Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[CH:8]2.[N-:13]=[N+:14]=[N-:15].[Na+]>CN(C=O)C.CCOC(C)=O>[N:13]([CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[CH:8]2)=[N+:14]=[N-:15]
Reactant: BrCc1cccc2cccnc12
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1cccc2cccnc12
Reaction time: 4.5 h

Procedure:
To a solution of 1.0119 g (4.56 mmol) 20 in 25 mL of DMF was added 0.3557 g (5.47 mmol) sodium azide. After 4.5 h at room temperature, the reaction mixture was diluted with 80 mL EtOAc and washed with 40 mL brine. The aqueous layer was extracted with 20 mL EtOAc. The combined organics were dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography (60×220 mm silica gel, linear gradient 5-20% (EtOAc:hexane) provided 21. 1H NMR (CDCl3, 400 MHz) δ 8.965 (dd, 1H, J=1.74, 4.21 Hz, ArH); 8.185 (dd, 1H, J=1.74, 8.32 Hz, ArH); 7.823 (dd, 1H, J=1.12, 8.32 Hz, ArH); 7.743 (d, 1H, J=6.95 Hz, ArH); 7.555 (dd, 1H, J=7.18, 8.10 Hz, ArH); 7.455 (dd, 1H, J=4.21, 8.23 Hz, ArH); 5.065 (s, 2H, ArCH2).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:18][C:17](=[O:19])[N:16]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:15][CH:14]2[C:28]([O:30][CH3:31])=[O:29])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-])=O.O.O.Cl[Sn]Cl.C([O-])(O)=O.[Na+].CCN(CC)CC.[Cl:49][C:50]1[CH:58]=[CH:57][C:53]([C:54](Cl)=[O:55])=[CH:52][CH:51]=1>CO>[Cl:49][C:50]1[CH:58]=[CH:57][C:53]([C:54]([NH:1][C:4]2[CH:9]=[CH:8][C:7]([S:10]([N:13]3[CH2:18][C:17](=[O:19])[N:16]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:15][CH:14]3[C:28]([O:30][CH3:31])=[O:29])(=[O:12])=[O:11])=[CH:6][CH:5]=2)=[O:55])=[CH:52][CH:51]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CCCCCCCCN1CC(C(=O)OC)N(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)CC1=O
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: O
Product: CCCCCCCCN1CC(C(=O)OC)N(S(=O)(=O)c2ccc(NC(=O)c3ccc(Cl)cc3)cc2)CC1=O
Temperature: 50 °C
Reaction time: 1 h
Yield: 91.6 %

Procedure:
The compound of Example 56 (0.55 g, 1.2 mmol) was put into 10 mL of a MeOH solution to which SnCl2.2H2O (1.1 g, 4.8 mmol) was added, and stirred for 1 hour while maintaining the temperature at 50° C. A saturated NaHCO3 aqueous solution was introduced and the mixture was stirred for 1 hour, and then it was extracted with ethyl acetate. After distillation under reduced pressure and vacuum drying, the mixture was dissolved in 20 mL of dichloromethane and Et3N (0.41 mL, 2.9 mmol), and 4-chlorobenzoyl chloride (0.31 mL, 2.4 mmol) was added while maintaining the temperature at 0° C. After reaction for 6 hours, the reactant was washed with a saturated NaHCO3 aqueous solution and a 1N HCl aqueous solution, and dried and concentrated under reduced pressure. It was then recrystallized with hexane and ethyl acetate to obtain a white solid (0.62 g, 91%).
Reaction SMILES: [NH2:1][CH:2]1[C:11]2[CH:10]=[N:9][CH:8]=[C:7]([C:12]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=3)[C:6]=2[CH2:5][CH2:4][CH2:3]1.[CH2:20]([NH:23][S:24](Cl)(=[O:26])=[O:25])[CH2:21][CH3:22].CCN(CC)CC.CO>C(Cl)Cl>[C:16]([C:15]1[CH:14]=[CH:13][C:12]([C:7]2[C:6]3[CH2:5][CH2:4][CH2:3][CH:2]([NH:1][S:24](=[O:26])(=[O:25])[NH:23][CH2:20][CH2:21][CH3:22])[C:11]=3[CH:10]=[N:9][CH:8]=2)=[CH:19][CH:18]=1)#[N:17]
Reactant: N#Cc1ccc(-c2cncc3c2CCCC3N)cc1
Reactant: CCCNS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: CCCNS(=O)(=O)NC1CCCc2c(-c3ccc(C#N)cc3)cncc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
A cooled (0° C.) solution of (rac)-4-(8-amino-5,6,7,8-tetrahydroisoquinolin-4-yl)benzonitrile (example 1) (62.3 mg, 250 μmol) in CH2Cl2 (3 ml) was treated with propylsulfamoyl chloride (98.5 mg, 625 μmol) in CH2Cl2 (0.6 ml) and Et3N (69.7 μL, 500 μmol). After 1 h the mixture was stirred at room temperature for 1 h, cooled down (0° C.) and treated again with Et3N (69.7 μL, 500 μmol). After ½ h at room temperature, the mixture was treated with MeOH (0.2 mL) and extracted with water/AcOEt (3×). The organic phases were dried over Na2SO4, filtered and evaporated under reduced pressure. Purification by flash chromatography (50 g SiO2, Telos-cartridge, CH2Cl2/MeOH (1 to 3%)) and precipitation from CH2Cl2 with n-pentane gave the title compound (63 mg, 68%) as off-white powder. MS: 371.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][N:12]=1)=O.P(Cl)(Cl)(Cl)(Cl)Cl.[NH2:23][NH2:24].O>C1(C)C=CC=CC=1>[NH2:23][NH:24][C:9]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][N:12]=1)=[N:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: O=C(Nc1ccccc1Cl)c1ccncn1
Reactant: NN
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: O
Solvent: Cc1ccccc1
Product: NNC(=Nc1ccccc1Cl)c1ccncn1

