Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[C:5]([C:7]1[CH:8]=[CH:9][C:10]([OH:17])=[C:11]([CH:16]=1)[C:12](OC)=[O:13])#[N:6]>CS(C)=O.O>[CH:1]1([NH:4][C:12](=[O:13])[C:11]2[CH:16]=[C:7]([C:5]#[N:6])[CH:8]=[CH:9][C:10]=2[OH:17])[CH2:3][CH2:2]1
Reactant: NC1CC1
Reactant: COC(=O)c1cc(C#N)ccc1O
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1ccc(O)c(C(=O)NC2CC2)c1
Temperature: 80 °C

Procedure:
Cyclopropyl amine (14.3 g) and Na (100 mg) were added to a solution of methyl 5-cyano-2-hydroxybenzoate (10.0 g; from step (b) above) in DMSO (40 mL). The reaction mixture was heated at 80° C. in a sealed steel vessel overnight, diluted with H2O, acidified and extracted with EtOAc giving the sub-title compound (11.0 g), after concentration of the organic layer.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:22])[NH:4][N:5]=[C:6]([O:9][CH2:10][CH2:11][S:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)[C:7]=1Br.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH2:33][NH2:34])[CH:28]=[CH:29][C:30]=1[O:31][CH3:32]>O.O1CCOCC1>[Br:1][C:2]1[C:3](=[O:22])[NH:4][N:5]=[C:6]([O:9][CH2:10][CH2:11][S:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)[C:7]=1[NH:34][CH2:33][C:27]1[CH:28]=[CH:29][C:30]([O:31][CH3:32])=[C:25]([O:24][CH3:23])[CH:26]=1
Reactant: COc1ccc(CN)cc1OC
Reactant: O=c1[nH]nc(OCCSc2ccc([N+](=O)[O-])cc2)c(Br)c1Br
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(CNc2c(OCCSc3ccc([N+](=O)[O-])cc3)n[nH]c(=O)c2Br)cc1OC
Temperature: 25 °C
Yield: 61.6 %

Procedure:
1.5 g of 4,5-dibromo-6-[2-(4-nitrophenylthio)ethyloxy]-3(2H)-pyridazinone and 1.32 g of 3,4-dimethoxyphenylmethyl amine were disolved in water-dioxane (1:1) and refluxed for 7 hr. The reaction mixture was cooled to room temperature. The resulting crystals was collected by filtration and recrystallized from dioxane to give 1.1 g of the objective compound. Yield, 60%, Melting point, 170°-171° C.
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:37]=[CH:36][CH:35]=[CH:34][C:8]=2[C:9]=1[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[C:19]([NH2:33])[CH:18]=2)=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH3:4].C(N(C(C)C)CC)(C)C.Cl[C:48](=[O:54])[C:49]([O:51][CH2:52][CH3:53])=[O:50]>ClCCl.O>[CH2:52]([O:51][C:49](=[O:50])[C:48]([NH:33][C:19]1[CH:18]=[C:17]([C:14]2[CH:13]=[CH:12][C:11]([CH2:10][C:9]3[C:8]4[CH:34]=[CH:35][CH:36]=[CH:37][C:7]=4[O:6][C:5]=3[CH2:1][CH2:2][CH2:3][CH3:4])=[CH:16][CH:15]=2)[CH:22]=[CH:21][C:20]=1[O:23][CH2:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:54])[CH3:53]
Reactant: CCCCc1oc2ccccc2c1Cc1ccc(-c2ccc(OCCCc3ccccc3)c(N)c2)cc1
Reactant: CCOC(=O)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCCCc1oc2ccccc2c1Cc1ccc(-c2ccc(OCCCc3ccccc3)c(NC(=O)C(=O)OCC)c2)cc1
Reaction time: 2 h
Yield: 77.1 %

