Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][N:15]=[C:16]3[Cl:19])=[CH:11][CH:10]=2)[C:4]1=[O:20].C(N(CC)CC)C.[CH3:28][O:29][C:30]1[CH:39]=[C:38]2[C:33]([CH:34]=[CH:35][C:36]([S:40](Cl)(=[O:42])=[O:41])=[CH:37]2)=[CH:32][CH:31]=1>CC#N>[Cl:19][C:16]1[C:17]2[C:12](=[CH:11][CH:10]=[C:9]([CH2:8][N:5]3[CH2:6][CH2:7][C@H:3]([NH:2][S:40]([C:36]4[CH:35]=[CH:34][C:33]5[C:38](=[CH:39][C:30]([O:29][CH3:28])=[CH:31][CH:32]=5)[CH:37]=4)(=[O:42])=[O:41])[C:4]3=[O:20])[CH:18]=2)[CH:13]=[CH:14][N:15]=1
Reactant: COc1ccc2ccc(S(=O)(=O)Cl)cc2c1
Reactant: N[C@H]1CCN(Cc2ccc3ccnc(Cl)c3c2)C1=O
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc2ccc(S(=O)(=O)N[C@H]3CCN(Cc4ccc5ccnc(Cl)c5c4)C3=O)cc2c1
Reaction time: 8 h
Yield: 96.4 %

Procedure:
3-(S)-Amino-1-(1-chloro-isoquinolin-7-ylmethyl)-pyrrolidin-2-one hydrochloride (1.74 g, 5.6 mmol) is suspended in CH3CN (120 mL). To this solution is added triethylamine (2.35 mL, 16.9 mmol) followed by 7-methoxynaphthalene-2-sulfonyl chloride (1.52 g, 5.93 mmol). The mixture is stirred overnight, then concentrated to dryness. The crude product is purified by column chromatography eluting with a gradient of 2% MeOH/CH2Cl2 to 5% MeOH/CH2Cl2 to give the title compound (2.7 g, 5.4 mmol) as a light yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([C:14]([OH:16])=O)[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:48][C:49]1[CH:54]=[C:53]([O:55][C:56]2[CH:61]=[C:60]([F:62])[C:59]([NH2:63])=[CH:58][C:57]=2[F:64])[N:52]=[CH:51][N:50]=1>CN(C)C=O>[NH2:48][C:49]1[CH:54]=[C:53]([O:55][C:56]2[C:57]([F:64])=[CH:58][C:59]([NH:63][C:14]([C:11]3([C:9]([NH:8][C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[O:10])[CH2:12][CH2:13]3)=[O:16])=[C:60]([F:62])[CH:61]=2)[N:52]=[CH:51][N:50]=1
Reactant: Nc1cc(Oc2cc(F)c(N)cc2F)ncn1
Reactant: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1cc(Oc2cc(F)c(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ncn1
Reaction time: 0.5 h
Yield: 39.6 %

Procedure:
To a solution of 1-(4-fluorophenylaminocarbonyl)cyclopropanecarboxylic acid (378 mg) in N,N-dimethylformamide (3 ml) were added triethylamine (0.236 ml) and HATU (644 mg) at room temperature under a nitrogen atmosphere, followed by stirring for 30 min. To the resultant mixture was added 4-amino-6-(4-amino-2,5-difluorophenoxy)pyrimidine (270 mg) in N,N-dimethylformamide (3 ml) at room temperature, followed by stirring for 6 hr. Triethylamine (0.079 ml) and HATU (215 mg) were added again and the resultant mixture was stirred overnight. The reaction mixture was partitioned between ethyl acetate (20 ml) and a 1N aqueous solution of sodium hydroxide (10 ml). The organic layer was washed with a 1N aqueous solution of sodium hydroxide (10 ml, twice) and brine (10 ml), dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure and the resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; heptane:ethyl acetate=1:2 to 1:4). Fractions containing the target compound were concentrated under reduced pressure and the residue was dried under reduced pressure to provide the titled compound as pale brown powder (199 mg, 40%).
Reaction SMILES: [NH2:1][C@H:2]([C:4]([N:6]1[C:12](=[O:13])[CH:11]([CH3:14])[C:10]2[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=2[C:8]2[C:19]([NH2:23])=[CH:20][CH:21]=[CH:22][C:7]1=2)=[O:5])[CH3:3].[C:24](O)(=[O:26])[CH3:25]>>[C:24]([NH:1][C@H:2]([C:4]([N:6]1[C:12](=[O:13])[CH:11]([CH3:14])[C:10]2[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=2[C:8]2[C:19]([NH2:23])=[CH:20][CH:21]=[CH:22][C:7]1=2)=[O:5])[CH3:3])(=[O:26])[CH3:25]
Reactant: CC1C(=O)N(C(=O)[C@H](C)N)c2cccc(N)c2-c2ccccc21
Reactant: CC(=O)O
Product: CC(=O)N[C@@H](C)C(=O)N1C(=O)C(C)c2ccccc2-c2c(N)cccc21

