Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[NH2:12][C:13]1[S:14][C:15]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:17]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:12][C:13]1[S:14][C:15]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:17]=1)=[O:9]
Reactant: Nc1nc(-c2ccccc2)c(-c2ccccc2)s1
Reactant: O=C(O)c1cc(Br)ccc1O
Product: O=C(Nc1nc(-c2ccccc2)c(-c2ccccc2)s1)c1cc(Br)ccc1O

Procedure:
Using 5-bromosalicylic acid and 2-amino-4,5-diphenylthiazole as the raw materials, the same operation as the example 195(3) gave the title compound. (2-Amino-4,5-diphenylthiazole: refer to Nihon Kagaku Zasshi, 1962, 33, 209.)
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][C:5]([C:12]2[NH:13][C:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)([CH3:25])[C:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)([CH3:17])[N:16]=2)=[C:4]([O:33][CH2:34][CH3:35])[CH:3]=1.[C:36](Cl)([Cl:38])=[O:37]>C(N(CC)CC)C>[Cl:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][C:5]([C:12]2[N:16]([C:36]([Cl:38])=[O:37])[C:15]([C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)([CH3:17])[C:14]([C:26]3[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=3)([CH3:25])[N:13]=2)=[C:4]([O:33][CH2:34][CH3:35])[CH:3]=1
Reactant: CCOc1cc(Cl)c(S(C)(=O)=O)cc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1
Reactant: O=C(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOc1cc(Cl)c(S(C)(=O)=O)cc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl

Procedure:
In a manner analogous to the method described in example 3, rac-(4S*,5R*)-2-(4-chloro-2-ethoxy-5-methanesulfonyl-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole was reacted with phosgene in the presence of triethylamine to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]3[S:14][CH:15]=[CH:16][C:17]=3[Cl:18])[O:10][N:9]=2)=[CH:4][CH:3]=1.N([O-])=O.[Na+].[N-:23]=[N+:24]=[N-].[Na+]>C(O)(=O)C.O>[N:1]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]3[S:14][CH:15]=[CH:16][C:17]=3[Cl:18])[O:10][N:9]=2)=[CH:4][CH:3]=1)=[N+:23]=[N-:24]
Reactant: [N-]=[N+]=[N-]
Reactant: Nc1ccc(-c2noc(-c3sccc3Cl)n2)cc1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: [N-]=[N+]=Nc1ccc(-c2noc(-c3sccc3Cl)n2)cc1
Temperature: 2.5 °C
Reaction time: 0.33 h
Yield: 105.4 %

Procedure:
To a mixture of 3-(4-aminophenyl)-5-(3-chloro-thiophen-2-yl)-[1,2,4]-oxadiazole (15.5 mg, 0.05 mmol) in acetic acid (2 mL) and conc. sulfinuric acid (0.3 mL) was added sodium nitrite (3.8 mg, 0.055 mmol) in water (0.5 mL). The mixture was stirred vigorously at 0-5° C. for 20 min, then sodium azide (3.6 mg, 0.055 mmol) in water (0.5 mL) was added. It was stirred at 0-5° C. for 3 h and then poured into ice water (30 mL). The resultant mixture was extracted with ethyl acetate (3×10 mL). The organic layer was washed with water, dried over anhydrous sodium sulfate, and evaporated. The crude residue was purified by flash chromatography to yield 16 mg (100%) of the title compound. 1H NMR (CDCl3): 8.18 (d, J=8.7 Hz, 2H), 7.63 (d, J=5.4 Hz, 1H), 7.18 (d, J=8.7 Hz, 1H), 7.16 (d, J=5.4 Hz, 2H).
Reaction SMILES: [CH:1](=O)/[CH:2]=[CH:3]/[CH3:4].[Si:6]([O:13][NH2:14])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]>C(Cl)Cl>[Si:6]([O:13][N:14]=[CH:1][CH:2]=[CH:3][CH3:4])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: CC(C)(C)[Si](C)(C)ON
Reactant: C/C=C/C=O
Solvent: ClCCl
Product: CC=CC=NO[Si](C)(C)C(C)(C)C
Temperature: 5 °C
Reaction time: 18 h

