Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[C:16](=[O:17])[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[N:9]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]4[CH:25]=[N:26][C:27]([O:30]CC5C=CC=CC=5)=[CH:28][CH:29]=4)[CH:19]=3)[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCCl.C(Cl)Cl.C(=O)(O)[O-].[Na+]>[CH:1]1([NH:4][C:5]([C:7]2[C:16](=[O:17])[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[N:9]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]4[CH:29]=[CH:28][C:27](=[O:30])[NH:26][CH:25]=4)[CH:19]=3)[CH:8]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: O=C(NC1CC1)c1cn(-c2cccc(-c3ccc(OCc4ccccc4)nc3)c2)c2ncccc2c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(NC1CC1)c1cn(-c2cccc(-c3ccc(=O)[nH]c3)c2)c2ncccc2c1=O
Temperature: 60 °C
Reaction time: 18 h

Procedure:
To a solution of N-cyclopropyl-1-[3-(6-benzyloxypyridin-3-yl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide from Example 42 in 1,2-dichloroethane (25 ml/mmol) was added trifluoroacetic acid (1.5 ml/mmol) and the resulting mixture was stirred at 60° C. for 18 hours. More trifluoroacetic acid was added (0.75 ml/mmol) and heating was continued for a further 24 hours. The cooled mixture was diluted with methylene chloride and saturated aqueous sodium bicarbonate was added, resulting in precipitation of a solid which was filtered. From the filtrate the organic phase was collected and evaporated to a solid which was combined with the previous filtered solid. This mixture was chromatographed on silica gel eluting with 10% methanol in methylene chloride to afford the title compound as a white fluffy solid.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:3]=1[C:4]([C:6]1[C:11]([F:12])=[CH:10][CH:9]=[CH:8][C:7]=1[F:13])=O.[OH-].[K+]>C(O)COCCO>[F:18][C:15]1[CH:14]=[C:3]([CH2:4][C:6]2[C:7]([F:13])=[CH:8][CH:9]=[CH:10][C:11]=2[F:12])[C:2](=[CH:17][CH:16]=1)[NH2:1]
Reactant: Nc1ccc(F)cc1C(=O)c1c(F)cccc1F
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Product: Nc1ccc(F)cc1Cc1c(F)cccc1F

Procedure:
In the manner given in Preparation 11, 2-amino-2',5,6'-trifluorobenzophenone is refluxed with potassium hydroxide in diethylene glycol to give 4-fluoro-α-(2,6-difluorophenyl)-0-toluidene.
Reaction SMILES: [CH:1]1([N:4]([CH:12]([C:14]2[CH:23]=[C:22]([OH:24])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)[CH3:13])[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH2:3][CH2:2]1.[C:25](=O)([O-])[O-].[K+].[K+].CN(C)C=O.CI>O>[CH:1]1([N:4]([CH:12]([C:14]2[CH:23]=[C:22]([O:24][CH3:25])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)[CH3:13])[C:5](=[O:11])[O:6][C:7]([CH3:9])([CH3:10])[CH3:8])[CH2:2][CH2:3]1
Reactant: CC(c1cc(O)c2ccccc2c1)N(C(=O)OC(C)(C)C)C1CC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(C)N(C(=O)OC(C)(C)C)C2CC2)cc2ccccc12
Yield: 73.6 %

