Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[C:14]([S:17](Cl)(=[O:19])=[O:18])[CH:15]=[CH:16][C:7]=3[CH2:6][CH2:5][C:4]=2[N:3]=1.[N+:21]([C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1)([O-:23])=[O:22]>N1C=CC=CC=1>[CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[C:14]([S:17]([NH:28][C:27]4[CH:29]=[CH:30][C:24]([N+:21]([O-:23])=[O:22])=[CH:25][CH:26]=4)(=[O:19])=[O:18])[CH:15]=[CH:16][C:7]=3[CH2:6][CH2:5][C:4]=2[N:3]=1
Reactant: Cc1nc2c(c(=O)[nH]1)-c1cc(S(=O)(=O)Cl)ccc1CC2
Reactant: Nc1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Product: Cc1nc2c(c(=O)[nH]1)-c1cc(S(=O)(=O)Nc3ccc([N+](=O)[O-])cc3)ccc1CC2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
1,2,5,6-Tetrahydro-3-methyl-1-oxobenzo[f]quinazolin-9-sulfonylchloride (0.53 g, 1.7 mole) and p-nitroaniline (0.25 9, 1.8 mmole) (Eastman) were dissolved in pyridine (5 ml) and the reaction mixture stirred at room temperature for 48 hours. The pyridine was removed in vacuo, and the residue washed with water. The dried solid was subjected to chromatography on silica (80 g), eluting with methanol-methylene chloride(1:19). Fractions containing product were evaporated to dryness, the residue sonicated with ether (75 ml) and filtered. The beige solid was washed with ether and dried under high vacuum to yield 1,2,5,6-tetrahydro-3-methyl-4′-nitro-1-oxobenzo[f]quinazoline-9-sulfonanilide. (0.18 g, 26%). Mp>240° C. 1H NMR (DMSO-d6, 300 MHz) δ: 2.32 (s, 3H, CH3); 2.72 (m, 2H, Ar CH2); 2.91 (m, 2H, ArCH2); 7.33 (d, J=9 Hz, 2H, Ar); 7.43 (d, J=8 Hz, 1H, Ar); 7.69(dd, J=2.8 Hz, Ar); 8.13 (d, J=9 Hz, 2H, Ar); 9.23 (d, J=2 Hz, 1H, Ar); 11.13 (s, 1H, NH); 12.73 (s, 1H, NH). Anal Calculated for C19H16N4O5S.13/25 H2O: C,54.10; H,4.07; N,13.28; S,7.60. Found: C,54.07; H,3.98; N,13.19; S,7.66.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH2:11][NH:12][CH3:13])=[CH:8][C:6]=2[N:7]=1.O=[C:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1>>[C:30]([O:29][C:27]([N:24]1[CH2:25][CH2:26][CH:21]([N:12]([CH2:11][C:9]2[S:10][C:5]3[C:4]([N:14]4[CH2:15][CH2:16][O:17][CH2:18][CH2:19]4)=[N:3][C:2]([Cl:1])=[N:7][C:6]=3[CH:8]=2)[CH3:13])[CH2:22][CH2:23]1)=[O:28])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CNCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Product: CN(Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1)C1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-methylamine was reacted with 1-tert-butyl 4-oxo-1-piperidinecarboxylate using standard reductive amination conditions. The resulting crude solid was triturated with diethylether to give 4-[(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-methyl-amino]-piperidine-1-carboxylic acid tert-butyl ester as an off white solid (72% yield), which was reacted with 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine according to General Procedure A. The resulting solid was stirred in a solution of 2N HCl (5 ml) and methanol (5 ml) overnight, before the solution was evaporated in vacuo to remove the methanol and the acidic solution made basic with sat. aq. K2CO3. The resulting solid was filtered and washed with diethyl ether to give 342 as a solid (52% yield). NMR (CDCl3, 400 MHz), 1.48-1.55 (3H, m), 1.86 (2H, d, J=12.7), 2.38 (3H, s), 2.58-2.64 (3H, m), 3.18 (2H, d, J=12.2), 3.88-3.91 (4H, m), 3.94 (2H, s), 4.03-4.06 (4H, m), 5.23 (2H, br s), 7.28 (1H, s), 9.30 (2H, s). MS: (ESI+): MH+=441
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:11]([NH2:14])(=[O:13])=[O:12])[CH:5]=[CH:6][C:7]=1[N:8]=[C:9]=[O:10].[CH3:15][O:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.CO>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([S:11](=[O:12])(=[O:13])[NH2:14])[CH:5]=[CH:6][C:7]=1[NH:8][C:9]([N:20]1[CH2:21][CH2:22][CH:17]([O:16][CH3:15])[CH2:18][CH2:19]1)=[O:10]
Reactant: NS(=O)(=O)c1ccc(N=C=O)c(Cl)c1
Reactant: COC1CCNCC1
Solvent: CO
Solvent: C1CCOC1
Product: COC1CCN(C(=O)Nc2ccc(S(N)(=O)=O)cc2Cl)CC1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a solution of EXAMPLE 392A in anhydrous tetrahydrofuran (6 mL) was added 4-methoxypiperidine (451 mg). The mixture was stirred at 60° C. for 3 hours. The mixture was cooled, mixed with methanol (20 mL) and silica gel (6 g) and concentrated. The material was purified on a silica gel column and was eluted with 10% methanol in dichloromethane to provide the title compound.
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[CH:9][O:10][C:6]=2[CH:5]=[C:4]([C:11]([OH:13])=[O:12])[C:3]=1[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[F:21].C1C(=O)N([I:29])C(=O)C1.FC(F)(F)C(O)=O>CN(C=O)C>[F:1][C:2]1[C:7]2[N:8]=[CH:9][O:10][C:6]=2[CH:5]=[C:4]([C:11]([OH:13])=[O:12])[C:3]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([I:29])=[CH:17][C:16]=1[F:21]
Reactant: O=C(O)c1cc2ocnc2c(F)c1Nc1ccccc1F
Reactant: O=C1CCC(=O)N1I
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: O=C(O)c1cc2ocnc2c(F)c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.2 %