Procedure:
The procedure followed was that described by Behforouz et al., J. Org. Chem. 58:7089-7091 (1993). In a 50 mL round bottom flask dry, 4 Å molecular sieves (Fisher, 3.4 g) were added to dry CH2Cl2 (distilled from CaH2, 10 mL) and cooled to 5° C. with an ice bath. Freshly distilled crotonaldehyde (Matheson Coleman & Bell, 0.725 mL, 0.618 g, 8.84 mmol) was added. A solution of O-(tert-butyldimethylsilyl)hydroxylamine (Aldrich, used without purification, 1.0 g, 6.80 mmol) in dry CH2Cl2 (distilled from CaH2, 3 mL) was added dropwise over a period of 5 min. The ice bath was removed and the mixture was stirred at rt under N2 for 18 h. The sieves were removed by filtration and the CH2Cl2 was evaporated to dryness (roto-vap). Column chromatography on silica gel with CHCl3 as eluent afforded 1-(tert-butyldimethylsilyloxy)-1-aza-1,3-pentadiene as a colorless light oil (1.2 g, 88%, interpretation of the 1H NMR showed a 1:1 anti/syn mixture): 1H NMR (CDCl3) δ (anti) 0.18 (s, 6H), 0.95 (s, 9H), 1.85-1.88 (m, 3H), 5.93-6.23 (m, 1H), 6.7-6.9 (m, 1H), 7.18 (d, 1H); (syn) 0.18 (s, 6H), 0.95 (s, 9H), 1.85-1.88 (m, 3H), 5.93-6.15 (m, 2H), 7.81 (d, 1H).
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]2[C:7]([C:17]([O:19][CH3:20])=[O:18])=[CH:8][C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:10][C:4]=2[N:3]=1.Cl[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[C:25]([CH3:30])[CH:24]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:30][C:25]1[CH:24]=[C:23]([CH2:22][N:3]2[C:4]3[CH:10]=[C:9]([N:11]4[CH2:12][CH2:13][O:14][CH2:15][CH2:16]4)[CH:8]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[C:5]=3[N:6]=[C:2]2[CH3:1])[CH:28]=[CH:27][C:26]=1[CH3:29]
Reactant: COC(=O)c1cc(N2CCOCC2)cc2nc(C)[nH]c12
Reactant: Cc1ccc(CCl)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(N2CCOCC2)cc2c1nc(C)n2Cc1ccc(C)c(C)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
To a solution of methyl 2-methyl-5-(4-morpholinyl)-1H-benzimidazole-7-carboxylate prepared as described in Example 26, step d (0.22 g, 0.799 mmol) in N,N-Dimethylformamide (DMF) (10 mL) was added in 4-(chloromethyl)-1,2-dimethylbenzene (0.185 g, 1.199 mmol) and potassium carbonate (0.331 g, 2.397 mmol). The resulting reaction mixture was stirred at 80° C. for 3 h. It was cooled to room temperature and poured into water (30 mL). The mixture was extracted with EtOAc (50 mL×3). The combined organic phases were washed with brine (50 mL) and concentrated. The crude material was subjected to normal phase purification (0→40% EtOAc/Hexane) then (0→1% MeOH/DCM) to give the product (0.24 g, 76%). MS (ES+) m/e 394.0 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([N:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1)=[O:5].C1(CC(O)=O)C=CC=CC=1.[C:22]1([NH:28][C:29](=[O:52])[CH:30]([CH:36]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:37]([C:39]2[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=2)=O)[C:31](=O)[CH:32]([CH3:34])[CH3:33])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1>[C:22]1([NH:28][C:29]([C:30]2[C:36]([C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=3)=[C:37]([C:39]3[CH:40]=[CH:41][C:42]([F:45])=[CH:43][CH:44]=3)[N:1]([CH2:2][CH2:3][C:4]([N:6]3[CH2:11][CH2:10][O:9][CH2:8][CH2:7]3)=[O:5])[C:31]=2[CH:32]([CH3:34])[CH3:33])=[O:52])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCCC(=O)N1CCOCC1
Reactant: CC(C)C(=O)C(C(=O)Nc1ccccc1)C(C(=O)c1ccc(F)cc1)c1ccccc1
Agent: O=C(O)Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)c1c(C(=O)Nc2ccccc2)c(-c2ccccc2)c(-c2ccc(F)cc2)n1CCC(=O)N1CCOCC1

