Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1](=[O:4])([OH:3])[O-:2].[Na+:5].[OH-].[Ca+2:7].[OH-]>>[S:1]([O-:4])([O-:3])=[O:2].[Na+:5].[Na+:5].[S:1]([O-:4])([O-:3])=[O:2].[Ca+2:7]
Reactant: O=S([O-])O
Agent: [Ca+2]
Agent: [Na+]
Agent: [OH-]
Product: O=S([O-])[O-]

Procedure:
In a system for removing sulfur oxides from flue gas, the gas is contacted by a primary extraction solution containing sodium sulfite as the active compound and some sodium bisulfite in a scrubber, and the resultant extract containing more sodium bisulfite is mixed with an alkaline solution containing regenerated sodium sulfite in a mixer to produce the primary extraction solution. A portion of the latter is bled off to a regenerator wherein the quantity of sodium bisulfite made in the scrubber reacts with calcium hydroxide to form regenerated sodium sulfite and large diameter calcium sulfite precipitates that remain suspended in the parent solution. This mixture is drawn off the regenerator by overflow, without pumping, for gravity flow to the eye of a thickener, wherein an increased density slurry of the mixture is withdrawn from the thickener well and directed to a rotary filter to produce a calcium sulfite filter cake. The resultant filtrate and the solids free overflow from the thickener provide the sodium sulfite solution inputs to a holding tank, from which the liquor is pumped through a back washed polishing filter and back to the mixer. Flyash, initially present in the incoming flue gas, is separated from the gas in the scrubber and passes through the system to the filter, where it acts as a filter-aid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14](S(C)(=O)=O)=[N:15][CH:16]=2)[N:11]([CH3:23])[C:10]1=[O:24].[F:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1.Cl>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14]([NH:30][C:29]3[CH:31]=[CH:32][C:26]([F:25])=[CH:27][CH:28]=3)=[N:15][CH:16]=2)[N:11]([CH3:23])[C:10]1=[O:24]
Reactant: Nc1ccc(F)cc1
Reactant: CN1C(=O)N(c2c(Cl)cccc2Cl)Cc2cnc(S(C)(=O)=O)nc21
Agent: Cl
Solvent: CCOC(C)=O
Product: CN1C(=O)N(c2c(Cl)cccc2Cl)Cc2cnc(Nc3ccc(F)cc3)nc21
Temperature: 180 °C
Yield: 36.8 %

Procedure:
A mixture of 100 mg (0.26 mmol) of 3-(2,6-dichlorophenyl)-7-methane-sulfonyl-3,4-dihydro-1-methylpyrimido[4,5-d]pyrimidin-2(1H)-one and 0.25 ml (2.6 mmol) of 4-fluoroaniline was heated at 180° C. for 30 minutes and then cooled. 30 ml of ethyl acetate and 30 ml of 2M hydrochloric acid were added to the residue. The phases were separated and the organic phase was washed with 20 ml of brine, dried over magnesium sulfate, filtered and evaporated. The residue was chromatographed on silica gel using ethyl acetate/hexane (2:3) for the elution. Product-containing fractions were combined and evaporated to give 40 mg (37%) of 3-(2,6-dichlorophenyl)-7-(4-fluoroanilino)-3,4-dihydro-1-methylpyrimido[4,5-d]-pyrimidin-2(1H)-one as a light grey solid of melting point 208-211° C.
Reaction SMILES: [SH:1][C:2]1[N:11]([CH3:12])[C:10](=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[OH-].[Na+].[Cl:16][C:17]1[CH:32]=[CH:31][C:20]([C:21]([C:23]2[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=2)=[O:22])=[CH:19][CH:18]=1>C(O)C.CN(C=O)C.O>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]([C:23]2[CH:30]=[CH:29][C:26]([CH2:27][S:1][C:2]3[N:11]([CH3:12])[C:10](=[O:13])[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[N:3]=3)=[CH:25][CH:24]=2)=[O:22])=[CH:31][CH:32]=1
Reactant: Cn1c(S)nc2ccccc2c1=O
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(SCc2ccc(C(=O)c3ccc(Cl)cc3)cc2)nc2ccccc2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.9 %

