Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[CH:11][C:12]2[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=2/[C:14](/[NH:17]O)=[N:15]\[H])=[N:2]1.[C:23]([O:27][CH3:28])(=[O:26])[C:24]#[CH:25].O>CO>[CH3:28][O:27][C:23]([C:24]1[NH:15][C:14]([C:13]2[CH:19]=[CH:20][CH:21]=[CH:22][C:12]=2/[CH:11]=[CH:10]/[C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][N:2]=2)=[N:17][CH:25]=1)=[O:26]
Reactant: C#CC(=O)OC
Reactant: [H]/N=C(/NO)c1ccccc1C=Cc1n[nH]c2ccccc12
Solvent: O
Solvent: CO
Product: COC(=O)c1cnc(-c2ccccc2/C=C/c2n[nH]c3ccccc23)[nH]1
Yield: 4.5 %

Procedure:
(E)-2-[2-(1H-indazol-3-yl)vinyl]-N-hydroxybenzamidine (0.30 g, 0.83 mmol) obtained in Step 1 of Example 175 was dissolved in methanol (8.0 mL) and after heating methyl propiolate (0.21 mL, 2.5 mmol) under reflux for 5 hours, water was added to stop the reaction. The mixture was extracted with ethyl acetate and the organic layer was concentrated. The residue was purified by preparative thin-layer chromatography (chloroform/acetone=4/1) to obtain Compound 195 (13 mg, 5%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=2)[C:11]2[C:16]([CH3:17])=[C:15]([CH3:18])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=3)[C:11]3[C:16]([CH3:17])=[C:15]([CH3:18])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1ncc[nH]1
Reactant: Cc1sc2nc(Cl)nc(NCc3ccc(Cl)c(Cl)c3)c2c1C
Product: Cc1sc2nc(-n3ccnc3C)nc(NCc3ccc(Cl)c(Cl)c3)c2c1C

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-5,6-dimethyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-5,6-dimethyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:20][CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[C:6]([CH:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)O)[CH:7]=1.[SH:26][CH:27]([CH2:31][C:32]([OH:34])=[O:33])[C:28](O)=[O:29].C(O)(=O)CC>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:20]([CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C:28](=[O:29])[CH:27]([CH2:31][C:32]([OH:34])=[O:33])[S:26][CH:8]([C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:13]=[CH:12][CH:11]=3)[C:6]=2[CH:7]=1
Reactant: O=C(O)CC(S)C(=O)O
Reactant: CC(C)(C)CNc1ccc(Cl)cc1C(O)c1cccc2ccccc12
Solvent: O
Solvent: CCC(=O)O
Product: CC(C)(C)CN1C(=O)C(CC(=O)O)SC(c2cccc3ccccc23)c2cc(Cl)ccc21
Temperature: 130 °C
Reaction time: 48 h
Yield: 92.2 %

Procedure:
A stirred mixture of 50.0 g (141 mmol) of (5-chloro-2-neopentylamino-phenyl)-naphthalen-1-yl-methanol, 27.58 g (184 mmol, 1.3 equivalents) of mercaptosuccinic acid, and 340 mL of propionic acid was heated to 130° C. with a nitrogen purge. After 48 hours, the reaction mixture was cooled to room temperature giving a precipitate, treated with 200 mL of water, cooled to -5° C. with stirring, and filtered giving 60.83 g (92% yield) of the title compound as an off white solid.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]3[C:14]([O:23][CH3:24])=[C:15]4[C:20](=[O:21])[N:19]([CH3:22])[CH2:18][CH2:17][N:16]4[C:10]=3[C:9]([CH:25](O)[CH3:26])=[N:8]2)=[CH:4][CH:3]=1.S(Cl)([Cl:32])=O>>[F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]3[C:14]([O:23][CH3:24])=[C:15]4[C:20](=[O:21])[N:19]([CH3:22])[CH2:18][CH2:17][N:16]4[C:10]=3[C:9]([CH:25]([Cl:32])[CH3:26])=[N:8]2)=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: COc1c2n(c3c(C(C)O)nn(Cc4ccc(F)cc4)c(=O)c13)CCN(C)C2=O
Product: COc1c2n(c3c(C(C)Cl)nn(Cc4ccc(F)cc4)c(=O)c13)CCN(C)C2=O

