Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[C:18]2[C:19]3[C:6]([CH2:7][C@@H:8]4[C@@H:13]([C:14]=3[CH:15]=[CH:16][CH:17]=2)[CH2:12][C@@H:11]([C:20](O)=[O:21])[CH2:10][N:9]4[CH3:23])=[CH:5]1)([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].ClC(OCC(C)C)=O.[CH:38]1([NH2:44])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1.[OH-].[NH4+]>CN(C)C=O>[CH:38]1([NH:44][C:20]([C@@H:11]2[CH2:12][C@H:13]3[C@@H:8]([CH2:7][C:6]4[C:19]5[C:18](=[CH:17][CH:16]=[CH:15][C:14]3=5)[N:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=4)[N:9]([CH3:23])[CH2:10]2)=[O:21])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: NC1CCCCC1
Reactant: CC(C)n1cc2c3c(cccc31)[C@H]1C[C@@H](C(=O)O)CN(C)[C@@H]1C2
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)n1cc2c3c(cccc31)[C@H]1C[C@@H](C(=O)NC3CCCCC3)CN(C)[C@@H]1C2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 80.4 %

Procedure:
To a 250 ml three-neck round bottom flask was added 10.0 g (32.01 mmol) of (8β)-1-isopropyl-6-methyl ergoline-8-carboxylic acid, 4.43 g (32.1 mmol) of potassium carbonate and 200 ml of N,N-dimethylformamide. The mixture was refluxed and 25 ml of a distillate was collected. The remaining solution was cooled in an ice bath, and then with an acetonitrile/carbon dioxide bath which lowered the temperature of the reaction mixture to about -45° C. To this mixture was added 4.59 g (33.62 mmol) of isobutyl chloroformate dropwise. The resulting mixture was stirred for approximately five minutes and 3.49 g (35.21 mmol) of cyclohexylamine was added. The reaction mixture was allowed to warm to room temperature and stirred for approximately 19 hours. To the mixture was added 500 ml of ice water containing 25 ml of concentrated ammonium hydroxide. The mixture was cooled and the precipitated solid was collected by vacuum filtration. The resulting solid was washed with water and dried in vacuo to provide 10.13 g of the title compound having a purity of 92.3%. Yield 76.8%.
Reaction SMILES: C([Li])(CC)C.Br[C:7]1[CH:8]=[C:9]([O:13][CH3:14])[CH:10]=[CH:11][CH:12]=1.[CH3:15][N:16]([CH2:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C:20]1=[O:25])[CH3:17]>O1CCCC1.[Fe].[Cl-]>[CH3:17][N:16]([CH2:18][CH:19]1[C:20]([OH:25])([C:7]2[CH:8]=[C:9]([O:13][CH3:14])[CH:10]=[CH:11][CH:12]=2)[CH2:21][CH2:22][CH2:23][CH2:24]1)[CH3:15]
Reactant: COc1cccc(Br)c1
Reactant: CN(C)CC1CCCCC1=O
Agent: [Fe]
Agent: [Cl-]
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: COc1cccc(C2(O)CCCCC2CN(C)C)c1
Reaction time: 0.17 h
Yield: 89.2 %

Procedure:
To 120 mL of anhydrous tetrahydrofuran (THF) cooled to −50° C. was added 400 mL of sec-butyl lithium (0.52 mol, 1.3 M solution in cyclohexane). The resulting yellow suspension was stirred for 10 min and then 63.56 g of neat 3-bromoanisole (0.34 mol) was added dropwise with stirring. The yellow suspension turned red, and then a white precipitate formed. The resulting white suspension was stirred for 30 min. In a separate vessel 52.75 g of (±) 2-((dimethylamino)methyl) cyclohexanone was dissolved in 107 mL of anhydrous THF at 0° C. To the resulting solution of (±) 2-((dimethylamino)methyl) cyclohexanone was added, dropwise with stirring, a solution of 1.03 g of iron (mH) chloride (6.3 mmol, 1 mol percent) in anhydrous THF. The resulting violet solution was transferred dropwise to the stirred white suspension at −50° C. using a metering pump. The resulting reaction mixture was quenched with 100 mL of water, the organic phase separated, the aqueous phase was extracted twice with 100 mL diethyl ether, and the diethyl ether extracts combined. The combined diethyl ether extracts were dried over sodium sulfate, filtered, and the diethyl ether solvent was removed under reduced pressure to provide 89.82 g (0.303 mol, 89% yield) of the above-titled mixture in a ratio of 93.9:6.1 as determined using HPLC.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:5]=[CH:6][C:7]([CH3:10])=[N:8][CH:9]=1)[NH2:3].[CH3:11][C:12]([CH3:19])([CH3:18])[C:13](=O)[CH2:14][C:15]#[N:16]>CCO>[C:12]([C:13]1[CH:14]=[C:15]([NH2:16])[N:2]([C:4]2[CH:9]=[N:8][C:7]([CH3:10])=[CH:6][CH:5]=2)[N:3]=1)([CH3:19])([CH3:18])[CH3:11]
Reactant: CC(C)(C)C(=O)CC#N
Reactant: Cc1ccc(NN)cn1
Agent: Cl
Solvent: CCO
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2N)cn1
Yield: 71 %