Procedure:
2-Mercapto-3-methyl-4(3H)-quinazolinone (1.0 g) as synthesized by the method described in Chemical Pharmaceutical Bulletin 17, 2357, 1969 and sodium hydroxide (250 mg) were dissolved in 50% ethanol (15 ml)-DMF (15 ml). To this solution was added 4-(4-chlorobenzoyl)benzyl bromide (1.8 g) and the mixtrue was stirred at room temperature for 1 hour. This-reaction mixture was poured in water and the resulting crystals were collected by filtration, rinsed with water and methanol, and recrystallized from ethyl acetate-methanol to provide the title compound as colorless solid (1.29 g). 1H-NMR (CDCl3) δ: 3.61(3H,s), 4.62(2H,s), 7.35-7.50(3H,m), 7.55-7.80(8H,m), 8.24(1H,d,J=8.OHz).
Reaction SMILES: [Br:1][CH2:2]/[CH:3]=[CH:4]/[C:5]([OH:7])=O.C(Cl)(=O)C(Cl)=O.[NH2:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][C:19]([C:25]#[N:26])=[C:18]2[NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([Br:34])[CH:29]=1.C(N(C(C)C)CC)(C)C>ClCCl.CN(C)C=O.O1CCCC1.C(OCC)(=O)C.O>[Br:34][C:30]1[CH:29]=[C:28]([NH:27][C:18]2[C:17]3[C:22](=[CH:23][CH:24]=[C:15]([NH:14][C:5](=[O:7])[CH:4]=[CH:3][CH2:2][Br:1])[CH:16]=3)[N:21]=[CH:20][C:19]=2[C:25]#[N:26])[CH:33]=[CH:32][CH:31]=1
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(Br)c1
Reactant: O=C(O)/C=C/CBr
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cnc2ccc(NC(=O)C=CCBr)cc2c1Nc1cccc(Br)c1
Yield: 68.1 %

Procedure:
A solution of 1.65 grams (0.01 mole) of 4-bromo crotonic acid (Giza Braun, J. Am. Chem. Soc. 52, 3167 1930) in 15 ml of dichloromethane was treated with 1.74 ml (0.02 moles) of oxalyl chloride and 1 drop of N,N-dimethylformamide. After an hour the solvents were removed on the rotary evaporator. The residual oil was taken up in ml of tetrahydrofuran, and 3.39 grams of 6-Amino-4-(3-bromo-phenylamino)-quinoline-3-carbonitrile in 25 ml of tetrahydrofuran was added dropwise. This was followed by the dropwise addition of 1.92 ml (0.011 moles) of diisopropylethylamine. After the addition of 25 ml of water and 50 ml of ethyl acetate, the layers were separated. The organic layer was dried over anhydrous sodium sulfate, and taken to a solid in vacuo. This solid was digested for an hour with refluxing ethyl acetate then filtered from the ethyl acetate while still hot. Thus was obtained 3.31 grams (68%) of 4-bromo-but-2-enoic acid [4-(3-bromo-phenylamino)-3-cyano-quinolin-6-yl]-amide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14]([OH:16])=O)(=[O:11])=[O:10])=[C:4]([C:21]([F:24])([F:23])[F:22])[CH:3]=1.Cl.[CH2:26]([O:28][C:29](=[O:34])[C@H:30]([CH2:32][OH:33])[NH2:31])C.O.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>>[CH3:26][O:28][C:29](=[O:34])[CH:30]([NH:31][C:14](=[O:16])[C:13]1[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=1[S:9](=[O:11])(=[O:10])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[C:21]([F:22])([F:23])[F:24])[CH2:32][OH:33]
Reactant: O=C(O)c1ccccc1S(=O)(=O)Nc1ccc(F)cc1C(F)(F)F
Reactant: CCOC(=O)[C@@H](N)CO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)C(CO)NC(=O)c1ccccc1S(=O)(=O)Nc1ccc(F)cc1C(F)(F)F