Procedure:
To a mixture of tert-butyl cyclopropyl[1-(4-hydroxy2-naphthyl)ethyl]carbamate (43 mg) and potassium carbonate (27 mg) was added N,N-dimethylformamide (2.0 mL), and then thereto added methyl iodide (0.016 mL), and the mixture was stirred at room temperature for 4 hours. After cooling, to the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was sequentially washed with water twice and saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=10/1→4/1) to give tert-butyl cyclopropyl[1-(4-methoxy-2-naphthyl)ethyl]carbamate [REx(4-1)] (33 mg) as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]=[C:11]=[S:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH:13]1[C:18]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=2)=[CH:17][CH:16]=[C:15]([NH2:27])[CH:14]=1>O1CCOCC1>[CH2:19]([C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:11]([NH:10][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)=[S:12])=[CH:22][CH:21]=1)[C:18]1[CH:13]=[CH:14][C:15]([NH:27][C:11]([NH:10][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)=[S:12])=[CH:16][CH:17]=1
Reactant: O=[N+]([O-])c1ccc(N=C=S)cc1
Reactant: Nc1ccc(Cc2ccc(N)cc2)cc1
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc(NC(=S)Nc2ccc(Cc3ccc(NC(=S)Nc4ccc([N+](=O)[O-])cc4)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 4-nitrophenyl isothiocyanate (0.45 g, 2.52 mmol) in dioxane (25 mL) is slowly added, with magnetic stirring, to a solution of 4,4'-diaminodiphenyl methane (0.25 g, 1.26 mmol) in dioxane (10 mL). After 24 hours of stirring at room temperature, the solvent is removed by vacuum evaporation. The solid obtained is washed with n-hexane (3×25 mL) and isopropanol (3×10 mL). Next, the solid is dissolved in ethyl acetate (50 mL) and washed with water (3×25 mL). The organic phase is dried with sodium sulfate. The solvent is removed by vacuum evaporation. The titled compound is obtained as a yellow powder. mp: 115° C.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[CH3:25][C:26]1[CH:30]=[C:29]([CH3:31])[NH:28][N:27]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([N:27]3[C:26]([CH3:25])=[CH:30][C:29]([CH3:31])=[N:28]3)[O:3][C:4]=2[CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])=[CH:8][CH:9]=1
Reactant: Cc1ccccc1OCCCc1oc(Cl)nc1-c1ccc(Cl)cc1
Reactant: Cc1cc(C)[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C)n(-c2nc(-c3ccc(Cl)cc3)c(CCCOc3ccccc3C)o2)n1
Temperature: 125 °C
Reaction time: 1 h
Yield: 16.1 %

Procedure:
A mixture of 2-chloro-4-(4-chlorophenyl)-5-[3-(2-methylphenoxy)propyl]oxazole (1.00 g), 3,5-dimethylpyrazole (1.00 g), potassium carbonate (1.38 g) and N,N-dimethylformamide (10 ml) was stirred at 120-130° C. for 1 hour. The reaction mixture was poured into water (100 ml), and the resulting solid precipitate was filtered, air-dried and recrystallized from acetone-isopropyl ether to give 4-(4-chlorophenyl)-2-(3,5-dimethyl-1-pyrazolyl)-5-[3-(2-methylphenoxy)propyl]oxazole as pale yellow prisms (187 mg, 16%). Melting point 103-104° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16](=O)[C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:30][OH:31].[OH-].[K+]>C(O)C.CO>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16](=[N:30][OH:31])[C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=C(CCC1CCN(Cc2ccccc2)CC1)c1ccc(N2CCCC2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CO
Product: ON=C(CCC1CCN(Cc2ccccc2)CC1)c1ccc(N2CCCC2)cc1
Temperature: 0 °C
Yield: 66.1 %

Procedure:
To a mixed solution (20 ml) containing 0.8 g of the 1-benzyl-4-[2-(4-pyrrolidinobenzoyl)ethyl]piperidine prepared in Example 59 and 0.7 g of hydroxylamine hydrochloride in ethanol was added a solution (7 ml) of 1.4 g of potassium hydroxide in methanol dropwise with warming at 50°-55° C. The mixture was further heated at 50°-55° C. for one hour, at the end of which time it was added to 200 ml of ice-water. The resulting precipitate was collected by filtration, rinsed and dissolved in dichloromethane. The solution was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure to give crude crystals. Recrystallization from dichloromethane-ether yielded 0.55 g of colorless crystals melting at 153°-158° C.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:3]=1[CH:4]=[C:5]1[S:9]C(=S)N[C:6]1=[O:11].[OH-:17].[Na+].Cl>O>[Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:3]=1/[CH:4]=[C:5](\[SH:9])/[C:6]([OH:17])=[O:11]
Reactant: O=C1NC(=S)SC1=Cc1c(Cl)cccc1Cl
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C(O)/C(S)=C/c1c(Cl)cccc1Cl
Temperature: 25 °C

