Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[CH2:7][C:8]1[C:9]([CH2:24][CH3:25])=[N:10][N:11]([CH2:15][C:16]2[CH:21]=[CH:20][C:19](Br)=[CH:18][C:17]=2[F:23])[C:12]=1[CH2:13][CH3:14])([CH3:4])([CH3:3])[CH3:2].O1CCOCC1.C(N(C(C)C)CC)(C)C.[C:42](=O)([O-:44])[O-:43].[K+].[K+]>[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[Mo].O>[C:1]([O:5][C:6]([CH2:7][C:8]1[C:9]([CH2:24][CH3:25])=[N:10][N:11]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:42]([OH:44])=[O:43])=[CH:18][C:17]=2[F:23])[C:12]=1[CH2:13][CH3:14])=[O:26])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCc1nn(Cc2ccc(Br)cc2F)c(CC)c1CC(=O)OC(C)(C)C
Agent: [Mo]
Agent: [C-]#[O+]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CCc1nn(Cc2ccc(C(=O)O)cc2F)c(CC)c1CC(=O)OC(C)(C)C
Temperature: 150 °C

Procedure:
To a microwave vial was added [1-(4-bromo-2-fluorobenzyl)-3,5-diethyl-1H-pyrazol-4-yl]acetic acid tert.-butyl ester (6.5 g), dioxane (30 ml), water (15 ml), molybdenum hexacarbonyl (2.1 g), Hermann's catalyst (1.5 g) and diisopropylethylamine (6 ml). After 20 min microwave heating at 150° C., the vial is allowed to cool to room temperature and the content is added to water. The reaction mixture is made alkaline with potassium carbonate and extracted twice with ethyl acetate. The aqueous phase is separated, acidified with glacial acetic acid and extracted several times with dichloromethane. The organic phase is then separated, dried over magnesium sulfate and concentrated in vacuo to yield 4-(4-tert.-butoxycarbonylmethyl-3,5-diethylpyrazol-1-ylmethyl)-3-fluorobenzoic acid (3.4 g; [M+H]=391; HPLC retention time 1.00 min (Method K)).
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:5]=2[N:6]=1.C(O[C@@H:17]1[O:29][C@H:28]([CH2:30][O:31][C:32](=[O:34])[CH3:33])[C@@H:23]([O:24][C:25](=[O:27])[CH3:26])[C@H:18]1[O:19][C:20](=[O:22])[CH3:21])(=O)C.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C>C(Cl)CCl.C(Cl)(Cl)Cl>[Cl:1][C:2]1[N:3]([C@@H:17]2[O:29][C@H:28]([CH2:30][O:31][C:32](=[O:34])[CH3:33])[C@@H:23]([O:24][C:25](=[O:27])[CH3:26])[C@H:18]2[O:19][C:20](=[O:22])[CH3:21])[C:4]2[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:5]=2[N:6]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: Fc1cc2nc(Cl)[nH]c2cc1F
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCCl
Solvent: ClC(Cl)Cl
Product: CC(=O)OC[C@H]1O[C@@H](n2c(Cl)nc3cc(F)c(F)cc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 75 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 0.943 g (5 mmole) of 12 in 25 mL of ClCH2CH2Cl, was added 1.25 mL (5 mmole) of BSA at 75° C. The reaction mixture was stirred at 75° C. for 30 min. To this solution, was added 1.75 g (5.5 mmole) of 1,2,3,5-tetra-O-acetyl-β-D-ribofuranose and 1.07 mL (5.5 mmole) of TMSOTf. Stirring was continued at 75° C. for 30 min. The reaction mixture was cooled to room temperature, diluted with 100 mL of CHCl3, and extracted with sat. NaHCO3 solution (100 mL×2) and sat. NaCl solution (100 mL). The CHCl3 phase was dried (Na2SO4) and evaporated. The residue was chromatographed on a silica column (3×25 cm, eluted successively with 0.5%, 1% MeOH/CHCl3). Evaporation of the appropriate fractions and recrystallization of the residue from MeOH gave 1.257 g (3 crops, 56%) of 64 as crystalline needles. MP 90°-91° C.; MS m/e 446.0694 (5%, M+ =446.0692); 1H NMR (DMSO-d6) d 7.93 (dd, 1, 7-H, 3JF-H =10.5 Hz, 4JF-H =7.5 Hz), 7.82 (dd, 1, 4-H, 3JF-H =10.5 Hz, 4JF-H =7.5 Hz), 6.23 (d, 1, 1'-H, J1'-2' =7.0 Hz), 5.55 (t, 1, 2'-H, J2'-3' =7.0 Hz), 5.44 (m, 1, 3'-H, J3-4 =4.5 Hz), 4.45 (m, 3, 4'-H and 5'-H), 2.13, 2.10, 2.02 (3×s, 9, 3×Ac); 13C NMR (DMSO-d6) d 169.95, 169.50, 169.18 (3×OCOCH3), 148.76, 148.62, 146.10, 145.93 (C5 and C6, 1JF-C =242 Hz), 140.16 (C2), 137.01 (C3a, 3JF-C =12 Hz), 128.54 (C7a, 3JF-C =12 Hz), 107.31, 107.09 (C4, JF-C =20 Hz), 100.93, 100.66 (C7, JF-C =24 Hz), 86.89 (Cl'), 79.41 (C4'), 70.40 (C2'), 68.62 (C3'), 62.67 (C5'), 20.43, 20.28, 20.00 (3×OCOCH3).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][C:24](C(F)(F)F)=[CH:23][CH:22]=4)=[O:19])[CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.ClC1C=C2C(C(N3CCNCC3)=CC=N2)=CC=1.C(N(C(C)C)CC)(C)C.[CH2:57]([O:59]C1C=CC(N=C=O)=CC=1)[CH3:58]>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:13][CH2:14][N:15]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][C:24]([O:59][CH2:57][CH3:58])=[CH:23][CH:22]=4)=[O:19])[CH2:16][CH2:17]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc(C(F)(F)F)cc1)N1CCN(c2ccnc3cc(Cl)ccc23)CC1
Reactant: CCOc1ccc(N=C=O)cc1
Agent: Clc1ccc2c(N3CCNCC3)ccnc2c1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1ccc(NC(=O)N2CCN(c3ccnc4cc(Cl)ccc34)CC2)cc1