Procedure:
A solution of 2-(4-fluorobenzyl)-10-methoxy-4-(1-hydroxyethyl)-8-methyl-7,8-dihydropyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyridazine-1,9(2H,6H)-dione (0.12 g, 0.30 mmol) in thionyl chloride (3.3 mL) was stirred at room temperature for 3 hours. The reaction mixture was concentrated under vacuum. The residue was concentrated from a solution in benzene under vacuum and triturated with diethyl ether. The solid precipitated was filtered and vacuum dried to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([OH:12])=[CH:7]2.[C:13]([O-:16])([O-])=O.[K+].[K+].[Cl-].O>C(Cl)Cl>[OH:12][C:6]1[CH:7]=[C:8]2[C:3](=[CH:4][CH:5]=1)[C:2]([NH:1][C:13](=[O:16])[C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:3]=1)=[CH:11][CH:10]=[CH:9]2
Reactant: O=C([O-])[O-]
Reactant: Nc1cccc2cc(O)ccc12
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: O=C(Nc1cccc2cc(O)ccc12)c1ccccc1

Procedure:
To a round bottom flask containing 1.00 g (6.3 mmol) 5-amino-naphthalene-2-ol in 10 mL CH2Cl2, was added 2.61 g (0.0189 mmol) K2CO3, followed by 1.46 mL (0.0126 mmol) benzolyl chloride. The solution mixture was stirred under inert atmosphere until completion. After stirring for 18 h, water was added into the mixture and diluted with CH2Cl2. The organics were separated by sep. funnel, while extracting the organics 3× with CH2Cl2. The organic layers were combined, dried over Na2SO4, filtered and concentrated in-vacuo. The crude was purified by crystallization in CH2Cl2/Hexanes. A gray colored powder was collected, which was titled compound. MS (ESI pos. ion) m/z: 264 (M+H)
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@H:15]([OH:17])[CH2:14][C@H:13]2[CH2:18][CH2:19][C:20](O)=[O:21])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].ClC(OCC)=O.[CH3:31][NH2:32]>O1CCCC1.C(N(CC)CC)C>[N+:1]([C:4]1[CH:24]=[CH:23][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@H:15]([OH:17])[CH2:14][C@H:13]2[CH2:18][CH2:19][C:20]([NH:32][CH3:31])=[O:21])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(O)CC[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: CN
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CNC(=O)CC[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 0.25 h

Procedure:
To a solution of (2R,4R)-1-p-nitrobenzyloxycarbonyl-2-(2-carboxyethyl)-4-hydroxypyrrolidine (57.73 g) in dry tetrahydrofuran (500 ml), triethylamine (29.27 ml) was added, and ethyl chloroformate (18.74 ml) was further added thereto at -20° to -25° C. under nitrogen stream. The resulting mixture was stirred at the same temperature for 15 minutes and 30% (w/w) ethanolic solution of methylamine (57.5 g) was added thereto, followed by stirring at the same temperature for 1 hour. The solvent was removed, and the residue was combined with water and ether. The precipitated crystals were collected by filtration to give (2R,4R)-1-p-nitrobenzyloxycarbonyl-2-(2-methylaminocarbonylethyl)-4-hydroxypyrrolidine.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]([CH3:31])[C:10]([NH:12][CH2:13][C:14]2[C:15]([C:24]3[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=3)=[N:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=2)=[O:11])[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>ClCCl>[CH3:39][S:40]([NH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]([CH3:31])[C:10]([NH:12][CH2:13][C:14]2[C:15]([C:24]3[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=3)=[N:16][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:18][CH:19]=2)=[O:11])[CH:6]=[CH:7][CH:8]=1)(=[O:42])=[O:41]
Reactant: Cc1cccc(-c2nc(C(F)(F)F)ccc2CNC(=O)C(C)c2cccc(CN)c2)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cccc(-c2nc(C(F)(F)F)ccc2CNC(=O)C(C)c2cccc(CNS(C)(=O)=O)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 0.6 %

