2:18][CH2:19][O:20][Si:8]1([CH3:10])[O:9][SiH:2]([CH3:1])[O:3][SiH:4]([CH3:12])[O:5][SiH:6]([CH3:11])[O:7]1)(=[O:16])[CH:14]=[CH2:15]
Reactant: C[SiH]1O[SiH](C)O[SiH](C)O[SiH](C)O1
Reactant: C=CC(=O)OCCO
Agent: CC(=O)O[Zn]OC(C)=O
Solvent: O
Solvent: c1ccccc1
Product: C=CC(=O)OCCO[Si]1(C)O[SiH](C)O[SiH](C)O[SiH](C)O1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution containing 1M of 2,4,6,8-tetramethylcyclotetrasiloxane and 0.01 g of (CH3CO2)2Zn was slowly added 1M of 2-hydroxyethyl acrylate. The resulting mixture was stirred for 12 hours at a room temperature. Thereafter, 200 mL of benzene and 200 mL of cold water were added. The organic layer was separated, washed with 200 mL of cold water, dried over MgSO4, filtered and concentrated by distillation to provide the title compound of Formula 1A (yield: 97%).
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:12][C:13]([OH:15])=O)=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2.[Br:16][C:17]1[C:18]([C:23]2[NH:27][N:26]=[CH:25][N:24]=2)=[C:19]([NH2:22])[S:20][CH:21]=1>>[Br:16][C:17]1[C:18]([C:23]2[NH:27][N:26]=[CH:25][N:24]=2)=[C:19]([NH:22][C:13](=[O:15])[CH2:12][C:3]2[C:2]([F:1])=[CH:11][CH:10]=[C:9]3[C:4]=2[CH:5]=[CH:6][N:7]=[CH:8]3)[S:20][CH:21]=1
Reactant: Nc1scc(Br)c1-c1ncn[nH]1
Reactant: O=C(O)Cc1c(F)ccc2cnccc12
Product: O=C(Cc1c(F)ccc2cnccc12)Nc1scc(Br)c1-c1ncn[nH]1

Procedure:
N-(4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(6-fluoroisoquinolin-5-yl)acetamide was prepared from 2-(6-fluoroisoquinolin-5-yl)acetic acid and 4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-amine according to protocol A. Retention time (min)=1.901, method [7], MS (ESI) 432.0 (M+H); 1H NMR (300 MHz, DMSO-d6) 11.96 (b s, 1H), 9.58 (s, 1H), 8.64 (d, J=6.05 Hz, 1H), 8.46-8.41 (m, 1H), 8.24 (d, J=6.05 Hz, 1H), 7.84 (t, J=9.34 Hz, 1H), 7.27 (s, 1H), 4.46 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][C:3]=1[O:25][CH3:26].[Cl:27][C:28]1[CH:38]=[CH:37][CH:36]=[CH:35][C:29]=1[CH2:30][S:31](Cl)(=[O:33])=[O:32]>>[Cl:27][C:28]1[CH:38]=[CH:37][CH:36]=[CH:35][C:29]=1[CH2:30][S:31]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][C:3]=1[O:25][CH3:26])(=[O:33])=[O:32]
Reactant: O=S(=O)(Cl)Cc1ccccc1Cl
Reactant: COc1cc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)ccc1N
Product: COc1cc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)ccc1NS(=O)(=O)Cc1ccccc1Cl

Procedure:
By using 5-(4-amino-3-methoxyphenyl)-1H-naphtho[2,1-b][1,4]diazepine-2,4(3H,5H)-dione obtained in Example 63, (3), and 2-chlorobenzylsulfonyl chloride, the title compound was obtained in the same manner as that of Example 145.
Reaction SMILES: N#N.[CH3:3][C:4]1([CH3:15])[C:8]2([CH3:14])[C:9]([O:11][C:12](=[O:13])[CH:5]1[CH2:6][CH2:7]2)=O.[OH:16][CH2:17][CH2:18][CH2:19][CH2:20][NH2:21].C1(C)C=CC=CC=1>O>[OH:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]1[C:12](=[O:13])[CH:5]2[C:4]([CH3:3])([CH3:15])[C:8]([CH3:14])([CH2:7][CH2:6]2)[C:9]1=[O:11]
Reactant: NCCCCO
Reactant: CC12CCC(C(=O)OC1=O)C2(C)C
Agent: N#N
Solvent: Cc1ccccc1
Solvent: O
Product: CC12CCC(C(=O)N(CCCCO)C1=O)C2(C)C