Procedure:
A suspension of 2,6-dichlorobenzylidenerhodanine (160.4 g) and water (800 ml) was stirred at room temperature, and sodium hydroxide (83.0 g) was added over a period of 1 hour. The resulting mixture was heated with stirring for another 0.5 hours. The reaction mixture was cooled with ice (10° C.), and concentrated hydrochloric acid (192 ml) was added. After the mixture was stirred while cooling with ice for 0.5 hours, the precipitated crystals were collected by filtration. The crystals obtained by filtration were washed with water and then dried to obtain an equivalent amount of (Z)-3-(2,6-dichlorophenyl)-2-mercapto-2-propenoic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[C:9]([O:11][CH2:12][C@@:13]2([OH:30])[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][C:19]=3[O:23][CH2:24][C:25]([O:27]CC)=[O:26])[CH2:14]2)=[O:10])=[CH:4][CH:3]=1.[OH-].[Na+:39]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:31]2[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=2)[C:9]([O:11][CH2:12][C@@:13]2([OH:30])[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][C:19]=3[O:23][CH2:24][C:25]([O-:27])=[O:26])[CH2:14]2)=[O:10])=[CH:4][CH:3]=1.[Na+:39]
Reactant: CCOC(=O)COc1cccc2c1CC[C@](O)(COC(=O)N(c1ccc(F)cc1)c1ccc(F)cc1)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C([O-])COc1cccc2c1CC[C@](O)(COC(=O)N(c1ccc(F)cc1)c1ccc(F)cc1)C2

Procedure:
A solution of (2R)-2-{[N,N-di(4-fluorophenyl)-carbamoyloxy]methyl}-5-[(ethoxycarbonyl)methoxy]-2-hydroxy-1,2,3,4-tetrahydronaphthalene (0.155 g) and 1N-NaOH (0.286 ml) in MeOH (1.5 ml) was stirred for 16 hours at room temperature. After evaporating in vacuo, the residue was crystallized from ether to give sodium {{(2R)-2-{[N,N-di(4-fluorophenyl)carbamoyloxy]methyl}-2-hydroxy-1,2,3,4-tetrahydro-5-naphthyl}oxy}acetate (sodium salt of (2R)-5-(carboxymethoxy)-2-{[N,N-di(4-fluorophenyl)carbamoyloxy]methyl}-2-hydroxy-1,2,3,4-tetrahydronaphthalene) (111 mg) as white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([O:18]C)[N:15]=[C:14]3[S:20][C:21]([CH3:31])=[C:22]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=4)[C:13]=23)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.Cl>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[C:13]3[C:22]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=4)=[C:21]([CH3:31])[S:20][C:14]=3[NH:15][C:16](=[O:18])[CH:17]=2)(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cccc(-c2c(C)sc3nc(OC)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Agent: Cl
Solvent: ClCCl
Product: COc1cccc(-c2c(C)sc3[nH]c(=O)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Temperature: 25 °C
Yield: 59.1 %

