Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH2:24]([CH:26]1[NH:30][C:29](=[O:31])[N:28]([CH3:32])[C:27]1=[O:33])[CH3:25]>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:4]=[CH:3][C:2]([N:30]4[CH:26]([CH2:24][CH3:25])[C:27](=[O:33])[N:28]([CH3:32])[C:29]4=[O:31])=[N:7][CH:6]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)nc3)CC2)c(C)c1
Reactant: CCC1NC(=O)N(C)C1=O
Product: CCC1C(=O)N(C)C(=O)N1c1ccc(C(=O)N2CCN(c3ncc(C)cc3C)CC2)cn1
Yield: 54.4 %

Procedure:
Using (6-bromopyridin-3-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (150 mg) described in Preparation Example 127 and 5-ethyl-3-methylimidazolidine-2,4-dione (63 mg) described in Preparation Example 215 and by the reaction and treatment in the same manner as in Example 536, the title compound (95 mg) was obtained.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](=O)[CH3:9])[CH:5]=[CH:4][CH:3]=1.[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH3:9])[N:7]=1
Reactant: CC(=O)c1cccc(Br)n1
Reactant: C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(c1cccc(Br)n1)N1CCCCC1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 1-(6-bromo-pyridin-2-yl)-ethanone (600 mg, 3.01 mmol) in dry CH2Cl2 (20 mL) was added piperidine (0.5 mL) followed by NaBH(OAc)3 (1.3 g, 12.06 mmol) and HOAc (0.7 mL, 6.03 mmol). The mixture was heated at 40° C. for 72 h. The reaction was quenched with 2M Na2CO3 and stirred 1 h. The organic layer was collected, dried over MgSO4 and concentrated in vacuo. This crude compound was purified by chromatography on silica gel. Elution with hexane:acetone mixture (90:10) gave a light yellow solid. MS m/z: 269.2 (M+H). Calc'd. for C12H17BrN2-268.06.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:16]([O-:18])=[O:17])=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])[CH:7]=1.[Na].[CH3:20][OH:21]>>[CH3:20][O:21][C:2]1[CH:3]=[CH:4][C:5]([N+:16]([O-:18])=[O:17])=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])[CH:7]=1
Reactant: CO
Reactant: Cc1ccccc1Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: [Na]
Product: COc1ccc([N+](=O)[O-])c(Nc2ccccc2C)c1
Temperature: 0 °C

Procedure:
1 g of 5-chloro-2-nitrophenyl-o-tolylamine was added to a solution of 1 g of sodium in 20 ml of methanol, and it was refluxed for 72 hours. Then, it is cooled to 0° C., and the crystalline product is suctioned off.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([C:14](=[N:16][NH2:17])[CH3:15])=[C:11]([CH3:13])[N:12]=2)=[CH:4][CH:3]=1.[OH:18][C:19]1[C:26]([CH3:27])=[CH:25][C:22]([CH:23]=O)=[CH:21][C:20]=1[CH3:28]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]([C:14](=[N:16][N:17]=[CH:23][C:22]3[CH:25]=[C:26]([CH3:27])[C:19]([OH:18])=[C:20]([CH3:28])[CH:21]=3)[CH3:15])=[C:11]([CH3:13])[N:12]=2)=[CH:6][CH:7]=1
Reactant: CC(=NN)c1sc(-c2ccc(Cl)cc2)nc1C
Reactant: Cc1cc(C=O)cc(C)c1O
Solvent: CCO
Product: CC(=NN=Cc1cc(C)c(O)c(C)c1)c1sc(-c2ccc(Cl)cc2)nc1C
Yield: 38.4 %

Procedure:
In ethanol (3 ml), {1-[2-(4-chlorophenyl)-4-methylthiazol-5-yl]ethylidene}-hydrazine (40 mg) prepared in the Step 30-1-2 and 4-hydroxy-3,5-dimethylbenzaldehyde (29 mg) was heated under reflux for 20 hours. After the mixture was allowed to cool, the precipitated crystal was separated by filtration to give the title compound (23 mg, 38%).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][OH:5].[H-].[Na+].[CH2:10]([O:12][CH:13]([O:16][CH2:17][CH3:18])[CH2:14]Br)[CH3:11]>C1COCC1>[CH2:10]([O:12][CH:13]([O:16][CH2:17][CH3:18])[CH2:14][O:5][CH2:4][CH:3]([O:6][CH3:7])[O:2][CH3:1])[CH3:11]
Reactant: COC(CO)OC
Reactant: CCOC(CBr)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(COCC(OC)OC)OCC
Temperature: 25 °C