Procedure:
To a 125 ml round-bottomed flask equipped with Dean-Stark trap, condenser, and N2 inlet were added 5.35 g (29 mmol) of d-camphoric anhydride, 2.49 g (28 mmol) of 4-hydroxybutylamine, and 60 ml of toluene. The reaction was refluxed with separation of water for 20 hours. It was then cooled, concentrated to an oil, and the oil dissolved in ethyl acetate. The ethyl acetate solution was washed with 5% HCl, 5% NaOH, and brine, dried over sodium sulfate, and evaporated to an oil, 6.0 g (85%).
Reaction SMILES: [F:1][CH:2]([F:27])[O:3][C:4]1[CH:5]=[CH:6][C:7]2[NH:11][C:10](=[O:12])[N:9]([CH:13]3[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]3)[C:8]=2[CH:26]=1.[ClH:28]>CO.C(O)C>[ClH:28].[F:27][CH:2]([F:1])[O:3][C:4]1[CH:5]=[CH:6][C:7]2[NH:11][C:10](=[O:12])[N:9]([CH:13]3[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]3)[C:8]=2[CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3ccc(OC(F)F)cc32)CC1
Agent: Cl
Solvent: CCO
Solvent: CO
Product: O=c1[nH]c2ccc(OC(F)F)cc2n1C1CCNCC1
Reaction time: 1 h

Procedure:
A solution of 1,1-dimethylethyl 4-{6-[(difluoromethyl)oxy]-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl}-1-piperidinecarboxylate (D53, 0.54 g) in methanol (5 ml) was treated with a saturated solution of hydrogen chloride in ethanol (5 ml). The mixture was stirred for 1 hour when the solvent was removed to give the title compound as a white solid (0.45 g). Mass Spectrum 284 M+H+
Reaction SMILES: [Cl:1][C:2]([Cl:11])([Cl:10])[C:3]([C:5]1[NH:6][CH:7]=[CH:8][CH:9]=1)=[O:4].[Br:12]Br.O>C(Cl)(Cl)Cl>[Br:12][C:8]1[CH:9]=[C:5]([C:3](=[O:4])[C:2]([Cl:1])([Cl:10])[Cl:11])[NH:6][CH:7]=1
Reactant: BrBr
Reactant: O=C(c1ccc[nH]1)C(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(c1cc(Br)c[nH]1)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.8 %

