Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Si](C1C=CC=CC=1)(C1C=CC=CC=1)[O:6][CH:7]1[CH2:35][CH2:34][C:10]2([C:14](=[O:15])[N:13]([C:16]3[C:17]([CH3:33])=[N:18][C:19]([N:22]4[CH2:26][CH2:25][C@@H:24]([N:27]5[CH2:31][CH2:30][CH2:29][C@@H:28]5[CH3:32])[CH2:23]4)=[CH:20][CH:21]=3)[CH2:12][CH2:11]2)[CH2:9][CH2:8]1)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[OH:6][CH:7]1[CH2:8][CH2:9][C:10]2([C:14](=[O:15])[N:13]([C:16]3[C:17]([CH3:33])=[N:18][C:19]([N:22]4[CH2:26][CH2:25][C@@H:24]([N:27]5[CH2:31][CH2:30][CH2:29][C@@H:28]5[CH3:32])[CH2:23]4)=[CH:20][CH:21]=3)[CH2:12][CH2:11]2)[CH2:34][CH2:35]1
Reactant: Cc1nc(N2CC[C@@H](N3CCC[C@@H]3C)C2)ccc1N1CCC2(CCC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)CC2)C1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(N2CC[C@@H](N3CCC[C@@H]3C)C2)ccc1N1CCC2(CCC(O)CC2)C1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 29.4 %

Procedure:
To a solution of 8-(tert-butyl-diphenyl-silanyloxy)-2-[2-methyl-6-((2S,3′R)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-3-yl]-2-aza-spiro[4.5]decan-1-one (89 mg, 0.14 mmol) in tetrahydrofuran (2 mL) was added 1 M solution of tetrabutylammoniumfluoride in tetrahydrofuran (0.15 mL, 0.15 mmol). The resulting mixture was stirred for 24 hours at ambient temperature and then added additional 1 M solution of tetrabutylammoniumfluoride in tetrahydrofuran (0.15 mL, 0.15 mmol). The resulting mixture was heated to 70° C. for 30 hours then allowed the mixture to cool to ambient temperature. Water (10 mL) was added to the reaction mixture, extracted with EtOAc (2×10 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated to afford a crude solid which was then purified by flash column chromatography (5% 7N NH3 in MeOH/CH2Cl2) to provide 17 mg (29% yield) of the title compound as a solid.
Reaction SMILES: [CH3:1][N:2]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[NH:18][C:17]([C:20]1[S:21][CH:22]([CH2:25][C:26](=[O:33])[N:27]3[CH2:32][CH2:31][S:30][CH2:29][CH2:28]3)[CH2:23][N:24]=1)=[CH:16]2)[S:3]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)(=[O:5])=[O:4].[OH:34]OS([O-])=O.[K+].S([O-])([O-])=O.[Na+].[Na+].[OH2:46]>O1CCCC1.C(O)C>[O:46]=[S:30]1(=[O:34])[CH2:29][CH2:28][N:27]([C:26](=[O:33])[CH2:25][CH:22]2[S:21][C:20]([C:17]3[NH:18][C:19]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[N:2]([CH3:1])[S:3]([C:6]3[S:7][CH:8]=[CH:9][CH:10]=3)(=[O:5])=[O:4])=[N:24][CH2:23]2)[CH2:32][CH2:31]1
Reactant: O
Reactant: O=S([O-])OO
Reactant: CN(c1cccc2cc(C3=NCC(CC(=O)N4CCSCC4)S3)[nH]c12)S(=O)(=O)c1cccs1
Agent: O=S([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CN(c1cccc2cc(C3=NCC(CC(=O)N4CCS(=O)(=O)CC4)S3)[nH]c12)S(=O)(=O)c1cccs1
Reaction time: 1 h
Yield: 44 %