Procedure:
To a solution of 4-fluoro-5-((2-fluorophenyl)amino)benzo[d]oxazole-6-carboxylic acid (7.22 g, 24.90 mmol) in DMF (50 mL) was added NIS (6.08 g, 26.37 mmol) followed by trifluoroacetic acid (3 mL). After stirring for 4 h at ambient temperature, the reaction was quenched with saturated NH4Cl (aq., 100 mL). The solution was extracted with ethyl acetate (150 mL×3). The combined organic extracts were washed with water (50 mL×3) and brine (100 mL) successively, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (petroleum ether/ethyl acetate, 3:1, v/v) and gave the desired product (brown solid, 6.339 g, 69% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.97 (s, 1H), 8.18 (s, 1H), 8.08 (s, 1H), 7.58 (dd, J=11.0, 1.7 Hz, 1H), 7.34 (d, J=8.5 Hz, 1H), 6.55 (m, 1H).
Reaction SMILES: [CH3:1][C:2]12[CH2:7][CH:6]1[CH2:5][CH:4]([CH2:8][CH:9]=O)[C:3]2([CH3:12])[CH3:11].C[O-].[Na+].[CH:16](=[O:19])[CH2:17][CH3:18].C(O)(=O)C>CO>[CH3:18][C:17](=[CH:9][CH2:8][CH:4]1[CH2:5][CH:6]2[C:2]([CH3:1])([CH2:7]2)[C:3]1([CH3:12])[CH3:11])[CH:16]=[O:19]
Reactant: CCC=O
Reactant: CC1(C)C(CC=O)CC2CC21C
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C=O)=CCC1CC2CC2(C)C1(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 43.1 %

Procedure:
30 g (0.18 mol) of (1,2,2-trimethylbicyclo[3.1.0]hex-3-yl)ethanal was added to 5.0 ml (24 mmol) of stirred 5.4 M methanolic solution of sodium methylate diluted with 40 ml of methanol. 35 g (0.61 mol) of propionaldehyde was added at 25° C. with cooling during 10 minutes, the reaction mixture stirred at room temperature for 1.5 hours, neutralized with acetic acid and the solvent removed in vacuo. The residue was dissolved in 100 ml of ether, washed with 3×80 ml of water, dried (MgSO4) and evaporated in vacuo. Purification by Kugelrohr distillation at 94° C./0.1 Torr followed by flash chromatography on silica gel (eluent: hexane/MTBE 4:1) gave 16.0 g (43% yield) of 2-methyl-4-(1,2,2-trimethylbicyclo[3.1.0]hex-3-yl)but-2-enal.
Reaction SMILES: [OH:1][C:2]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:13]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N:25]=[C:26]=[O:27])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[OH:1][C:2]1[CH:8]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:6]=[CH:5][C:3]=1[NH:4][C:26]([NH:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:27]
Reactant: O=C=Nc1ccccc1-c1ccccc1
Reactant: Nc1ccc(C(F)(F)F)cc1O
Product: O=C(Nc1ccc(C(F)(F)F)cc1O)Nc1ccccc1-c1ccccc1
Yield: 64 %