Procedure:
2-trichloroacetyl pyrrole 6 (5.00 g, 23.3 mmol) was dissolved in anhydrous chloroform (20 mL). The solution was cooled to −10° C. before the drop-wise addition of bromine (1.20 mL, 23.3 mmol) to the flask. Once addition was complete the reaction was allowed to warm to room temperature on its own accord while stirring for an additional 30 minutes. The reaction was poured into water (40 mL) and extracted with chloroform (3×20 mL). The combined organic layers were washed with sat. NaHCO3 (2×30 mL), brine (1×20 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. Purification of the residue by column chromatography (Hexanes/Diethyl Ether 95:5) yielded the title compound 7 (6.37 g, 93%) as an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ 12.86 (s, 1H), 7.54 (s, 1H), 7.32 (s, 1H); 13C NMR (100 MHz, DMSO-d6) δ 171.67, 129.06, 122.01, 121.54, 97.60, 94.56; HRMS (FAB) calcd for C6H3BrCl3NO (M+) 288.8464, found 288.8479.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11](C2C(=O)N(CC(C)C)N=C(C3C=CC(C)=C(F)C=3)C=2C)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH:34]1([CH2:37][N:38]2[C:43](=[O:44])[C:42]([CH2:45][CH2:46][CH2:47]OS(C)(=O)=O)=[CH:41][C:40]([C:53]3[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[C:55]([F:61])[CH:54]=3)=[N:39]2)[CH2:36][CH2:35]1.CN1CCNCC1>>[CH:34]1([CH2:37][N:38]2[C:43](=[O:44])[C:42]([CH2:45][CH2:46][CH2:47][N:11]3[CH2:12][CH2:13][N:8]([CH3:6])[CH2:9][CH2:10]3)=[CH:41][C:40]([C:53]3[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[C:55]([F:61])[CH:54]=3)=[N:39]2)[CH2:36][CH2:35]1
Reactant: Cc1ccc(-c2nn(CC(C)C)c(=O)c(N3CCN(C(=O)OC(C)(C)C)CC3)c2C)cc1F
Reactant: COc1ccc(-c2cc(CCCOS(C)(=O)=O)c(=O)n(CC3CC3)n2)cc1F
Agent: CN1CCNCC1
Product: COc1ccc(-c2cc(CCCN3CCN(C)CC3)c(=O)n(CC3CC3)n2)cc1F
Yield: 62 %

Procedure:
Following the procedure of Example 1 (10), 2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(3-methanesulfonyloxypropyl)-2H-pyridazin-3-one and 1-methylpiperazine were reacted to yield the title compound as a yellow oil (yield: 62.0%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]3[N:11]([N:16]=[C:17]([NH2:19])[N:18]=3)[CH:12]=[C:13]([F:15])[CH:14]=2)[CH:5]=[CH:6][C:7]=1[F:8].Cl>C(O)C.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][CH:13]([F:15])[CH2:12][N:11]3[N:16]=[C:17]([NH2:19])[N:18]=[C:10]23)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Nc1nc2c(-c3ccc(F)c(F)c3)cc(F)cn2n1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Nc1nc2n(n1)CC(F)CC2c1ccc(F)c(F)c1

Procedure:
A solution of 8-(3,4-difluorophenyl)-6-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-amine (prepared in analogy to example 66a-c starting with 3-bromo-5-fluoropyridin-2-amine, 237 mg, 897 μmol) in ethanol (8 mL) and HCl (25% in water, 144 mg, 120 μL, 987 μmol) was hydrogenated at 80° C. and 80 bar for 18 hours in the presence of Pd/C (237 mg, 222 μmol). The catalyst was filtered off, washed thoroughly with MeOH and the solvents were evaporated. The crude material was purified by flash chromatography (silica gel, 50 g, 0% to 15% MeOH/NH4OH (9:1) in dichloromethane). The title compound was obtained as white foam (76 mg, 32%). MS ISP (m/e): 269.2 (100) [(M+H)+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:13]([NH:14][CH3:15])[CH2:12][N:11]([C:16]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([C:26]4([CH3:29])[CH2:28][CH2:27]4)=[O:25])[CH2:20][CH2:19]3)=[O:17])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[F:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][C:38]([OH:40])=O)=[CH:33][CH:32]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:10][N:11]([C:16]([CH:18]3[CH2:19][CH2:20][N:21]([C:24]([C:26]4([CH3:29])[CH2:27][CH2:28]4)=[O:25])[CH2:22][CH2:23]3)=[O:17])[CH2:12][CH:13]2[N:14]([CH3:15])[C:38](=[O:40])[CH2:37][C:34]2[CH:33]=[CH:32][C:31]([F:30])=[CH:36][CH:35]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CNC1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)CC1c1ccc(Cl)c(Cl)c1
Reactant: O=C(O)Cc1ccc(F)cc1
Product: CN(C(=O)Cc1ccc(F)cc1)C1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)CC1c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for the synthesis of example 97, the title compound N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-2-(4-fluoro-phenyl)-N-methyl-acetamide was prepared from {4-[(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone using 4-fluorophenylacetic acid instead of 4-chloro-3-(trifluoromethyl)benzoic acid and was obtained as a light brown foam. MS m/e: 574.2 [M]+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:34]=[C:33]([F:35])[C:7]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([C:18]3[N:23]=[C:22]([NH:24][C:25]4[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=4)[C:21]([O:31]C)=[CH:20][N:19]=3)=[N:10]2)=[C:6]([F:36])[CH:5]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].C1(S)C=CC=CC=1.[Cl-].[NH4+]>CN1CCCC1=O.ClCCl.C(O)(C)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([F:36])[C:7]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([C:18]3[N:23]=[C:22]([NH:24][C:25]4[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=4)[C:21]([OH:31])=[CH:20][N:19]=3)=[N:10]2)=[C:33]([F:35])[CH:34]=1)[CH3:2]
Reactant: CCOc1cc(F)c(Cn2nc(-c3ncc(OC)c(Nc4ccncc4)n3)c3ccccc32)c(F)c1
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [Cl-]
Solvent: ClCCl
Solvent: CC(C)O
Solvent: CN1CCCC1=O
Product: CCOc1cc(F)c(Cn2nc(-c3ncc(O)c(Nc4ccncc4)n3)c3ccccc32)c(F)c1
Temperature: 190 °C