Procedure:
Under the conditions of Example 2(a), 3.633 g (10 mmol) of 2-[N-(4-fluoro-2-trifluoromethylphenyl)sulfamoyl]benzoic acid, 1.556 g (10 mmol) of L-serine ethyl ester hydrochloride, 1.531 g (10 mmol) of hydroxybenzotriazole, hydrate, as well as 1.012 g (10 mmol) of triethylamine and 2.063 g (10 mmol) of dicyclohexylcarbodiimide are reacted and worked up analogously. The crude product is chromatographed on silica gel. The title compound is eluted with ethyl acetate.
Reaction SMILES: [C:1]([N:5]1[C:19]2[C:20]3[C:7]([CH2:8][C@@H:9]4[C@@:14]([O:21][CH3:22])([C:15]=3[CH:16]=[CH:17][CH:18]=2)[CH2:13][C@@H:12]([CH2:23][OH:24])[CH2:11][N:10]4[CH3:25])=[CH:6]1)([CH3:4])([CH3:3])[CH3:2].[S:26](Cl)([C:29]1[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=1)(=[O:28])=[O:27].O>N1C=CC=CC=1>[C:1]([N:5]1[C:19]2[C:20]3[C:7]([CH2:8][C@@H:9]4[C@@:14]([O:21][CH3:22])([C:15]=3[CH:16]=[CH:17][CH:18]=2)[CH2:13][C@@H:12]([CH2:23][O:24][S:26]([C:29]2[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=2)(=[O:28])=[O:27])[CH2:11][N:10]4[CH3:25])=[CH:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CO[C@]12C[C@@H](CO)CN(C)[C@@H]1Cc1cn(C(C)(C)C)c3cccc2c13
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: CO[C@]12C[C@@H](COS(=O)(=O)c3ccc(C)cc3)CN(C)[C@@H]1Cc1cn(C(C)(C)C)c3cccc2c13
Reaction time: 6 h
Yield: 76.6 %

Procedure:
To a solution of 1.8 g of 1-(t-butyl)-10-methoxy-6-methyl-8β-hydroxymethyl-ergoline, prepared as described in Example 2,.in 20 ml of pyridine, 2.8 g of tosyl chloride in 15 ml of pyridine were slowly added. After the addition had been completed, the mixture was stirred for about six hours and was then poured into cold water and extracted with dichloromethane. The organic layer was evaporated off and the residue was chromatographed over 18 g of silica gel using dichloromethane with increasing amounts of methanol (from 0 to 4 percent) as the eluant. 2 g of 1-(t-butyl)-10-methoxy-6-methyl-8β-tosyloxymethyl-ergoline were obtained, melting at about 150 to 152° C.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[C:32](=[O:33])[C:18]2=[C:19]([CH3:31])[N:20]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)[C:21](=[O:23])[CH:22]=[C:17]2[NH:16]1.C([O-])(=O)C.[Na+]>>[C:1]([N:16]1[C:17]2[C:18](=[C:19]([CH3:31])[N:20]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)[C:21](=[O:23])[CH:22]=2)[C:32](=[O:33])[N:15]1[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[Cl:8])(=[O:3])[CH3:2]
Reactant: Cc1c2c(=O)n(-c3ccccc3Cl)[nH]c2cc(=O)n1Cc1ccccn1
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Product: CC(=O)n1c2cc(=O)n(Cc3ccccn3)c(C)c2c(=O)n1-c1ccccc1Cl
Temperature: 40 °C
Yield: 82 %