Procedure:
A solution of 4′-(2-butyl-benzofuran-3-ylmethyl)-4-(3-phenyl-propoxy)-biphenyl-3-ylamine (129 mg, 0.264 mmol) and diisopropylethylamine (0.115 mL, 2.5 equiv., 0.66 mmol) in dichloromethane (5 mL) was treated with a solution of ethyl chlorooxoacetate (44 mg, 1.2 equiv., 0.317 mmol) in dichloromethane (1 mL). After stirring for 2 h, the solution was diluted with water and extracted with dichloromethane (2×15 mL). The combined organic layers were washed with water, sat'd aq NaCl, dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification by prep thin layer chromatography (25% ethyl acetate in heptane) afforded N-[4′-(2-butyl-benzofuran-3-ylmethyl)-4-(3-phenyl-propoxy)-biphenyl-3-yl]-oxalamic acid ethyl ester (120 mg, 77%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:24])=[C:4]([N+:21]([O-])=O)[CH:5]=[C:6]([CH3:20])[C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([Cl:19])=[CH:11][CH:10]=1.[H][H]>C1(C)C=CC=CC=1.[Pt]>[Cl:1][C:2]1[C:3]([CH3:24])=[C:4]([CH:5]=[C:6]([CH3:20])[C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([Cl:19])=[CH:11][CH:10]=1)[NH2:21]
Reactant: [H][H]
Reactant: Cc1cc([N+](=O)[O-])c(C)c(Cl)c1Oc1ccc(Cl)c2ccccc12
Agent: [Pt]
Solvent: Cc1ccccc1
Product: Cc1cc(N)c(C)c(Cl)c1Oc1ccc(Cl)c2ccccc12
Yield: 91.6 %

Procedure:
Into a solution containing 13.8 grams (38.1 mmol) of 3-chloro-4-(4-chloro-1-naphthoxy)-2.5-dimethyl-1-nitrobenzene prepared in Part A in 400 milliliters of toluene was added 2.0 grams of a 5% platinum on carbon catalyst. The resulting mixture was placed in a one liter rocking Parr hydrogenation vessel. Hydrogen was introduced into the vessel to a pressure of 120 psi. The hydrogen pressure was maintained between 100-120 psi until hydrogen uptake ceased. The contents of the reactor vessel were then removed and filtered. Removal of the solvents from the filtrate afforded 11.6 grams of 3-chloro-4-(4-chloro-1-naphthoxy)-2.5-dimethylaniline as a white solid having a melting point of 118° C.-125° C.
Reaction SMILES: C(O)(C(F)(F)F)=O.[Cl:8][C:9]1[C:14]([O:15][CH2:16][C@@H:17]2[CH2:22][O:21][CH2:20][CH2:19][N:18]2CC2C=CC(OC)=CC=2OC)=[CH:13][C:12]([C:34]#[N:35])=[CH:11][C:10]=1[NH:36][C:37]1[N:42]=[C:41]([N:43]([CH:53]2[CH2:55][CH2:54]2)CC2C=CC(OC)=CC=2)[C:40]2=[N:56][CH:57]=[C:58]([C:59]#[N:60])[N:39]2[N:38]=1.C1(OC)C=CC=CC=1>ClC(Cl)C>[Cl:8][C:9]1[C:14]([O:15][CH2:16][C@@H:17]2[CH2:22][O:21][CH2:20][CH2:19][NH:18]2)=[CH:13][C:12]([C:34]#[N:35])=[CH:11][C:10]=1[NH:36][C:37]1[N:42]=[C:41]([NH:43][CH:53]2[CH2:54][CH2:55]2)[C:40]2=[N:56][CH:57]=[C:58]([C:59]#[N:60])[N:39]2[N:38]=1
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(OC[C@@H]4COCCN4Cc4ccc(OC)cc4OC)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Solvent: COc1ccccc1
Solvent: CC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c(Cl)c(OC[C@@H]2COCCN2)c1
Temperature: 60 °C
Yield: 68.9 %