Procedure:
Alternatively, a solution of 3-chloro-N-{2-methyl-6-(methyloxy)-3-[3-(methyloxy)phenyl]thieno[2,3-b]pyridin-4-yl}benzenesulfonamide (Example 115) (710 mg, 1.495 mmol) in 37% HCl (8 mL, 97 mmol) was heated to 100° C. under nitrogen atmosphere overnight. The reaction mixture was cooled to RT, diluted with DCM (ca. 50 mL) and washed with water (ca. 50 mL×2). The combined aqueous layer was re-extracted with DCM (ca. 25 mL) and the combined organic layers passed through phase separator and the solvent concentrated in vacuo. The residue was further triturated with DCM, to afford the title compound (407 mg).
Reaction SMILES: [C:1]([NH:8][C@@H:9]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH2:41][O:42][CH3:43])=[CH:35][CH:34]=1)[C@@H:10]([OH:31])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:19][CH:18]=1)[C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:44]([Si:48]([CH3:51])([CH3:50])Cl)([CH3:47])([CH3:46])[CH3:45].N1C=CN=C1>CN(C=O)C>[C:1]([NH:8][C@@H:9]([CH2:32][C:33]1[CH:34]=[CH:35][C:36]([O:39][CH2:40][CH2:41][O:42][CH3:43])=[CH:37][CH:38]=1)[C@@H:10]([O:31][Si:48]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:51])[CH3:50])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:19][CH:18]=1)[C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:6])([CH3:5])[CH3:7])=[O:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COCCOc1ccc(C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)C[C@@H](Cc2ccc(OCc3ccccc3)cc2)C(=O)O)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COCCOc1ccc(C[C@H](NC(=O)OC(C)(C)C)[C@H](C[C@@H](Cc2ccc(OCc3ccccc3)cc2)C(=O)O)O[Si](C)(C)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3.85 g (6.48 mmol) of 5(S)-(Boc-amino)-4(S)-hydroxy-6-[p-(2-methoxyethoxy)phenyl]-2(R)-[(p-benzyloxyphenyl)methyl]hexanoic acid in 11 ml of DMF are silylated, at RT for 16 h and under a protective gas, with 4.49 g (29.8 mmol) of tert-butyldimethylchlorosilane and 3.6 g (53.1 mmol) of imidazole. The reaction mixture is poured onto ice-water and the whole is extracted 3 times with ethyl acetate. The organic phases are washed with 10% citric acid solution, 2 times with water and with saline, dried with Na2 SO4 and evaporated. The residue is dissolved in 79 ml of methanol and 30 ml of THF, and this solution is treated with 5.37 g of potassium carbonate and 30 ml of water and stirred at RT for 3 h. The reaction mixture is subsequently poured onto an ice-cold 10% citric acid solution, and this mixture is extracted 3 times with ethyl acetate. The organic phases are washed with 2 portions of H2O and saline, dried with Na2SO4 and evaporated. Column chromatography (SiO2, hexane/ethyl acetate, 1:1) affords the title compound: TLC Rf (C)=0,28; tRet (II)=20.9 min.
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([CH2:9][CH:10]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=2[NH:24]C(=O)OC(C)(C)C)[C:11](=O)[CH:12]([CH3:14])[CH3:13])[CH:6]=[CH:5][CH:4]=1)#[N:2].FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>ClCCl>[CH:12]([C:11]1[NH:24][C:17]2[C:16]([C:10]=1[CH2:9][C:7]1[N:8]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][CH:6]=1)=[CH:21][CH:20]=[C:19]([O:22][CH3:23])[CH:18]=2)([CH3:14])[CH3:13]
Reactant: COc1ccc(C(Cc2cccc(C#N)n2)C(=O)C(C)C)c(NC(=O)OC(C)(C)C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(Cc3cccc(C#N)n3)c(C(C)C)[nH]c2c1
Temperature: 25 °C
Reaction time: 2.75 h
Yield: 93.3 %