Procedure:
A nitrogen inerted reactor, equipped with a suitable reflux condenser and soxhlet extractor containing freshly activated 3A molecular sieves (4-8 mesh; 97.2 g), is charged with 3-amino-1-morpholin-4-yl-propan-1-one, compound with phenylacetic acid (765 mmol) and 2-[2-(4-fluorophenyl)-2-oxo-1-phenyl-ethyl]-4-methyl-3-oxo-pentanoic acid phenylamide (450 mmol). THF (360 mL) is added, and the resulting solution is stirred vigorously as the reaction is heated at reflux temperature for ca. 24 hours, during which time the product begins to precipitate. Half-saturated aqueous NaHCO3 (100 mL) is added, and the reaction mixture is cooled with continued stirring to ca. 0° C. MtBE (100 mL) is added, and the solids are collected via filtration. The solid is washed with distilled water (100 mL) and MtBE (2×100 mL), collected, and dried under vacuum at ≦50° C. to afford 5-(4-fluorophenyl)-2-isopropyl-1-(3-morpholin-4-yl-3-oxo-propyl)-4-phenyl-1H-pyrrole-3-carboxylic acid phenylamide as a white solid (194 g). This material is carried on to subsequent steps without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][C:9]=2[OH:18])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:25][O:26][CH2:27][CH2:28]Br>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][C:9]=2[O:18][CH2:28][CH2:27][O:26][CH3:25])=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(-c2ccc(F)cc2)c(O)c1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COCCOc1cc(C(=O)OC)ccc1-c1ccc(F)cc1
Temperature: 80 °C
Yield: 101.5 %

Procedure:
To a suspension of methyl 4′-fluoro-2-hydroxy-1,1′-biphenyl-4-carboxylate (D75) (400 mg, 1.6 mmol) in DMF (10 ml) was added cesium carbonate (1.27 g, 3.9 mmol) and 2-methoxyethylbromide (400 mg, 1.6 mmol) and the reaction was heated at 80° C. overnight. The solvent was evaporated and the residue was dissolved in EtOAc, washed with water and brine, then dried over MgSO4 to give the title compound (494 mg) which was used without further purification in the next step. MS(ES): (M-MeOH)H+ 273.
Reaction SMILES: C(OC([C:6]1[C:14]2[CH2:13][CH2:12][N:11]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][C:22]4=[O:27])=[CH:17][CH:16]=3)[C:10](=[O:28])[C:9]=2[N:8]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)[N:7]=1)=O)C.C[Mg+].[Br-]>C1COCC1>[OH:35][C:32]([C:6]1[C:14]2[CH2:13][CH2:12][N:11]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][C:22]4=[O:27])=[CH:17][CH:16]=3)[C:10](=[O:28])[C:9]=2[N:8]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)[N:7]=1)([CH3:33])[CH3:31]
Reactant: CCOC(=O)c1nn(-c2ccc(OC)cc2)c2c1CCN(c1ccc(N3CCCCC3=O)cc1)C2=O
Agent: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: COc1ccc(-n2nc(C(C)(C)O)c3c2C(=O)N(c2ccc(N4CCCCC4=O)cc2)CC3)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 99 %