Procedure:
To a solution of N-methyl-N-{2-[5-(2-oxo-2-thiomorpholinoethyl)-4,5-dihydro-1,3-thiazol-2-yl]-1H-indol-7-yl}thiophene-2-sulfonamide (560 mg) in tetrahydrofuran (15 mL), ethanol (5 mL) and water (5 mL) was added OXONE (registered trade mark, 986 mg) at room temperature, and the mixture was stirred for 1 hr. Sodium sulfite (3 g) was added to the reaction mixture, and the mixture was stirred for 10 min. Water was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography to give the title compound (242 mg, yield 44%) as white crystals from a fraction eluted with ethyl acetate. melting point 158° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.[C:12](=[O:15])([O-])[O-:13].[Na+].[Na+].[N+:18]([C:21]1[CH:22]=[C:23]([C:30](Cl)=[O:31])[CH:24]=[C:25]([CH:29]=1)[C:26](Cl)=[O:27])([O-:20])=[O:19].Cl>O.C(O)C.C(#N)C>[N+:18]([C:21]1[CH:22]=[C:23]([C:30]([NH:1][C:2]2[CH:10]=[C:6]([C:12]([OH:13])=[O:15])[C:5]([OH:11])=[CH:4][CH:3]=2)=[O:31])[CH:24]=[C:25]([C:26]([NH:1][C:2]2[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=2)=[O:27])[CH:29]=1)([O-:20])=[O:19]
Reactant: O=C([O-])[O-]
Reactant: O=C(Cl)c1cc(C(=O)Cl)cc([N+](=O)[O-])c1
Reactant: Nc1ccc(O)c(C(=O)O)c1
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CC#N
Product: O=C(Nc1ccc(O)c(C(=O)O)c1)c1cc(C(=O)Nc2ccc(O)c(C(=O)O)c2)cc([N+](=O)[O-])c1
Yield: 56.9 %

Procedure:
To a solution of 3.2 g of 5-aminosalicylic acid and 4.4 g of sodium carbonate in 60 ml of water (stirred vigourously at room temperature) is added dropwise a solution of 2.5 g of 5-nitroisophthaloyl chloride in a minimum amount of acetonitrile with formation of a gel. The gel is dissolved by acidification with dilute hydrochloric acid and a gray solid is formed. The material is filtered, washed once with dilute hydrochloric acid and several times with water resulting in a gray gum. The gum is crystallized by evaporation with ethanol to give a gray solid. The solid is boiled with ethanol, filtered and dried by conventional means to yield 2.76 g of the product of the example as a light brown powder.
Reaction SMILES: [O:1]1[CH2:5][CH2:4]CC1.C([O:8][C:9]([C:11]1[S:12][C:13]([NH:23][CH:24]([C:30]([O:32]CC)=[O:31])C(OCC)=O)=[C:14]([C:21]#[N:22])[C:15]=1[CH2:16][C:17]([O:19]C)=[O:18])=[O:10])C.[OH-:35].[Li+].[Cl-].[Sr+2:38].[Cl-]>O>[CH2:16]([C:17]([O-:19])=[O:18])[C:15]1[C:14]([C:21]#[N:22])=[C:13]([N:23]([CH2:24][C:30]([O-:32])=[O:31])[CH2:4][C:5]([O-:1])=[O:35])[S:12][C:11]=1[C:9]([O-:8])=[O:10].[OH2:1].[OH2:1].[OH2:1].[OH2:1].[OH2:1].[OH2:1].[OH2:1].[OH2:1].[Sr+2:38].[Sr+2:38]
Reactant: CCOC(=O)c1sc(NC(C(=O)OCC)C(=O)OCC)c(C#N)c1CC(=O)OC
Reactant: C1CCOC1
Reactant: [OH-]
Agent: [Cl-]
Agent: [Li+]
Agent: [Sr+2]
Solvent: O
Product: N#Cc1c(N(CC(=O)[O-])CC(=O)[O-])sc(C(=O)[O-])c1CC(=O)[O-]
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of tetrahydrofuran (375 ml), 5-(bis-ethoxycarbonylmethyl-amino)-4-cyano-3-methoxycarbonylmethyl-thiophene-2-carboxylic acid ethyl ester (250 g) and 1200 ml 10% aq. solution of lithium hydroxide was stirred at room temperature for about 4 to 6 hours in a round bottom flask. The reaction mass was filtered off to remove any insoluble material. The clear filtrate was further stirred with 2.2 moles of strontium chloride in 1.7 liters of water for 15 to 20 hours at room temperature. The precipitated solid, distrontium salt of 2-[N-N-di(carboxymethyl-)amino]-3-cyano-4-carboxymethylthiophene-5-carboxylic acid in the form of an octahydrate, was filtered off and washed with water to form a wet cake. The resulting wet cake was dried to yield 333 grams of strontium ranelate octahydrate having a purity greater than 99.5% as determined by HPLC.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:6][CH:5]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:29](Br)[CH:30]=[CH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.Cl>CN(C=O)C>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][N:13]([S:14]([CH3:17])(=[O:16])=[O:15])[CH2:29]/[CH:30]=[CH:31]/[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:6][CH:5]=1
Reactant: BrCC=Cc1ccccc1
Reactant: COC(=O)c1ccc(OCCNS(C)(=O)=O)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCCN(C/C=C/c2ccccc2)S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 78.1 %