Procedure:
To a solution of glycolaldehyde dimethyl acetal (25 g, 236 mmol) in 750 mL of THF at 0° C. was added portionwise 14.1 g (353 mmol) of a 60% suspension of NaH in oil. The solution was warmed to room temperature, and then to 60° C. overnight. After cooling to room temperature, and then to 0° C., 69.9 g (353 mmol) of bromoacetaldehyde diethyl acetal in 200 mL of THF was added dropwise over 30 minutes. The reaction was warmed to room temperature, and then to reflux for 2 days. The reaction was cooled to room temperature, filtered through a pad of celite, and concentrated by rotary evaporation while keeping the bath temperature below 40° C. The residue was purified by column chromatography on silica gel (0 to 30% EtOAc in hexanes) to provide C-1 as a yellow oil. Data for C-1:1 H NMR (CDCl3, 500 MHz) δ 4.65 (m, 1H), 4.5 (m, 1H), 3.7 (m, 2H), 3.55 (m, 6H), 3.4 (s, 6H), 1.2 (M, 6H) ppm.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8](COCC[Si](C)(C)C)COCC[Si](C)(C)C)[N:5]2[N:25]=[CH:26][C:27]([C:28]3[CH:29]=[N:30][C:31]4[C:36]([CH:37]=3)=[CH:35][CH:34]=[CH:33][CH:32]=4)=[C:4]2[N:3]=1.C(N(CC)C(C)C)(C)C.[NH:47]1[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1>CN1C(=O)CCC1>[O:50]1[CH2:51][CH2:52][N:47]([C:2]2[CH:7]=[C:6]([NH2:8])[N:5]3[N:25]=[CH:26][C:27]([C:28]4[CH:29]=[N:30][C:31]5[C:36]([CH:37]=4)=[CH:35][CH:34]=[CH:33][CH:32]=5)=[C:4]3[N:3]=2)[CH2:48][CH2:49]1
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(Cl)nc2c(-c3cnc4ccccc4c3)cnn12
Reactant: C1COCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Nc1cc(N2CCOCC2)nc2c(-c3cnc4ccccc4c3)cnn12
Temperature: 185 °C

Procedure:
A mixture of 5-chloro-3-(quinolin-3-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (72 μmol, 40 mg), N,N-diisopropylethylamine (220 μmol, 38 μL), NMP (2 mL), and morpholine (220 μmol, 19 μL) was heated to 185° C. in microwave synthesizer for 45 minutes. Upon completion, the reaction was cooled to room temperature and then purified via prep-LC to yield 5-morpholino-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-7-amine as brown-yellow solid. LCMS tR=1.29 Min (5 min run, UV254nm). Mass calculated for, M+ 346.1, observed LC/MS m/z 347.2 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][O:7][CH2:8][C:9]2[N:14]=[C:13]([NH2:15])[CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[F:18][C:19]([F:32])([F:31])[O:20][C:21]1[CH:22]=[C:23]([S:27](Cl)(=[O:29])=[O:28])[CH:24]=[CH:25][CH:26]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][CH2:8][C:9]2[N:14]=[C:13]([NH:15][S:27]([C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([O:20][C:19]([F:18])([F:31])[F:32])[CH:22]=3)(=[O:29])=[O:28])[CH:12]=[CH:11][CH:10]=2)=[CH:16][CH:17]=1
Reactant: Nc1cccc(COCc2ccc(F)cc2)n1
Reactant: O=S(=O)(Cl)c1cccc(OC(F)(F)F)c1
Product: O=S(=O)(Nc1cccc(COCc2ccc(F)cc2)n1)c1cccc(OC(F)(F)F)c1