Procedure:
As described for 7-chloro-4-[4-(4-trifluoromethylphenylaminocarbonyl)piperazin-1-yl]quinoline, 7-chloro-4-(piperazin-1-yl)quinoline (150 mg, 0.61 mmol), diisopropyl(ethyl)amine (158 mg, 1.22 mmol), and 4-ethoxyphenyl isocyanate (119 mg, 0.73 mmol) are reacted to give the title product after flash chromatography with CH2Cl2-MeOH.
Reaction SMILES: [CH2:1]([N:5]1[C:9]2=[C:10](Cl)[N:11]=[N:12][CH:13]=[C:8]2[C:7]([CH3:15])=[C:6]1[CH2:16][CH3:17])[CH:2]=[CH:3][CH3:4].[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][OH:24])=[CH:21][CH:20]=1>>[CH2:1]([N:5]1[C:9]2=[C:10]([O:24][CH2:23][C:22]3[CH:25]=[CH:26][C:19]([F:18])=[CH:20][CH:21]=3)[N:11]=[N:12][CH:13]=[C:8]2[C:7]([CH3:15])=[C:6]1[CH2:16][CH3:17])[CH:2]=[CH:3][CH3:4]
Reactant: CC=CCn1c(CC)c(C)c2cnnc(Cl)c21
Reactant: OCc1ccc(F)cc1
Product: CC=CCn1c(CC)c(C)c2cnnc(OCc3ccc(F)cc3)c21
Yield: 41.7 %