Procedure:
To 1-(4-methoxy-phenyl)-7-oxo-6-[4-(2-oxo-piperidin-1-yl)-phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (0.1, 0.2 mmol) in THF (15 mL) at 0° C. was added MeMgBr (0.21 mL, 0.6 mmol) and the reaction was stirred at rt for 24 h. The reaction was quenched with water and purified by HPLC to afford 47 mg (48%) of a white solid; Mass Spec (M+H)+475.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][N:4]([S:7]([N:10]([CH3:12])[CH3:11])(=[O:9])=[O:8])[N:3]=1.C([Li])CCC.C1CCCCC1.[Cl:24]C(Cl)(Cl)C(Cl)(Cl)Cl>O1CCCC1>[Cl:1][C:2]1[CH:6]=[C:5]([Cl:24])[N:4]([S:7]([N:10]([CH3:12])[CH3:11])(=[O:9])=[O:8])[N:3]=1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: CN(C)S(=O)(=O)n1ccc(Cl)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: CN(C)S(=O)(=O)n1nc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.9 %

Procedure:
Under a nitrogen atmosphere, a solution of 3-chloro-N,N-dimethyl-1H-pyrazole-1-sulfonamide (1.68 g, 8 mmol) (i.e. the product of Example 12, Step B) in tetrahydrofuran (10 mL) was cooled to −78° C. and then treated with a solution of 2 M n-butyllithium in cyclohexane (4.5 mL, 9 mmol) dropwise. The solution formed a thick precipitate and was allowed to stir for 30 minutes after the addition. To the stirred suspension, a solution of hexachloroethane (2.0 g, 8.5 mmol) in tetrahydrofuran (10 mL) was added dropwise. After 1.5 h the resulting clear solution was warmed to ambient temperature and quenched with the addition of water (20 mL). The reaction mixture was extracted with dichloromethane and dried over MgSO4. The solution was filtered and concentrated under reduced pressure to give 1.97 g of the title compound. This compound was of sufficient purity to use in subsequent reactions.
Reaction SMILES: [NH2:1][CH:2]([C:8]#[N:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(N(CC)CC)C.[CH:17]1([C:23](Cl)=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C(=O)([O-])O.[Na+]>ClCCl>[C:8]([CH:2]([NH:1][C:23]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:24])[C:3]([O:5][CH2:6][CH3:7])=[O:4])#[N:9]
Reactant: CCOC(=O)C(N)C#N
Reactant: O=C(Cl)C1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C#N)NC(=O)C1CCCCC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 71.3 %

Procedure:
To a solution of 18.3 g (143 mmol) of ethyl amino(cyano)acetate in 500 mL of anhydrous dichloromethane were added 30 mL (214 mmol) of triethylamine and 23 mL (171 mmol) of cyclohexanecarbonyl chloride, and the mixture was stirred for 3 hours at 0° C. Then, saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture and the mixture was extracted with dichloromethane. The organic layer was washed with water and saturated saline solution, then, dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was treated with ethyl acetate to give the solid substance. The obtained solid substance was collected and the filtrate was removed under reduced pressure. The obtained residue was treated with ethyl acetate to give solid substance. This treatment was further repeated. The filtrate was purified by silica gel column chromatography (eluent: dichloromethane/methanol=50/1) to give crude crystalline. The obtained crude crystalline was washed with ether and combined with the above all solid products to give 24.3 g (71%) of the title compound.
Reaction SMILES: BrC1C=C(C)C(C(N2CCC(N3CCCC3)CC2)=O)=C(C)C=1.BrC1C=C(C)C(C(N2CCC(N3CCC[C@H]3CO)CC2)=O)=C(C)C=1.[CH3:47][C:48]1[C:53]([C:54]([OH:56])=O)=[C:52]([CH3:57])[N:51]=[C:50]([C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([C:64]([F:67])([F:66])[F:65])[CH:59]=2)[N:49]=1.[N:68]1([CH:83]2[CH2:88][CH2:87][NH:86][CH2:85][CH2:84]2)[CH2:73][CH2:72][CH:71]([O:74]C(=O)C2C=CC=CC=2)[CH2:70][CH2:69]1>>[CH3:57][C:52]1[C:53]([C:54]([N:86]2[CH2:85][CH2:84][CH:83]([N:68]3[CH2:73][CH2:72][CH:71]([OH:74])[CH2:70][CH2:69]3)[CH2:88][CH2:87]2)=[O:56])=[C:48]([CH3:47])[N:49]=[C:50]([C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([C:64]([F:65])([F:66])[F:67])[CH:59]=2)[N:51]=1
Reactant: Cc1nc(-c2cccc(C(F)(F)F)c2)nc(C)c1C(=O)O
Reactant: O=C(OC1CCN(C2CCNCC2)CC1)c1ccccc1
Agent: Cc1cc(Br)cc(C)c1C(=O)N1CCC(N2CCCC2)CC1
Agent: Cc1cc(Br)cc(C)c1C(=O)N1CCC(N2CCC[C@H]2CO)CC1
Product: Cc1nc(-c2cccc(C(F)(F)F)c2)nc(C)c1C(=O)N1CCC(N2CCC(O)CC2)CC1