Procedure:
This material was prepared in analogy to example 1 from 6-(4-fluoro-benzyloxymethyl)-pyridin-2-ylamine (0.07 g) and 3-(trifluoromethoxy)-benzenesulfonyl chloride (0.086 g) as a light yellow gum (0.097 g). MS (ESI−): 455.2 ([M−H]−).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[S:9][C:8]([N:10]([CH3:13])[CH:11]=[O:12])=[N:7][C:6]=1[CH3:14])=O.[C:15]([NH:18][C:19]([NH2:21])=[S:20])(=[NH:17])[NH2:16]>CO>[NH:18]([C:19]1[S:20][CH:2]=[C:3]([C:5]2[S:9][C:8]([N:10]([CH3:13])[CH:11]=[O:12])=[N:7][C:6]=2[CH3:14])[N:21]=1)[C:15]([NH2:17])=[NH:16]
Reactant: Cc1nc(N(C)C=O)sc1C(=O)CBr
Reactant: N=C(N)NC(N)=S
Solvent: CO
Product: Cc1nc(N(C)C=O)sc1-c1csc(NC(=N)N)n1
Temperature: 5 °C
Yield: 93.2 %

Procedure:
A solution of 5-(2-bromoacetyl)-2-(N-methylformamido)-4-methylthiazole (2.77 g) and N-amidinothiourea (2.37 g) in methanol (30 ml) was stirred for 4 hours at ambient temperature and for 60 minutes under refluxing. The reaction mixture was cooled to 5° C. The resulting precipitate was collected by filtration, washed with cold methanol (5 ml×2) and dried under reduced pressure to give 5-(2-guanidinothiazol-4-yl)-2-(N-methylformamido)-4-methylthiazole (2.76 g).
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH2:16].[CH3:17][CH:18]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:19][C:20](Cl)=[O:21]>ClC(Cl)C>[CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH:16][C:20](=[O:21])[CH2:19][CH:18]([CH3:17])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(CC(=O)Cl)CC(C)(C)C
Reactant: Nc1ccc2oc3c(c2c1)CCCCCC3
Solvent: CC(Cl)Cl
Product: CC(CC(=O)Nc1ccc2oc3c(c2c1)CCCCCC3)CC(C)(C)C
Yield: 100.5 %

Procedure:
Following the procedure of Example 1, 6,7,8,9,10,11-Hexahydro-benzo[b]-cycloocta[d]furan-2-ylamine (0.15 g, 0.70 mmol), 3,5,5-trimethylhexanoyl chloride (0.14 mL, 0.73 mmol), and poly(vinylpyridine) (0.5 g) in dichloroethane (15 mL) provided N-(6,7,8,9,10,11-hexahydrobenzo[b]cycloocta[d]furan-2-yl)-3,5,5-trimethylhexanamide (0.25 g). MS (ESI) m/z 356 ([M+H]+).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=O)[O:24]C3C=CC=CC=3)=[CH:16][CH:15]=2)[N:3]=1.[Cl:32][C:33]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=1[S:40]([NH2:43])(=[O:42])=[O:41]>>[Cl:32][C:33]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=1[S:40]([NH:43][C:23]([NH:22][CH2:21][CH2:20][C:17]1[CH:16]=[CH:15][C:14]([N:4]2[C:5]([CH3:13])=[C:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:2]([CH3:1])=[N:3]2)=[CH:19][CH:18]=1)=[O:24])(=[O:41])=[O:42]
Reactant: NS(=O)(=O)c1ccc(F)cc1Cl
Reactant: Cc1nn(-c2ccc(CCNC(=O)Oc3ccccc3)cc2)c(C)c1-c1ccccc1
Product: Cc1nn(-c2ccc(CCNC(=O)NS(=O)(=O)c3ccc(F)cc3Cl)cc2)c(C)c1-c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 42 from phenyl 2-[4-(3,5-dimethyl-4-phenyl-1H-pyrazol-1-yl)phenyl]ethylcarbamate (step 1 of Example 22) and 2-chloro-4-fluorobenzenesulfonamide: 1H-NMR (CDCl3) δ 8.12-8.07 (1H, m), 7.46-7.04 (11H, m), 6.29 (1H, br.s), 3.42-3.36 (2H, m), 2.79-2.75 (2H, m), 2.29 (3H, s), 2.21 (3H, s).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[S:15][C:14]([C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23]3[CH:24]=[C:25]([CH3:29])[CH:26]=[CH:27][CH:28]=3)[N:17]=2)=[CH:13][CH:12]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C1C=CN=CC=1)C.CN(C=O)C.CS(C)=O>[C:25]1([CH3:29])[CH:26]=[CH:27][CH:28]=[C:23]([NH:22][C:18]2[N:17]=[C:16]([C:14]3[S:15][C:11]([NH:10][C:1](=[O:9])[C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:12][CH:13]=3)[CH:21]=[CH:20][N:19]=2)[CH:24]=1
Reactant: O=C(O)c1ccccc1
Reactant: Cc1cccc(Nc2nccc(-c3ccc(N)s3)n2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: Cc1cccc(Nc2nccc(-c3ccc(NC(=O)c4ccccc4)s3)n2)c1
Temperature: 70 °C
Reaction time: 16 h
Yield: 22.2 %