Procedure:
A cooled solution of 2-(3-(aminomethyl)phenyl)-N-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide (90 mg, 21 mmol) in dichloromethane was added triethylamine (45 μL, 42 mmol) at 0° C. The resulting solution was treated dropwise with methanesulfonyl chloride (24.4 μL, 31.6 mmol) over 10 min and stirred for 1 h at room temperature. After aqueous workup, the residue was purified by flash column chromatography to obtain 2-(3-(methylsulfonamidomethyl)phenyl)-N-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide (example 1) (67 mg, 60%).
Reaction SMILES: [N+:1]([C:4]1[CH:26]=[CH:25][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@@H:15]([S:17][C:18](=[O:20])[CH3:19])[CH2:14][C@H:13]2[CH2:21][C:22]([OH:24])=[O:23])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:27](Cl)(=O)C(Cl)=O.CN(C)C=O>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@@H:15]([S:17][C:18](=[O:20])[CH3:19])[CH2:14][C@H:13]2[CH2:21][C:22]([O:24][CH3:27])=[O:23])=[O:11])=[CH:25][CH:26]=1)([O-:3])=[O:2]
Reactant: CC(=O)S[C@H]1C[C@@H](CC(=O)O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)C[C@@H]1C[C@H](SC(C)=O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(2R,4S)-1-(p-Nitrobenzyloxycarbonyl)-2-carboxymethyl-4-acetylthiopyrrolidine (148 mg) was dissolved in 2 ml of dry methylene chloride, and 0.2 ml of oxalyl chloride and a catalytic amount of dimethylformamide were added thereto, followed by stirring at room temperature for 2 hours. The reaction mixture was distilled to remove the solvent, and dry benzene was added thereto, followed by distillation of benzene. After two times repetition of the above procedure, the residue was dissolved in 2 ml of dry methylene chloride. The solution was added to a mixture of methanol (125 mg), triethylamine (81 mg) and dry methylene chloride (1 ml) under nitrogen stream with ice-cooling and stirred at the same temperature for 2 hours. The reaction mixture was washed successively with water and dilute hydrochloric acid, dried over anhydrous sodium sulfate and distilled to remove the solvent to obtain (2R,4S)-1-(p-nitrobenzyloxycarbonyl)-2-methoxycarbonylmethyl-4-acetylthiopyrrolidine.
Reaction SMILES: [CH2:1]([N:5]([S:32]([C:35]1[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=1)(=[O:34])=[O:33])[C@H:6]([C:29]([OH:31])=[O:30])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([O:14][CH2:15][CH:16]1[C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:13])[CH:2]([CH3:4])[CH3:3].[N+](=[CH2:44])=[N-]>>[CH3:44][O:30][C:29](=[O:31])[C@H:6]([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([O:14][CH2:15][CH:16]1[C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:13])[N:5]([CH2:1][CH:2]([CH3:3])[CH3:4])[S:32]([C:35]1[CH:36]=[CH:37][C:38]([CH3:41])=[CH:39][CH:40]=1)(=[O:33])=[O:34]
Reactant: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Reactant: C=[N+]=[N-]
Product: COC(=O)[C@H](CCCCNC(=O)OCC1c2ccccc2-c2ccccc21)N(CC(C)C)S(=O)(=O)c1ccc(C)cc1
Yield: 68 %