Procedure:
The title compound (trans) was prepared as a white powder in 41.7% yield in a similar procedure to that described in Example 1 by using 1-(2-butenyl)-7-chloro-2-ethyl-3-methylpyrrolo[2,3-d]pyridazine (cis/trans=4/96) and 4-fluorobenzyl alcohol.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:13]([F:16])([F:15])[F:14])[NH:6]2.Cl[CH2:18][C:19]1[N:23]=[C:22]([C:24]2[C:25]([CH3:30])=[N:26][O:27][C:28]=2[CH3:29])[O:21][N:20]=1>>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:13]([F:14])([F:15])[F:16])[N:6]2[CH2:18][C:19]1[N:23]=[C:22]([C:24]2[C:25]([CH3:30])=[N:26][O:27][C:28]=2[CH3:29])[O:21][N:20]=1
Reactant: N#Cc1ccc2[nH]c(C(F)(F)F)cc2c1Cl
Reactant: Cc1noc(C)c1-c1nc(CCl)no1
Product: Cc1noc(C)c1-c1nc(Cn2c(C(F)(F)F)cc3c(Cl)c(C#N)ccc32)no1

Procedure:
Synthesized as described in Example 4 from 4-chloro-2-(trifluoromethyl)-1H-indole-5-carbonitrile and 3-(chloromethyl)-5-(3,5-dimethyl-4-isoxazolyl)-1,2,4-oxadiazole: 1H NMR (400 MHz, DMSO-d6) δ 7.97 (d, J=8.5 Hz, 1 H), 7.87 (d, J=8.5 Hz 1 H), 7.50 (s, 1 H), 5.93 (s, 2H), 2.64 (s, 3H), 2.37 (s, 3H); MS (ES) m/z 422 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[S:14][CH:13]=[N:12][CH:11]=2)=[CH:6][C:3]=1[C:4]#[N:5].C([O-])(=O)C.[K+].[Br:20]Br.[OH-].[Na+]>C(O)(=O)C>[Br:20][C:13]1[S:14][C:10]([C:7]2[CH:8]=[CH:9][C:2]([F:1])=[C:3]([CH:6]=2)[C:4]#[N:5])=[CH:11][N:12]=1
Reactant: BrBr
Reactant: N#Cc1cc(-c2cncs2)ccc1F
Agent: CC(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(=O)O
Product: N#Cc1cc(-c2cnc(Br)s2)ccc1F
Temperature: 25 °C
Reaction time: 48 h
Yield: 30 %

Procedure:
To a stirring solution of 2-fluoro-5-(thiazol-5-yl)benzonitrile THZ INT-3 (0.429 g, 2.1 mmol) in acetic acid (10.5 mL) was added potassium acetate (0.412 g, 4.2 mmol). Bromine (0.647 mL, 12.6 mmol) was added dropwise over 10 minutes and the reaction mixture stirred at room temperature for 48 h. The reaction mixture was basified with 1N NaOH and washed with EA and brine. The combined organic layers were dried over MgSO4, filtered, and concentrated. The crude product was purified by chromatography (20% EA/Hexanes) to produce 0.10 g (30%) of 5-(2-bromothiazol-5-yl)-2-fluorobenzonitrile THZ INT-4. LCMS-ESI (m/z) calculated for C10H4BrFN2S: 283.1; found 284.9 [M+H]+, tR=3.33 min.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.CN1CCOCC1.[NH2:39][C@@H:40]([CH2:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:41]([NH:43][CH3:44])=[O:42].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([NH:39][C@@H:40]([CH2:45][CH2:46][C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1)[C:41]([NH:43][CH3:44])=[O:42])=[O:5]
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: CNC(=O)[C@@H](N)CCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CNC(=O)[C@H](CCc1ccccc1)NC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 8 h
Yield: 26.1 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 20 mg, 0.046 mmol) was dissolved in DMF (1 mL) prior to the addition of 4-methylmorpholine (0.031 mL, 0.278 mmol), (S)-2-amino-N-methyl-4-phenylbutanamide (8.91 mg, 0.046 mmol), and HATU (31.7 mg, 0.083 mmol). The reaction mixture was stirred overnight and was then purified via preparative LCMS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 methanol:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 methanol:water with 10-mM ammonium acetate; Gradient: 50-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow rate=20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give (S)-2-((R/S)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)-N-methyl-4-phenylbutanamide (7.3 mg, 0.012 mmol, 25.7% yield): LCMS=606.2 [M+H]+, 1H NMR (Mixture of diastereomers, 400 MHz, methanol-d4) δ ppm 8.10-8.25 (4 H, m), 7.48-7.83 (14 H, m), 6.95-7.30 (10 H, m), 5.20 (2 H, d, J=2.01 Hz), 4.24-4.42 (2 H, m), 2.74 (3 H, s), 2.71 (3 H, s), 2.43-2.68 (4 H, m), 1.88-2.16 (4 H, m); Analytical LCMS: column: Mac-mod Halo C18, 4.6×50 mm, 2.7-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 90:10 acetonitrile:water with 10 mM ammonium acetate; Temperature: 45° C.; Gradient: 0-100% B over 4 minutes, flow rate=4 mL/min, product retention=2.7 min+2.8 min (mixture of diastereomers).
Reaction SMILES: [CH:1]1([SH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])[CH2:18][CH2:17]2>>[CH:1]1([S:7][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[CH2:18][CH2:17]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCc2cc(OCCCCCl)ccc2N1
Reactant: SC1CCCCC1
Product: O=C1CCc2cc(OCCCCSC3CCCCC3)ccc2N1