Procedure:
10.0 ml of acetic anhydride was added to a mixture of 2-(2-chlorophenyl)-4-methyl-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione (Compound of Formula (Ia) (0.250 g, 0.682 mmol, 1 equiv.) and sodium acetate (0.056 g, 0.682 mmol, 1 equiv). The resulting mixture was heated at 40° C. for 1 h and then concentrated in vacuo. The resulting residue was dissolved in EtOAc and washed with water. The organic phase was dried over Na2SO4 and concentrated in vacuo until dryness to afford 0.228 g of the desired compound 1-acetyl-2-(2-chlorophenyl)-4-methyl-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione as a white solid (82% yield). Rf (EtOAc) 0.34; 1H NMR (500 MHz, CDCl3) 2.08 (s, 3H), 2.95 (s, 3H), 5.47 (s, 2H), 7.04 (s, 1H), 7.21 (m, 1H), 7.37-7.32 (m, 4H), 7.56 (m, 1H), 7.67 (td, J 7.6, 1.9 Hz, 1H), 8.51 (m, 1H); MS (ESI+): 409.2; MS (ESI−): 407.7.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:10]([C:20]([O:22][CH3:23])=[O:21])[CH:9]=2)=[CH:4][C:3]=1[C:24]1[CH:29]=[CH:28][C:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[C:26]([F:37])[CH:25]=1>CO.[Pd]>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14])[C@H:10]([C:20]([O:22][CH3:23])=[O:21])[CH2:9]2)=[CH:4][C:3]=1[C:24]1[CH:29]=[CH:28][C:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[C:26]([F:37])[CH:25]=1
Reactant: COC(=O)[C@@H]1C=C(c2cnc(N)c(-c3ccc(C(=O)OC(C)(C)C)c(F)c3)c2)CN1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@@H]1C[C@H](c2cnc(N)c(-c3ccc(C(=O)OC(C)(C)C)c(F)c3)c2)CN1C(=O)OC(C)(C)C
Yield: 63.6 %

Procedure:
A degassed solution of (S)-1-tert-butyl 2-methyl 4-(6-amino-5-(4-(tert-butoxycarbonyl)-3-fluorophenyl)pyridin-3-yl)-1H-pyrrole-1,2(2H,5H)-dicarboxylate (470 mg, 0.915 mmol) in methanol (40 mL) was treated with 10 wt. % Pd/C (3.214 g, 3.02 mmol). The system was degassed again, then charged with 1 atm hydrogen overnight. At completion, the reaction degassed, then treated ammonia gas then filtered over Celite. The cake was reslurried in methanol, treated with ammonia gas, and filtered to retrieve additional product. The process was repeated until no further product eluted from filter cake. The combined organics were concentrated to provide (2S,4R)-1-tert-butyl 2-methyl 4-(6-amino-5-(4-(tert-butoxycarbonyl)-3-fluorophenyl)pyridin-3-yl)pyrrolidine-1,2-dicarboxylate (300 mg, 64%). LCMS (m/z): 516.1 (MH+), 0.89 min.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH2:10][OH:11])[CH:7]=[CH:8][CH:9]=1.Cl[C:13]1[CH:18]=[CH:17][N+:16]([O-:19])=[CH:15][CH:14]=1>C1COCC1>[Cl:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[CH2:10][O:11][C:13]1[CH:18]=[CH:17][N+:16]([O-:19])=[CH:15][CH:14]=1
Reactant: OCc1cccc(Cl)c1
Reactant: [O-][n+]1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: [O-][n+]1ccc(OCc2cccc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.4 %

Procedure:
To an ice-cold suspension of NaH (40% oil dispersion, 1.51 g) in THF (60 ml) was added (3-chlorophenyl)methanol (3.0 g) at 0° C. The reaction mixture was stirred at the same temperature for 30 min followed by the portionwise addition of 4-chloropyridine 1-oxide (2.73 g) at 0° C. The resulting reaction mixture was stirred for 1 h at 0° C. and then warmed to room temperature. After 2 h, the reaction mixture was poured into ice-water (100 g) and extracted with DCM. The DCM layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was triturated with Et2O to give the title compound (2.2 g) as a brown solid.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([O:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12]O)=[CH:10][CH:9]=1)[CH3:6].CN(C=O)C>C(Cl)Cl>[CH2:5]([O:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12][Cl:3])=[CH:10][CH:9]=1)[CH3:6]
Reactant: CCOc1ccc(CO)cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOc1ccc(CCl)cc1
Reaction time: 0.12 h