Procedure:
The product from example 45 was treated with excess diazomethane, yielding the title compound in 68% yield.
Reaction SMILES: [C:1]([C:5]([CH2:7][N:8]1[C:14]2[CH:15]=[C:16]([CH3:19])[CH:17]=[CH:18][C:13]=2[N:12]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:11][CH:10]([NH:26][C:27]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([O:38]CC)=[O:37])[CH:31]=2)=[O:28])[C:9]1=[O:41])=[O:6])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+]>CO>[C:1]([C:5]([CH2:7][N:8]1[C:14]2[CH:15]=[C:16]([CH3:19])[CH:17]=[CH:18][C:13]=2[N:12]([CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)[CH2:11][CH:10]([NH:26][C:27](=[O:28])[NH:29][C:30]2[CH:31]=[C:32]([CH:33]=[CH:34][CH:35]=2)[C:36]([OH:38])=[O:37])[C:9]1=[O:41])=[O:6])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cccc(NC(=O)NC2CN(C3CCCCC3)c3ccc(C)cc3N(CC(=O)C(C)(C)C)C2=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccc2c(c1)N(CC(=O)C(C)(C)C)C(=O)C(NC(=O)Nc1cccc(C(=O)O)c1)CN2C1CCCCC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 85.3 %

Procedure:
1-(1-tert-Butylcarbonylmethyl-2-oxo-5-cyclohexyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-ethoxycarbonylphenyl)urea (370 mg) was suspended in methanol (5 ml), aqueous lithium hydroxide monohydrate (142 mg) solution (5 ml) was added to the suspension, and the mixture was stirred at 50° C. for 2 hours. The reaction mixture was filtrated. The filtrate was acidified with 1N hydrochloric acid, and methanol was evaporated. The mixture was extracted with ethyl acetate, the organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. The residue was recrystallized from isopropyl alcohol, to thereby obtain 300 mg of the title compound (Yield: 83%).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:6]=1[CH:7]=O)[CH2:2][CH3:3].C1(P(=[CH:36][C:37]([O:39][CH3:40])=[O:38])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:40][O:39][C:37](=[O:38])[CH:36]=[CH:7][C:6]1[CH:9]=[CH:10][C:11]([C:13]([F:16])([F:15])[F:14])=[CH:12][C:5]=1[O:4][CH2:1][CH2:2][CH3:3]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCOc1cc(C(F)(F)F)ccc1C=O
Solvent: Cc1ccccc1
Product: CCCOc1cc(C(F)(F)F)ccc1C=CC(=O)OC
Yield: 68.7 %