Procedure:
To a suspension of N-(2-chlorophenyl)pyrimidine-4-carboxamide 3 (0.2 g, 0.86 mmol) in 20 mL of PhMe was added 0.65 g of PCl5. The mixture was stirred at reflux for 3 h. To this solution was added 3 mL of NH2NH2.H2O. The mixture was stirred at ambient temperature for 2 h. After removal of all solvent, the residue was purified by column (2:1 of hexane/ethyl acetate) to give N-amino-N′-(2-chlorophenyl)pyrimidine-4-carboxamidine 5 as a solid. Yield: 0.15 g, 70%. 1HNMR (DMSO-d6) δ (ppm): 9.15 (s, 1H); 8.70 (d, 1H); 7.98 (d, 1H); 7.35 (m, 1H); 7.15 (m, 1H); 6.80 (m, 1H); 6.45 (d, 1H); 5.60 (s, 2H).
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)[C:10]([N:12]1[C:16]2=[N:17][CH:18]=[CH:19][CH:20]=[C:15]2[CH2:14][C@H:13]1[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:11])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C@@H:9]([CH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)[C:10]([N:12]1[C:16]2=[N:17][CH:18]=[CH:19][CH:20]=[C:15]2[CH2:14][C@H:13]1[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:11]
Reactant: CCOC(=O)[C@@H]1Cc2cccnc2N1C(=O)[C@@H](NC(=O)OC(C)(C)C)C1CCOCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1Cc2cccnc2N1C(=O)[C@@H](N)C1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.8 %

Procedure:
In a 100 mL round-bottomed flask, (S)-ethyl 1-((S)-2-(tert-butoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (220 mg, 507 μmol, Eq: 1.00) was combined with DCM (10 mL) to give a colorless solution. TFA (5 mL, 64.9 mmol, Eq: 128) was added and the reaction was stirred at rt for 2 h. The reaction mixture was concentrated in vacuo and the residue was treated with saturated aqueous NaHCO3 (10 mL). The resulting mixture was extracted with DCM (2×10 mL), the combined organic layers dried over Na2SO4, and then concentrated in vacuo to give (S)-ethyl 1-((S)-2-amino-2-(tetrahydro-2H-pyran-4-yl)acetyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (140 mg), m/z=334 (M+H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:21]=[CH:20][C:10]([CH2:11][NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:9][CH:8]=2)[N:6]=1.C(N(CC)CC)C.[CH:29]1([C:32](Cl)=[O:33])[CH2:31][CH2:30]1>C(Cl)Cl.O1CCOCC1>[CH2:30]1[CH2:31][CH:29]1[C:32]([NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:21]=[CH:20][C:10]([CH2:11][NH:12][C:13]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14])=[CH:9][CH:8]=2)[N:6]=1)=[O:33]
Reactant: CC(C)(C)OC(=O)NCc1ccc(-c2csc(N)n2)cc1
Reactant: O=C(Cl)C1CC1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCc1ccc(-c2csc(NC(=O)C3CC3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.3 %