Procedure:
Prepared analogous to Example 1 from cyclohexyl-mercaptan and 6-(4-chloro-butoxy)-3,4-dihydro-carbostyril
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-])=O)[C:4]=1[NH:12][C:13]([CH:15]1[CH2:17][CH2:16]1)=O>C(O)(=O)C.[Fe]>[CH:15]1([C:13]2[NH:12][C:4]3[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[CH:6][C:5]=3[N:9]=2)[CH2:17][CH2:16]1
Reactant: COc1cccc([N+](=O)[O-])c1NC(=O)C1CC1
Agent: [Fe]
Solvent: CC(=O)O
Product: COc1cccc2nc(C3CC3)[nH]c12
Yield: 78.9 %

Procedure:
Cyclopropanecarboxylic acid (2-methoxy-6-nitro-phenyl)-amide (5013) (7.80 g, 33.1 mmol) and iron powder (7.60 g) were suspended in acetic acid (200 mL) for 25 min at reflux. The reaction was concentrated and redissolved in ethyl acetate, and washed with NaHCO3 (sat. aq) and NaCl (sat. aq). The combined washings were dried (Na2SO4), filtered and concentrated. The crude product was purified by flash chromatography with 2% MeOH/CH2Cl2 and recrystallization from diethyl ether/hexane (3:1), yielding white crystals of 2-(cyclopropyl)-4-methoxylbenzimidazole (5014) (4.90 g, 26.1 mmol, 79% yield). 1H-NMR (200 MHz, CD2Cl2:) δ 7.07 (cm, 2H), 6.65 (cm, 1H), 3.90 (s, 3H, OCH3), 2.17-2.03 (m, 1H), 1.22-0.96 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:23]2[C:22]([CH3:25])([CH3:24])[CH:21]=[CH:20][C:19]=2[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[CH:20]=[CH:21][C:22]([CH3:25])([CH3:24])[C:23]=4[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCC2=C1C(C)(C)C=C2
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CC1C2=C(C=CC2(C)C)CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1,7,7-trimethyl-2,3,4,7-tetrahydro-1H-[2]pyrindine to provide the title compound.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.Cl.[NH2:12][OH:13].C([O-])(O)=O.[Na+]>CO>[OH:13][NH:12][C:7](=[NH:8])[C:6]1[CH:9]=[CH:10][C:3]([CH2:2][OH:1])=[CH:4][CH:5]=1
Reactant: NO
Reactant: N#Cc1ccc(CO)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: N=C(NO)c1ccc(CO)cc1
Yield: 113.6 %

Procedure:
A mixture of 4-hydroxymethylbenzonitrile (5.0 g, 37.6 mmol), hydroxylamine hydrochloride (2.87 g, 41.3 mmol) and NaHCO3 (4.10 g, 48.8 mmol) in methanol (200 mL) is refluxed for 20 h, filtered and the solvent of the filtrate is evaporated to give N-hydroxy-4-hydroxymethyl-benzamidine (7.1 g) as a white solid; LC-MS: tR=0.22 min.
Reaction SMILES: [C:1]1(=[O:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=[O:17]>>[C:1]1(=[O:13])[O:17][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: O=C1CCCCCCCCCCC1
Reactant: O=C(O)C(F)(F)F
Product: O=C1CCCCCCCCCCCO1
Yield: 75 %