Procedure:
To a solution of tert-butyl {2-[1-(6-cyanopyridin-2-ylmethyl)-3-methyl-2-oxobutyl]-5-methoxyphenyl}carbamate (269 mg) in dichloromethane (13 mL) was added trifluoroacetic acid (2.6 mL) under ice-cooling, and the mixture was stirred at room temperature for 2.75 hours. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (181 mg). 1H-NMR (CDCl3) δ ppm: 1.28 (6H, d, J=7.0 Hz), 3.21-3.35 (1H, m), 3.83 (3H, s), 4.26 (2H, s), 6.73 (1H, dd, J=2.3, 8.8 Hz), 6.86 (1H, d, J=2.3 Hz), 7.19-7.29 (2H, m), 7.45-7.52 (1H, m), 7.55-7.64 (1H, m), 7.80 (1H, br s).
Reaction SMILES: [CH:1]1([C:4](O)=[O:5])[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[NH2:33][CH2:34][C:35]1[CH:40]=[CH:39][N:38]=[C:37]([C:41]2([NH:44][C:45]([C:47]3([NH:50][C:51]([C:53]4[N:57]5[C@@:58]([CH2:71][C:72]6[CH:77]=[CH:76][C:75]([C:78]#[N:79])=[CH:74][CH:73]=6)([CH3:70])[C:59](=[O:69])[N:60]([C:61]6[CH:66]=[C:65]([Cl:67])[CH:64]=[C:63]([Cl:68])[CH:62]=6)[C:56]5=[N:55][CH:54]=4)=[O:52])[CH2:49][CH2:48]3)=[O:46])[CH2:43][CH2:42]2)[CH:36]=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(#N)C.O>[CH:1]1([C:4]([NH:33][CH2:34][C:35]2[CH:40]=[CH:39][N:38]=[C:37]([C:41]3([NH:44][C:45]([C:47]4([NH:50][C:51]([C:53]5[N:57]6[C@@:58]([CH2:71][C:72]7[CH:77]=[CH:76][C:75]([C:78]#[N:79])=[CH:74][CH:73]=7)([CH3:70])[C:59](=[O:69])[N:60]([C:61]7[CH:66]=[C:65]([Cl:67])[CH:64]=[C:63]([Cl:68])[CH:62]=7)[C:56]6=[N:55][CH:54]=5)=[O:52])[CH2:48][CH2:49]4)=[O:46])[CH2:42][CH2:43]3)[CH:36]=2)=[O:5])[CH2:3][CH2:2]1
Reactant: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(C(=O)NC3(C(=O)NC4(c5cc(CN)ccn5)CC4)CC3)n21
Reactant: O=C(O)C1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(C(=O)NC3(C(=O)NC4(c5cc(CNC(=O)C6CC6)ccn5)CC4)CC3)n21
Reaction time: 0.08 h
Yield: 70.7 %

Procedure:
Cyclopropanecarboxylic acid (0.00903 mL, 0.108 mmol) and HATU (25.605 mg, 0.0673 mmol) were dissolved in dry DMF (1 mL). Stirred for 5 min. To this solution was added (R)-5-(4-Cyano-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylic acid {1-[1-(4-aminomethyl-pyridin-2-yl)-cyclopropylcarbamoyl]-cyclopropyl}-amide dihydrochloric acid salt (40 mg, 0.0539 mmol) followed by DIPEA (0.038 mL, 0.215 mmol). Stirred at room temperature for 30 min. Diluted with ACN (1 mL) and water (1 mL) and filtered. The crude product was purified by reverse phase HPLC using 20-95% ACN/water as the gradient. Solvent was evaporated. The resultant product was redissolved in 10% MeOH/DCM and filtered through a basic (NH2) cartridge. Solvent was evaporated to afford 28.1 mg of the title compound as a white solid, m/z 737.7 [M+1]+.
Reaction SMILES: Cl[S:2]([N:5]=C=O)(=[O:4])=[O:3].[OH:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=1)[C:12]([O:14][CH3:15])=[O:13]>C1(C)C=CC=CC=1>[CH3:15][O:14][C:12]([C:11]1[CH:10]=[C:9]([O:8][S:2](=[O:3])(=[O:4])[NH2:5])[CH:18]=[CH:17][CH:16]=1)=[O:13]
Reactant: COC(=O)c1cccc(O)c1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(OS(N)(=O)=O)c1
Yield: 45.5 %