Procedure:
A mixture of 5-hydrazinyl-2-methylpyridine hydrochloride from Example B27 (5.0 g, 31.4 mmol) and 4,4-dimethyl-3-oxopentanenitrile (8.3 g, 66.3 mmol) in EtOH (50 mL) was heated at reflux overnight. The reaction was concentrated and the residue was dissolved in EtOAc and neutralized with saturated Na2CO3 solution. The organic layer was dried (Na2SO4), concentrated in vacuo and purified by column chromatography to yield 3-tert-butyl-1-(6-methylpyridin-3-yl)-1H-pyrazol-5-amine (5.2 g, 71% yield). 1HNMR (400 MHz, CDCl3) δ 8.72 (s, 1 H), 7.81 (dd, J=8.0, 2.4 Hz, 1 H), 7.23 (d, J=8.4 Hz, 1 H), 5.54 (s, 1 H), 3.71 (br s, 1 H), 2.58 (s, 3 H), 1.29 (s, 9 H); MS (ESI) m/z: 231.2 (M+H+).
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@H:7]([C@@H:9]([CH2:11]O)[OH:10])[OH:8])[OH:6])[OH:4].O.[NH2:14][NH2:15]>CO>[CH:11](=[N:14][NH2:15])[C@@H:9]([C@H:7]([C@H:5]([C@@H:3]([CH2:2][OH:1])[OH:4])[OH:6])[OH:8])[OH:10]
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO
Reactant: NN
Solvent: CO
Solvent: O
Product: NN=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO
Reaction time: 8 h

Procedure:
A 2.0 g portion of D-galactose was dissolved in a mixture of 5 ml of methanol and 5 ml of hydrazine hydrate and stirred overnight, then evaporated to dryness in vacuo. About 5 ml of methanol was added, the mixture was stirred for 48 hours and the solid was collected giving 1.9 g of D-galactose hydrazone.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH2:32][CH3:33])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.[CH3:77][N:78]([CH3:83])[CH2:79][CH2:80][CH2:81][NH2:82]>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:82][CH2:81][CH2:80][CH2:79][N:78]([CH3:83])[CH3:77])=[O:28])=[CH:24][C:23]=4[O:31][CH2:32][CH3:33])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: CN(C)CCCN
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOc1cc(C(=O)NCCCN(C)C)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 0.17 h
Yield: 62 %

Procedure:
To a mixture of 0.0651 g (0.141 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-ethoxy-benzoic acid (I-214) and 4 mL of dimethylformamide was added 0.0309 g (0.229 mmole) of 1-hydroxybenzotriazole, 0.0825 g (0.229 mmole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate and 0.1113 g (0.862 mmole) of diisopropylethylamine. The mixture was stirred for 10 minutes, then 0.0216 g (0.211 mmole) of 3-(dimethylamino)-propylamine was added. The reaction mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in 80 mL of ethyl acetate and washed three times with 10 mL of 1M sodium hydroxide, twice with 15 mL of brine, dried, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 95:5-80:20) gave 0.0477 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(3-dimethylamino-propyl)-3-ethoxy-benzamide (I-219) as a white solid.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:9]([F:10])=[CH:8][C:7]([C:11](=[O:17])[CH2:12][NH:13][CH:14]([CH3:16])[CH3:15])=[CH:6][C:5]=1[Br:18].[BH4-].[Na+]>>[NH2:3][C:4]1[C:9]([F:10])=[CH:8][C:7]([CH:11]([OH:17])[CH2:12][NH:13][CH:14]([CH3:15])[CH3:16])=[CH:6][C:5]=1[Br:18]
Reactant: CC(C)NCC(=O)c1cc(F)c(N)c(Br)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Product: CC(C)NCC(O)c1cc(F)c(N)c(Br)c1