Procedure:
Cyclododecanone was treated with trifluoroacetic acid to form the lactone (Huisgen, R. et al., ibid), dodecanolid (yield 75%; bp 111°-115° C. at 8 mm). The lactone was hydrolyzed to form 12-hydroxydodecanoic acid (Smissman, E. et al., ibid) (yield 92%; mp 82°-4° C.). The hydroxy acid was converted to 12-bromododecanoic acid (VI) with 48% HBr in the presence of H2SO4 (Jocelyn, P. et al., ibid) (yield 88%; mp 52°-55° C.).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([CH:14]=[O:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[B:18](OC)([O:21]C)[O:19]C.CC1C=C(C2C=CC(C(F)(F)F)=CC=2)SC=1C=O>>[CH:14]([C:12]1[S:13][C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:16])([F:1])[F:17])=[CH:8][CH:7]=2)=[CH:10][C:11]=1[B:18]([OH:21])[OH:19])=[O:15]
Reactant: COB(OC)OC
Reactant: O=Cc1ccc(-c2ccc(C(F)(F)F)cc2)s1
Agent: Cc1cc(-c2ccc(C(F)(F)F)cc2)sc1C=O
Product: O=Cc1sc(-c2ccc(C(F)(F)F)cc2)cc1B(O)O

Procedure:
The titled compound is prepared from 5-(4-Trifluoromethyl-phenyl)-thiophene-2-carbaldehyde (2.70 g, 10 mmole) and trimethyl borate (5.68 g, 50.0 mmole) in a similar manner to 3-Methyl-5-(4-trifluoromethyl-phenyl)-thiophene-2-carbaldehyde (Preparation 2, Step A).
Reaction SMILES: C([O:8][C:9]([C@H:11]1[CH2:15][C:14]([F:17])([F:16])[CH2:13][N:12]1[C:18](=[O:46])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([N:29]2[CH2:33][C:32]([F:35])([F:34])[CH2:31][C@@H:30]2[C:36]([O:38]CC2C=CC=CC=2)=[O:37])=[O:28])=[CH:22][CH:21]=1)=[O:10])C1C=CC=CC=1>C(O)C.[Pd]>[C:9]([C@H:11]1[CH2:15][C:14]([F:16])([F:17])[CH2:13][N:12]1[C:18](=[O:46])[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][C:27]([N:29]2[CH2:33][C:32]([F:35])([F:34])[CH2:31][C@@H:30]2[C:36]([OH:38])=[O:37])=[O:28])=[CH:24][CH:25]=1)([OH:10])=[O:8]
Reactant: O=C(OCc1ccccc1)[C@H]1CC(F)(F)CN1C(=O)Cc1ccc(CC(=O)N2CC(F)(F)C[C@@H]2C(=O)OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Product: O=C(O)[C@H]1CC(F)(F)CN1C(=O)Cc1ccc(CC(=O)N2CC(F)(F)C[C@@H]2C(=O)O)cc1
Yield: 60.8 %

Procedure:
0.64 g (0.001 mol) (R)-1-[[4-[2-[(R)-2-Benzyloxycarbonyl-4,4-difluoropyrrolidin-1-yl]-2-oxo-ethyl]-phenyl]-acetyl]-4,4-difluoropyrrolidine-2-carboxylic acid benzyl ester in 20 ml ethanol were hydrogenated at room temperature and atmospheric pressure in the presence of 0.13 g 5% palladium/carbon. After completion of the reaction the catalyst was filtered off, the solvent was distilled off, and the residue was dissolved in dichloromethane. Evaporation gave 0.28 g (61%) (R)-1-[[4-[2-[(R)-2-carboxy-4,4-difluoropyrrolidin-1-yl]-2-oxo-ethyl]-phenyl]-acetyl]-4,4-difluoropyrrolidine-2-carboxylic acid as a light yellow foam. ISP-
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]([Cl:24])=[C:10]([NH:16]C(=O)OC(C)(C)C)[CH:11]=[C:12]([C:14]#[N:15])[CH:13]=2)[CH2:4][C@H:3]1[OH:25].CCN(C(C)C)C(C)C.Cl[C:36]([O:38][CH2:39][CH3:40])=[O:37].C(O)(C(F)(F)F)=O>CO.ClCCCl>[NH2:16][C:10]1[C:9]([Cl:24])=[C:8]([N:5]2[CH2:6][CH2:7][C@@H:2]([NH:1][C:36](=[O:37])[O:38][CH2:39][CH3:40])[C@H:3]([OH:25])[CH2:4]2)[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=1
Reactant: CCOC(=O)Cl
Reactant: CC(C)(C)OC(=O)Nc1cc(C#N)cc(N2CC[C@@H](N)[C@H](O)C2)c1Cl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)N[C@@H]1CCN(c2cc(C#N)cc(N)c2Cl)C[C@H]1O
Reaction time: 1 h
Yield: 39.7 %