Procedure:
To a solution of 4-(2-methanesulfonylamino-ethoxy)-benzoic acid methyl ester (62 mg, 0.23 mmol) in DMF (10 mL) at 0° C. was added sodium bis(trimethylsilyl)amide (1.0 M in THF, 0.24 mL, 0.24 mmol) dropwise. After 20 minutes, cinnamyl bromide (51 mg, 0.26 mmol) was added and the reaction was stirred at room temperature for 2 h. Aqueous 1N HCl was added and the product was extracted into EtOAc. The organic solution was washed with 1N HCl (3×) followed by brine. The organic solution was dried (Na2SO4), filtered, and concentrated. Radial chromatography (20% EtOAc in hexanes) provided trans-4-{2-[methanesulfonyl-(3-phenyl-allyl)-amino]-ethoxy}-benzoic acid methyl ester (70 mg). 1NMR (400 MHz, CDCl3) δ7.97 (d, 2H), 7.35-7.23 (m, 5H), 6.88 (d, 2H), 6.58 (d, 1H), 6.18 (m, 1H), 4.20 (t, 2H), 4.12 (d, 2H), 3.88 (s, 3H), 3.68 (t, 2H), 2.95 (s, 3H).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH2:9]1[CH2:13][O:12][CH2:11][CH2:10]1.[Se:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[C:19]1[Se:20][C:21]([C:24]2[Se:25]C=CC=2)=[CH:22][CH:23]=1.CN(C=O)C>C(OCC)(=O)C>[CH:11]([C:10]1[Se:25][C:24]([C:21]2[Se:20][C:19]([C:15]3[Se:14][CH:18]=[CH:17][CH:16]=3)=[CH:23][CH:22]=2)=[CH:13][CH:9]=1)=[O:12]
Reactant: c1c[se]c(-c2ccc(-c3ccc[se]3)[se]2)c1
Reactant: C1CCOC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=Cc1ccc(-c2ccc(-c3ccc[se]3)[se]2)[se]1
Temperature: -78 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
LDA (1.0 M solution in THF, 310 mL) was added to an anhydrous THF solution (4 mL) containing 2,2′:5′,2″-terselenophene (100 mg) under N2 at −78° C. The solution was stirred at −78° C. for 3 h, anhydrous DMF (1 mL) was added, stirred at −78° C. for 1 h, and slowly warmed to room temperature. The reaction solution was diluted with ethyl acetate (100 mL) and washed with H2O (4×100 mL). The organic layer was separated, dried over MgSO4, filtered, and the solvent was removed under vacuum. The residue was chromatographed over silica gel using CH2Cl2 to afford 2-formyl-5,2′:5′,2″-terselenophene in 75% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([CH:7]=[CH:8][C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[Br:17][CH2:18][CH2:19][CH:20]1[O:25][CH2:24][CH2:23][CH2:22][O:21]1>>[Br-:17].[O:21]1[CH2:22][CH2:23][CH2:24][O:25][CH:20]1[CH2:19][CH2:18][N+:12]1[CH:11]=[CH:10][C:9]([CH:8]=[CH:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:16][CH:15]=2)=[CH:14][CH:13]=1
Reactant: BrCCC1OCCCO1
Reactant: COc1ccc(C=Cc2ccncc2)cc1
Product: COc1ccc(C=Cc2cc[n+](CCC3OCCCO3)cc2)cc1
Product: [Br-]