Procedure:
Thionyl chloride (10.4 g, 87.7 mmol) was added dropwise to a 0° C. solution of 4-ethoxybenzyl alcohol (11.0 g, 72.4 mmol) in dry CH2Cl2 (150 mL) with a catalytic amount of DMF (1 mL). Upon addition, reaction was allowed to stir for 5-10 minutes, while monitoring through TLC (CH2Cl2) for completion. Reaction mixture was concentrated under reduced pressure and the residue dissolved in minimal THF and then precipitated in cold H2O to yield a white precipitate. The solid was collected, taken up in CH2Cl2, dried and concentrated. The resulting oil was solidified by cooling with CO2/acetone. The compound as a white solid, which decomposes upon melting 11.3 g(92%).
Reaction SMILES: [OH:1]C1C=C(C=CC=1)C(N(OC)C)=O.[C:14]1([P:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1C=CC=CC=1CO.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:27]1([P:20](=[O:1])([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CON(C)C(=O)c1cccc(O)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: OCc1ccccn1
Solvent: C1CCOC1
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
To a solution of 1.21 g (10.0 mmol) B2, 2.89 g (11.0 mmol) triphenylphosphine and 1.20 g (11.0 mmol) pyridine-2-methanol in 30 ml dry tetrahydrofuran a solution of 1.92 g (11.0 mmol) diethyl azodicarboxylate in 5 ml dry tetrahydrofuran was added and the mixture was stirred at room temperature for 2 hours. After removal of the solvent and column chromatography on Silica (hexane/ethyl acetate 2:1) 2.81 g B3 were obtained as a light yellow oil (72% yield assuming 30 mol % impurity of triphenylphosphine oxide (measured by NMR)). Due to the problems with the separation of the impurities in this particular example the experiment was repeated with PS-bound triphenylphosphine to give pure B3 in 58% yield.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([CH3:14])[CH:11]=[C:10]([C:15]3[CH:16]=[N:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.[C:25]([NH:29][S:30]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)(=[O:32])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([NH:29][S:30]([C:33]1[CH:34]=[CH:35][CH:36]=[C:37]([C:2]2[CH:7]=[C:6]([C:8]3[N:13]=[C:12]([CH3:14])[CH:11]=[C:10]([C:15]4[CH:16]=[N:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=4)[N:9]=3)[CH:5]=[CH:4][N:3]=2)[CH:38]=1)(=[O:32])=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)nc2)nc(-c2ccnc(Cl)c2)n1
Product: Cc1cc(-c2ccc(C(F)(F)F)nc2)nc(-c2ccnc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)c2)n1

Procedure:
3-{4-[4-Methyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonic acid tert-butylamide was prepared from 2-(2-chloro-pyridin-4-yl)-4-methyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidine (example B.10) (0.175 g, 0.5 mmol) and commercially available 3-(tert.-butylsulfamoyl)-phenylboronic acid (0.15 g, 0.6 mmol) according to the general procedure III. Obtained as off-white solid (0.08 g), which was subsequently deprotected.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]2[C:8](=[O:25])[N:9]([CH2:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:6]=2[N:5]([CH3:26])[C:4]=1[C:27]([NH:29][CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)=[O:28].C1COCC1.[CH2:41]([N:43]=[C:44]=[O:45])[CH3:42]>C(OCC)(=O)C>[CH2:41]([NH:43][C:44]([N:33]1[CH2:32][CH2:31][CH:30]([NH:29][C:27]([C:4]2[N:5]([CH3:26])[C:6]3[C:15]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[N:9]([CH2:16][C:17](=[O:24])[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:8](=[O:25])[C:7]=3[C:3]=2[O:2][CH3:1])=[O:28])[CH2:35][CH2:34]1)=[O:45])[CH3:42]
Reactant: COc1c(C(=O)NC2CCNCC2)n(C)c2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Reactant: CCN=C=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCNC(=O)N1CCC(NC(=O)c2c(OC)c3c(=O)n(CC(=O)c4ccccc4)c4ccccc4c3n2C)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 74.8 %