Procedure:
In analogy to the procedures described for intermediate 1 and for intermediate 4 B, 4,6-dimethyl-2-(3-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid (intermediate 5) was converted into its acid chloride, reacted with benzoic acid [1,4′]bipiperidinyl-4-yl ester (example 22) and subsequently saponified to give the title compound as colorless solid. MS: 463.3 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:29])[CH2:9][CH2:10][CH2:11][N:12]2[CH2:28][CH2:27][C@@H:15]3[N:16]4[C:25]5[C:24]([C@@H:14]3[CH2:13]2)=[CH:23][CH:22]=[CH:21][C:20]=5[N:19]([CH3:26])[CH2:18][CH2:17]4)=[CH:4][CH:3]=1.[CH3:30][Mg]Br.CCOCC>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:29])([CH2:9][CH2:10][CH2:11][N:12]2[CH2:28][CH2:27][C@@H:15]3[N:16]4[C:25]5[C:24]([C@@H:14]3[CH2:13]2)=[CH:23][CH:22]=[CH:21][C:20]=5[N:19]([CH3:26])[CH2:18][CH2:17]4)[CH3:30])=[CH:4][CH:3]=1
Reactant: C[Mg]Br
Reactant: CN1CCN2c3c(cccc31)[C@@H]1CN(CCCC(=O)c3ccc(F)cc3)CC[C@@H]12
Agent: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CN1CCN2c3c(cccc31)[C@@H]1CN(CCCC(C)(O)c3ccc(F)cc3)CC[C@@H]12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(4-fluoro-phenyl)-4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-butan-1-one (99 mg, 0.25 mmol) in THF is added 3.0 M methyl magnesium bromide in ether (0.25 mL, 0.75 mmol) dropwise at 0° C. Upon the completion of the addition of CH3MgBr, the cooling bath is removed and the reaction mixture is stirred at room temperature for 2 hours. Another batch of 3.0 M methyl magnesium bromide in ether (0.25 mL, 0.75 mmol) is added dropwise, and the reaction mixture was stirred at room temperature overnight. The mixture is carefully quenched with water, basified with saturated sodium bicarbonate, and then extracted with methylene chloride four times. The combined organic phase is evaporated to dryness, and the residue is purified on a basic alumina column to give 28 mg of pure product as a white solid. 1H NMR (500 MHz, Chloroform-d) δ 8.22 (br, 1H), 7.58-7.37 (m, 2H), 7.07 (t, J=8.5 Hz, 1H), 7.01 (t, J=8.7 Hz, 1H), 6.65 (dt, J=10.6, 7.7 Hz, 1H), 6.57-6.29 (m, 2H), 3.59 (td, J=11.1, 3.0 Hz, 1H), 3.37-3.12 (m, 4H), 3.00-2.65 (m, 5H), 2.55-2.13 (m, 5H), 2.12-1.78 (m, 4H), 1.69-1.30 (m, 5H). MS (ESI) m/z 410.2 [M+H]+.
Reaction SMILES: C([O:5][C:6](=[O:53])[C:7]([O:10]/[N:11]=[C:12](/[C:40]1[N:41]=[C:42]([NH:45]C(OC(C)(C)C)=O)[S:43][CH:44]=1)\[C:13]([NH:15][C@@H:16]1[C:19](=[O:20])[N:18]([S:21]([OH:24])(=[O:23])=[O:22])[C@@H:17]1[CH2:25][N:26]1[C:30]([CH2:31][NH:32]C(OC(C)(C)C)=O)=[N:29][N:28]=[N:27]1)=[O:14])([CH3:9])[CH3:8])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:32][CH2:31][C:30]1[N:26]([CH2:25][C@@H:17]2[C@H:16]([NH:15][C:13](=[O:14])/[C:12](=[N:11]\[O:10][C:7]([CH3:9])([CH3:8])[C:6]([OH:53])=[O:5])/[C:40]3[N:41]=[C:42]([NH2:45])[S:43][CH:44]=3)[C:19](=[O:20])[N:18]2[S:21]([OH:24])(=[O:23])=[O:22])[N:27]=[N:28][N:29]=1
Reactant: CC(C)(C)OC(=O)NCc1nnnn1C[C@@H]1[C@H](NC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c2csc(NC(=O)OC(C)(C)C)n2)C(=O)N1S(=O)(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1Cn1nnnc1CN)c1csc(N)n1)C(=O)O
Yield: 27.9 %