Procedure:
m.p. of the hydrochloride: 171°-173° C. (decomp.), was prepared from 4'-amino-3'-bromo-5'-fluoro-2-isopropylamino-acetophenone hydrochloride and sodium borohydride analogous to Example 1.
Reaction SMILES: [O:1]=[C:2]1[C:10](=[CH:11][C:12]2[NH:16][C:15]([CH3:17])=[C:14]([C:18]([OH:20])=O)[C:13]=2[CH3:21])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[NH2:22][CH2:23][CH:24]([OH:32])[CH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[OH:32][CH:24]([CH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)[CH2:23][NH:22][C:18]([C:14]1[C:13]([CH3:21])=[C:12](/[CH:11]=[C:10]2\[C:2](=[O:1])[NH:3][C:4]3[C:9]\2=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:16][C:15]=1[CH3:17])=[O:20]
Reactant: Cc1[nH]c(C=C2C(=O)Nc3ccccc32)c(C)c1C(=O)O
Reactant: NCC(O)CN1CCOCC1
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccccc32)c(C)c1C(=O)NCC(O)CN1CCOCC1

Procedure:
5-(2-Oxo-1,2-dihydro-indol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (113 mg, 0.4 mmol) was condensed with 1-amino-3-morpholin-4-yl-propan-2-ol (74 mg, 0.48 mmol) to precipitate 2,4-dimethyl-5-[2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-1H-pyrrole-3-carboxylic acid (2-hydroxy-3-morpholin-4-yl-propyl)-amide (77 mg, 45.3%). 1H NMR (DMSO-d6) δ 2.27 (m, 1H), 2.32 (m, 1H), 2.40 (m, 4H), 2.40, 2.42 (2×s, 6H, 2×CH3), 3.15 (s, 1H), 3.32 (m, 1H), 3.55 (m, 4H), 3.77 (m, 1H), 4.74 (d, J=4.8 Hz, 1H, OH), 6.86 (d, J=7.6 Hz, 1H), 6.96 (t, J=7.2 Hz, 1H), 7.10 (t, J=7.6 Hz, 1H), 7.49 (t, J=5.6 Hz, 1H), 7.61 (s, 1H), 7.77 (d, J=8.0 Hz, 1H) (aromatic and vinyl), 10.88 (s, 1H, CONH), 13.62 (s, 1H, NH). LC-MS (m/z) 425.4 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[Cl-].C([O-])(O)=O.[Na+].[CH2:15]1[CH2:19]OC[CH2:16]1>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>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([CH:16]2[CH2:15][CH2:19]2)=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: C1CCOC1
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: [Cl-]
Product: Brc1ccc(C2CC2)nc1
Temperature: 70 °C
Reaction time: 3 h
Yield: 103 %

Procedure:
To a solution 2,5-dibromopyridine [CAS 624-28-2, commercially available] (5 g, 21 mmol) and Pd(PPh3)4 (244 mg, 1 mol %) in THF (25 mL) was added cycloropylzinc chloride (0.4M in THF, 53 mL, 26 mmol), and the mixture was stirred under argon atmosphere at 70° C. for 3 h. Cooled to 23° C., poured into sat. NaHCO3-solution, extracted with ether, washed with brine, dried over Na2SO4. Removal of the solvent in vacuum left a brown oil, which was purified by silica gel chromatography with heptane-EtOAc (9:1) to give the title compound as a colorless liquid (4.3 g, 103%). MS (EI) 197 [(M)+] and 199 [(M+2)+].
Reaction SMILES: C(O)(=O)C.[C:5]([C:8]1[N:13]=[CH:12][C:11]([NH:14][C:15](=[O:17])[CH3:16])=[CH:10][CH:9]=1)(=[NH:7])[NH2:6].[CH3:18][CH:19]([C:25](=O)[CH3:26])[C:20](OCC)=[O:21].C(=O)([O-])[O-].[Na+].[Na+]>O.C(O)C>[OH:21][C:20]1[C:19]([CH3:18])=[C:25]([CH3:26])[N:6]=[C:5]([C:8]2[N:13]=[CH:12][C:11]([NH:14][C:15](=[O:17])[CH3:16])=[CH:10][CH:9]=2)[N:7]=1
Reactant: CCOC(=O)C(C)C(C)=O
Reactant: CC(=O)Nc1ccc(C(=N)N)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)Nc1ccc(-c2nc(C)c(C)c(O)n2)nc1
Temperature: 25 °C
Reaction time: 26 h