Procedure:
2-Propoxy-4-trifluoromethyl-benzaldehyde (232 mg, 1 mmol) in toluene was reacted with methyl (triphenylphosphoranylidene)acetate (382 mg, 1.14 mmol) at 110° C. overnight. The reaction solvent was removed under reduced pressure. Water (30 ml) was added to the resulting residue, which was extracted with ethyl acetate (30 ml×3). The combined organic layer was washed with brine (30 ml) and dried over MgSO4. The filterate was purified with column chromatography to yield title compound (198 mg, 69%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:39]=[CH:40][CH:41]=1)[C:6]([NH:8][C:9]1[CH:32]=[CH:31][C:30]([N:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)=[CH:29][C:10]=1[C:11]([NH:13][C:14]1[CH:18]=[CH:17][N:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)[N:15]=1)=[O:12])=[O:7].C(=O)([O-])[O-].[K+].[K+].[SH:48][C:49]1[CH:50]=[C:51]([CH2:55][C:56]([OH:58])=[O:57])[CH:52]=[CH:53][CH:54]=1>CN(C=O)C>[N:33]1([C:30]2[CH:31]=[CH:32][C:9]([NH:8][C:6]([C:5]3[CH:4]=[C:3]([CH:41]=[CH:40][CH:39]=3)[CH2:2][S:48][C:49]3[CH:50]=[C:51]([CH2:55][C:56]([OH:58])=[O:57])[CH:52]=[CH:53][CH:54]=3)=[O:7])=[C:10]([C:11](=[O:12])[NH:13][C:14]3[CH:18]=[CH:17][N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:27])([F:28])[F:26])[CH:20]=4)[N:15]=3)[CH:29]=2)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: O=C(Nc1ccc(N2CCCCC2)cc1C(=O)Nc1ccn(-c2cccc(C(F)(F)F)c2)n1)c1cccc(CCl)c1
Reactant: O=C(O)Cc1cccc(S)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)Cc1cccc(SCc2cccc(C(=O)Nc3ccc(N4CCCCC4)cc3C(=O)Nc3ccn(-c4cccc(C(F)(F)F)c4)n3)c2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a round bottom flask was placed a solution of 2-(3-(chloromethyl)benzamido)-5-(piperidin-1-yl)-N-(1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)benzamide 21b (0.23 mmol, 1 equiv) in DMF (1.2 mL), potassium carbonate (127.1 mg, 0.92 mmol, 4 equiv), and (3-mercaptophenyl)acetic acid (42.6 mg, 0.253 mmol, 1.1 equiv). The solution was stirred overnight at room temperature. The reaction progress was monitored by LCMS. After 16.5 h, more (3-mercaptophenyl)acetic acid (7 mg) was added to the solution, and the solution was stirred another 1 h. The solvent was removed. The residue was dissolved with DCM, washed with H2O and brine, and dried over sodium sulfate. The product was purified by reverse phase HPLC, eluting with 0.05% TFA in a water/acetonitrile gradient. MS (ES, m/z) 714 [M+H]+.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH:11]([NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH:21]=[CH:20][C:18]=2[N:19]=1)([CH3:13])[CH3:12].[F:29][C:30]1[CH:39]=[CH:38][CH:37]=[CH:36][C:31]=1[C:32](OC)=[O:33].Cl>C1COCC1>[F:29][C:30]1[CH:39]=[CH:38][CH:37]=[CH:36][C:31]=1[C:32](=[O:33])[CH:24]([C:22]1[CH:21]=[CH:20][C:18]2[N:19]=[C:15]([NH:14][CH:11]([CH3:12])[CH3:13])[S:16][C:17]=2[CH:23]=1)[C:25]([O:27][CH3:28])=[O:26]
Reactant: COC(=O)c1ccccc1F
Reactant: COC(=O)Cc1ccc2nc(NC(C)C)sc2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(C(=O)c1ccccc1F)c1ccc2nc(NC(C)C)sc2c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 120.2 %

Procedure:
To a solution of lithium bis(trimethylsilyl)amide (1.0 M in THF, 15.1 mL) in THF (30 mL) was added a solution of methyl 2-(2-(isopropylamino)benzo[d]thiazol-6-yl)acetate (1.60 g, 6.05 mmol) in THF (20 mL) at −78° C. over 40 min. The resulting solution was stirred at −78° C. for 15 min before a solution of methyl 2-fluorobenzoate (1.08 mL, 8.48 mmol) in THF (10 mL) was added over 5 min. The mixture was stirred at −78° C. for 1 hr and then at rt for 3 hr before it was poured into ice-cold water (100 mL). After its pH value was adjusted to 9 with 6 N HCl, the mixture was extracted with AcOEt (3×40 mL). The combined extract was washed with brine and dried over anhydrous MgSO4. Evaporation of solvent under vacuum give the title compound (2.81 g) as an orange yellowish oil. This product was 63% pure by LCMS, but it was used in the next step without further purification.
Reaction SMILES: Br.[CH:2]([NH:5][C:6]1[S:7][CH:8]=[C:9]([C:11]([OH:13])=O)[N:10]=1)([CH3:4])[CH3:3].[NH2:14][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=1[C:23](=[O:25])[CH3:24].O=P(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>N1C=CC=CC=1>[C:23]([C:16]1[CH:17]=[CH:18][C:19]([O:21][CH3:22])=[CH:20][C:15]=1[NH:14][C:11]([C:9]1[N:10]=[C:6]([NH:5][CH:2]([CH3:3])[CH3:4])[S:7][CH:8]=1)=[O:13])(=[O:25])[CH3:24]
Reactant: CC(C)Nc1nc(C(=O)O)cs1
Reactant: COc1ccc(C(C)=O)c(N)c1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(C(C)=O)c(NC(=O)c2csc(NC(C)C)n2)c1
Temperature: -30 °C
Reaction time: 1 h
Yield: 101.8 %