Procedure:
Following General Procedure C-P using acetic acid and 5-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one, as described in Example 7-B, the title compound was prepared. The molecular weight as determined by mass spectrometry (FD) was: 352 (M+H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:27]=[CH:26][C:12]([C:13]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([CH3:25])=[C:20]([CH:24]=3)[C:21](O)=[O:22])=[O:14])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[NH2:28][C:29]1[CH:30]=[C:31]2[CH:37]=[C:36]([C:38]([O:40][CH3:41])=[O:39])[NH:35][C:32]2=[N:33][CH:34]=1.C(N(CC)CC)C.OC1C2N=NNC=2C=CC=1.C(=O)(O)O.CN(C)CCCN=C=NCC>ClCCl>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([CH2:8][C:9]2[CH:27]=[CH:26][C:12]([C:13]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([CH3:25])=[C:20]([CH:24]=3)[C:21]([NH:28][C:29]3[CH:30]=[C:31]4[CH:37]=[C:36]([C:38]([O:40][CH3:41])=[O:39])[NH:35][C:32]4=[N:33][CH:34]=3)=[O:22])=[O:14])=[CH:11][CH:10]=2)[CH2:6][CH2:7]1
Reactant: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)cc2)cc1C(=O)O
Reactant: COC(=O)c1cc2cc(N)cnc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: O=C(O)O
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc2cc(NC(=O)c3cc(NC(=O)c4ccc(CN5CCN(C)CC5)cc4)ccc3C)cnc2[nH]1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 8.3 %

Procedure:
A reactor is charged successively with 150 mg (0.4 mmol) of the solid obtained in step 3, 15 ml of anhydrous dichloromethane, 90 mg (0.4 mmol) of methyl 5-amino-1H-pyrrolo[2,3-b]pyridine-2-carboxylate, 0.12 g (0.49 mmol) of triethylamine and 93 mg (0.61 mmol) of hydroxybenzotriazole. The mixture is stirred at room temperature for 15 min and then 90 mg (0.49 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrogen carbonate (EDCl) is added. The mixture is stirred for 16 hours. The solvent is then evaporated under reduced pressure and the residue is taken off in 100 ml of water. The aqueous phase is extracted by 6*50 ml dichloromethane. The aqueous phases are combined, dried on sodium sulphate and then evaporated under reduced pressure. The raw product obtained is purified by preparative HPLC and 18 mg (8%) of a solid is obtained.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:9]#[C:10][Si](C)(C)C)[C:5]([NH2:8])=[N:6][CH:7]=1.[H-].[Na+].[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>CN(C=O)C>[Br:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:10][N:8]([S:23]([C:20]3[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=3)(=[O:25])=[O:24])[C:5]2=[N:6][CH:7]=1
Reactant: C[Si](C)(C)C#Cc1nc(Br)cnc1N
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(Br)cnc32)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 55.3 %