Procedure:
The urea was prepared from 2-hydroxy 4-trifluoromethyl aniline (example 7a, 0.171 g, 1 mmol)) and 2-phenyl phenyl isocyanate by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the desired compound (0.24 g, 64%). EI-MS m/z 373 (M+H)+
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[F:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[CH2:10][CH2:9]2.[Cl-].[NH4+]>CCOCC>[CH2:1]([C:11]1([OH:15])[C:12]2[C:8](=[CH:7][C:6]([F:5])=[CH:14][CH:13]=2)[CH2:9][CH2:10]1)[CH3:2]
Reactant: O=C1CCc2cc(F)ccc21
Reactant: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CCC1(O)CCc2cc(F)ccc21
Yield: 92.9 %

Procedure:
Add ethyl magnesium bromide (1.3 ml, 3.90 mmol, 1.30 equivalents, 3.0 M in tetrahydrofuran) drop wise to a solution of 5-fluoroindanone (450 mg, 3.00 mmol) in. anhydrous ether (5 ml) under nitrogen at room temperature and stir overnight. Quench the reaction by drop wise addition of 10% aqueous ammonium chloride, dilute with ether, wash with water (2×), dry over anhydrous sodium sulfate, filter, and concentrate to obtain the'title compound (502 mg, 93%). NMR (400 MHz, CDCl3): δ 0.94 (t, 3H), 1.79 (m, 1H), 1.92 (m, 1H), 2.12 (m, 1H), 2.31 (m, 1H), 2.81 (m, 1H), 2,98 (m, 1H), 6.91 (m, 2H), 7.24 (m, 1H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].C([Li:14])CCC.CCCCCC>O1CCCC1>[CH3:9][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Li:14]
Reactant: [Li]CCCC
Reactant: COc1ccccc1I
Solvent: CCCCCC
Solvent: C1CCOC1
Product: [Li]c1ccccc1OC
Reaction time: 0.75 h

Procedure:
To a solution of 2-iodoanisole (4.97g, 21.24 mmol, Aldrich 98%) in anhydrous tetrahydrofuran (33 mL) at −78° C., was added a solution of n-butyllithium in hexane (2.5 M, 8.5 mL, 21.25 mmol, Aldrich). The reaction was stirred at −78 OC for 0.5-1 hr to give a solution of the 2-methoxyphenyl lithium for the following reaction.
Reaction SMILES: O1CC[CH:4]([O:7][CH2:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:16]=[CH:17][C:18]4[N:19]([C:21]([C:24]([F:27])([F:26])[F:25])=[N:22][N:23]=4)[N:20]=3)[CH2:11][CH2:10]2)[CH2:3][CH2:2]1.[Cl:28][C:29]1[N:34]=C(O)C=C[CH:30]=1>>[Cl:28][C:29]1[N:34]=[C:4]([O:7][CH2:8][CH:9]2[CH2:10][CH2:11][N:12]([C:15]3[CH:16]=[CH:17][C:18]4[N:19]([C:21]([C:24]([F:27])([F:25])[F:26])=[N:22][N:23]=4)[N:20]=3)[CH2:13][CH2:14]2)[CH:3]=[CH:2][CH:30]=1
Reactant: Oc1cccc(Cl)n1
Reactant: FC(F)(F)c1nnc2ccc(N3CCC(COC4CCOCC4)CC3)nn12
Product: FC(F)(F)c1nnc2ccc(N3CCC(COc4cccc(Cl)n4)CC3)nn12
Yield: 75 %