Procedure:
To a mixture of the compound of Example 77 (200 mg, 0.423 mmol) and THF (10 mL) was added ethyl isocyanate (101 μL, 1.27 mmol) at 0° C., and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by aminosilica gel chromatography (eluate; ethyl acetate). Recrystallization of the obtained solid from ethyl acetate-THF gave the title compound (172 mg, 75%) as a white powder.
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH2:8][C:9]1[C:10]([C:26]2[O:30][C:29]([C:31]3[CH:32]=[C:33]([CH2:37][NH:38]C(=O)OC(C)(C)C)[CH:34]=[CH:35][CH:36]=3)=[N:28][N:27]=2)=[N:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:25])[N:22]([CH3:24])[CH3:23])=[CH:17][CH:16]=2)=[CH:13][N:14]=1.C(=O)(O)[O-]>ClCCl.CO>[NH2:8][C:9]1[N:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([N:22]([CH3:24])[CH3:23])=[O:25])=[CH:19][CH:20]=2)=[N:11][C:10]=1[C:26]1[O:30][C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][NH2:38])[CH:32]=2)=[N:28][N:27]=1
Reactant: CN(C)C(=O)c1ccc(-c2cnc(N)c(-c3nnc(-c4cccc(CNC(=O)OC(C)(C)C)c4)o3)n2)cc1
Agent: O=C([O-])O
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)C(=O)c1ccc(-c2cnc(N)c(-c3nnc(-c4cccc(CN)c4)o3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.1 %

Procedure:
TFA (131.1 mg, 88.58 μL, 1.150 mmol) was added to a solution of tert-butyl N-[[3-[5-[3-amino-6-[4-(dimethylcarbamoyl)phenyl]pyrazin-2-yl]-1,3,4-oxadiazol-2-yl]phenyl]methyl]carbamate (60 mg, 0.1150 mmol) in dichloromethane (2 mL) and the resulting solution stirred at room temperature overnight. The reaction mixture was passed through a bicarbonate cartridge, which was flushed further with methanol (5 mL). The filtrate was concentrated in vacuo to leave a yellow/orange solid. The solid was taken up in a mixture of methanol and dichloromethane and passed through an SCX cartridge. The cartridge was washed initially with methanol and then the product eluted with 2M ammonia in methanol solution over 4 fractions. A yellow solid crystallised out of the filtrate which was isolated by filtration to give the product (44 mg, 90% yield) 1H NMR (400 MHz, DMSO) d 2.98 (m, 6H), 3.87 (s, 2H), 7.55 (m, 2H), 7.59-7.66 (m, 2H), 7.81 (br s, 2H), 8.00 (m, 1H), 8.17 (m, 3H) and 8.99 (s, 1H) ppm; MS (ES+) 416.26
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][CH2:10][C:11]([CH3:14])([CH3:13])[N:12]=2)[O:5][C:6]=1[Br:7].C([N-]C(C)C)(C)C.[Li+].[CH:23]([S:26]C(C)C)([CH3:25])[CH3:24].Cl>O1CCCC1>[Br:1][C:2]1[C:3]([S:26][CH:23]([CH3:25])[CH3:24])=[C:4]([C:8]2[O:9][CH2:10][C:11]([CH3:14])([CH3:13])[N:12]=2)[O:5][C:6]=1[Br:7]
Reactant: CC1(C)COC(c2cc(Br)c(Br)o2)=N1
Reactant: CC(C)SC(C)C
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)Sc1c(C2=NC(C)(C)CO2)oc(Br)c1Br
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A solution of 9.63 g (29.81 mmol) of 2-(4,5-dibromo-2-furanyl)-4,4-dimethyloxazoline in dry tetrahydrofuran (30 mL) is added dropwise to a -78° C. solution of freshly generated lithium diisopropylamide (33.89 mmol, 1.14 equiv) in tetrahydrofuran (80 mL) under an argon atmosphere. The resulting solution is stirred at -78° C. for 10 min and a solution of 5.49 g (46.49 mmol, 1.56 equiv) of isopropyl sulfide in tetrahydrofuran (20 mL) is added dropwise to the reaction. The reaction is stirred for 3.75 hr at -78° to -10° C. and poured onto 5% aqueous HCl (350 mL). The resulting aqueous solution is extracted with diethyl ether (4X). The combined organic extracts are washed with aqueous saturated NaCl, dried (Na2SO4), and concentrated in vacuo. Flash chromatography (SiO2, 7×25 cm, 10% CH2Cl2 /10% ethyl acetate/hexane) affords 7.67 g (11.84 g theo.; 65%) of the desired product as a yellow solid. Recrystallization from hexane affords an analytical sample; mp 71°-72° C.
Reaction SMILES: Cl.[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]([C:10]([OH:12])=[O:11])[CH2:3]2.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([CH:34]([C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=2)O)=[CH:30][CH:29]=1>C1COCC1>[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]([C:10]([O:12][CH:34]([C:31]1[CH:32]=[CH:33][C:28]([Cl:27])=[CH:29][CH:30]=1)[C:36]1[CH:37]=[CH:38][C:39]([Cl:42])=[CH:40][CH:41]=1)=[O:11])[CH2:3]2
Reactant: OC(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: O=C(O)C1CN2CCC1CC2
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: C1CCOC1
Product: O=C(OC(c1ccc(Cl)cc1)c1ccc(Cl)cc1)C1CN2CCC1CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.9 %