Procedure:
To a solution of 5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine (3.00 g, 11.1 mmol) in DMF (60 mL) at about 0° C. was added NaH (60% dispersion in mineral oil, 0.577 g, 14.4 mmol) in three portions. After about 15 min, p-toluenesulfonyl chloride (2.75 g, 14.4 mmol) was added and the reaction was allowed to warm slowly to ambient temperature. After about 16 h, the reaction mixture was poured onto ice-cold water (120 mL) and the precipitate was collected by vacuum filtration. The crude solid was dissolved in DCM (15 mL) and purified by silica gel chromatography eluting with DCM to give 2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (2.16 g, 52%): LC/MS (Table 1, Method c) Rt=1.58 min; MS m/z: 352, 354 (M+H)+.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15](O)=[O:16])[N:12]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:11]2=[O:24])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:25][C:26]1[C:27]([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)=[N:28][CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1>>[C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15]([N:39]3[CH2:40][CH2:41][N:36]([C:27]4[C:26]([Cl:25])=[CH:31][C:30]([C:32]([F:35])([F:34])[F:33])=[CH:29][N:28]=4)[CH2:37][CH2:38]3)=[O:16])[N:12]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:11]2=[O:24])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: FC(F)(F)c1cnc(N2CCNCC2)c(Cl)c1
Reactant: O=C(O)C1CN(S(=O)(=O)c2ccccc2)C(=O)N1C1CCCCC1
Product: O=C(C1CN(S(=O)(=O)c2ccccc2)C(=O)N1C1CCCCC1)N1CCN(c2ncc(C(F)(F)F)cc2Cl)CC1

Procedure:
In analogy to example 1, (RS)-1-benzenesulfonyl-3-cyclohexyl-2-oxo-imidazolidine-4-carboxylic acid (example 39, step 4) was coupled with 1-[3-chloro-5-(trifluoromethyl)pyrid-2-yl]piperazine to give the title compound as an off-white solid. MS: 600.3 ([M+H]+)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([C@@H:12]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:28][CH3:29])[CH:20]=1)[CH2:13][C:14]([N:16]([CH3:18])[CH3:17])=[O:15])[CH2:7]2.[CH3:30][N:31]([CH3:35])[C:32](Cl)=[O:33]>C1COCC1>[CH3:30][N:31]([CH3:35])[C:32](=[O:33])[NH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([C@@H:12]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:28][CH3:29])[CH:20]=1)[CH2:13][C:14]([N:16]([CH3:18])[CH3:17])=[O:15])[CH2:7]2
Reactant: CCOc1cc([C@@H](CC(=O)N(C)C)N2Cc3cccc(N)c3C2=O)ccc1OC
Reactant: CN(C)C(=O)Cl
Solvent: C1CCOC1
Product: CCOc1cc([C@@H](CC(=O)N(C)C)N2Cc3cccc(NC(=O)N(C)C)c3C2=O)ccc1OC
Yield: 34.3 %

Procedure:
A solution of (3R)-3-(7-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-3-(3-ethoxy-4-methoxy-phenyl)-N,N-dimethyl-propionamide (1.1 g, 2.8 mmol) and dimethylcarbamyl chloride (0.5 mL, 5.4 mmol) in THF (5 mL) was heated to reflux for 2 days. The solvent was removed in vacuo to give a solid, which was purified with prep HPLC to give (3R)-3-[7-(3,3-dimethyl-ureido)-1-oxo-1,3-dihydro-isoindol-2-yl]-3-(3-ethoxy-4-methoxy-phenyl)-N,N-dimethyl-propionamide as a white solid (450 mg, 34% yield): mp 105-107° C.; 1HNMR (CDCl3) δ 1.44 (t, J=7 Hz, 3H, CH3), 2.90 (s, 3H, CH3), 3.05 (dd, J=6, 16 Hz, 1H, CHH), 3.09 (s, 9H,3CH3), 3.46 (dd, J=9.15 Hz, 1H, CHH), 3.85 (s, 3H, CH3), 4.07 (q, J=7 Hz, 2H, CH2), 4.22 (d, J=17 Hz, 1H, NCHH), 4.41 (d, J=17 Hz, 1H, NCHH), 5.63 (dd, J=6, 9 Hz, 1H, NCH), 6.91-6.96 (m, 4H, Ar), 7.39 (t, J=8 Hz, 1H, Ar), 8.30 (d, J=8 Hz, 1H, Ar), 9.99 (s, 1H, NH); 13CNMR (CDCl3) δ 14.76, 35.57, 36.31, 36.38, 37.45, 48.70, 53.35, 55.97, 64.53, 111.46, 112.63, 115.07, 116.27, 117.57, 119.16, 131.90, 133.02, 139.61, 141.54, 148.55, 149.08, 155.49, 149.69, 170.15. Analy. Calculated for C25H32N4O5+1.2H2O: C, 61.26; H, 7.07; N, 11.43; H2O, 4.41. Found: C, 60.89; H, 6.95; N, 11.10; H2O, 4.04.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18]Br)[CH:13]=1.BrCC1C=CC=C(F)C=1>>[Br:11][C:12]1[CH:13]=[C:14]([CH:15]=[CH:16][CH:17]=1)[CH2:18][O:10][C:6]1[CH:5]=[C:4]([NH2:1])[CH:9]=[CH:8][CH:7]=1
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: BrCc1cccc(Br)c1
Agent: Fc1cccc(CBr)c1
Product: Nc1cccc(OCc2cccc(Br)c2)c1