Procedure:
Obtained in 75% yield by an analogous method to Example 447, starting from [1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]methanol (obtained as described in Example 294, preparation of starting materials) and 6-chloropyridin-2-ol.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:3]=1[CH:4]=[O:5].[H-].[Na+].I[CH2:15][C:16]([NH2:18])=[O:17]>CN(C=O)C>[CH:4]([C:3]1[C:6]([O:10][CH3:11])=[CH:7][CH:8]=[CH:9][C:2]=1[O:1][CH2:15][C:16]([NH2:18])=[O:17])=[O:5]
Reactant: COc1cccc(O)c1C=O
Reactant: NC(=O)CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(OCC(N)=O)c1C=O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 59 %

Procedure:
1.1 1.0 g (6.57 mmol) of 2-hydroxy-6-methoxybenzaldehyde 1 is dissolved in 30 ml of DMF, 0.29 g of NaH (60% suspension in paraffin oil) is carefully added with cooling, and the mixture is stirred at RT for 45 min. 1.34 g of 2-iodoacetamide 2 are then added, and the reaction mixture is stirred overnight. The mixture is subsequently subjected to conventional work-up, giving 0.81 g (59%) of 2-(2-formyl-3-methoxyphenoxy)acetamide 3 as solid. MS-EI (M+)=209.
Reaction SMILES: [CH2:1]([N:5]1[C:10](=[O:11])[CH:9]=[C:8]([NH:12][NH2:13])[N:7]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:6]1=[O:22])[CH2:2][CH2:3][CH3:4].[CH3:23][N:24]=[C:25]=S.C(O)C>CN(C=O)C>[CH2:1]([N:5]1[C:10](=[O:11])[C:9]2[C:23]([NH:24][CH3:25])=[N:13][NH:12][C:8]=2[N:7]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)[C:6]1=[O:22])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)cc(NN)n(Cc2ccc(Cl)cc2)c1=O
Reactant: CN=C=S
Solvent: CCO
Solvent: CN(C)C=O
Product: CCCCn1c(=O)c2c(NC)n[nH]c2n(Cc2ccc(Cl)cc2)c1=O
Yield: 57 %

Procedure:
A solution of 3-butyl-1-(4-chlorobenzyl)-6-hydrazinouracil (3.0 g, 9.3 mM) and methyl isothiocyanate (2.0 ml, 29 mM) in DMF (30 ml) was stirred at 120° C. for 20 hours. To the solution was added ethanol (20 ml) and the mixture was cooled to give crude crystals. Recrystallization from DMF/ethanol gave pale yellow crystals (1.91 g, 57%), m.p. 292°-294° C.
Reaction SMILES: [O:1]=[C:2]1[N:6]2[CH2:7][CH:8]=[CH:9][CH:10]([C:11]([O:13][CH3:14])=[O:12])[N:5]2[C:4](=[O:15])[NH:3]1.[CH2:16]=[O:17]>>[OH:17][CH2:16][N:3]1[C:2](=[O:1])[N:6]2[CH2:7][CH:8]=[CH:9][CH:10]([C:11]([O:13][CH3:14])=[O:12])[N:5]2[C:4]1=[O:15]
Reactant: COC(=O)C1C=CCn2c(=O)[nH]c(=O)n21
Reactant: C=O
Product: COC(=O)C1C=CCn2c(=O)n(CO)c(=O)n21
Yield: 50 %

Procedure:
7.02 g (0.033 mol) of methyl 2,3,5,8-tetrahydro-1,3-dioxo-1H-1,2,4-triazolo[1,2-a]pyridazine-5-carboxylate and 9 ml of 40% aqueous formaldehyde were heated on a steam-bath for 4.5 hours. The mixture was evaporated in vacuo to give a colourless oil which was crystallized from dichloromethane/hexane, there being obtained 3.97 g (50%) of methyl 2-hydroxymethyl-2,3,5,8-tetrahydro-1,3-dioxo-1H-1,2,4-triazolo[1,2-a]pyridazine-5-carboxylate of melting point 123°-125° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[N:18]3[C:13]([CH:14]=[CH:15][CH:16]=[CH:17]3)=[C:12]([O:19][CH3:20])[C:11]=2[CH3:21])=[O:9])=[CH:4][C:3]=1[O:22][CH3:23].Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>>[CH3:23][O:22][C:3]1[CH:4]=[C:5]([C:8]([C:10]2[N:18]3[C:13]([CH:14]=[CH:15][CH:16]=[CH:17]3)=[C:12]([O:19][CH3:20])[C:11]=2[CH3:21])=[O:9])[CH:6]=[CH:7][C:2]=1[NH:1][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: COc1cc(C(=O)c2c(C)c(OC)c3ccccn23)ccc1N
Reactant: CCOC(=O)CBr
Product: CCOC(=O)CNc1ccc(C(=O)c2c(C)c(OC)c3ccccn23)cc1OC