Procedure:
By the procedure described in Ex. 8, 4-(4-methoxystyryl) pyridine and 2-(2-bromoetyl) 1,3-dioxane were reacted to obtain N-[2-(1,3-dioxane-2-yl) ethyl]-4-(4methoxystyryl) pyridinium bromide.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[C:16]2[C:11](=[CH:12][C:13]([Br:18])=[C:14]([OH:17])[CH:15]=2)[N:10]([CH:19]2[CH2:21][CH2:20]2)[C:9]=1[CH3:22])=[O:7])[CH3:4].[CH3:23]I>CN(C=O)C.O.CCOCC>[CH2:3]([O:5][C:6]([C:8]1[C:16]2[C:11](=[CH:12][C:13]([Br:18])=[C:14]([O:17][CH3:23])[CH:15]=2)[N:10]([CH:19]2[CH2:20][CH2:21]2)[C:9]=1[CH3:22])=[O:7])[CH3:4]
Reactant: CI
Reactant: CCOC(=O)c1c(C)n(C2CC2)c2cc(Br)c(O)cc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)n(C2CC2)c2cc(Br)c(OC)cc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 88.1 %

Procedure:
Sodium hydride (60% in mineral oil, 71 mg, 1.8 mmol) is added to a solution of 6-bromo-1-cyclopropyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid ethyl ester (200 mg, 0.590 mmol) in DMF (4.0 mL). The mixture is stirred for 20 minutes at room temperature. Methyl iodide (110 μL, 1.77 mmol) is added and the mixture is stirred for 1 h at room temperature. The mixture is diluted with water and ether. The layers are separated. The ether layer is washed with water and brine, dried over MgSO4, and concentrated under reduced pressure. The residue is triturated in ethyl acetate-hexane to give the title compound as an off-white solid (183 mg, 88%). ES/MS m/e 353.8 (M+1).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[CH:5][N:6]([C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=1.[Cl:27][C:28]1[C:33]([Cl:34])=[CH:32][CH:31]=[CH:30][C:29]=1[OH:35].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[Cl:27][C:28]1[C:33]([Cl:34])=[CH:32][CH:31]=[CH:30][C:29]=1[O:35][CH2:2][C:3]1[N:4]=[CH:5][N:6]([C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:7]=1
Reactant: Oc1cccc(Cl)c1Cl
Reactant: ClCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Clc1cccc(OCc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)c1Cl
Temperature: 80 °C
Yield: 66.5 %

Procedure:
To a stirred solution of 4-chloromethyl-1-trityl-1H-imidazole (400 mg; CAS 103057-10-9) at r.t. in DMF (5 ml) under an argon atmosphere were added 2,3-dichlorophenol (273 mg) and K2CO3 (385 mg). The reaction mixture was heated to 80° C. for 5 hours, then cooled to r.t., diluted with EtOAc and washed with 1 N NaOH. The aqueous phase was back extracted with EtOAc. The combined organics were washed with H2O and brine, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (silica gel; gradient: cyclohexane→cyclohexane/EtOAc 1:1) to give 4-(2,3-dichloro-phenoxymethyl)-1-trityl-1H-imidazole (360 mg) as white solid. MS (ISP): 243.3 ([Trt]+)
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([NH:6][C:7]2[CH2:8][S:9][CH2:10][C:11]=2[C:12]#[N:13])=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1.C1(Cl)C(=O)C(Cl)=C(Cl)C(=O)C=1Cl>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([NH:6][C:7]2[C:11]([C:12]#[N:13])=[CH:10][S:9][CH:8]=2)=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1
Reactant: N#CC1=C(Nc2ccc(Cl)cc2[N+](=O)[O-])CSC1
Agent: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Solvent: Cc1ccccc1C
Product: N#Cc1cscc1Nc1ccc(Cl)cc1[N+](=O)[O-]

Procedure:
3-(4-Chloro-2-nitroanilino)-2,5-dihydrothiophene-4-nitrile (14,09 g, 0.05 mol) dissolved in xylene (150 ml) was added to a solution of chloranil (12.3 g, 0.05 mol) in hot xylene (100 ml). The mixture was allowed to reflux for two hours. After cooling, the xylene was evaporated off under vacuum to leave a red-brown solid which was triturated with methanol to give a brick-red solid. The solid was recrystallised from hot methanol to give red crystals which were filtered off, washed with methanol and dried at 50° C. under vacuum. The dried product so obtained was the title compound, m.p. 214° C.
Reaction SMILES: [N+]([O-])(O)=O.[N+]([O-])(O)=O.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([NH:23][C:24]([NH2:26])=[NH:25])[CH:14]=[CH:15][C:16]=1[N:17]1[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]1.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([CH3:43])([CH3:42])[C:35](=O)[CH:36]=[CH:37]N(C)C)=[CH:30][CH:29]=1.C(N(CC)CC)C>CN1CCCC1=O>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([C:35]2[CH:36]=[CH:37][N:26]=[C:24]([NH:23][C:13]3[CH:14]=[CH:15][C:16]([N:17]4[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]4)=[C:11]([O:10][CH3:9])[CH:12]=3)[N:25]=2)([CH3:42])[CH3:43])=[CH:30][CH:29]=1
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Reactant: CN(C)C=CC(=O)C(C)(C)c1ccc(Cl)cc1
Solvent: O=[N+]([O-])O
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: COc1cc(Nc2nccc(C(C)(C)c3ccc(Cl)cc3)n2)ccc1-n1cnc(C)c1
Reaction time: 2 h