Procedure:
1.32 g of 2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazol-3-yl]-5-methoxy-N-(pyridin-4-yl)pyrimidin-4-amine (2-5-1, 2.70 mmol, 1. eq.) were dissolved in 117 ml of dry 1-methylpyrrolidin-2-one. 142 mg of potassium carbonate were added under nitrogen atmosphere. Then 0.42 ml of benzenethiol were added dropwise. The reaction mixture was stirred for an hour at 190° C. and cooled over the weekend at room temperature. Then the mixture was portioned between half saturated aq. ammonium chloride solution and dichloromethane/isopropanol 4:1. The phases were separated and the aqueous layer was extracted twice with dichloromethane/isopropanol 4:1. The combined organic layers were washed with brine, dried over a silicone filter and concentrated in vacuo. The residue was purified by flash chromatography to yield 781 mg (1.65 mmol, 60.9%) of the analytically pure target compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:3]=1.[F:28][C:29]1[C:34](B(O)O)=[CH:33][C:32]([CH2:38][N:39]2[CH2:44][CH2:43][S:42][CH2:41][CH2:40]2)=[CH:31][N:30]=1.C([O-])(=O)C.[K+]>CCO.O>[F:28][C:29]1[C:34]([C:2]2[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[CH2:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[N:3]=2)=[CH:33][C:32]([CH2:38][N:39]2[CH2:44][CH2:43][S:42][CH2:41][CH2:40]2)=[CH:31][N:30]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(Cl)n2)cc1
Reactant: OB(O)c1cc(CN2CCSCC2)cnc1F
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCSCC4)cnc3F)n2)cc1
Temperature: 100 °C
Yield: 67.3 %