Procedure:
A mixture of compound 69 (4.4 g, 16.5 mmol) and the aniline derivative 66 (2.75 g, 16.5 mmol) in pyridine (140 mL) was cooled to −30° C. (upon cooling, the clear solution became partially a suspension). POCl3 (3.3 mL, 35 mmol) was added slowly over a 5 min period. The mixture was stirred at −30° C. for 1 h, and was then allowed to assume rt. After stirring at rt for 1.5 h the reaction mixture was poured over ice, and the pH was adjusted to about 9-10 using solid and saturated NaHCO3. The crude product was extracted into CH2Cl2 (3×) and the combined organic phases were dried (MgSO4) and evaporated. The crude dark-beige solid was purified by flash column chromatography (hexane/EtOAc 55:45) to give compound 70 (5.6 g, 76%) as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([O:24][CH3:25])[C:8]=1[CH:9]([NH:17]S(C(C)(C)C)=O)[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14].Cl.O1CCOCC1>CO>[NH2:17][CH:9]([C:8]1[C:7]([O:24][CH3:25])=[CH:6][N:5]=[CH:4][C:3]=1[O:2][CH3:1])[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)CCCC(NS(=O)C(C)(C)C)c1c(OC)cncc1OC
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)CCCC(N)c1c(OC)cncc1OC
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A cooled (0° C.) yellow solution of methyl 5-(3,5-dimethoxypyridin-4-yl)-5-(1,1-dimethylethylsulfinamido)pentanoate (780 mg; 2.09 mmol) in MeOH (16 ml) was treated dropwise with a solution of 4 M HCl in 1,4-dioxane (1.05 ml; 4.20 mmol). The resulting yellow mixture was further stirred at 0° C., under nitrogen, for 10 min., and then at rt for 1 h. The reaction mixture was then concentrated to dryness under reduced pressure and the yellow oily residue was further dried under HV to give the chlorhydrate salt of methyl 5-amino-5-(3,5-dimethoxypyridin-4-yl)pentanoate as a beige solid. LC-MS (conditions B): tR=0.43 min.; [M+H]+: 269.02 g/mol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:10][C@@H:9]1/[CH:21]=[CH:22]/[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[C].[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][Si:14]([C:17]([CH3:18])([CH3:19])[CH3:20])([CH3:15])[CH3:16])[CH2:10][C@H:9]1[CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CCOC(=O)/C=C/[C@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Yield: 77.8 %

Procedure:
To a solution of (2R,4R)-N-tert-butoxycarbonyl-4-tert-butyldimethylsiloxy-2-[(E)-2-ethoxycarbonylvinyl]-pyrrolidine (20 g, 50 mmol) in ethanol (500 ml) was added 10% palladium-carbon (5 g), and the mixture was stirred under atmospheric pressure in a hydrogen atmosphere at room temperature for 2 h. Further, 10% palladium-carbon (2 g) was added thereto, and the mixture was stirred under atmospheric pressure in a hydrogen atmosphere at room temperature for 1.5 h. The catalyst was filtered off, and the solvent was removed in vacuo. The residue was subjected to silica gel column chromatography (Wakogel™ C-300, heptane-ethyl acetate) to give (2R,4R)-N-tert-butoxycarbonyl-4-tert-butyldimethylsiloxy-2-(2-ethoxycarbonylethyl)pyrrolidine (15.62 g, yield: 78%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][C:13]1[N:18]=[CH:17][C:16]([CH:19]([N:22]2[CH2:26][C:25]([F:28])([F:27])[C:24]([F:30])([F:29])[CH2:23]2)[CH2:20][NH2:21])=[CH:15][N:14]=1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:21][CH2:20][CH:19]([C:16]1[CH:17]=[N:18][C:13]([CH3:12])=[N:14][CH:15]=1)[N:22]1[CH2:23][C:24]([F:29])([F:30])[C:25]([F:27])([F:28])[CH2:26]1)=[O:6]
Reactant: Cc1ncc(C(CN)N2CC(F)(F)C(F)(F)C2)cn1
Reactant: O=C(O)c1cccc(Cl)c1Cl
Product: Cc1ncc(C(CNC(=O)c2cccc(Cl)c2Cl)N2CC(F)(F)C(F)(F)C2)cn1