Procedure:
3-Nitro-phenol was reacted with 1-bromo-3-bromomethyl-benzene according to the procedure from Example 199A substituting 1-bromo-3-bromomethyl-benzene for 1-bromomethyl-3-fluoro-benzene then reduced according to the procedure from Example 199B to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][C@@:11]3([CH2:16][C@@H:15]([C:17]([OH:19])=O)[N:14]([C:20](=[O:36])[C@@H:21]([NH:26][C:27](=[O:35])[CH2:28][CH:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)[C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:13]3)[O:10][C:9]2=[O:37])[CH:5]=[CH:6][CH:7]=1.[NH2:38][C@@H:39]([CH2:48][CH2:49][CH3:50])[CH:40]([OH:47])[C:41]([NH:43][CH:44]1[CH2:46][CH2:45]1)=[O:42]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][C@@:11]3([CH2:16][C@@H:15]([C:17]([NH:38][C@@H:39]([CH2:48][CH2:49][CH3:50])[CH:40]([OH:47])[C:41]([NH:43][CH:44]4[CH2:45][CH2:46]4)=[O:42])=[O:19])[N:14]([C:20](=[O:36])[C@@H:21]([NH:26][C:27](=[O:35])[CH2:28][CH:29]4[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]4)[C:22]([CH3:25])([CH3:23])[CH3:24])[CH2:13]3)[O:10][C:9]2=[O:37])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[C@H](NC(=O)CC1CCCCC1)C(=O)N1C[C@@]2(C[C@H]1C(=O)O)CN(c1cccc(Cl)c1)C(=O)O2
Reactant: CCC[C@H](N)C(O)C(=O)NC1CC1
Product: CCC[C@H](NC(=O)[C@@H]1C[C@@]2(CN(c3cccc(Cl)c3)C(=O)O2)CN1C(=O)[C@@H](NC(=O)CC1CCCCC1)C(C)(C)C)C(O)C(=O)NC1CC1
Yield: 32.6 %

Procedure:
Following the procedure from Example 1 step 1 using (5S,8S)-3-(3-chlorophenyl)-7-((S)-2-(2-cyclohexylacetamido)-3,3-dimethylbutanoyl)-2-oxo-1-oxa-3,7-diazaspiro[4.4]nonane-8-carboxylic acid (D5) (23 mg, 43 μmol) and (3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide (15 mg, 65 μmol) gave 10 mg (14 μmol) of (5S,8S)-3-(3-chlorophenyl)-7-((S)-2-(2-cyclohexylacetamido)-3,3-dimethylbutanoyl)-N-((3S)-1-(cyclopropylamino)-2-hydroxy-1-oxohexan-3-yl)-2-oxo-1-oxa-3,7-diazaspiro[4.4]nonane-8-carboxamide (E5). LC MS+/−: 702.54/700.62 at 3.63 min (10-90%, 3-5 min, Formic Acid).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[CH:7]=[C:6]([C:19]([NH2:21])=O)[C:5]2=[O:22].N1C(Cl)=NC(Cl)=NC=1Cl>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=1)[CH:7]=[C:6]([C:19]#[N:21])[C:5]2=[O:22]
Reactant: NC(=O)c1cn(-c2ccc(F)cc2)c2ccc(Br)cc2c1=O
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1cn(-c2ccc(F)cc2)c2ccc(Br)cc2c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.5 %