Procedure:
50% TFA in dichloroethane (1 ml) was added to a solution of (S)-2-((2-chloro-5-cyano-3-((4-(2,4-dimethoxybenzyl)morpholin-3-yl)methoxy)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (80 mg, 0.109 mmol) and anisole (0.095 ml, 0.869 mmol) in a 1-dram vial and the reaction mixture was heated at 60° C. for 4 hours. The reaction mixture was concentrated and residue was dried under vacuum overnight. The crude was dissolved in acetonitrile (2 ml) and neutralized with 2N ammonia in methanol (2 ml); white precipitate formed and was collected by filtration. This material was further purified by flash chromatography on silica gel using an automated ISCO system (24 g gold column, eluting with 1-6% 2 N ammonia in methanol/dichloromethane). (S)-2-((2-chloro-5-cyano-3-(morpholin-3-ylmethoxy)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (35 mg) was obtained as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.Cl[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][N:12]2[CH:13]=[C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]3)[CH:10]=[N:11]2)=[CH:18][CH:19]=1
Reactant: COc1ccc(CCl)cc1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(Cn2cc(B3OC(C)(C)C(C)(C)O3)cn2)cc1
Temperature: 80 °C
Yield: 93.8 %

Procedure:
According to Scheme 2 Step 1: A suspension of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (25.8 mmol, 5.00 g), 1-(chloromethyl)-4-methoxybenzene (25.8 mmol, 3.49 mL) and K2CO3 (25.8 mmol, 3.56 g) in acetonitrile (40 mL) was heated at 80° C. for 5 hours. After filtration over celite, the filtrate was evaporated and the resulting crude product was purified by flash chromatography over silica gel using EtOAc/cyclohexane (90:10 to 70:30) as eluent to afford 1-(4-methoxybenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (24.2 mmol, 7.61 g, 94%) as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([S:8][CH2:9][CH3:10])[CH:5]=[CH:4][C:3]=1[NH:11][C:12]([NH:14][C:15]([O:17][CH3:18])=[O:16])=[S:13].Cl.[CH3:20][N:21]([CH3:26])[CH2:22][C:23](Cl)=[O:24]>CN(C)C=O.C(OCC)C>[CH2:9]([S:8][C:6]1[CH:5]=[CH:4][C:3]([NH:11][C:12]([NH:14][C:15]([O:17][CH3:18])=[O:16])=[S:13])=[C:2]([NH:1][C:23](=[O:24])[CH2:22][N:21]([CH3:26])[CH3:20])[CH:7]=1)[CH3:10]
Reactant: CCSc1ccc(NC(=S)NC(=O)OC)c(N)c1
Reactant: CN(C)CC(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCSc1ccc(NC(=S)NC(=O)OC)c(NC(=O)CN(C)C)c1
Reaction time: 0.33 h
Yield: 78.4 %

Procedure:
A stirred solution of 2-amino-4-ethylthio-1-(3-methoxycarbonyl-2-thioureido)benzene (8.35 g.) in dry dimethylformamide (60 ml.) was treated at room temperature with N,N-dimethylglycyl chloride hydrochloride (5.53 g.). The mixture was heated to 40°-50° C. for 45 minutes, then cooled, and diluted with diethyl ether (900 ml.). An oil precipitated which crystallised on standing. This solid was filtered off, washed with diethyl ether (100 ml.), and suspended in a mixture of chloroform (100 ml.) and water (100 ml.). Sodium carbonate (3.5 g.) was added and the mixture was stirred for 20 minutes. The chloroform layer was separated and the aqueous layer was extracted twice with chloroform (2× 50 ml.). The organic layers were combined, dried over magnesium sulphate and evaporated to dryness. The residual solid was recrystallised from isopropanol to give 4-ethylthio-1-(3-methoxycarbonyl-2-thioureido)-2-(2-dimethylaminoacetamido)benzene (8.5 g.), m.p. 142° C. (with decomposition).
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH:8]2[CH:9]=[CH:10][CH2:11][CH:7]2[C:6]([CH2:12][O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][O:4]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:41](=O)(O)[O-:42].[Na+].CCCCCC.C(OC(=O)C)C>O1CCCC1>[OH:42][CH2:41][C:9]1[C@H:8]2[C@H:3]([O:2][CH3:1])[O:4][CH:5]=[C:6]([CH2:12][O:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C@H:7]2[CH2:11][CH:10]=1
Reactant: COc1ccc(COCC2=COC(OC)C3C=CCC23)cc1
Reactant: O=C([O-])O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc(COCC2=CO[C@@H](OC)[C@@H]3C(CO)=CC[C@H]23)cc1
Reaction time: 2 h
Yield: 70 %