Procedure:
To a mixture of 4-(2-aminothiazol-4-yl)-N-(tert-butoxycarbonyl)-benzylamine (2.98 g, 9.76 mmol) in DCM/dioxane (2:1, 150 mL) at room temperature, add triethylamine (2.0 mL, 15 mmol) and cyclopropanecarbonyl chloride (1.1 mL, 12 mmol). Stir at room temperature overnight and partition the reaction mixture between EtOAc (500 mL) and saturated aqueous NaHCO3 (250 mL). Dry the organic extract over Na2SO4, filter and concentrate in vacuo. Combine the residue with DCM and silica gel (12 g) and concentrate to a powder. Load powder on to a dry column attached to an Analogix® column (330 g) and purify by preparative liquid chromatography (0:1 to 1:4 EtOAc/hexane over 33 min, 1:4 EtOAc/hexane over 33 min, 1:4 to 1:1 EtOAc/hexane over 33 min, 1:1 EtOAc/hexane over 66 min; 35 mL/min) to afford the desired intermediate (2.381 g, 65%) as a yellow solid. MS (ES+) m/z: 374.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[S:6][CH:5]=[C:4]([C:7]([OH:9])=O)[CH:3]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=N[C:29]2[CH:30]=[CH:31][CH:32]=[N:33][C:28]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1CCCCC1>CN(C=O)C>[Br:1][C:2]1[S:6][CH:5]=[C:4]([C:7]([N:33]2[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]2)=[O:9])[CH:3]=1
Reactant: O=C(O)c1csc(Br)c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1csc(Br)c1)N1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.6 %

Procedure:
5-Bromo-thiophene-3-carboxylic acid (150 mg, 0.72 mmol) was dissolved in DMF (3 mL). DIPEA (2.16 mmol), HATU (0.72 mmol) and piperidine (0.72 mmol) were added and the reaction mixture stirred at room temperature for 1 hour. The mixture was partitioned between ethyl acetate and water and the organic solution separated, washed with 1 N hydrochloric acid, dried over magnesium sulfate, filtered and the solvent evaporated. The residue was purified by flash chromatography on silica, eluting with 0%-50% ethyl acetate in cyclohexane. The fractions containing the desired product were concentrated under vacuum to give the title compound (86 mg). LCMS m/z 273.97 [M+H]+ R.T.=3.19 min (Analytical Method 5).
Reaction SMILES: [CH3:1][C:2](=[CH:7]OS(C1C=CC(C)=CC=1)(=O)=O)[C:3]([O:5][CH3:6])=[O:4].[C:19]1([OH:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH3:7]/[C:2](=[CH:1]\[O:25][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)/[C:3]([O:5][CH3:6])=[O:4]
Reactant: Oc1ccccc1
Reactant: COC(=O)C(C)=COS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)/C(C)=C/Oc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 13.2 %

Procedure:
To a solution of 6.98 g (25.8 mmol) of methyl 2-methyl-3-(p-toluenesulfonyloxy)-2-propenoate in 30 ml of DMF was added 2.67 g (28.3 mmol) of phenol and 10 g (30.6 mmol) of cesium carbonate and stirred at room temperature for 12 hours. The reaction solution was poured into water and extracted with tert-butyl methyl ether (twice). The combined organic layer was washed sequentially with a 1N aqueous NaOH solution, water, and a saturated NaCl solution, dried over anhydrous MgSO4, and then concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain 657 mg of (E)-methyl 2-methyl-3-phenoxy-2-propenoate.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:8][C:6]=2[N:7]=1.[C:24](O)(=[O:28])[CH:25]([CH3:27])[OH:26]>>[Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:24](=[O:28])[C@@H:25]([OH:26])[CH3:27])[CH2:14][CH2:13]3)[S:8][C:6]=2[N:7]=1
Reactant: CC(O)C(=O)O
Reactant: Clc1nc(N2CCOCC2)c2cc(CN3CCNCC3)sc2n1
Product: C[C@H](O)C(=O)N1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1