Procedure:
From 2,3-dichlorobenzoic acid and 2-(2-methylpyrimidin-5-yl)-2-(3,3,4,4-tetrafluoropyrrolidin-1-yl)ethanamine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5](P(OCC)(OCC)=O)[F:6])[CH3:2].[H-].[Na+].O=[C:19]1[CH:26]2[CH2:27][C:22]3([O:29][C:30](=[O:36])[CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:23][CH:24]([CH2:28][CH:20]1[CH2:21]3)[CH2:25]2>C1COCC1>[F:6][C:5](=[C:25]1[CH:26]2[CH2:27][C:22]3([O:29][C:30](=[O:36])[CH2:31][C:32]([CH3:34])([CH3:33])[CH3:35])[CH2:21][CH:20]([CH2:28][CH:24]1[CH2:23]3)[CH2:19]2)[C:4]([O:3][CH2:1][CH3:2])=[O:15]
Reactant: CC(C)(C)CC(=O)OC12CC3CC(C1)C(=O)C(C3)C2
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(F)=C1C2CC3CC1CC(OC(=O)CC(C)(C)C)(C3)C2

Procedure:
1.48 ml of (diethoxy-phosphoryl)-fluoro-acetic acid ethyl ester are added dropwise to a suspension of 317 mg of NaH (55% in mineral oil) in 30 ml of THF at 0°. The mixture obtained is stirred, 1.37 g of 3,3-dimethyl-butyric acid 4-oxo-adamantan-1-yl ester in 10 ml of THF are added slowly and the mixture obtained is stirred at RT overnight. The mixture obtained is diluted with EtAc and the diluted mixture obtained is washed with 1M aqueous NaH2PO4 and saturated aqueous NaHCO3 solution. The organic layer obtained is dried, solvent is evaporated and the evaporation residue obtained is subjected to chromatography on silica gel. 3,3-Dimethyl-butyric acid 4-(fluoro-ethoxycarbonyl-methylene)-adamantan-1-yl ester is obtained in the form of an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9](=[O:15])[NH:8][CH2:7][CH2:6]2.I[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:22]=1[CH3:23].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9](=[O:15])[N:8]([C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:22]=1[CH3:23])[CH2:7][CH2:6]2
Reactant: COc1cc2c(cc1OC)C(=O)NCC2
Reactant: Cc1ccncc1I
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1cc2c(cc1OC)C(=O)N(c1cnccc1C)CC2
Yield: 24.3 %

Procedure:
Using analogous reaction conditions as described in Example 1, 6,7-dimethoxy-3,4-dihydro-2H-isoquinolin-1-one (I-40d: 100 mg, 0.483 mmol) was reacted with 3-iodo-4-methyl-pyridine (105 mg, 0.483 mmol), 1,4-dioxane (10 mL), copper iodide (9.2 mg, 0.0483 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (21.5 mg, 0.144 mmol) and potassium phosphate (255 mg, 1.207 mmol) to afford the crude product. Purification by column chromatography on silica gel (40% ethylacetate in hexane) afforded 35 mg of the product (24% yield).