Procedure:
To a solution of compound of example 44 (0.01 g, 0.56 mmol) in water (2 mL) and ethanol (1 mL) was added ethyl 2-methyl-3-oxobutanoate (0.013 g, 0.89 mmol) and sodium carbonate (0.0107 g, 1.011 mmol) and the reaction mixture was stirred at room temperature for 26 hours. Ethanol was removed under reduced pressure, and the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by column chromatography using silica gel and 1% methanol in chloroform as an eluent to obtain the title compound.
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5](=[O:9])[O:6][C:7]=1[CH3:8].[I-].[Na+].C(O)=[O:13].C>ClCCl.O.C(N(CC)CC)C>[OH:13][CH2:2][C:3]1[O:4][C:5](=[O:9])[O:6][C:7]=1[CH3:8]
Reactant: O=CO
Reactant: Cc1oc(=O)oc1CCl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1oc(=O)oc1CO
Temperature: 12.5 °C
Reaction time: 5.5 h

Procedure:
4-Chloromethyl-5-methyl-1,3-dioxol-2-one (25 g) was dissolved in dichloromethane (250 ml) at 20-25° C., sodium iodide (2.5 g) and formic acid (22 g) was added at 20-25° C. Resulting mixture was cooled to 10-15° C. and triethyl amine (46.8 g) was added at 10-15° C. in 20-25 minutes. Resulting mixture was stirred for 5.0-6.0 hrs at 40-45° C., cooled to 20-25° C. and added DM water (250 ml). Organic layer was separated and washed with brine solution, and distilled out. Residue was dissolved in methanol (300 ml), methanolic HCl was added drop wise and resulting mixture was stirred for 1 hrs at 60-65° C. Active charcoal (1 g) was added to the reaction mass and stirred for 20-25 minutes at 50-55° C. Reaction mass was filtered through hyflo bed and bed was washed by MeOH (12 ml). The filtrate was evaporated under vacuum at 40-45° C. Obtained product was diluted with ethyl acetate (75 ml) and evaporated under vacuum to remove methanol content. (Yield: 0.67 g; 76.5%)
Reaction SMILES: [C:1]([NH:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:17])[CH2:15]Br)=[CH:10][C:9]=1[C:18]#[N:19])([CH3:4])([CH3:3])[CH3:2].O(C(NC1C=CC(C(=O)CBr)=CC=1C#N)=O)C1C=CC=CC=1.[C:43]([NH2:47])([CH3:46])([CH3:45])[CH3:44]>>[C:18]([C:9]1[CH:10]=[C:11]([CH:14]([OH:17])[CH2:15][NH:47][C:43]([CH3:46])([CH3:45])[CH3:44])[CH:12]=[CH:13][C:8]=1[NH:7][C:6]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:20])#[N:19]
Reactant: CC(C)(C)NC(=O)Nc1ccc(C(=O)CBr)cc1C#N
Reactant: CC(C)(C)N
Agent: N#Cc1cc(C(=O)CBr)ccc1NC(=O)Oc1ccccc1
Product: CC(C)(C)NCC(O)c1ccc(NC(=O)NC(C)(C)C)c(C#N)c1

Procedure:
The 4'-(3-tert.butylureido)-2-bromo-3'-cyano-acetophenone used as starting material was prepared by reaction of 4'-phenoxycarbonylamino-2-bromo-3'-cyano-acetophenone and tert.butylamine at room temperature.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.CCN(C(C)C)C(C)C.[Cl:33][C:34]1[S:35][C:36]2[C:37](=[C:39]([C:43](Cl)=[O:44])[CH:40]=[CH:41][CH:42]=2)[N:38]=1>CC#N>[CH3:23][C:13]1[S:14][C:15]([C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[C:11]([C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:43]([C:39]2[CH:40]=[CH:41][CH:42]=[C:36]3[S:35][C:34]([Cl:33])=[N:38][C:37]=23)=[O:44])=[O:10])[N:12]=1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Reactant: O=C(Cl)c1cccc2sc(Cl)nc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cccc3sc(Cl)nc23)c1
Reaction time: 0.5 h