Procedure:
2-Chloro-4-morpholino-6-((piperazin-1-yl)methyl)thieno[2,3-d]pyrimidine (600 mg) was reacted with lactic acid via General Procedure B to give (S)-1-(4-((2-chloro-4-morpholinothieno[2,3-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:5][N:6]([CH3:18])[C:7](=[O:17])[CH:8]=[C:9]1[C:13](=[O:14])OC(C)(C)[O:10]1.C=O.NCCCN1CCOCC1.ClC1C=C(C=CC=1Cl)C[N:40]([CH3:60])[C:41]([C:43]1[CH2:47][N:46]([CH2:48][CH2:49]C(NCCC(O)=O)=O)[C:45](=O)[C:44]=1[OH:59])=O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:5][N:6]([CH3:18])[C:7]([C:8]1[CH2:60][N:40]([CH2:41][CH2:43][CH2:47][N:46]2[CH2:48][CH2:49][O:59][CH2:44][CH2:45]2)[C:13](=[O:14])[C:9]=1[OH:10])=[O:17]
Reactant: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C=C1OC(C)(C)OC1=O
Reactant: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CCC(=O)NCCC(=O)O)C1
Agent: C=O
Agent: NCCCN1CCOCC1
Product: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CCCN2CCOCC2)C1

Procedure:
N-(3,4-Dichloro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methyl-acetamide (Compound 37-A) was treated with paraformaldehyde and N-(3-aminopropyl)morpholine as described in the preparation of Compound 37. The title compound was isolated as a white solid (0.1345 g, 61% yield). 1H NMR (500 MHz, DMSO) δ: 1.69 (t, J=6.4 Hz, 2H), 2.25 (s, 2H), 2.32 (s, 4H), 2.97 (s, 3H), 3.40 (t, J=6.4 Hz, 2H), 3.55 (s, 4H), 4.05 (s, 2H), 4.59 (s, 2H), 7.24 (s, 1H), 7.51 (s, 1H), 7.62 (d, J=8.3 Hz, 1H). HRMS (M−H) calcd for C20H25N3Cl2O4: 442.13005. found: 442.1296.
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[CH:4][CH:3]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[C:44]1([CH2:50][C:51]([N:53]=[C:54]=[S:55])=[O:52])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>C(O)C.C1(C)C=CC=CC=1>[CH3:26][N:24]([CH3:25])[CH2:23][CH2:22][N:19]1[CH2:18][CH2:17][N:16]([C:14]([NH:13][C:9]2[CH:8]=[C:7]([O:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:54]([NH:53][C:51](=[O:52])[CH2:50][C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=4)=[S:55])=[CH:28][CH:27]=3)[CH:12]=[CH:11][N:10]=2)=[O:15])[CH2:21][CH2:20]1
Reactant: CN(C)CCN1CCN(C(=O)Nc2cc(Oc3ccc(N)cc3)ccn2)CC1
Reactant: O=C(Cc1ccccc1)N=C=S
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: Cc1ccccc1
Solvent: CCO
Product: CN(C)CCN1CCN(C(=O)Nc2cc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3)ccn2)CC1
Reaction time: 3 h
Yield: 45 %

Procedure:
To a solution of 4-(4-aminophenoxy)-2-{[4-(2-dimethylaminoethyl)piperazin-1-yl]carbonylamino}pyridine (137 mg) and (+)-10-camphorsulfonic acid (151 mg) in ethanol (3.5 ml) was added a solution of 2-phenylacetyl isothiocyanate in toluene (0.25 M, 2.73 ml) at room temperature, followed by stirring for 3 hours. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine in this order, dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=98:2) to provide the titled compound (86.5 mg, 45%) as white powder.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][C:5]=1[O:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.Cl[CH2:20][C:21]([NH:23][CH3:24])=[O:22].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[C:8]([C:7]1[CH:10]=[CH:11][C:4]([O:3][CH3:2])=[C:5]([CH:6]=1)[O:12][CH:13]1[CH2:18][CH2:17][N:16]([CH2:20][C:21]([NH:23][CH3:24])=[O:22])[CH2:15][CH2:14]1)#[N:9]
Reactant: COc1ccc(C#N)cc1OC1CCNCC1
Reactant: CNC(=O)CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CNC(=O)CN1CCC(Oc2cc(C#N)ccc2OC)CC1
Temperature: 20 °C
Yield: 96.2 %