Procedure:
Followed the general procedure for the acid mediated deprotection using (2R,3S)-3-((Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2-((5-(((tert-butoxycarbonyl)amino)methyl)-1H-tetrazol-1-yl)methyl)-4-oxoazetidine-1-sulfonic acid (100 mg, 0.126 mmol), DCM (1.26 mL) and TFA (584 μL, 7.58 mmol) for 1.5 h. The crude residue purified by reverse phase prep HPLC (XSelect CSH, 19×100 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 24 mL/min), affording the title compound (18.7 mg, 28%) as a white powder. LCMS: Rt=0.31 min, m/z=533.2 (M+1) Method 2m_acidic; 1H NMR (400 MHz, DMSO-d6) δ 9.21 (d, J=8.8 Hz, 1H), 7.28 (s, 2H), 6.79 (s, 1H), 5.35 (dd, J=8.8, 5.8 Hz, 1H), 4.79-4.61 (m, 2H), 4.59-4.53 (m, 1H), 4.47-4.35 (m, 2H), 1.36 (br s, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([OH:7])=O.CCN(C(C)C)C(C)C.Cl.Cl.[NH2:26][CH2:27][CH:28]1[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][NH:36][S:37]([C:40]([F:43])([F:42])[F:41])(=[O:39])=[O:38])[CH2:30][CH2:29]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([NH:26][CH2:27][CH:28]1[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][NH:36][S:37]([C:40]([F:43])([F:42])[F:41])(=[O:39])=[O:38])[CH2:30][CH2:29]1)=[O:7]
Reactant: O=C(O)c1cc(Br)cc(C(F)(F)F)c1
Reactant: NCC1CCN(CCNS(=O)(=O)C(F)(F)F)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCC1CCN(CCNS(=O)(=O)C(F)(F)F)CC1)c1cc(Br)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-bromo-5-(trifluoromethyl)benzoic acid (0.1 g, 0.37 mmol) in CH2Cl2 (4 mL) was added DIPEA (0.3 mL, 1.8 mmol), N-(2-(4-(aminomethyl)piperidin-1-yl)ethyl)-1,1,1-trifluoromethanesulfonamide dihydrochloride salt (0.1 g, 0.3 mmol) and HATU (0.17 g, 0.4 mmol). The reaction mixture was stirred at room temperature for 2 h. The organic layer was washed with sat. NaHCO3 aq. (8 mL), dried over Na2SO4, and concentrated to give crude product as gummy solid. Purification of the crude material was done using High Throughput Purification System (HiTOPs).
Reaction SMILES: [CH3:1][N:2]1[C:6]([Sn](CCCC)(CCCC)CCCC)=[CH:5][N:4]=[CH:3]1.[C:20]([N:23]1[C:32]2[C:27](=[CH:28][C:29](Br)=[CH:30][CH:31]=2)[C@H:26]([NH:34][C:35](=[O:40])[O:36][CH:37]([CH3:39])[CH3:38])[CH2:25][C@@H:24]1[CH3:41])(=[O:22])[CH3:21]>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.CCOC(C)=O.CCCCCC>[CH3:39][CH:37]([O:36][C:35](=[O:40])[NH:34][C@H:26]1[C:27]2[C:32](=[CH:31][CH:30]=[C:29]([C:6]3[N:2]([CH3:1])[CH:3]=[N:4][CH:5]=3)[CH:28]=2)[N:23]([C:20](=[O:22])[CH3:21])[C@@H:24]([CH3:41])[CH2:25]1)[CH3:38]
Reactant: CC(=O)N1c2ccc(Br)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncn1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(=O)N1c2ccc(-c3cncn3C)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 140 °C
Reaction time: 16 h
Yield: 13 %