Procedure:
The title compound was prepared in analogous manner as described in example 4c) from N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]guanidine dinitrate and 4-(4-chloro-phenyl)-1-dimethylamino-4-methyl-pent-1-en-3-one, and triethylamine using 1-methyl-2-pyrrolidone as solvent. The reaction was performed in a microwave oven at 200° C. for 2 h. The title compound was isolated as a brown solid in 20% yield.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:10]([CH3:11])=[CH:9][S:8][C:7]=1[NH:12][C:13]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:14])=[O:5])C.O[Li].O>C(O)C.C1COCC1>[CH3:11][C:10]1[C:6]([C:4]([OH:5])=[O:3])=[C:7]([NH:12][C:13]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:14])[S:8][CH:9]=1
Reactant: CCCCCCCCOC(=O)Nc1scc(C)c1C(=O)OCC
Agent: [Li]O
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCCCCCOC(=O)Nc1scc(C)c1C(=O)O
Temperature: 25 °C
Reaction time: 120 h

Procedure:
(8.1) To a stirring solution of 4-methyl-2-octyloxycarbonylamino-thiophene-3-carboxylic acid ethyl ester (254 mg, 0.74 mmol) in ethanol (2 mL) and THF (2 mL) was added LiOH—H2O (31 mg, 0.74 mmol). The reaction was stirred at RT for 5 days, and then solvent was removed under reduced pressure to give a solid. The product was taken on without further purification: 1H NMR (CDCl3) δ 6.02 (s, 1H), 4.07 (t, 2H, J=6.6 Hz), 2.32 (s, 3H), 1.60-1.40 (m, 2H), 1.27 (bs, 10H), 0.86 (t, 3H, J=6.6 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:25])([C:16]([C:18]1[CH:23]=[CH:22][C:21](I)=[CH:20][CH:19]=1)=[CH2:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.[C:26](=[O:29])([O-])[O-].[K+].[K+].[Na+].[Na+].C(N(CC(O)=O)CC(O)=O)C[N:36](CC([O-])=O)CC([O-])=O>O.[Cu].C(N)=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:25])([C:16]([C:18]1[CH:23]=[CH:22][C:21]([NH:36][CH:26]=[O:29])=[CH:20][CH:19]=1)=[CH2:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: O=C([O-])CN(CCN(CC(=O)O)CC(=O)O)CC(=O)[O-]
Reactant: C=C(c1ccc(I)cc1)C(O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: O=C([O-])[O-]
Agent: [Cu]
Agent: [K+]
Agent: [Na+]
Solvent: NC=O
Solvent: O
Product: C=C(c1ccc(NC=O)cc1)C(O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 140 °C
Reaction time: 2 h
Yield: 213.6 %

Procedure:
An intimate mixture of 2-(2,4-difluorophenyl)-3-(4-iodophenyl)-1-(1,2,4-triazol-1-yl)-3-buten-2-ol (12 g, 26 mmol-see Preparation 20), formamide (18 ml, 0.25 mmol), copper (3.6 g, 57 mmol) and potassium carbonate (6.0 g, 43 mmol) was heated, with stirring, to 140° C. for 2 hours. The mixture was cooled to 100° C. and treated with a suspension of ethylenediaminetetracetic acid disodium salt (25 g, 6.7 mmol) in water (250 ml). After further cooling to room temperature, the mixture was extracted with dichloroniethane (2×200 ml). The combined organic extracts were dried (MgSO4) and evaporated under reduced pressure to give 2-(2,4-difluorophenyl)-3-(4-formamidophenyl)-1-(1,2,4-triazol-1-yl)but-3-en-2-ol (5.3 g, 55%), which was used crude in the next step.
Reaction SMILES: COC(C1N=C2N(CC(N3CC(C)CC(C)C3)=O)C=C(CSC)N2C(=O)C=1O)=O.[Cl:30][C:31]1[CH:32]=[C:33]([CH:38]=[CH:39][CH:40]=1)[C:34]([O:36]O)=[O:35]>ClCCl>[Cl:30][C:31]1[CH:32]=[C:33]([CH:38]=[CH:39][CH:40]=1)[C:34]([OH:36])=[O:35]
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: COC(=O)c1nc2n(CC(=O)N3CC(C)CC(C)C3)cc(CSC)n2c(=O)c1O
Solvent: ClCCl
Product: O=C(O)c1cccc(Cl)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 269.8 %