Procedure:
4-Methoxy-3-(piperidin-4-yloxy)benzonitrile hydrochloride salt (3, 28.36 g, 95.82 mmoles), 2-chloro-N-methylacetamide (12.37 g, 114.98 mmoles) and potassium carbonate (33.11 g, 239.55 mmoles) were suspended in acetonitrile (161.36 g). The reaction mixture was heated at reflux for 3 hours. The reaction mixture was cooled to 20° C. and water (386.26 g) was charged. The reaction was heated to 75° C. and the volume reduced by distillation. Upon cooling crystallisation occurred. The resulting solid was isolated by filtration, washed twice with water (77.25 g and 128.75 g) and then dried to give the title compound (27.95 g, 94% yield); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.68 (m, 2H) 1.91 (m, 2H) 2.29 (m, 2H) 2.61 (d, J=4.7 Hz, 3H) 2.67 (m, 2H) 2.88 (s, 2H) 3.83 (s, 3H) 4.41 (tt, J=8.3, 4.0 Hz, 1H) 7.11 (d, J=8.4 Hz, 1H) 7.40 (dd, J=8.4, 1.9 Hz, 1H) 7.47 (d, J=1.9 Hz, 1H) 7.68 (q, J=4.7 Hz, 1H); Mass Spectrum: m/z (M+H)+ 304.2.
Reaction SMILES: P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+].[OH:9]O.[Br:11][C:12]1[S:16][C:15]([CH:17]=[O:18])=[C:14]([CH3:19])[CH:13]=1.[Na]>O.C(#N)C>[Br:11][C:12]1[S:16][C:15]([C:17]([OH:9])=[O:18])=[C:14]([CH3:19])[CH:13]=1
Reactant: OO
Reactant: Cc1cc(Br)sc1C=O
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CC#N
Solvent: O
Product: Cc1cc(Br)sc1C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 50.4 g of sodium phosphate, monobasic, (1.5 mol) in 600 mL of water, followed by 131 mL of a 35% hydrogen peroxide solution were added to a solution of 5-bromo-3-methyl-thiophene-2-carbaldehyde (300 g, 1.46 mol), example 1-a, in 1.5 L of acetonitrile. The resultant solution was cooled to 0° C. with an external ice bath, and a solution of 170 g of sodium perchlorite in 2 L of water was added dropwise over a 2 hour period. The reaction mixture was allowed to warm to room temperature, and stirred for 1.5 h. The reaction was quenched with the addition of 10 g of sodium sulfite, and stirred for 15 min. The mixture was acidified to ca. pH 3 with 1 N HCl solution, and cooled to 0° C. An off-white precipitate was collected on a medium glass filter funnel. The precipitate was washed twice with water and then dissolved in ethyl acetate. The aqueous acetonitrile solution was extracted once with ethyl acetate, and the organic fraction was combined with the pervious ethyl acetate solution. The combined organic fractions were dried over anhydrous magnesium sulfate and concentrated under hi-vacuum to produce 305 g of a tan solid. 1H NMR (CDCl3, 200 MHz): δ=6.91 (s, 1H), 2.52 (s, 3H); MS: (−) m/z 218.92, 220.94 (M−1, 79Br/81Br)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:13][CH2:12][C@H:11]([C:14]([OH:16])=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:17]([O:24][N:25]1[C:31](=[O:32])[N:30]2[CH2:33][C@H:26]1[CH2:27][CH2:28][C@H:29]2[C:34]([NH:36][NH2:37])=[O:35])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH2:17]([O:24][N:25]1[C:31](=[O:32])[N:30]2[CH2:33][C@H:26]1[CH2:27][CH2:28][C@H:29]2[C:34]([NH:36][NH:37][C:14]([C@H:11]1[CH2:12][CH2:13][C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10]1)=[O:16])=[O:35])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](C(=O)O)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](C(=O)NNC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 54 %

Procedure:
To a 0° C. solution of (1S,3R)-3-(tert-butoxycarbonylamino)cyclopentanecarboxylic acid (3.8 g, 16.6 mmol) and (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbohydrazide (5.3 g, 18.26 mmol) in DMF (30 mL) were added HATU (7.6 g, 19.92 mmol) and DIPEA (11.6 ml, 66.4 mmol). The reaction mixture was stirred at 0° C. for 1.5 hrs. The reaction mixture was diluted with water and extracted with EtOAc (2×). The combined organic layer was washed with saturated sodium chloride (4×) and citric acid (5% aq.), dried over Na2SO4, and concentrated. The residue was purified by silica gel column (gradient elution 50-80% EtOAc/petroleum ether) to afford tert-butyl (1R,3S)-3-(2-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbonyl)hydrazinecarbonyl)cyclopentylcarbamate (4.5 g, 55%) as a white solid. ESI-MS (EI+, m/z): 502.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].ClC(Cl)C.[CH3:19][N:20]1[CH:24]=[C:23]([CH3:25])[C:22]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:21]1[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]>ClCCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([C:24]2[N:20]([CH3:19])[C:21]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[C:22]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:23]=2[CH3:25])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c(C)cn1C
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: CC(Cl)Cl
Product: CCOC(=O)Cc1c(C(=O)OCC)c(C)c(C(=O)c2ccc(Cl)cc2)n1C