Procedure:
Benzoic acid (5.2 mg, 0.042 mmol), [4-(5-aminothiophen-2-yl)-pyrimidin-2-yl]-m-tolyl-amine (10 mg, 0.035 mmol), DMAP (4.2 mg, 0.035 mmol) and HATU (15.9 mg, 0.042 mmol) were combined in 400 uL DMF and the solution was heated on a hot plate in a capped vial at 70° C. After 16 hours, the mixture was diluted with DMSO and prep purified to afford N-[5-(2-m-tolylamino-pyrimidin-4-yl)-thiophene-2-yl]-benzamide (3.0 mg, 22%). 1H NMR (500 MHz, DMSO-d6) δ1.29 (s, 3H), 6.70 (d, J=7.5 Hz, 1H), 6.93 (d, J=4 Hz, 1H), 7.10 (t, J=8 Hz, 1H), 7.16 (d, J=5.5 Hz, 1H), 7.47 (d, J=7.5 Hz, 1H), 7.51 (m, 2H), 7.58 (m, 1H), 7.74 (d, J=4 Hz, 1H), 7.78 (s, 1H), 7.95 (m, 2H), 8.31 (d, J=5.5 Hz, 1H), 9.42 (s, 1H). MS: m/z 387 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([CH2:18][OH:19])[NH:5][C:6]=1[C:7]1[C:8]([CH3:17])=[CH:9][C:10]([CH3:16])=[C:11]([CH:15]=1)[C:12]([OH:14])=O.Cl.[F:21][C:22]1([C:26]2[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][CH:27]=2)[CH2:25][NH:24][CH2:23]1.CCN=C=NCCCN(C)C.Cl>CN(C)C=O.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([CH2:18][OH:19])[NH:5][C:6]=1[C:7]1[C:8]([CH3:17])=[CH:9][C:10]([CH3:16])=[C:11]([CH:15]=1)[C:12]([N:24]1[CH2:23][C:22]([C:26]2[CH:27]=[CH:28][C:29]([C:30]#[N:31])=[CH:32][CH:33]=2)([F:21])[CH2:25]1)=[O:14]
Reactant: N#Cc1ccc(C2(F)CNC2)cc1
Reactant: Cc1cc(C)c(-c2[nH]c(CO)nc2Cl)cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1cc(C)c(-c2[nH]c(CO)nc2Cl)cc1C(=O)N1CC(F)(c2ccc(C#N)cc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.9 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of 5-(4-chloro-2-(hydroxymethyl)-1H-imidazol-5-yl)-2,4-dimethylbenzoic acid (compound 230.6, 180 mg, 0.64 mmol) in N,N-dimethylformamide (15 mL). 4-(3-fluoroazetidin-3-yl)benzonitrile hydrochloride (compound 43.4, 165 mg, 0.78 mmol), EDC.HCl (245 mg, 1.28 mmol) and 4-dimethylaminopyridine (310 mg, 2.54 mmol) were added to the reaction. The reaction mixture was stirred overnight at 25° C. The reaction was then quenched with 5 mL of water. The reaction mixture was extracted with 3×10 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 5×10 mL of brine. The resulting mixture was concentrated under reduced pressure. The crude product (200 mg) was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-001 (SHIMADZU)): Column, SunFire Prep C18 OBD Column, 5 μm, 19*150 mm; mobile phase, WATER WITH 0.05% TFA and ACN (26.0% ACN up to 39.0% in 10 min, up to 100.0% in 2 min, down to 26.0% in 1 min); Detector, Waters 2489, 254 and 220 nm. This resulted in 84 mg (30%) of the title compound as a white solid. m/z (ES+) 439 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][CH:13]=[CH:12][C:11]3=O)=[O:7])=[CH:4][CH:3]=1.P(Br)(Br)[Br:22].C([O-])(O)=O.[Na+]>CN(C=O)C.O>[Br:22][C:11]1[C:10]2[C:15](=[CH:16][CH:17]=[C:8]([C:6]([C:5]3[CH:19]=[CH:20][C:2]([Cl:1])=[CH:3][CH:4]=3)=[O:7])[CH:9]=2)[N:14]=[CH:13][CH:12]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc2[nH]ccc(=O)c2c1
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1ccc(Cl)cc1)c1ccc2nccc(Br)c2c1
Reaction time: 0.5 h