Procedure:
A mixture of 4-chloro-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (312 mg, 0.811 mmol), 2-fluoro-5-(thiomorpholinomethyl)pyridin-3-ylboronic acid (249 mg, 0.973 mmol), Am-Phos (40 mg, 0.057 mmol), and potassium acetate (239 mg, 2.432 mmol) in EtOH (3.5 mL) and water (1.5 mL) was heated in a microwave at 100° C. for 30 min. The mixture was partitioned between EtOAc (20 mL) and 1 N NaOH (3 mL). The separated EtOAc layer was washed with brine, concentrated and purified on a Redi-Sep pre-packed silica gel column (40 g) eluting with a gradient of 30-70% EtOAc in hexanes to give 4-(2-fluoro-5-(thiomorpholinomethyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (306 mg, 67.3% yield) as a yellow viscous oil. 1H NMR (400 MHz) δ 8.47 (dd, J=9.3, 1.9 Hz, 1H); 8.28 (s, 1H); 7.24 (d, J=8.4 Hz, 4H); 6.90 (t, J=8.5 Hz, 4H); 4.76 (d, J=4.9 Hz, 4H); 3.74 (s, 3H); 3.73 (s, 3H); 3.60 (s, 2H); 2.66-2.58 (m, 8H); 2.47 (s, 3H). m/z (ESI, +ve ion) 561 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]=[CH:10][C:9]2[N:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[S:14][C:8]=2[C:7]=1[OH:22])=[O:5])[CH3:2].[Br:23]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10]([Br:23])[C:9]2[N:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[S:14][C:8]=2[C:7]=1[OH:22])=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1ncc2nc(-c3ccc(F)cc3)sc2c1O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1nc(Br)c2nc(-c3ccc(F)cc3)sc2c1O
Temperature: 25 °C
Yield: 43.9 %

Procedure:
A mixture of 2-(4-fluoro-phenyl)-7-hydroxy-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (547 mg, 1.72 mmol), N-bromosuccinimide (321 mg, 1.80 mmol) and benzoyl peroxide (21 mg, 0.08 mmol) in carbon tetrachloride (10 mL) was refluxed for 5 h before it was cooled to room temperature and partitioned between dichloromethane and water. The organic layer was washed with saturated aqueous sodium bicarbonate solution, brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and dichloromethane to give the title compound as a white solid (300 mg): MS: (−) m/z 395.07, 396.93 (M−1, 79Br/81Br).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:16])[C@H:11]1[CH2:15][CH2:14][CH2:13][NH:12]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[S:17]1[C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=[C:18]1[C:25]([OH:27])=O>CCOC(C)=O>[CH2:2]([O:9][C:10]([C@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:22]([C:21]1[S:17][C:18]([C:25]([N:12]2[CH2:13][CH2:14][CH2:15][C@@H:11]2[C:10]([O:9][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[O:16])=[O:27])=[CH:19][CH:20]=1)=[O:24])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(OCc1ccccc1)[C@H]1CCCN1
Reactant: O=C(O)c1ccc(C(=O)O)s1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)[C@H]1CCCN1C(=O)c1ccc(C(=O)N2CCC[C@@H]2C(=O)OCc2ccccc2)s1
Yield: 82.1 %

Procedure:
Using General Procedure A with 2.0 g (8.2 mmol) D-Proline benzyl ester hydrochloride and 700 mg (4.1 mmol) thiophene-2,5-dicarboxylic acid afforded, after flash chromatography (EtOAc), 1.84 g (84%) of the title compound as a yellow crystalline solid. MS m/e (%): 564 (M+NH4+, 70), 547 (M+H+, 100).
Reaction SMILES: [F:1][CH:2]([F:39])[C:3]1[CH:7]=[C:6]([CH:8]([F:10])[F:9])[N:5]([CH2:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[S:21][CH:22]=[C:23]([C:25]4[CH2:29][CH:28]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=5[N+:36]([O-])=O)[O:27][N:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=[O:13])[N:4]=1>CO.[Pd]>[NH2:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[CH:28]1[O:27][N:26]=[C:25]([C:23]2[N:24]=[C:20]([CH:17]3[CH2:16][CH2:15][N:14]([C:12](=[O:13])[CH2:11][N:5]4[C:6]([CH:8]([F:10])[F:9])=[CH:7][C:3]([CH:2]([F:39])[F:1])=[N:4]4)[CH2:19][CH2:18]3)[S:21][CH:22]=2)[CH2:29]1
Reactant: O=C(Cn1nc(C(F)F)cc1C(F)F)N1CCC(c2nc(C3=NOC(c4ccccc4[N+](=O)[O-])C3)cs2)CC1
Agent: [Pd]
Solvent: CO
Product: Nc1ccccc1C1CC(c2csc(C3CCN(C(=O)Cn4nc(C(F)F)cc4C(F)F)CC3)n2)=NO1
Temperature: 25 °C
Reaction time: 3 h
Yield: 33 %