Procedure:
1.578 g (3.53 mmol) of (1R,4aS,7aS)-7-t-butyldimethylsilyloxymethyl)-1-methoxy-4-(p-methoxybenzyloxymethyl)-1,4a,5,7a-tetrahydrocyclopenta[c]pyran was dissolved in 13 mg of tetrahydrofuran and then 3.8 ml (3.89 mmol) of tetrabutylammoniumfluoride (1M in THF) was added thereto. After stirring for 2 hours, the reaction was stopped by adding saturated aqueous sodium bicarbonate solution. The reaction solution was extracted with diethylether and saturated saline solution, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was subjected to silica gel column chromatography (eluent: n-hexane/ethylacetate=3/1, v/v) to obtain 0.821 g (Yield 70%) of (1R,4aS,7aS)-7-hydroxymethyl-1-methoxy-4-(p-methoxybenzyloxymethyl)-1,4a,5,7a-tetrahydrocyclopenta[c]pyran as a colorless oil.
Reaction SMILES: Cl.[C:2]1([CH2:8][S:9][C@@H:10]2[CH2:14][NH:13][C@H:12]([C:15]([OH:17])=[O:16])[CH2:11]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:20])=O.[CH3:22]O>>[ClH:20].[C:2]1([CH2:8][S:9][C@@H:10]2[CH2:14][NH:13][C@H:12]([C:15]([O:17][CH3:22])=[O:16])[CH2:11]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1C[C@H](SCc2ccccc2)CN1
Reactant: O=S(Cl)Cl
Reactant: CO
Agent: Cl
Product: COC(=O)[C@@H]1C[C@H](SCc2ccccc2)CN1

Procedure:
A solution of cis-4-[(phenylmethyl) thio]-L-proline, hydrochloride in methanol is treated with thionyl chloride according to the procedure of Example 95(e) to yield cis-4-[(phenylmethyl) thio]-L-proline, methyl ester, hydrochloride.
Reaction SMILES: [CH2:1]([C:3]1[S:28][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[NH:9][C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].Br[CH2:30][C:31]([C:33]1[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[C:35]([O:41][CH3:42])[CH:34]=1)=[O:32].CN(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[CH3:42][O:41][C:35]1[CH:34]=[C:33]([C:31](=[O:32])[CH2:30][N:9]2[C:10](=[O:11])[C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[S:28][C:6]=3[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8]2=[O:12])[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=1
Reactant: CCc1cc2c(=O)[nH]c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Reactant: COc1cc(OC)cc(C(=O)CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1cc2c(=O)n(CC(=O)c3cc(OC)cc(OC)c3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.2 %

Procedure:
To a mixture of 4′-[(6-ethyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)methyl]biphenyl-2-carbonitrile (1.5 g), 2-bromo-1-(3,5-dimethoxyphenyl)ethanone (1 g) and N,N-dimethylformamide (20 mL) was added 60% sodium hydride (0.19 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% potassium hydrogensulfate and then saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as colorless crystals (1.14 g, 52%).
Reaction SMILES: [F:1][C:2]([F:22])([C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[CH:15][C:14]([O:20][CH3:21])=[CH:13]2)[C:3]([O:5]C(C)(C)C)=[O:4].FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(Cl)Cl>[F:22][C:2]([F:1])([C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[CH:15][C:14]([O:20][CH3:21])=[CH:13]2)[C:3]([OH:5])=[O:4]
Reactant: COc1cnc2ccc(C(F)(F)C(=O)OC(C)(C)C)cc2c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cnc2ccc(C(F)(F)C(=O)O)cc2c1
Temperature: 25 °C
Reaction time: 40 h
Yield: 101.2 %