Procedure:
Compound E (30 mg, 0.083 mmol, 1.0 eq) and cyanuric chloride (15 mg, 0.083 mmol, 1.0 eq) were dissolved in DMF (0.5 mL) and the reaction was stirred at room temperature for 30 minutes. The reaction was diluted with ethyl acetate and washed with saturated sodium bicarbonate. The organic phase was dried (MgSO4), filtered and concentrated in vacuo. Purification by reverse phase chromatography afforded 10.1 mg (68%) of the title compound as white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.94 (s, 1H), 8.30 (d, J=2.4 Hz, 1H), 7.86 (dd, J=9.0, 2.4 Hz, 1H), 7.75-7.72 (m, 2H), 7.53 (t, J=8.7 Hz, 2H), 6.96 (d, J=9.1 Hz, 1H); ES-MS [M+1]+: 343.2.
Reaction SMILES: [CH2:1]([N:8]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][OH:27])=[CH:22][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:31]>CN(C=O)C.C(OCC)C>[CH2:1]([N:8]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][O:27][CH3:31])=[CH:22][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CI
Reactant: Cc1c(N(Cc2ccccc2)Cc2ccc(CO)cc2)cccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COCc1ccc(CN(Cc2ccccc2)c2cccc([N+](=O)[O-])c2C)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
The product from Example 38A (0.1 g, 0.276 mmoles) in DMF (0.7 mL) was treated with sodium hydride (0.012 g, 0.3 mmoles, 60% dispersion). After 10 minutes, the reaction mixture was treated with iodomethane (0.02 mL, 0.36 mmoles) and then stirred overnight at room temperature. The mixture was diluted with diethyl ether (100 mL), washed with saturated ammonium chloride (50 mL) and water (50 mL) twice, washed with brine (50 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provide the title compound which was used in the next step without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[S:11][CH:10]=[C:9]([C:12]([OH:14])=O)[CH:8]=2)=[CH:5][CH:4]=[N:3]1.[NH2:15][CH:16]([C:29]([CH3:37])([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:30])[CH2:17][N:18]1[C:26](=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]1=[O:28].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(Cl)(Cl)Cl>[O:28]=[C:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:26](=[O:27])[N:18]1[CH2:17][CH:16]([NH:15][C:12]([C:9]1[CH:8]=[C:7]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=2)[S:11][CH:10]=1)=[O:14])[C:29]([CH3:30])([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:37]
Reactant: Cn1nccc1-c1cc(C(=O)O)cs1
Reactant: CC(C)(c1ccccc1)C(N)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nccc1-c1cc(C(=O)NC(CN2C(=O)c3ccccc3C2=O)C(C)(C)c2ccccc2)cs1
Reaction time: 16 h
Yield: 29.6 %

Procedure:
To a heterogeneous mixture of 5-(1-methyl-1H-pyrazol-5-yl)-3-thiophenecarboxylic acid (155 mg, 0.74 mmol), 2-(2-amino-3-methyl-3-phenylbutyl)-1H-isoindole-1,3(2H)-dione (200 mg, 0.65 mmol)[from Preparation 4] and PyBrOP (426 mg, 0.91 mmol) in CHCl3 (10 mL) at 25° C. was added diisopropylethyl amine (0.5 mL, 2.9 mmol) dropwise. After 16 h, the mixture was adsorbed onto silica and the mixture purified via column chromatography (silica, 35-50% EtOAc/Hex) affording the title compound (96 mg, 26%) as a white solid: LC-MS (ES) m/z=499 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[F:15][C:16]([F:33])([O:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH:31]=[CH:30][NH:29][C:28]2=[O:32])=[CH:23][CH:22]=1)[CH:17]([F:19])[F:18]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([O:10][CH2:11]1)[C@H:12]([N:29]1[CH:30]=[CH:31][N:27]([C:24]2[CH:23]=[CH:22][C:21]([O:20][C:16]([F:33])([F:15])[CH:17]([F:19])[F:18])=[CH:26][CH:25]=2)[C:28]1=[O:32])[CH3:13]
Reactant: O=c1[nH]ccn1-c1ccc(OC(F)(F)C(F)F)cc1
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Product: C[C@@H](n1ccn(-c2ccc(OC(F)(F)C(F)F)cc2)c1=O)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 18.9 %