Procedure:
This compound was obtained according to the same procedure as that described in Example 192, by alkylating (4-amino-3-methoxyphenyl)(1-methoxy-2-methylindolizin-3-yl)methanone, a compound of Example 94, with ethyl bromoacetate. A yellow powder is obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:69]=[CH:68][C:13]([O:14][CH2:15][C@@H:16]([CH2:42][O:43][C:44](=[O:67])[C@H:45]([CH3:66])[NH:46][C:47](=[O:65])[CH2:48][C@H:49]([NH:57]C(OC(C)(C)C)=O)[C:50]([O:52]C(C)(C)C)=[O:51])[O:17][C:18](=[O:41])[C@H:19]([CH3:40])[NH:20][C:21](=[O:39])[CH2:22][C@H:23]([NH:31]C(OC(C)(C)C)=O)[C:24]([O:26]C(C)(C)C)=[O:25])=[CH:12][CH:11]=2)[C:5]([C:70]#[N:71])=[C:4]([S:72][CH2:73][C:74]2[N:75]=[C:76]([C:79]3[CH:84]=[CH:83][C:82]([Cl:85])=[CH:81][CH:80]=3)[O:77][CH:78]=2)[N:3]=1.[F:86][C:87]([F:92])([F:91])[C:88]([OH:90])=[O:89]>ClCCl>[F:86][C:87]([F:92])([F:91])[C:88]([OH:90])=[O:89].[F:86][C:87]([F:92])([F:91])[C:88]([OH:90])=[O:89].[NH2:31][C@@H:23]([CH2:22][C:21](=[O:39])[NH:20][C@@H:19]([CH3:40])[C:18](=[O:41])[O:17][C@@H:16]([CH2:15][O:14][C:13]1[CH:12]=[CH:11][C:10]([C:6]2[C:5]([C:70]#[N:71])=[C:4]([S:72][CH2:73][C:74]3[N:75]=[C:76]([C:79]4[CH:80]=[CH:81][C:82]([Cl:85])=[CH:83][CH:84]=4)[O:77][CH:78]=3)[N:3]=[C:2]([NH2:1])[C:7]=2[C:8]#[N:9])=[CH:69][CH:68]=1)[CH2:42][O:43][C:44](=[O:67])[C@H:45]([CH3:66])[NH:46][C:47](=[O:65])[CH2:48][C@H:49]([NH2:57])[C:50]([OH:52])=[O:51])[C:24]([OH:26])=[O:25]
Reactant: C[C@H](NC(=O)C[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC[C@H](COc1ccc(-c2c(C#N)c(N)nc(SCc3coc(-c4ccc(Cl)cc4)n3)c2C#N)cc1)OC(=O)[C@H](C)NC(=O)C[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](NC(=O)C[C@H](N)C(=O)O)C(=O)OC[C@H](COc1ccc(-c2c(C#N)c(N)nc(SCc3coc(-c4ccc(Cl)cc4)n3)c2C#N)cc1)OC(=O)[C@H](C)NC(=O)C[C@H](N)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
An amount of 190 mg (0.156 mmol) of the compound from example 22A was introduced in 1 ml of dichloromethane, admixed with 0.120 ml (1.559 mmol) of trifluoroacetic acid and stirred at RT overnight. The reaction mixture was then concentrated and the residue was purified by means of preparative HPLC (eluent gradient: acetonitrile/water 10:90→95:5 with addition of 0.1% TFA). This gave 76 mg (43% of theory) of the target compound.
Reaction SMILES: C(OC([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][C@@H:20]([N:23]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH3:24])[CH2:19][C@H:18]2[C:29]([O:31][CH3:32])=[O:30])[C:13]1=[O:33])=O)C1C=CC=CC=1>CO.[Pd]>[NH2:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][C@@H:20]([N:23]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH3:24])[CH2:19][C@H:18]2[C:29]([O:31][CH3:32])=[O:30])[C:13]1=[O:33]
Reactant: COC(=O)[C@@H]1C[C@H](N(C)C(C)(C)C)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@@H]1C[C@H](N(C)C(C)(C)C)CC[C@@H]1N1CC[C@H](N)C1=O
Yield: 94.5 %