Procedure:
A 200 mL round bottom flask was charged with tert-butyl 2,2-difluoro-2-(3-methoxyquinolin-6-yl)acetate (5.06 g, 16 mmol) then CH2Cl2, then trifluoroacetic acid (16 ml, 213 mmol) followed by triethylsilane (6.5 ml, 41 mmol). The solution was maintained at rt for 24 h until LCMS showed disappearance of starting material. The solution was concentrated and was subjected to high vacuum for 40 h to give 4.1 g (99% yield) of 2,2-difluoro-2-(3-methoxyquinolin-6-yl)acetic acid as a brown solid. The material was of sufficient purity for use in subsequent steps.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C:16]1[C:17]([C:21]#[N:22])=[CH:18][NH:19][CH:20]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Ni].C(O)(=O)C>[Cl:15][C:13]1[CH:12]=[CH:11][C:10]2[C:16]3[C:17](=[CH:18][NH:19][CH:20]=3)[CH2:21][N:22]=[C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:9]=2[CH:14]=1
Reactant: N#Cc1c[nH]cc1-c1ccc(Cl)cc1C(=O)c1ccccc1
Agent: [Ni]
Solvent: CC(=O)O
Product: Clc1ccc2c(c1)C(c1ccccc1)=NCc1c[nH]cc1-2
Reaction time: 4 h

Procedure:
A mixture of 4.0 g (13 mmol) of 4-[2-benzoyl-4-chlorophenyl]-1H-pyrrole-3-carbonitrile, 4 g of Raney nickel, and 300 ml of acetic acid were hydrogenated on a Parr apparatus for 4 hours. The Raney nickel was removed by filtration, and the filtrate was diluted with 400 ml of ice water. The acetic acid was neutralized with sodium bicarbonate, and the resulting solution extracted with methyene chloride. The methylene chloride solution was washed with water and dried over sodium sulfate. Concentration of the methylene chloride solution gave a yellow solid. Recrystallization from methylene chloride/ether gave end product as white solid, mp 203°-206° C.
Reaction SMILES: C([O:14][C:15]([C:17]1([O:20]/[N:21]=[C:22](/[C:56]2[N:57]=[C:58]([NH:61]C(OC(C)(C)C)=O)[S:59][CH:60]=2)\[C:23]([NH:25][C@@H:26]2[C:29](=[O:30])[N:28]([S:31]([OH:34])(=[O:33])=[O:32])[C@@H:27]2[CH2:35][N:36]2[N:40]=[C:39]([CH2:41][N:42]3[CH2:47][CH2:46][CH:45]([NH:48]C(OC(C)(C)C)=O)[CH2:44][CH2:43]3)[CH:38]=[N:37]2)=[O:24])[CH2:19][CH2:18]1)=[O:16])(C1C=CC=CC=1)C1C=CC=CC=1.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:48][CH:45]1[CH2:44][CH2:43][N:42]([CH2:41][C:39]2[CH:38]=[N:37][N:36]([CH2:35][C@@H:27]3[C@H:26]([NH:25][C:23](=[O:24])/[C:22](=[N:21]\[O:20][C:17]4([C:15]([OH:16])=[O:14])[CH2:18][CH2:19]4)/[C:56]4[N:57]=[C:58]([NH2:61])[S:59][CH:60]=4)[C:29](=[O:30])[N:28]3[S:31]([OH:34])(=[O:32])=[O:33])[N:40]=2)[CH2:47][CH2:46]1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)N[C@@H]2C(=O)N(S(=O)(=O)O)[C@@H]2Cn2ncc(CN3CCC(NC(=O)OC(C)(C)C)CC3)n2)cs1
Solvent: COc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc(/C(=N/OC2(C(=O)O)CC2)C(=O)N[C@@H]2C(=O)N(S(=O)(=O)O)[C@@H]2Cn2ncc(CN3CCC(N)CC3)n2)cs1
Yield: 7.5 %