Procedure:
1-[2-(3,5-dimethyl-piperidin-1-yl)-2-oxo-ethyl]-6-hydroxy-3-methylsulfanylmethyl-5-oxo-1,5-dihydro-imidazo[1,2-a]pyrimidine-7-carboxylic acid methyl ester from example 54 (0.35 g, 0.83 mmol) was dissolved in dichloromethane (10 ml) and cooled to 0° C. M-Chloroperoxybenzoic acid (0.286 g, 2 equivalents) were added. The reaction mixture was stirred for 2 hours, then more MCPBA (150 mg) was added, and the stirring was continued for one hour. The reaction was quenched with a solution of Na2S2O3, the aqueous phase was extracted with dichloromethane, dried over MgSO4 and evaporated to dryness to give the product as mixture with m-chlorobenzoic acid (0.7 g, treated as 100% yield, contains ˜50% m-Cl-benzoic acid by NMR).
Reaction SMILES: [C:1](Cl)(=O)C(Cl)=O.C([O:10][C:11]1[C:19]([O:20][CH3:21])=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[C:13]([N+:22]([O-:24])=[O:23])[C:12]=1[O:25][CH3:26])(=O)C>CN(C=O)C.C1COCC1>[CH3:26][O:25][C:12]1[C:13]([N+:22]([O-:24])=[O:23])=[C:14]([CH:18]=[C:19]([O:20][CH3:21])[C:11]=1[OH:10])[C:15]([O:17][CH3:1])=[O:16]
Reactant: COc1cc(C(=O)O)c([N+](=O)[O-])c(OC)c1OC(C)=O
Reactant: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OC)c(O)c(OC)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.2 %

Procedure:
A catalytic amount of DMF (5 drops) was added to a solution of oxalyl chloride (6.3 g, 49.8 mmol) and o-nitrobenzoic acid 83 (12.4 g, 45.2 mmol) in anhydrous THF (100 mL) and the reaction mixture allowed to stir at room temperature for 16 h. The resulting acid chloride was quenched dropwise with anhydrous methanol (100 mL) at 0° C. The reaction mixture was treated with potassium carbonate and allowed to stir at room temperature for 3 h. Excess solvent was removed by rotary evaporation at reduced pressure and the residue dissolved in water. The aqueous solution was acidified to pH 8 and the resulting white precipitate was collected by filtration, washed with water (2×100 mL) and dried to afford the product as an off-white solid (10.6 g, 83%). H1 NMR (270 MHz, CDCl3) δ10.07 (br s, 1H), 7.26 (s, 1H), 3.97 (s, 3H), 3.91 (s, 3H), 3.85 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[CH:6][C:5]([C:15]([O:17][CH3:18])=[O:16])=[CH:4][C:3]=1[NH:19][CH2:20][C:21]([OH:24])([CH3:23])[CH3:22].C(N(CC)CC)C.Cl[C:33](Cl)([O:35]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl.C(=O)(O)[O-].[Na+]>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:7]2[C:2]3[NH:1][C:33](=[O:35])[N:19]([CH2:20][C:21]([OH:24])([CH3:22])[CH3:23])[C:3]=3[CH:4]=[C:5]([C:15]([O:17][CH3:18])=[O:16])[CH:6]=2)=[CH:9][CH:10]=1
Reactant: COC(=O)c1cc(NCC(C)(C)O)c(N)c(-c2ccc(F)cc2)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(-c2ccc(F)cc2)c2[nH]c(=O)n(CC(C)(C)O)c2c1
Temperature: 30 °C
Yield: 83.4 %

