Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O-2].[Mg+2].[OH:3][CH2:4][CH2:5][N:6]([C:30](=[O:46])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH2:7][CH2:8][N:9]([C:13](=[O:29])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:10][CH2:11][OH:12].[C:47](Cl)(=O)[CH2:48]CCCCCCCCCCCCCC.C(Cl)(=O)CCCCCCC/C=C\CCCCCCCC>O1CCOCC1.O>[OH:3][CH2:4][CH2:5][N:6]([C:30](=[O:46])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH2:7][CH2:8][N:9]([CH2:10][CH2:11][OH:12])[C:13](=[O:29])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:47][CH3:48]
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: CCCCCCCCCCCCCCCC(=O)N(CCO)CCN(CCO)C(=O)CCCCCCCCCCCCCCC
Agent: CCCCCCCC/C=C\CCCCCCCC(=O)Cl
Agent: [Mg+2]
Agent: [O-2]
Solvent: C1COCCO1
Solvent: O
Product: CCCCCCCC/C=C\CCCCCCCC(=O)N(CCO)CCN(CCO)C(=O)CCCCCCCCCCCCCCC
Reaction time: 1 h
Yield: 348.5 %

Procedure:
Into a 500 ml rounded-flask, were introduced 4.0 g of magnesium oxide and 80 g of distilled water. The mixture was stirred. Thereto was added 7.3 g of N,N'-bis(2-hydroxyethyl)-1,2-diaminoethane prepared in Example 27, and then was added 250 ml of 1,4-dioxane. 13.4 g of palmitoyl chloride was gradually added dropwise to the resulting mixture for 1 hour under violent stirring at 10° C. After stirring for 2 hours at 10° C., 14.7 g of oleoyl chloride was gradually added dropwise thereto for 1 hour. After stirring for 2 hours, the mixture was filtered, and then the filtrate was mixed with 200 ml of chloroform, and washed twice with 200 ml of distilled water. The organic phase was cooled to produce solid material, which was recovered by filtration. The solid material was dried and recrystallized from acetone, to give 26.5 g of the title compound as white powder, which was identified by IR and NMR. The results are shown in Table 3.
Reaction SMILES: C(N(CC)CC)C.O=[C:9]([CH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)[CH2:10][C:11]#[N:12].Cl.[CH:20]([NH:23][NH2:24])([CH3:22])[CH3:21]>C(O)C>[CH3:21][CH:20]([N:23]1[C:11]([NH2:12])=[CH:10][C:9]([CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[N:24]1)[CH3:22]
Reactant: CC(C)NN
Reactant: N#CCC(=O)C1CCOCC1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)n1nc(C2CCOCC2)cc1N
Reaction time: 1 h
Yield: 81.6 %

Procedure:
0.43 ml of triethylamine is added to a solution of 640 mg of 3-oxo-3-(tetrahydro-2H-pyran-4-yl)propanenitrile and 347 mg of isopropylhydrazine hydrochloride in 8 ml of ethanol under an argon atmosphere. The mixture is refluxed with magnetic stirring for 1 h and then concentrated to dryness under reduced pressure. The residue is taken up in 100 ml of ethyl acetate and the organic phase is washed twice with 40 ml of a saturated sodium hydrogen carbonate solution. The combined aqueous phases are extracted twice with 50 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate, filtered and concentrated under reduced pressure, so as to obtain 536 mg of 1-(propan-2-yl)-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-amine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([OH:12])=O.C(Cl)(=O)C(Cl)=O.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[CH2:8][CH2:9][C:10]2=[O:12]
Reactant: O=C(O)CCc1ccccc1Br
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C1CCc2c(Br)cccc21
Temperature: 0 °C