Procedure:
Followed the general procedure for the acid mediated deprotection using (2R,3S)-3-((Z)-2-((1-((benzhydryloxy)carbonyl)cyclopropoxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2-((4-((4-((tert-butoxycarbonyl)amino)piperidin-1-yl)methyl)-2H-1,2,3-triazol-2-yl)methyl)-4-oxoazetidine-1-sulfonic acid (58 mg, 59 μmol), DCM (590 μL), anisole (13 μL, 0.12 mmol) and TFA (273 μL, 3.54 mmol). The crude residue was purified by reverse phase prep HPLC (Xselect CSH, 30×100 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 60 mL/min), affording the title compound (2.7 mg, 7.3%) as an off-white powder. LCMS: Rt=0.50 min, m/z=613.4 (M+1) Method 2m_acidic_polar; 1H NMR (400 MHz, D2O) δ 7.93 (s, 1H), 7.12 (s, 1H), 5.59 (d, J=5.5 Hz, 1H), 5.07-5.00 (m, 1H), 4.99-4.96 (m, 1H), 4.93-4.90 (m, 1H), 4.39 (s, 2H), 3.75-3.62 (m, 2H), 3.63-3.51 (m, 1H), 3.28-3.08 (m, 2H), 2.33 (d, J=13.7 Hz, 2H), 2.04-1.89 (m, 2H), 1.38-1.11 (m, 4H).
Reaction SMILES: Cl[CH2:2][CH:3]=O.[CH3:5][O:6][C:7](=[O:15])[C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[N:10][CH:9]=1>C(O)C>[CH3:5][O:6][C:7]([C:8]1[CH:13]=[CH:12][C:11]2[N:10]([CH:2]=[CH:3][N:14]=2)[CH:9]=1)=[O:15]
Reactant: O=CCCl
Reactant: COC(=O)c1ccc(N)nc1
Solvent: CCO
Product: COC(=O)c1ccc2nccn2c1

Procedure:
To a solution of 50% aq. chloroacetaldehyde (1.1 eq, 36 mmol, 4.6 ml) in ethanol (120 ml) is added 6-amino-nicotinic acid methyl ester (1 eq, 33 mmol, 5 g) at room temperature. The reaction mixture is heated at reflux for 18 hours. The solvent is removed in vacuo and the crude product is dissolved in water (400 ml). The aqueous solution is treated with sodium bicarbonate to pH=8 and extracted with DCM (3×250 ml). The organic layer is dried (MgSO4) and evaporated to give the title compound as a beige solid.
Reaction SMILES: Cl.[F:2][C:3]([F:30])([F:29])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1.C(Cl)Cl.[OH:34][CH:35]([CH2:40][CH3:41])[C:36]([O:38][CH3:39])=[O:37].CN(C)C>CCOCC>[F:2][C:3]([F:30])([F:29])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([O:34][CH:35]([C:36]([O:38][CH3:39])=[O:37])[CH2:40][CH3:41])=[O:25])=[CH:22][CH:21]=1
Reactant: CCC(O)C(=O)OC
Reactant: O=C(Cl)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1
Agent: CN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CCC(OC(=O)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 10.0 g. 4-[15-(trifluoromethyl)-pentadecylamino]benzoyl chloride hydrochloride in 200 ml. methylene chloride is added dropwise a solution of 3 g. methyl α-hydroxybutyrate and 5 g. trimethylamine in 100 ml. ether. After 17 hours stirring at room temperature, the precipitate is collected and washed with several portions of ether. The ether solution is washed with water, dried and evaporated to yield the product as a white solid.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[C:4]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:5][CH:6]=[CH:7][CH:8]=1.[CH3:17][CH:18]1[CH2:23][CH2:22][CH:21]([CH2:24][C:25](O)=[O:26])[CH2:20][CH2:19]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[CH3:17][CH:18]1[CH2:23][CH2:22][CH:21]([CH2:24][C:25]([N:12]2[CH2:11][CH2:10][N:9]([C:4]3[C:3]([C:2]([F:1])([F:15])[F:16])=[CH:8][CH:7]=[CH:6][N:5]=3)[CH2:14][CH2:13]2)=[O:26])[CH2:20][CH2:19]1
Reactant: FC(F)(F)c1cccnc1N1CCNCC1
Reactant: CC1CCC(CC(=O)O)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC1CCC(CC(=O)N2CCN(c3ncccc3C(F)(F)F)CC2)CC1
Yield: 43 %