Procedure:
A solution of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone (0.24 mmol) in MeCN (1.0 mL) is treated successively with DIPEA (0.49 mmol) and 2-Chloro-benzothiazole-4-carbonyl chloride (0.24 mmol; U.S. Pat. No. 3,654,296). The mixture is stirred for 30 min and purified by prep. HPLC to give the desired amide. LC-MS: tR=1.03 min; [M+H]+=523.0.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[NH:32]1[CH2:37][CH2:36][CH2:35][C@@H:34]([C:38]([OH:40])=[O:39])[CH2:33]1>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:32]5[CH2:37][CH2:36][CH2:35][C@H:34]([C:38]([OH:40])=[O:39])[CH2:33]5)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:29])([F:30])[F:31])[CH:3]=1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: O=C(O)[C@@H]1CCCNC1
Product: O=C1N=C(N2CCC[C@H](C(=O)O)C2)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1

Procedure:
1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}piperidine-3-(S)-carboxylic acid was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and piperidine-3-(R)-carboxylic acid following General Procedure C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([OH:17])=O)[CH2:9]2)[CH:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([F:26])[CH:19]=2)[N:3]=1.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.[CH2:60]([CH:62]1[CH2:67][CH2:66][CH:65]([NH2:68])[CH2:64][CH2:63]1)[CH3:61]>CN(C=O)C.CCOC(C)=O.O>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:68][CH:65]3[CH2:66][CH2:67][CH:62]([CH2:60][CH3:61])[CH2:63][CH2:64]3)=[O:17])[CH2:9]2)[CH:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([F:26])[CH:19]=2)[N:3]=1
Reactant: C[C@@H]1CC[C@H](C(=O)O)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Reactant: CCC1CCC(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCC1CCC(NC(=O)[C@H]2CC[C@@H](C)N(c3cc(-c4ccc(C#N)c(F)c4)nc(N)n3)C2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 84.2 %

Procedure:
To a solution of (3S,6R)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-6-methyl-3-piperidinecarboxylic acid (170 mg, 0.478 mmol) and HATU (218 mg, 0.574 mmol) in DMF (3 mL) was added Hunig's base (0.167 mL, 0.957 mmol), and the resulting mixture was stirred at room temperature for 15 minutes. 4-Ethylcyclohexanamine (61 mg, 0.48 mmol) was added, and the reaction mixture was stirred at room temperature for 0.5 hours. LCMS showed reaction was completed. The reaction was poured into water, and EtOAc was added to extract the product. The product stayed in the EtOAc layer. The organic layer solution was concentrated, and the formed solid was recrystallized from CH3CN to afford the title compound (187 mg) as a light yellow solid. LC-MS (ES) m/z=465 [M+H]+.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:7]([CH3:26])=[C:8](C(O)=O)[NH:9][C:10]=1[CH:11]=[C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([Cl:21])[CH:19]=2)[NH:14][C:13]1=[O:22])([OH:3])=[O:2].[OH-].[K+].O.Cl>C(O)CO>[Cl:21][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:22])[C:12]2=[CH:11][C:10]1[NH:9][CH:8]=[C:7]([CH3:26])[C:6]=1[CH2:5][CH2:4][C:1]([OH:3])=[O:2]
Reactant: Cc1c(C(=O)O)[nH]c(C=C2C(=O)Nc3ccc(Cl)cc32)c1CCC(=O)O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: Cc1c[nH]c(C=C2C(=O)Nc3ccc(Cl)cc32)c1CCC(=O)O
Temperature: 200 °C
Yield: 29 %

Procedure:
4-(2-carboxyethyl)-3-methyl-5-(5-chloro-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-2-carboxylic acid suspended in ethylene glycol (5 mL) was heated in a sealed tube in a pre-heated oil bath at 200° C. for 2 hours. The reaction mixture was cooled to 90° C. and potassium hydroxide (2 pellets) were added. The mixture was then heated at 90° C. for 30 minutes, after which time it was cooled, poured into water, and acidified with 2 N hydrochloric acid to pH 2. The precipitate that formed was filtered, washed with water, and dried in a vacuum oven overnight to give 77 mg (29%) of 3-[2-(5-Chloro-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-4-methyl-1H-pyrrol-3-yl]-propionic acid.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[CH:14]=[C:13]([O:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH:12]=[CH:11]2)=[O:4].C(CN)[OH:22]>C(OC(C)=O)(C)C>[OH:22][CH2:2][C:3]([NH:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[CH:14]=[C:13]([O:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH:12]=[CH:11]2)=[O:4]
Reactant: CS(=O)(=O)Oc1ccc2cccc(NC(=O)CCl)c2c1
Reactant: NCCO
Solvent: CC(=O)OC(C)C
Product: CS(=O)(=O)Oc1ccc2cccc(NC(=O)CO)c2c1
Reaction time: 18 h