Procedure:
A solution of tert-butyl (3-((3R,4R)-4-amino-3-hydroxypiperidin-1-yl)-2-chloro-5-cyanophenyl)carbamate (Example 173A) (300 mg, 0.818 mmol) and DIPEA (0.428 mL, 2.453 mmol) in MeOH (15 mL) at 0° C. (ice bath) was treated with ethyl chloroformate (0.078 mL, 0.818 mmol). The reaction was stirred for 1 hour, then the mixture was concentrated in vacuo. To the residue was added EtOAc (50 ml) and the mixture washed with 0.5M citric acid, sat. NaHCO3, water and brine. The solution was dried over Na2SO4 and solvents removed. To the crude material was added. DCE (5 mL) and TFA (2 mL, 26.0 mmol); the reaction stirred 2 h at 25° C. and solvents removed. The material was diluted with DCM and washed with sat. NaHCO3 and water. The organics dried over Na2SO4 and removed solvent. The material was purified on silica gel 25% EtOAc-DCM to afford ethyl ((3R,4R)-1-(3-amino-2-chloro-5-cyanophenyl)-3-hydroxypiperidin-4-yl)carbamate (110 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:8](=[O:18])[C:7]12[CH2:20][CH2:19]1)([O-])=O.O>CCOC(C)=O.Cl[Sn]Cl>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:8](=[O:18])[C:7]12[CH2:20][CH2:19]1
Reactant: CCCCCN1C(=O)C2(CC2)c2cc([N+](=O)[O-])ccc21
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCCN1C(=O)C2(CC2)c2cc(N)ccc21
Yield: 11.1 %

Procedure:
5′-Nitro-1′-pentyl-spiro[cyclopropane-1,3′-indoline]-2′-one (29.3 g) is dissolved in EtOAc (266 ml) and SnCl2.2 H2O (96.0 g; 427 mmol) is added. The reaction mixture is refluxed overnight, cooled and filtered over Al2O3. After an aqueous work-up of the filtrate the compound (2.9 g) is obtained.
Reaction SMILES: Cl[C:2]([N:4]([C:12]1[C:20]2[O:19][CH:18]([CH3:21])[CH2:17][C:16]=2[CH:15]=[CH:14][CH:13]=1)[NH:5][C:6]([N:8]([O:10][CH3:11])[CH3:9])=[O:7])=[O:3].C(N(C(C)C)CC)(C)C>CO>[CH3:21][CH:18]1[CH2:17][C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([N:4]3[N:5]=[C:6]([N:8]([O:10][CH3:11])[CH3:9])[O:7][C:2]3=[O:3])[C:20]=2[O:19]1
Reactant: CON(C)C(=O)NN(C(=O)Cl)c1cccc2c1OC(C)C2
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CON(C)c1nn(-c2cccc3c2OC(C)C3)c(=O)o1
Reaction time: 18 h