Procedure:
To a suspension of 6-(4-chlorobenzoyl)quinolin-4(1H)-one (1.26 g, 4.45 mmol) in DMF (8 mL) at room temperature was added slowly phosphorous tribromide. The resulting mixture was stirred under argon for 30 min. The reaction mixture was made basic by the addition of solid NaHCO3 until pH was greater than 10, diluted with water and filtered. The product was washed with several portion of water and dried to yield (4-bromoquinolin-6-yl)(4-chlorophenyl)methanone. (M+H)+: 346, 348.
Reaction SMILES: [CH2:1]([N:3]1[C:7](=[O:8])[C:6](=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)[S:5][C:4]1=[O:19])[CH3:2]>[C].[Pd].O1CCCC1>[NH2:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][CH:6]2[S:5][C:4](=[O:19])[N:3]([CH2:1][CH3:2])[C:7]2=[O:8])=[CH:11][CH:12]=1
Reactant: CCN1C(=O)SC(=Cc2ccc([N+](=O)[O-])cc2)C1=O
Agent: [Pd]
Solvent: C1CCOC1
Product: CCN1C(=O)SC(Cc2ccc(N)cc2)C1=O

Procedure:
A mixture of 3-ethyl-5-(4-nitrobenzylidene)-1,3-thiazolidine-2,4-dione (3.60 g), 5% palladium carbon (5.0 g) and tetrahydrofuran (300 mL) was subjected to catalytic reduction under hydrogen pressure of 5.0 kgf·cm−2. The catalyst was removed by filtration, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography, and 5-(4-aminobenzyl)-3-ethyl-1,3-thiazolidine-2,4-dione was obtained as yellow crystals (3.05 g, yield 94%) from a fraction eluted with hexane-ethyl acetate (3:1-1:1, v/v). Recrystallization thereof from ethyl acetate-hexane gave yellow prism crystals. melting point: 103-104° C.
Reaction SMILES: [C:1]([C:3]1[NH:7][C:6]([CH2:8][CH2:9][CH3:10])=[N:5][C:4]=1[C:11]([OH:15])([CH3:14])[CH2:12][CH3:13])#[N:2].[H-].[Na+].[C:18]([N:37]1[C:41]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=2[C:48]2[CH:55]=[CH:54][C:51]([CH2:52]Br)=[CH:50][CH:49]=2)=[N:40][N:39]=[N:38]1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:1]([C:3]1[N:7]([CH2:52][C:51]2[CH:50]=[CH:49][C:48]([C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=3[C:41]3[N:37]([C:18]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[N:38]=[N:39][N:40]=3)=[CH:55][CH:54]=2)[C:6]([CH2:8][CH2:9][CH3:10])=[N:5][C:4]=1[C:11]([OH:15])([CH3:14])[CH2:12][CH3:13])#[N:2]
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCc1nc(C(C)(O)CC)c(C#N)[nH]1
Agent: [H-]
Agent: [Na+]
Product: CCCc1nc(C(C)(O)CC)c(C#N)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 77.4 %