Procedure:
To a solution of ester from Step B (11.0 g, 39.5 mmol) in 150 mL of i-PrOAc at room temperature was added ethanolamine (12.0 mL, 199 mmol). After 18 hours, the reaction was partitioned between EtOAc and water, and the organic layer was extracted with saturated brine, dried (Na2SO4), filtered, and concentrated in vacuo to provide a dark oil.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:7][CH:6]=1)=[O:4].[N:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1.CCOCC>C(#N)C>[N:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:24][CH2:25][N:26]([CH2:2][C:3]([C:5]3[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:7][CH:6]=3)=[O:4])[CH2:27][CH2:28]2)=[CH:19][CH:18]=1
Reactant: COC(=O)CCc1ccc(C(=O)CBr)cc1
Reactant: c1cc(N2CCNCC2)ccn1
Solvent: CC#N
Solvent: CCOCC
Product: COC(=O)CCc1ccc(C(=O)CN2CCN(c3ccncc3)CC2)cc1
Reaction time: 8 h

Procedure:
A solution of methyl 3-(4-bromoacetylphenyl)propionate (380 mg) in acetonitrile (4 ml) was added dropwise over 15 minutes to a stirred solution of 1-(4-pyridyl)piperazine (450 mg) in acetonitrile (10 ml) and the mixture stirred overnight. The mixture was then filtered and the filtrate concentrated in vacuo to give an oil. Purification by flash chromatography on silica eluting first with dichloromethane then 5% v/v methanol/dichloromethane gave a solid. Trituration with ether gave the title compound, 172 mg, as a solid: m.p. 141°-143° C.; NMR(d6DMSO) δ 8.15(2H,d), 7.92(2H,d), 7.37(2H,d), 6.83(2H,d), 3.89(2H,s), 3.59(3H,s), 3.37(4H,t), 2.93(2H,t), 2.69(2H,t), 2.65(4H,t); m/e 368(M+H)+ ; calculated for C21H25N3O3. 0.25H2O: C, 67.8; H, 6.9; N, 11.3. found: C, 67.8; H, 6.9; N,;11.1%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([C:25]#[N:26])=[C:11]([C:19]2[CH2:20][CH2:21][O:22][CH2:23][CH:24]=2)[S:12][C:13]=1[C:14]1[NH:18][CH:17]=[N:16][N:15]=1>CO.[Pd]>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([C:25]#[N:26])=[C:11]([CH:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[S:12][C:13]=1[C:14]1[NH:18][CH:17]=[N:16][N:15]=1
Reactant: N#Cc1c(C2=CCOCC2)sc(-c2nnc[nH]2)c1-c1ccc(Cl)cc1Cl
Agent: [Pd]
Solvent: CO
Product: N#Cc1c(C2CCOCC2)sc(-c2nnc[nH]2)c1-c1ccc(Cl)cc1Cl
Reaction time: 2 h
Yield: 79 %

Procedure:
4-(2,4-dichlorophenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-(4H-1,2,4-triazol-3-yl)thiophene-3-carbonitrile (20 mg, 0.05 mmol) was dissolved in methanol (2 mL) and 10% Pd/C was added (10 mg). The mixture was stirred under an atmosphere of hydrogen for 2 hours. The suspension was filtered through celite, solvent was evaporated and the residue was purified using ISCO chromatography on silica gel, elution 20% ethyl acetate in hexanes to ethyl acetate to afford the title compound (16 mg, 80%). LCMS: (FA) ES+, 405. 1H NMR (400 MHz, d4-methanol) δ: 8.53 (s, 1H), 7.78 (d, 1H), 7.51-7.46 (m, 2H), 4.12-4.08 (m, 1H), 3.99-3.95 (m, 1H), 3.53-3.30 (m, 2H), 3.20-3.15 (m, 1H), 2.00-1.95 (m, 1H), 1.83-1.72 (m, 1H).