Procedure:
3.4 g of 1F, 2.5 g of N,N-diisopropyl-N-ethylamine and 75 ml of methanol were mixed. The resulting solution was allowed to stand at room temperature for 18 hours, then was warmed on a steam bath for 24 hours. The solvent was evaporated under reduced pressure and the residue was flash chromatographed over silica gel, a 2:15:33 v:v:v mixture of tetrahydrofuran, ethyl acetate and hexane being used as eluent. One product, Rf =0.14, was obtained as an off-white solid. Recrystallization from ether/hexane gave 2, m.p.: 91°-93° C. A second product, Rf =0.17, was obtained as an off-white solid. Recrystallization from ether/hexane gave 1, m.p.: 147°-149° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].C([O:12][C:13](=O)[CH:14]([N:16]=[C:17]=[O:18])[CH3:15])C>>[Cl:1][C:2]1[CH:3]=[C:4]([N:5]2[C:13](=[O:12])[CH:14]([CH3:15])[NH:16][C:17]2=[O:18])[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: CCOC(=O)C(C)N=C=O
Reactant: Nc1ccc(F)c(Cl)c1
Product: CC1NC(=O)N(c2ccc(F)c(Cl)c2)C1=O

Procedure:
A mixture of 2.91 g (20 mmol) of 3-chloro-4-fluoroaniline and 3.01 g (21 mmol) of 2-isocyanato-propionic acid ethyl ester was maintained at 130°-140° C. for 91/2 hours. The resulting product was crystallized from chloroform/methanol to yield 3-(3-chloro-4-fluorophenyl)-5-methyl-hydantoin, m.p. 174°-175.5° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([S:20](=[O:23])(=[O:22])[NH2:21])[C:12]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:7]([OH:9])=[O:8])([O-:3])=[O:2].[OH-].[Li+].[C:26](OC(=O)C)(=[O:28])[CH3:27]>O>[C:26]([NH:21][S:20]([C:11]1[C:12]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8])(=[O:23])=[O:22])(=[O:28])[CH3:27]
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Oc1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CC(=O)NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Oc1ccccc1

Procedure:
3-Nitro-4-phenoxy-5-sulphamyl-benzoic acid (10 g) was dissolved in water (250 ml) by adjusting the pH to 8 by addition of 1N lithium hydroxide. Then acetic anhydride (12 g) was added dropwise, while stirring and keeping the pH constant at pH 9 by means of 1N lithium hydroxide, using an automatic titrator. After the acetic anhydride was consumed, the reaction mixture was acidified by addition of 4N hydrochloric acid. The precipitated 5-acetylsulphamyl-3-nitro-4-phenoxy-benzoic acid was isolated by filtration and recrystallized from aqueous ethanol. The compound was obtained with a melting point of 270°-271°C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH:10]([C:14]3[NH:15][CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[Cl:25])[N:18]=3)[CH2:9]2)[N:5]=[C:4]([NH2:26])[N:3]=1.[F:27][C:28]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[CH:32][C:29]=1[C:30]#[N:31].C([O-])([O-])=O.[Na+].[Na+].CC#N>O1CCOCC1.O.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>[NH2:26][C:4]1[N:3]=[C:2]([C:34]2[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[C:28]([F:27])[CH:35]=2)[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH:10]([C:14]3[NH:15][CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[Cl:25])[N:18]=3)[CH2:9]2)[N:5]=1
Reactant: CC1(C)OB(c2ccc(C#N)c(F)c2)OC1(C)C
Reactant: Nc1nc(Cl)cc(N2CCOC(c3nc(-c4ccccc4Cl)c[nH]3)C2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CC#N
Product: N#Cc1ccc(-c2cc(N3CCOC(c4nc(-c5ccccc5Cl)c[nH]4)C3)nc(N)n2)cc1F
Temperature: 140 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
A mixture of 4-chloro-6-{2-[4-(2-chlorophenyl)-1H-imidazol-2-yl]-4-morpholinyl}-2-pyrimidinamine (100 mg, 0.256 mmol), 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (82 mg, 0.332 mmol), Na2CO3 (67.7 mg, 0.639 mmol) and Pd(PPh3)4 (29.5 mg, 0.026 mmol) in 1,4-dioxane (4 mL) and water (1 mL) was heated at 140° C. under microwave conditions with stirring for 1 hour. The reaction mixture was filtered, washed by EtOAc (100 mL), and concentrated. The resulting residue was purified by prep-HPLC using CH3CN in water (10 mmol NH4HCO3 in water) from 60% to 70% in 7 minutes to afford the title compound (50 mg) as a yellow solid. LC-MS (ES) m/z=476 [M+H]+.