Procedure:
Following a procedure similar to than described in Example 18(a), but using 380 mg of 5-cyano-4-(1-hydroxy-1-methylpropyl)-2-propylimidazole (prepared as described in Preparation 20), 88 mg of sodium hydride (as a 55% w/w dispersion in mineral oil) and 1.07 g of 4-[2-(trityltetrazol-5-yl)phenyl]benzyl bromide, 0.97 g of the title compound were obtained as an amorphous solid.
Reaction SMILES: C[C:2]1([O:22][C@H:21]([CH2:23][O:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=2[Cl:33])[C@@H:10]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[C@H:5]1[O:6]C(=O)C)[O:3][CH3:4]>C(=O)([O-])[O-].[K+].[K+]>[Cl:20][C:14]1[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=1[CH2:12][O:11][C@@H:10]1[C@@H:21]([CH2:23][O:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=2[Cl:33])[O:22][CH:2]([O:3][CH3:4])[C@@H:5]1[OH:6]
Reactant: COC1(C)O[C@H](COCc2ccc(Cl)cc2Cl)[C@@H](OCc2ccc(Cl)cc2Cl)[C@H]1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC1O[C@H](COCc2ccc(Cl)cc2Cl)[C@@H](OCc2ccc(Cl)cc2Cl)[C@H]1O

Procedure:
The compound prepared in Step 3 above (85.75 g, 0.1636 mol) in 820 mL of saturated methanolic potassium carbonate was stirred at ambient temperature for 45 minutes and then concentrated in vacuo. The oily residue was suspended in 820 mL of CH2Cl2, washed with water (493 mL+5×328 mL) and brine (328 mL), dried (NaSO4), filtered, and concentrated to give the product. The oil (75.93 g, 0.1573 mol) was immediately used in the next step without further purification.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]([F:10])([F:9])[F:8])[C:4]([C:11]([OH:13])=O)=[N:3]1.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:25][C:26]1[CH:27]=[C:28]([CH:45]=[CH:46][CH:47]=1)[O:29][C:30]1[CH:31]=[CH:32][C:33]2[N:34]([N:36]=[C:37]([NH:39][C:40]([CH:42]3[CH2:44][CH2:43]3)=[O:41])[N:38]=2)[CH:35]=1>CN(C)C=O.CN(C)C(=O)C>[CH:42]1([C:40]([NH:39][C:37]2[N:38]=[C:33]3[CH:32]=[CH:31][C:30]([O:29][C:28]4[CH:27]=[C:26]([NH:25][C:11]([C:4]5[C:5]([C:7]([F:10])([F:9])[F:8])=[CH:6][N:2]([CH3:1])[N:3]=5)=[O:13])[CH:47]=[CH:46][CH:45]=4)=[CH:35][N:34]3[N:36]=2)=[O:41])[CH2:43][CH2:44]1
Reactant: Cn1cc(C(F)(F)F)c(C(=O)O)n1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: Cn1cc(C(F)(F)F)c(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)nn4c3)c2)n1
Yield: 47.8 %

Procedure:
In the same manner as in Example 18-4 and using 1-methyl-4-(trifluoromethyl)-1H-pyrazole-3-carboxylic acid (194 mg, 1.00 mmol), tetrahydrofuran (7 mL), oxalyl chloride (95.6 μL, 1.10 mmol), N-[6-(3-aminophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (281 mg, 0.910 mmol), N,N-dimethylformamide (1 drop) and N,N-dimethylacetamide (5 mL) as starting materials, the title compound (211 mg, 48%) was obtained as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]23[O:16][CH2:15][C:12]([CH2:17][CH2:18][CH3:19])([CH2:13][O:14]2)[CH2:11][O:10]3)=[CH:5][CH:4]=1)#[CH:2].[CH3:20][N:21]=[C:22]=[S:23]>>[CH3:20][NH:21][C:22](=[S:23])[C:2]#[C:1][C:3]1[CH:4]=[CH:5][C:6]([C:9]23[O:10][CH2:11][C:12]([CH2:17][CH2:18][CH3:19])([CH2:13][O:14]2)[CH2:15][O:16]3)=[CH:7][CH:8]=1
Reactant: C#Cc1ccc(C23OCC(CCC)(CO2)CO3)cc1
Reactant: CN=C=S
Product: CCCC12COC(c3ccc(C#CC(=S)NC)cc3)(OC1)OC2