Procedure:
In the same manner as in Reference Example 5, starting from 1.01 g of (1S)-1-[(2R)-(2,4-difluorophenyl)-2-oxiranyl]ethanol and 1.15 g of 1-[4-(1,1,2,2tetrafluoroethoxy)phenyl]-2(1H,3H)-imidazolone, 0.36 g of 1-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-3-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-2(1H,3H)-imidazolone was obtained as colorless needles.
Reaction SMILES: [N+:1]([C:4]1[N:9]=[CH:8][C:7]([N:10]2[CH2:23][C:12]3([CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]3)[CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.C(OCC)(=O)C>[Pd].CO>[C:19]([O:18][C:16]([N:14]1[CH2:13][C:12]2([CH2:23][N:10]([C:7]3[CH:8]=[N:9][C:4]([NH2:1])=[CH:5][CH:6]=3)[CH2:11]2)[CH2:15]1)=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CC2(C1)CN(c1ccc([N+](=O)[O-])nc1)C2
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC2(C1)CN(c1ccc(N)nc1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.3 %

Procedure:
In a 500 mL pear-shaped flask, tert-butyl 6-(6-nitropyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (4.54 g, 14.2 mmol) and 10% Pd/C (662 mg, 6.22 mmol) were combined with ethyl acetate (150 ml) and methanol (50 ml) to give a black suspension. The mixture was evacuated and filled with H2 twice, then stirred overnight at 25° C. under balloon pressure of H2. The mixture was filtered over celite and the filter cake was washed with MeOH. The filtrate was concentrated in vacuo to give a purple oily solid. The crude material was purified by flash chromatography (silica gel, 12 g, 0% to 4% MeOH in DCM) to afford 1.29 g (31%) of the title compound as an impure dark red solid. (M+H)+=291 m/e.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]#[C:13][Si](C)(C)C)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.CC(O)=O.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CCOCC>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([CH2:11][C:12]#[CH:13])[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cc(CC#C[Si](C)(C)C)cc(OC)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C#CCc1cc(OC)cc(OC)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 101.2 %

Procedure:
To a stirred solution of 7 (5.37 g, 21.6 mmol, 1 equiv) was dissolved in THF (100 mL) and AcOH (4.99 mL, 86.5 mmol, 4 equiv) was added followed by dropwise addition of TBAF (1 M in THF; 86.5 mL, 86.5 mmol, 4 equiv). The resulting reaction was allowed to stir at room temperature for 24 h. The reaction was diluted with Et2O, washed with brine (×2), dried (MgSO4), filtered, and concentrated under reduced pressure. The crude mixture was purified by chromatography on SiO2 (EtOAc/hexanes, 1:10) to give 3.85 g (100% yield) of the desired product as a colorless oil: Rf 0.36 (EtOAc/hexanes, 1:10); IR (CDCl3) 3286, 2999, 2954, 1593, 1457, 1428, 1344, 1323, 1288, 1204, 1154, 1064, 827; 1H NMR (400 MHz, CDCl3) δ 6.53 (d, 2 H, J=2.4 Hz), 6.35 (t, 1 H, J=2.4 Hz), 3.79 (s, 6 H), 3.56 (d, 2 H, J=2.8 Hz), 2.20 (t, 1H, J=2.8 Hz); 13C NMR (100 MHz, CDCl3) δ 160.9, 138.3, 105.9, 98.7, 81.7, 70.6, 55.3, 25.0; HRMS (EI+) m/z calcd for C11H12O2 176.0837, found 176.0834.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5](=[NH:13])[NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl[CH2:18][CH:19]=O.C(=O)(O)[O-].[Na+]>CC(O)C>[I:1][C:2]1[CH:3]=[C:4]([C:5]2[N:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:18]=[CH:19][N:13]=2)[CH:14]=[CH:15][CH:16]=1
Reactant: O=CCCl
Reactant: N=C(Nc1ccccc1)c1cccc(I)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: Ic1cccc(-c2nccn2-c2ccccc2)c1