Procedure:
To a solution of 2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]-1-(4-{4-[5-(2-nitrophenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidin-1-yl)ethanone (80 mg) in methanol (10 ml) is added, at room temperature, Pd/C (20 mg, 10%). The reaction mixture is stirred under a hydrogen atmosphere at room temperature for 3 hours, then volatile constituents are removed under reduced pressure. Purification by column chromatography gives 1-(4-{4-[5-(2-aminophenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidin-1-yl)-2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]ethanone (25 mg).
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[C:11](=[O:14])[N:10]([NH:15][C:16](=[O:42])[C@@H:17]([C@@H:22]([C:32](=[O:41])[NH:33][O:34]C2CCCCO2)[CH2:23]/[CH:24]=[CH:25]/[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:18][CH:19]([CH3:21])[CH3:20])[C:9]1=[O:43])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.C(OCC)(=O)C>[CH2:1]([N:8]1[C:12](=[O:13])[C:11](=[O:14])[N:10]([NH:15][C:16](=[O:42])[C@@H:17]([C@@H:22]([C:32](=[O:41])[NH:33][OH:34])[CH2:23]/[CH:24]=[CH:25]/[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:18][CH:19]([CH3:21])[CH3:20])[C:9]1=[O:43])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C[C@@H](C(=O)NN1C(=O)C(=O)N(Cc2ccccc2)C1=O)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: CC(C)C[C@@H](C(=O)NN1C(=O)C(=O)N(Cc2ccccc2)C1=O)[C@H](C/C=C/c1ccccc1)C(=O)NO
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.9 %

Procedure:
A solution of 0.045 g of (E)-N-(3-benzyl-2,4,5-trioxo-1-imidazolidinyl]-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-4-methylvaleramide in 2 ml of methanol was treated with 0.010 g of p-toluenesulphonic acid monohydrate and stirred at room temperature for 2 hours. The mixture was diluted with ethyl acetate and washed in sequence with 5% aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride. The organic layer was dried over anhydrous magnesium sulphate and evaporated to give a residue which was triturated with diethyl ether to give 0.032 g of (E)-N-(3-benzyl-2,4,5-trioxo-1-imidazolidinyl]-2(R)-[1(S)-(hydroxycarbamoyl)-4-phenyl-3-butenyl]-4-methylvaleramide in the form of a white solid.
Reaction SMILES: [CH:1]1([C:4]([NH:7][C:8]2[C:13]([C:14]#[N:15])=[CH:12][N:11]=[C:10]([S:16][CH3:17])[N:9]=2)([CH3:6])[CH3:5])[CH2:3][CH2:2]1.[OH:18]O.[OH-].[Na+].O>CS(C)=O>[CH:1]1([C:4]([NH:7][C:8]2[C:13]([C:14]([NH2:15])=[O:18])=[CH:12][N:11]=[C:10]([S:16][CH3:17])[N:9]=2)([CH3:6])[CH3:5])[CH2:3][CH2:2]1
Reactant: CSc1ncc(C#N)c(NC(C)(C)C2CC2)n1
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CSc1ncc(C(N)=O)c(NC(C)(C)C2CC2)n1
Temperature: 50 °C
Reaction time: 0.2 h
Yield: 55 %

Procedure:
To a stirring solution of 4-((2-cyclopropylpropan-2-yl)amino)-2-(methylthio)pyrimidine-5-carbonitrile (665 mg, 2.68 mmol) in DMSO (4 mL) was added aqueous hydrogen peroxide solution (0.162 mL, 30%) and aqueous sodium hydroxide (2.2 mL, 6 mol/L) solution. The resulting mixture was stirred at 50° C. for 12 min, and then water was added. The desired product was filtered and dried in vacuo to give the crude product (392 mg, 1.47 mmol, 55% yield) as a white solid. MS (ESI) m/z 267.3 [M+H]+.