Procedure:
Following the procedure of Example 50, a reaction of 8.8 ml (0.10 mole) chlorosulfonyl isocyanate and 15.2 g (0.10 mole) of methyl 3-hydroxybenzoate in 200 ml of toluene was heated at reflux for 7.5 hr and worked up to obtain 10.53 g of solid, mp 145°-146° C.
Reaction SMILES: C(=O)([O-])[O-].[Mg+2:5].O.[OH:7][P:8]([OH:11])([OH:10])=[O:9].[Cr]([O-])([O-])(=O)=O.[Pb+2]>C(O)C>[P:8]([O-:11])([O-:10])([O-:9])=[O:7].[Mg+2:5].[P:8]([O-:11])([O-:10])([O-:9])=[O:7].[Mg+2:5].[Mg+2:5]
Reactant: O=P(O)(O)O
Agent: O=[Cr](=O)([O-])[O-]
Agent: O=C([O-])[O-]
Agent: [Mg+2]
Solvent: O
Solvent: CCO
Product: O=P([O-])([O-])[O-]

Procedure:
A saturated solution of magnesium phosphate is prepared by mixing 75 gm of magnesium carbonate in 350 ml boiling water. 100 ml of 85% H3PO4 is then added. To one-half of the solution is added 48% HF to form the fluorophosphate complex. The two solutions are each slurried with lead chromate pigment after which ethanol is slowly added to each to cause formation of the sol which deposits on the particles. The encapsulated pigments are filtered and dried at 170°C for 2 hours without darkening and when incorporated into general purpose polystyrene both were thermally stable at 625°F.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10].[C:12](O)(=O)[CH2:13][CH2:14][C:15]#[CH:16].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>O1CCOCC1>[CH2:15]([C:16]1[O:1][N:2]=[C:3]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[CH3:10])[N:11]=1)[CH2:14][C:13]#[CH:12]
Reactant: Cc1ccccc1C(N)=NO
Reactant: C#CCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1COCCO1
Product: C#CCCc1nc(-c2ccccc2C)no1
Temperature: 80 °C
Reaction time: 3 h
Yield: 31.8 %

Procedure:
In a reactor tube, a mixture of N′-hydroxy-2-methylbenzamidine (555 mg, 3.7 mmol), 4-pentynoic acid (363 mg, 3.7 mmol), HOBT (0.56 g, 3.7 mmol) and EDCI.HCl (1.06 g, 5.55 mmol) in dioxane (7.4 mL) was stirred at R.T for 3 h. After this time the mixture was heated at 80° C. overnight in a reaction block. The mixture was concentrated. The organic layer was washed with water, NaOH 1N and water. The solvent was evaporated in a Genevac for 75 min at 40° C. using the low boiling point program. The crude product was purified by flash chromatography (Prepacked 10 g silicagel column) with DCM as eluent to afford 250 mg of 5-(but-3-ynyl)-3-o-tolyl-1,2,4-oxadiazole (Yield: 32%) as yellow oil.
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:8]([O-:13])(=[O:12])[C:9]([CH3:11])=[CH2:10].[CH2:14]([Sn+:18]([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][CH2:16][CH3:17].C([O-])(=O)C(C)=C.[CH2:33]([Sn+:36]([CH2:40][CH2:41][CH3:42])[CH2:37][CH2:38][CH3:39])[CH2:34][CH3:35].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C1C=CC=CC=1>[C:1]([O-:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH2:23]([Sn+:18]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:19][CH2:20][CH2:21][CH3:22])[CH2:24][CH2:25][CH3:26].[CH3:35][CH2:34][CH2:33][Sn:36]([O:12][C:8]([C:9]([CH3:11])=[CH2:10])=[O:13])([CH2:40][CH2:41][CH3:42])[CH2:37][CH2:38][CH3:39].[C:1]([O:6][CH3:7])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: CCC[Sn+](CCC)CCC
Agent: C=C(C)C(=O)OC
Agent: C=C(C)C(=O)[O-]
Agent: CCCC[Sn+](CCCC)CCCC
Solvent: c1ccccc1
Product: C=C(C)C(=O)O[Sn](CCC)(CCC)CCC