Procedure:
To a 500 mL round bottom flask was added 3-iodo-N-phenylbenzimidamide (7.84 g, 24.34 mmol), 2-chloroacetaldehyde solution (50%, 6.7 mL, 48.7 mmol), sodium bicarbonate (4.09 g, 48.7 mmol), and 150 mL 2-propanol. The reaction mixture was heated at reflux for 3 h under nitrogen. The solvent was removed under vacuum and the residue dissolved in ethyl acetate. The ethyl acetate solution was washed with water, brine, dried over magnesium sulfate, filtered, and evaporated. The residue was purified by column chromatography eluting with 20-40% ethyl acetate/hexane (4.67 g, 55%).
Reaction SMILES: C([CH2:3][NH:4][C:5]([C:7]1[S:11][C:10]([CH3:12])=[N:9][C:8]=1[CH3:13])=[O:6])#N.BrBr.C(O)C.[CH2:19]([N:21](CC)CC)C.C([O:29][CH2:30][CH3:31])(=O)C>O>[C:19]([CH:30]([O:29][CH2:3][NH:4][C:5]([C:7]1[S:11][C:10]([CH3:12])=[N:9][C:8]=1[CH3:13])=[O:6])[CH3:31])#[N:21]
Reactant: CCN(CC)CC
Reactant: Cc1nc(C)c(C(=O)NCC#N)s1
Reactant: CCOC(C)=O
Agent: BrBr
Solvent: O
Solvent: CCO
Product: Cc1nc(C)c(C(=O)NCOC(C)C#N)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.1 %

Procedure:
1.0 g of N-cyanomethyl-2,4-dimethylthiazole-5-carboxylic acid amide was dissolved in 30 ml of ethyl acetate. Bromine (0.3 ml) was added and the mixture was heated under reflux until the dark brown color of bromine disappeared. The reaction mixture was cooled over an ice bath, and 1.0 g of ethanol, 2.0 g of triethylamine and 10 ml of ethyl acetate were added at the above temperature. The mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried, and distilled under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography. Elution with hexane/ethyl acetate gave 0.53 g (yield 43.1%) of the desired N-(alpha-cyano-alpha-ethoxymethyl)-2,4-dimethylthiazole-5-carboxylic acid amide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-])[CH:5]=[CH:6][CH:7]=1.C[Si]([C:13]#[N:14])(C)C.CCN(CC)CC>C(#N)C>[Cl:1][C:2]1[C:3]([C:13]#[N:14])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)C#N
Reactant: [O-][n+]1cccc(Cl)c1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: N#Cc1ncccc1Cl
Yield: 66.4 %

Procedure:
Compound 44A (2.59 g, 20 mmol), trimethylsilylcyanide (5.95 g, 60 mmol), Et3N (4.05 g, 40 mmol), and acetonitrile (20 mL) were combined in a 3-necked 250-mL round-bottomed flask under nitrogen and refluxed for 6 h, at which time HPLC analysis indicated complete consumption of starting material. The cooled reaction mixture was concentrated under reduced pressure to give a brown semi-solid which was partitioned between 3 N aqueous Na2CO3 and CH2Cl2. The organic layer was washed with water, brine, dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography using 5% Et2O/CH2Cl2 as eluent to give the product 44B as a white crystalline solid (1.84 g, 67%). 1H NMR (CDCl3) 7.37 (dd, J=4.7, 8.4 Hz, 1H), 7.73 (dd, J=1.4, 8.2 Hz, 1H), 8.47 (dd, J=1.3, 4.6 Hz, 1H); LC/MS m/z 139 [M+H]+.