Procedure:
A solution of 17.5 g. (0.1 mole) p-chlorobenzoyl chloride and 13.3 g. (0.1 mole) aluminum chloride in 150 ml. of dichloroethane is added rapidly to a solution of 25.3 g. (0.1 mole) of ethyl 1,4 -dimethyl-3ethoxycarbonylpyrrole-2-acetate in 100 ml. of refluxing 1,2-dichloroethane. The solution is refluxed for 3.5 hours and poured into ice-hydrochloric acid. The organic layer is separated and the aqueous layer washed with 1,2-dichloroethane. The combined organics are washed successively with water, N,N-dimethylaminopropylamine, dilute HCl and brine. The solution is then dried over anhydrous magnesium sulfate and the solvent evaporated in vacuo. The residue product is crystallized from cyclohexane and recrystallized from methanol to give ethyl 5-(p-chlorobenzoyl)-1,4 dimethyl-3-ethoxycarbonylpyrrole-2-acetate as a white solid, m.p. 91°-93°C.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:10][N:11]([CH2:13][CH2:14][OH:15])[CH3:12]>>[C:1]1([NH:7][C:8](=[O:9])[O:15][CH2:14][CH2:13][N:11]([CH3:12])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN(C)CCO
Reactant: O=C=Nc1ccccc1
Product: CN(C)CCOC(=O)Nc1ccccc1
Reaction time: 0.5 h

Procedure:
With cooling, 128 g of phenyl isocyanate are added dropwise to 96 g of dimethylaminoethanol at 60°-70° C. in the course of 45 minutes. After a further 30 minutes at 65° C., low boiling constituents are removed at a pressure of 0.02 torr and a bath temperature of 90° C. The residue (218.4 g=97.6%) is a light yellow fluid and consists substantialy of the above ester. Titration: 1 equivalent=208.4 g (theory 208.2). IR spectrum 3320 cm-1NH, 1720 cm-1C=O; no bands between 2000 and 2500 cm-1, i.e. isocyanate is no longer present. Small amounts of 5-10 g can be distilled in a bulb tube at 135° C./0.015 torr; larger amounts decompose no distillation.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][C:3]=1[CH3:18].Br[C:20]1[N:25]=[CH:24][C:23]([CH3:26])=[CH:22][N:21]=1>>[Br:1][C:2]1[C:3]([CH3:18])=[CH:4][C:5]([C:20]2[N:25]=[CH:24][C:23]([CH3:26])=[CH:22][N:21]=2)=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1cnc(Br)nc1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C)c1Br
Product: Cc1cnc(-c2cc(C)c(Br)c(C)c2)nc1

Procedure:
The title compound is prepared from 2-bromo-1,3-dimethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzene and 2-bromo-5-methyl-pyrimidine following a procedure analogous to that described in Step 1 of Intermediate 56. LC (method 7): tR=1.20 min; Mass spectrum (ESI+): m/z=277/279 (Br) [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]1[O:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH:5]1[C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1.C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35].O>C1COCC1>[Cl:25][C:20]1[CH:19]=[C:18]([CH:5]2[CH:4]([CH2:3][CH2:2][NH:1][S:34]([CH3:33])(=[O:36])=[O:35])[O:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6]2)[CH:23]=[CH:22][C:21]=1[Cl:24]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCOC(CCN)C(c2ccc(Cl)c(Cl)c2)C1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCOC(CCNS(C)(=O)=O)C(c2ccc(Cl)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl (6RS,7RS)-7-(2-aminoethyl)-6-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (135 mg) obtained in Example 484, step A in THF (3.0 mL) were added triethylamine (0.145 mL) and methanesulfonyl chloride (0.054 mL) under ice-cooling, and the mixture was stirred at room temperature for 2 hr. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (157 mg).