Procedure:
The monomers of P51 were first synthesized. Tri-n-butyltin methacrylate was prepared as was tripropyltin methacrylate. These esters were isolated as crystals from petroleum ether. Methyl methacrylate was uninhibited. All uninhibited monomers were refrigerated below 40° F when stored for short periods of time. Tri-n-butyltin methacrylate (0.4 mole), tri-n-propyltin methacrylate (0.4 mole) and methyl methacrylate (0.4 mole) were reacted in 300 ml of benzene using benzoyl peroxide (0.5% by weight) as initiator. The reaction mixture was refluxed for 24 hours in a 1-liter, 3-necked resin flask equipped with a reflux condenser, a thermometer, such that it read the temperature of the reactants and a mechanical stirrer. The resultant polymer was clear and could be cast as a film from the benzene solution. Analysis showed 29.35% Sn.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:11]([N:13]1[CH2:66][CH2:65][CH2:64][C@H:14]1[C:15]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][N:25]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([NH:39][C:40](=[O:63])[C@@H:41]3[CH2:45][CH2:44][CH2:43][N:42]3[C:46](=[O:62])[C@H:47]([NH:54]C(OC(C)(C)C)=O)[C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[CH:35][CH:34]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:20][CH:19]=1)=[O:16])=[O:12])[C:7]([CH3:10])([CH3:9])[CH3:8])=[O:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][O:2][C:3]([NH:5][C@H:6]([C:11]([N:13]1[CH2:66][CH2:65][CH2:64][C@H:14]1[C:15]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][N:25]([CH2:32][C:33]2[CH:34]=[CH:35][C:36]([NH:39][C:40](=[O:63])[C@@H:41]3[CH2:45][CH2:44][CH2:43][N:42]3[C:46](=[O:62])[C@H:47]([NH2:54])[C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[CH:37][CH:38]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:20][CH:19]=1)=[O:16])=[O:12])[C:7]([CH3:10])([CH3:9])[CH3:8])=[O:4]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)Nc1ccc(CN(Cc2ccc(NC(=O)[C@@H]3CCCN3C(=O)[C@H](NC(=O)OC(C)(C)C)c3ccccc3)cc2)c2ccccc2)cc1)C(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)Nc1ccc(CN(Cc2ccc(NC(=O)[C@@H]3CCCN3C(=O)[C@H](N)c3ccccc3)cc2)c2ccccc2)cc1)C(C)(C)C
Temperature: 25 °C
Yield: 95 %

Procedure:
To a solution of the product from Example 74 (136.1 mg, 0.151 mmol) in CH2Cl2 (0.2 mL) was added trifluoroacetic acid (0.20 mL). The mixture was stirred at rt and concentrated in vacuo. The crude product was partitioned between CH2Cl2 and saturated aqueous NaHCO3, and the organic layer was dried (Na2SO4), filtered and concentrated in vacuo to afford the title compound (115 mg, 94%). 1H NMR (400 MHz, DMSO-D6) δ ppm 0.96 (s, 8 H), 1.53 (s, 1 H), 1.74 (s, 1 H), 1.82-1.91 (m, 3 H), 1.99 (s, 2 H), 2.15 (s, 1 H), 2.69 (s, 2 H), 2.84 (s, 1 H), 3.54 (s, 3 H), 3.63 (s, 1 H), 3.79 (s, 2 H), 4.21 (d, J=8.9 Hz, 1 H), 4.41-4.47 (m, 2 H), 4.60 (s, 4 H), 5.29 (s, 1 H), 6.57 (t, J=7.2 Hz, 1 H), 6.66 (d, J=8.2 Hz, 2 H), 7.05-7.11 (m, 3 H), 7.19 (t, J=8.3 Hz, 4 H), 7.42-7.49 (m, 4 H), 7.53 (dd, J=12.8, 8.5 Hz, 5 H), 10.00 (s, 1 H), 10.09 (s, 1 H); MS (ESI) m/z 802.5 (M+H)+.