Procedure:
To a solution of methy 6-amino-4′-fluoro-5-[(2-hydroxy-2-methylpropyl)amino]biphenyl-3-carboxylate (180 mg, 0.542 mmol) in dichloromethane (16.2 mL) was added triethylamine (0.091 mL, 0.650 mmol) followed by triphosgene (80.0 mg, 0.271 mmol) in dichloromethane (5.42 mL). Reaction heated at 30° C. for 4 h. Reaction was cooled, diluted with saturated sodium bicarbonate and dichloromethane. Adjusted aqueous layer to pH=14. Wash aqueous with dichloromethane (5×). Combined organics were dried over magnesium sulfate, filtered and concentrated. Purification by reverse phase HPLC (C-18, 95% water/acetonitrile→5% water/acetonitrile with 0.05% NOH) gave the title compound (81.0 mg): LC-MS [M+1]=359.2.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]([CH3:22])[C:16](=[O:21])[CH2:17][CH2:18][C:19]#[CH:20]>>[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]([CH3:22])[C:16](=[O:21])[CH2:17][CH2:18][C:19]#[C:20][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: C#CCCC(=O)N(C)c1ccccc1Cl
Reactant: Brc1ccccn1
Product: CN(C(=O)CCC#Cc1ccccn1)c1ccccc1Cl
Yield: 6600 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (157 mg, 1.00 mmol) and pent-4-ynoic acid (2-chloro-phenyl)-methyl-amide (220 mg, 1.00 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 98:2) to yield 20 mg (66 mmol, 7%) of N-(2-chlorophenyl)-N-methyl-5-(pyridin-2-yl)pent-4-ynamide as a brown liquid.
Reaction SMILES: Cl[C:2]1([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=2)[CH:7]2[CH2:8][CH2:9][CH:3]1[CH2:4][N:5]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)[CH2:6]2.C(O)(C)(C)C.[Na].CO>O1CCOCC1>[CH3:18][O:17][C:14]1[CH:13]=[CH:12][C:11]([CH2:10][N:5]2[CH2:4][CH:3]3[CH:2]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=4)[CH:7]([CH2:8][CH2:9]3)[CH2:6]2)=[CH:16][CH:15]=1
Reactant: COc1ccc(CN2CC3CCC(C2)C3(Cl)c2cccc(OC)c2)cc1
Agent: [Na]
Solvent: C1COCCO1
Solvent: CC(C)(C)O
Solvent: CO
Product: COc1ccc(CN2CC3CCC(C2)C3c2cccc(OC)c2)cc1
Temperature: 110 °C
Yield: 35 %

Procedure:
8-Chloro-3-(4-methoxy-benzyl)-8-(3-methoxy-phenyl)-3-aza-bicyclo[3.2.1]octane (2.46 g, 6.61 mmol) and t-butanol (9.48 mL, 99.1 mmol) in dioxane (25 mL) was heated to a gentle reflux with an oil bath (110° C.). Sodium (1.52 g, 66.1 mmol) was pre-washed sequentially with hexanes/ethanol/THF/hexanes then added portionwise to the above refluxing mixture over 20 min. The reaction mixture was heated overnight then cooled to room temperature. To this was added methanol (50 mL) to quench residual sodium. The solvent was removed in vacuo, and the product was partitioned between water (100 mL) and EtOAc (100 mL). The layers were separated and the product was further extracted with EtOAc (3×40 mL), washed with saturated aqueous NaCl solution (1×50 mL), dried over Na2SO4, filtered and concentrated to a light brown oil. Flash chromatography provided the title compound (780 mg, 35%). (TLC 20% EtOAc/hexanes Rf 0.60); 1H NMR (400 MHz, CDCl3) δ 7.29 (d, J=8.7 Hz, 2H), 7.23 (t, J=7.7 Hz, 1H), 6.89 (d, J=8.7 Hz, 2H), 6.88 (m, 1H), 6.84 (s, 1H), 6.74 (dd, J=7.9, 2.5 Hz, 1H), 3.82 (s, 3H), 3.81 (s, 3H), 3.52 (s, 2H), 2.86 (dd, J=10.8, 3.7 Hz, 2H), 2.75 (s, 1H), 2.51 (br s, 2H), 2.28 (d, J=10.0 Hz, 2H), 1.79 (dd, J=12.7, 5.8 Hz, 2H), 1.63 (m, 2H); GCMS m/z 337 (M)+.