Procedure:
A solution of (1R,2S,5R)-methyl 2-((S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)-5-(tert-butyl(methyl)amino)cyclohexanecarboxylate (330 mg, 0.65 mmol) in methanol was treated with 100 mg of 10% Pd/C and hydrogenated at 55 psi of H2 in a Parr shaker overnight. The catalyst was filtered and the filtrate concentrated in vacuo to give 200 mg of (1R,2S,5R)-methyl 2-((S)-3-amino-2-oxopyrrolidin-1-yl)-5-(tert-butyl(methyl)amino)-cyclohexanecarboxylate as a white solid. This was used without further purification. MS found: (M+H)+=326.50.
Reaction SMILES: [NH2:1][C:2]1[C:7]([S:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:19]Br.S(=O)(O)[O-].[Na+].C(OCC)(=O)C>C(O)(=O)C>[NH2:1][C:2]1[C:7]([S:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)=[CH:6][C:5]([Br:19])=[CH:4][N:3]=1
Reactant: BrBr
Reactant: COC(=O)c1ccc(Sc2cccnc2N)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COC(=O)c1ccc(Sc2cc(Br)cnc2N)cc1
Temperature: 0 °C
Yield: 68 %

Procedure:
Placed methyl 4-(2-aminopyridin-3-ylthio)benzoate (5.50 g, 21.1 mmol) in acetic acid (25 mL) and cooled to 0° C. Slowly added bromine (1.35 mL, 26.4 mmol) and stirred for an hour. Poured reaction mixture onto saturated sodium bisulfite and ice. Extracted with dichloromethane three times, washed with 2N NaOH, water, brine, dried, and concentrated. Subjected to MPLC (Biotage) eluting with 3:2 hexane:ethyl acetate to afford the title compound (4.87 g, 68.0% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][N:3]=1.[C:8]([CH2:11][C:12](=O)[CH3:13])(=O)[CH3:9]>C(O)(C)C>[CH3:7][C:5]1[CH:6]=[C:2]2[N:1]=[C:8]([CH3:9])[CH:11]=[C:12]([CH3:13])[N:3]2[N:4]=1
Reactant: CC(=O)CC(C)=O
Reactant: Cc1cc(N)n[nH]1
Solvent: CC(C)O
Product: Cc1cc(C)n2nc(C)cc2n1

Procedure:
A mixture of 9.7 g of 3-amino-5-methylpyrazole, 13 ml of acetylacetone and 50 ml of isopropanol is heated under reflux for 3 hours. After distilling isopropanol off, the residue is dissolved in dichloromethane, washed with water and dried over anhydrous magnesium sulfate when chloroform is distilled off, 12.7 g of the title compound is obtained as crystals. mp. 70°-73° C.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[NH:4][C:3]=1[C:15]([O:17]CC)=O.[CH:20](N)=[NH:21]>O1CCCC1.C(O)C>[CH3:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([C:5]2[NH:4][C:3]3[C:15]([OH:17])=[N:21][CH:20]=[N:1][C:2]=3[CH:6]=2)=[CH:12][CH:11]=1
Reactant: N=CN
Reactant: CCOC(=O)c1[nH]c(-c2ccc(OC)cc2)cc1N
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(-c2cc3ncnc(O)c3[nH]2)cc1
Temperature: 90 °C
Reaction time: 16 h
Yield: 11.5 %

Procedure:
Ethyl 3-amino-5-(4-methoxyphenyl)-1H-pyrrole-2-carboxylate (7.2 g) was dissolved in tetrahydrofuran (16 mL)/ethanol (32 mL), formamidine (3.46 g) was added, and the mixture was stirred at 90° C. for 16 hrs. After cooling to room temperature, tetrahydrofuran was evaporated under reduced pressure. The residue was diluted with ethanol (20 mL), and the precipitated powder was collected by filtration, washed with ethanol (15 mL) and dried under reduced pressure to give the title compound (769 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[N:9]=1.[H-].[Na+].[CH3:19][N:20]([CH3:24])[C:21](Cl)=[O:22]>C1(C)C=CC=CC=1>[CH3:19][N:20]([CH3:24])[C:21]([N:7]([CH2:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:16])[C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[N:9]=1)=[O:22]
Reactant: Cc1cc(C)nc(NCCCCN(C)C)c1
Reactant: CN(C)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1cc(C)nc(N(CCCCN(C)C)C(=O)N(C)C)c1
Reaction time: 2 h