Procedure:
A mixture of 1-methyl-5-(tributylstannyl)-1H-imidazole (200 mg, 0.54 mmol), 1-methylethyl [(2S,4R)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation, see Example 4) (199 mg, 0.54 mmol) and tetrakis(triphenylphosphine)palladium(0) (31 mg, 0.027 mmol) in dry, degassed DMF (5 mL) was stirred at 140° C. under nitrogen for 16 h then was cooled to room temperature and diluted with AcOEt (20 mL). The solution was washed with water (×2) then brine. The organic phase was dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (gradient: 0 to 6% MeOH in DCM) gave 1-methylethyl[(2S,4R)-1-acetyl-2-methyl-6-(1-methyl-1H-imidazol-5-yl)-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (27 mg, 0.073 mmol, 13%) as a colourless solid after trituration with AcOEt/hexane. LCMS (method G): Retention time 0.59 min, [M+H]+=402.1
Reaction SMILES: C([N:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11](=[O:16])[C:10]([C:17]2[N:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:20]=[CH:19][CH:18]=2)=[N:9]1)C1C=CC=CC=1>O1CCCC1.CO.[OH-].[OH-].[Pd+2]>[CH3:15][O:14][C:12]1[C:11]([OH:16])=[C:10]([C:17]2[N:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:20]=[CH:19][CH:18]=2)[N:9]=[N:8][CH:13]=1
Reactant: COc1cn(Cc2ccccc2)nc(-c2ccnn2-c2ccccc2)c1=O
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cnnc(-c2ccnn2-c2ccccc2)c1O
Yield: 81 %

Procedure:
1-Benzyl-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (15.0 g) and palladium hydroxide on carbon (5.88 g, palladium 20%, 50% water moistened product) were suspended in tetrahydrofuran (500 mL) and methanol (300 mL), and the mixture was stirred under a hydrogen atmosphere at room temperature for 2 days. The reaction mixture was filtered through celite, and the filtrate was concentrated and solidified with ethanol/hexane to give the title compound (9.10 g).
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][NH:14][C:15]([C:17]1[S:18][C:19]([Cl:22])=[CH:20][CH:21]=1)=[O:16].[F:23][C:24]1[CH:32]=[C:31]([N:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]2=[O:39])[CH:30]=[CH:29][C:25]=1[C:26](O)=[O:27]>>[F:23][C:24]1[CH:32]=[C:31]([N:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]2=[O:39])[CH:30]=[CH:29][C:25]=1[C:26]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][NH:14][C:15]([C:17]1[S:18][C:19]([Cl:22])=[CH:20][CH:21]=1)=[O:16])=[O:27]
Reactant: O=C(O)c1ccc(-n2ccccc2=O)cc1F
Reactant: O=C(NCC1CCCN1)c1ccc(Cl)s1
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCC1CCCN1C(=O)c1ccc(-n2ccccc2=O)cc1F)c1ccc(Cl)s1

Procedure:
Using general method H, rac-5-chloro-thiophene-2-carboxylic acid (pyrrolidin-2-ylmethyl)-amide trifluoro acetate (example 75.2) was reacted with 2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-benzoic acid (prepared according to example 54.1) to give rac-5-chloro-thiophene-2-carboxylic acid {1-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-benzoyl]-pyrrolidin-2-ylmethyl}-amide. White solid. MS 460.0 ([M+H]+)