Procedure:
Quinuclidine-3-carboxylic acid hydrochloride (150 mg, 0.78 mmol), EDC (225 mg, 1.17 mmol) and HOBT (180 mg, 1.17 mmol) were dissolved in dry THF (7.5 ml). Bis(4-chlorophenyl)methanol (218 mg, 0.86 mmol) was added followed by TEA (382 μl, 2.74 mmol). The resulting reaction was stirred at room temperature overnight. THF was removed under vacuum, and the crude was partitioned between EtOAc and water. The organic phase was washed with sat. NaHCO3, dried over sodium sulphate, filtered, and evaporated to dryness. The crude was purified by flash chromatography (EtOAc/MeOH=8/2 to 7:3+1% of NH4OH) to obtain bis(4-chlorophenyl)methyl quinuclidine-3-carboxylate (85.0 mg, racemic mixture).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[CH:7][C:8]=1F)#[N:2].Cl[C:19]1[CH:36]=[CH:35][C:22]([CH2:23][CH2:24][NH:25][C:26](=[O:34])[C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[C:1]([C:3]1[CH:4]=[C:5]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[CH:7][C:8]=1[O:33][C:30]1[CH:29]=[CH:28][C:27]([C:26](=[O:34])[NH:25][CH2:24][CH2:23][C:22]2[CH:21]=[CH:20][CH:19]=[CH:36][CH:35]=2)=[CH:32][CH:31]=1)#[N:2]
Reactant: O=C(NCCc1ccc(Cl)cc1)c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)Cc1ccc(F)c(C#N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccccc3)cc2)c(C#N)c1
Temperature: 90 °C
Reaction time: 24 h
Yield: 50.7 %

Procedure:
A mixture of tert-butyl 2-(3-cyano-4-fluorophenyl)acetate (0.122 g), N-(4-chlorophenethyl)-4-hydroxybenzamide (0.150 g), and potassium carbonate (0.086 g) was dissolved in 2 ml of DMSO and stirred at 90° C. After 1 day, the reaction was cooled, loaded onto a silica gel sample and product eluted with a solvent system gradient of 0.5% methanol/dichloromethane to 5% methanol/dichloromethane to give tert-butyl 2-(3-cyano-4-(4-(phenethylcarbamoyl)phenoxy)phenyl)acetate (0.120 g).