Procedure:
To 2-(4-dimethylaminobutylamino)-4,6-dimethylpyridine (3.7 g. 0.00168 mole) dissolved in toluene (150 ml) is added sodium hydride in mineral oil (50%) (0.96 g., 0.002 mole. The mixture is refluxed with stirring under nitrogen for 31/2 hours, cooled to 35°, and dimethylcarbamoyl chloride (2.15 g., 0.002 mole) in toluene (25 ml) is added. The mixture is then refluxed for 18 hours, cooled and extracted with dilute hydrochloric acid. The aqueous extracts are made alkaline with 10 N sodium hydroxide and extracted with diethyl ether then methylene chloride. The combined organic extracts are washed with brine, dried (sodium sulfate) and concentrated under vacuum. The residue is taken up in diethyl ether, filtered from insoluble matter and the filtrate concentrated. The residue is distilled and the product, a hygroscopic oil, is collected at 138°-141°/0.3 mm.
Reaction SMILES: [Cl:1][CH2:2][C:3]1([CH3:9])[O:7][C:6](=[O:8])[NH:5][CH2:4]1.Br[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][N:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>O1CCOCC1>[Cl:1][CH2:2][C:3]1([CH3:9])[O:7][C:6](=[O:8])[N:5]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][N:12]=2)[CH2:4]1
Reactant: Clc1ccc(Br)nc1
Reactant: CC1(CCl)CNC(=O)O1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CC1(CCl)CN(c2ccc(Cl)cn2)C(=O)O1
Temperature: 85 °C
Reaction time: 12 h
Yield: 38.8 %

Procedure:
A mixture of 5-(chloromethyl)-5-methyl-1,3-oxazolidin-2-one (1.50 g, INTERMEDIATE 16), 2-bromo-5-chloropyridine (1.92 g), cesium carbonate (4.89 g), bispalladium tribenzylideneacetone (1.37 g) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (1.30 g) in 25 ml of dioxane was stirred at 85° C. for 12 h. The sample was then cooled to room temperature, and filtered through a plug of silica gel (15×15 ml) of silica gel eluting with ethyl acetate. The eluent then was concentrated in vacuo and purified via column chromatography on a Biotage Horizon 65i column eluting with 0% ethyl acetate in hexanes (1 column volume), followed by a gradient to 60% ethyl acetate in hexanes (over 10 column volumes), and held at 60% ethyl acetate for 4 column volumes to provide the title compound (1.01 g, 39%). Mass spectrum (ESI) 262.9 (M+2).). 1H NMR (500 MHz, CDCl3): δ 8.27 (d, J=2.5 Hz, 1), 8.21 (d, J=8.9 Hz, 1H), 7.68 (dd, J=8.9, 2.5 Hz, 1H), 4.31 (d, J=10.8 Hz, 1H), 3.95 (d, J=10.7 Hz, 1H), 3.73 (d, J=11.7 Hz, 1H), 3.63 (d, J=11.7 Hz, 1H), 1.66 (s, 3H).
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][C:10](=[O:12])[CH3:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:13](Cl)[CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(COC)OC>[C:3]1([CH:9]([CH2:13][CH:14]=[CH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10](=[O:12])[CH3:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(=O)Cc1ccccc1
Reactant: ClCC=Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(=O)C(CC=Cc1ccccc1)c1ccccc1

Procedure:
Sodium hydride (10.5 g., 0.25 mole, oil dispersion) is suspended in glyme (200 ml.) and phenyl acetone (33.5 g., 0.25 mole) in glyme (25 ml.) is added dropwise with stirring. After complete addition, the mixture is heated to reflux for 0.5 hours. The mixture is cooled in a cold water bath and a solution of cinnamyl chloride (38 g., 0.25 mole) in glyme (25 ml.) is added dropwise. When addition is complete, the mixture is refluxed for 5 hours then allowed to cool. After filtration of inorganic salts and removal of solvent from the filtrate, vacuum distillation provides 44 g., b.p. 128°-134°/0.07-0.1 mm.