Procedure:
N-Methyl-3-[4-(4-n-propyl-2,6,7-trioxabicyclo[2,2,2]oct-1-yl)phenyl]-prop-2-yn-thioamide was prepared from 1-(4-ethynylphenyl)-4-n-propyl-2-yn-thioamide was prepared from 1-(4-ethynylphenyl)-4-n-propyl-2,6,7-trioxabicyclo[2,2,2]octane and methylisothiocyanate in a manner analogous to the synthesis of N-Methyl-3-[4-(4-n-propyl-2,6,7-trioxabicyclo[2,2,]oct-1-yl)phenyl]-prop-2-ynamide.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C@@H:10]([OH:20])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[F:28][C:29]([F:44])([F:43])[C:30]1[CH:31]=[C:32]([CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=1)[C:33](Cl)=[O:34]>C(Cl)Cl>[F:28][C:29]([F:43])([F:44])[C:30]1[CH:31]=[C:32]([CH:36]=[C:37]([C:39]([F:42])([F:40])[F:41])[CH:38]=1)[C:33]([O:20][C@@H:10]1[C@@H:11]([C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]1)=[O:34]
Reactant: CC(C)(C)OC(=O)N1C[C@H](c2ccc(F)cc2)[C@@H](O)C1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@H](OC(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H](c2ccc(F)cc2)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a 250 mL 3-neck round bottom flask equipped with septa, magnetic stir bar thermocouple and nitrogen line was added 5.0 g (17.77 mmol) (3R,4S) tert-butyl-3-hydroxy-4-(4-fluorophenyl)pyrrolidine-1-carboxylate (Example 2, Step B, Rt 13.686 min) and 100 mL methylene chloride. To the resulting solution was added 5.0 mL (35.54 mmol) triethylamine by syringe. The reaction mixture was cooled to 0° C. and 3.80 mL (19.55 mmol) 3,5-bis(trifluoromethyl)benzoyl chloride was added slowly by syringe over 10 min. A white precipitate formed after the addition was complete and the resulting mixture stirred for 1 hr at 0° C. when the cooling bath was removed. The reaction mixture was stirred an additional 2 hr at which time TLC (EtOAc/hex; 3:7) showed no starting material remained. The reaction mixture was poured into a separatory funnel which contained sat. aq. NaHCO3. The layers were separated, the organic layer dried over anhydrous sodium sulfate, filtered and the solvent removed under vacuum to give the title compound as a yellow oil which was used without further purification in the next reaction. 1H-NMR (CDCl3): δ: 1.55 (s, 9H), 3.4-4.09 (br. m, 6H), 5.41 (s, 1H), 7.06 (m, 2H), 7.30 (m, 2H), 8.12 (s, 1H), 8.44 (s, 2H)ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][C:13](=[O:21])[C:14]1[CH:19]=[CH:18][C:17](Cl)=[N:16][CH:15]=1.[CH2:22]([NH2:25])[CH2:23][NH2:24]>>[NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][C:13](=[O:21])[C:14]1[CH:19]=[CH:18][C:17]([NH:24][CH2:23][CH2:22][NH2:25])=[N:16][CH:15]=1
Reactant: NCCN
Reactant: Nc1cc(C(F)(F)F)ccc1NC(=O)c1ccc(Cl)nc1
Product: NCCNc1ccc(C(=O)Nc2ccc(C(F)(F)F)cc2N)cn1
Yield: 47 %

Procedure:
N-(2-Amino-4-trifluoromethylphenyl)-6-chloronicotinamide (316 mg, 1 mmol) and 5 ml of ethylenediamine were heated to 80° C. for 3 hours. The excess ethylenediamine was removed under vacuum. To the residue was added 5 ml of 0.20 M NaOH. The mixture was extracted with 100 ml of ethyl acetate. The ethyl acetate was removed under vacuum to give the title compound (159 mg, 47% yield) as a brown solid. LC-MS (m/z) 340 (M+1).