Procedure:
Coupling of 1-(3-(trifluoromethyl)pyridin-2-yl)piperazine (271 mg, 1.17 mmol) with 2-(4-methylcyclohexyl)acetic acid (100 mg, 0.64 mmol) was carried out according to a similar procedure described for example 19A using N,N-dimethylformamide (1 mL) as solvent and benzotriazole-1 yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (700 mg, 1.56 mmol) as coupling agent. 1-[(4-methylcyclohexyl)acetyl]-4-[3-(trifluoromethyl)pyridin-2-yl]piperazine was obtained in 43% yield (102 mg) as colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[CH2:11][CH2:12][OH:13].CCN(CC)CC.[Cl:21][C:22](OC(Cl)(Cl)Cl)=[O:23]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[CH2:11][CH2:12][O:13][C:22]([Cl:21])=[O:23]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1cccc(Br)c1CCO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Cl)OCCc1c(Br)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 99.8 %

Procedure:
A solution of 2-(2-bromo-6-nitrophenyl)ethanol (500 mg, 2.03 mmol) and Et3N (206 mg, 2.03 mmol, dist. over KOH) in THF (5 ml, dist. over CaH2) was dropped into a solution, cooled to 0° C., of trichloromethyl chloroformate (442 mg, 2.23 mmol) in THF (5 ml, see above) for 10 min. It was stirred for 5 min while being cooled in an ice bath and for 1 h 45 min at room temperature. The mixture was filtered over Celite. Rewashing the filter cake with THF and removing the solvent and the excess reagent from the pooled filtrates by distillation at 30° C. in a high vacuum yielded 2-(2-bromo-6-nitrophenyl)ethoxycarbonyl chloride (625 mg, 99.8%) as a light brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][NH:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[C:27]([O:32][CH3:33])[CH:26]=2)[CH:6]=[CH:5][C:4]=1[OH:34].C(OC([N:42]1[CH2:47][CH2:46][C:45]2[N:48]([CH2:57][CH2:58][CH2:59][NH:60]C(OCC3C=CC=CC=3)=O)[C:49]([C:51]3[CH:56]=[CH:55][N:54]=[CH:53][CH:52]=3)=[CH:50][C:44]=2[C:43]1=[O:71])=O)(C)(C)C.CCO>C1CCCCC=1.[Pd]>[CH3:33][O:32][C:27]1[CH:26]=[C:25]([CH2:24][NH:23][CH2:22][CH2:21][CH2:20][NH:19][CH2:18][CH2:17][CH2:16][CH2:15][NH:14][CH2:13][CH2:12][CH2:11][NH:10][CH2:9][C:7]2[CH:6]=[CH:5][C:4]([OH:34])=[C:3]([O:2][CH3:1])[CH:8]=2)[CH:30]=[CH:29][C:28]=1[OH:31].[NH2:60][CH2:59][CH2:58][CH2:57][N:48]1[C:45]2[CH2:46][CH2:47][NH:42][C:43](=[O:71])[C:44]=2[CH:50]=[C:49]1[C:51]1[CH:52]=[CH:53][N:54]=[CH:55][CH:56]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(cc(-c3ccncc3)n2CCCNC(=O)OCc2ccccc2)C1=O
Agent: [Pd]
Agent: COc1cc(CNCCCNCCCCNCCCNCc2ccc(O)c(OC)c2)ccc1O
Solvent: C1=CCCCC1
Solvent: CCO
Product: NCCCn1c(-c2ccncc2)cc2c1CCNC2=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
DL-6-(3-benzyloxycarbonylamino-propyl)-4-oxo-2-pyridin-4-yl-1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-5-carboxylic acid tert-butyl ester (0.4 g) was dissolved in cyclohexene (10 mL) and absolute EtOH (20 mL), 10% Pd on carbon (0.2 g) was added and the mixture was refluxed for 1.5 hours. After filtration through celite and solvent evaporation under reduced pressure, the compound was treated with 4N HCl in dioxane (20 mL) for 2.5 hours at room temperature. The solution was concentrated and the residue treated with ethyl acetate. The precipitate was filtered, washed with little ethyl acetate and dried. The residue was dissolved in 4M HCl in dioxane and stirred for 4 hours at room temperature. The solution was concentrated and the title compound, as the dihydrochloride, was recovered as a yellowish solid (0.29 g, quantitative).