Procedure:
4-Bromo-indan-1-one was obtained by the following procedure: A solution of 3-(2-bromo-phenyl)-propionic acid (commercially available from Oakwood Products) (15.0 g, 65.5 mmol) in CH2Cl2 at 0° C. was reacted with oxalyl chloride (7.2 mL, 1.5 eq) followed by 2-3 drops of DMF. The mixture was stirred until no more gas evolution was observed. As the mixture was concentrated and the residue was dissolved in CH2Cl2, cooled to 0° C., and treated with AlCl3 (9.6 g, 1.1 eq). After 1 h the mixture was quenched with water and the layers were separated. The aqueous layer was extracted with Et2O (3×150 mL) and the combined organic extracts were washed with H2O (3×100 mL), saturated NaHCO3 (3×100 mL), brine (1×100 mL), dried over MgSO4 and concentrated. 4-Bromoindan-1-one, 10.5 g (76%) was obtained by chromatography using 10% EtOAc:hexane as eluant. Use of 4-bromo-indan-1-one in Method NINETEEN produced 4-(4-bromo-indan-2-yl)-1,3-dihydro-imidazole-2-thione (Compound 149).
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([CH2:12][CH2:13][CH2:14]Br)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[C:16]1([CH:23]=[CH:22][C:20]([OH:21])=[CH:19][CH:18]=1)[OH:17].C(=O)([O-])[O-].[K+].[K+].CC(=O)CC>O>[CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([CH2:12][CH2:13][CH2:14][O:17][C:16]2[CH:23]=[CH:22][C:20]([OH:21])=[CH:19][CH:18]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: Oc1ccc(O)cc1
Reactant: CCCCC[C@H]1CC[C@H](CCCBr)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: CCCCC[C@H]1CC[C@H](CCCOc2ccc(O)cc2)CC1
Yield: 52.4 %

Procedure:
A mixture of 5.0 g of 3-(trans-4-pentylcyclohexyl)-1-propyl bromide, 10.0 g of hydroquinone, 10.0 g of anhydrous potassium carbonate and 250 ml of absolute butanone was heated under reflux overnight. Subsequently, the cooled reaction mixture was poured into water and extracted three times with 100 ml of dichloromethane each time. The combined organic phases were washed with 500 ml of water, dried over magnesium sulfate, filtered and concentrated. Chromatography of the residue on silica gel with toluene/ethyl acetate (vol. 4:1) gave 2.9 g of 4-[3-(trans-4-pentylcyclohexyl)-1-propyloxy]phenol; m.p. 100°-101° C.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:25][C:17]3=[C:18]4[C:22](=[CH:23][CH:24]=[C:16]3[O:15][CH2:14]2)[NH:21][CH:20]=[CH:19]4)(=O)=O)=CC=1.[NH:26]1[CH2:31][CH:30]=[C:29]([C:32]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[NH:34][CH:33]=2)[CH2:28][CH2:27]1>CS(C)=O.C(OCC)(=O)C>[NH:34]1[C:35]2[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:32]([C:29]2[CH2:30][CH2:31][N:26]([CH2:12][CH:13]3[O:25][C:17]4=[C:18]5[C:22](=[CH:23][CH:24]=[C:16]4[O:15][CH2:14]3)[NH:21][CH:20]=[CH:19]5)[CH2:27][CH:28]=2)=[CH:33]1
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4[nH]ccc4c3O2)cc1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: C1=C(c2c[nH]c3ccccc23)CCN(CC2COc3ccc4[nH]ccc4c3O2)C1

Procedure:
A solution of 0.65 g (1.8 mmole) of (2R)-2,3-dihydro-7H-[1,4]dioxino[2,3-e]indol-2-ylmethyl 4-methylbenzenesulfonate and 0.71 g (3.6 mmole) of 3-(1,2,3,6-tetrahydro-4-pyridinyl )-1H-indole in 30 mL of DMSO was heated at 65° C. for 4 hours. The mixture was diluted with 300 mL of ethyl acetate, washed with 200 ml portions of saturated aqueous sodium bicarbonate and saturated brine, dried over magnesium sulfate, filtered and concentrated in vacuum. The residue was column chromatographed on silica gel with 2-4% methanol in methylene chloride as eluant. The product fractions were combined and concentrated in vacuum, and the residue triturated with methylene chloride/hexane (1:1) to give 0.39 g of the (S)-enantiomer of the title compound as a yellow solid, m.p. 126° C., which retains one equivalent of DMSO.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:26])[N:10]([CH2:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([CH2:19][O:20][CH2:21][CH2:22][CH2:23][CH2:24]Br)[CH2:15][CH2:14]2)[CH3:11])=[CH:4][CH:3]=1.[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>CN(C)C(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:26])[N:10]([CH3:11])[CH2:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([CH2:19][O:20][CH2:21][CH2:22][CH2:23][CH2:24][N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH2:15][CH2:14]2)=[CH:4][CH:3]=1
Reactant: CN(C[C@H]1CC[C@H](COCCCCBr)CC1)C(=O)Oc1ccc(Cl)cc1
Reactant: C1CCNC1
Solvent: CC(=O)N(C)C
Product: CN(C[C@H]1CC[C@H](COCCCCN2CCCC2)CC1)C(=O)Oc1ccc(Cl)cc1

Procedure:
In analogy to the method described in example 12.1, trans-[4-(4-bromo-butoxymethyl)-cyclohexylmethyl]-methyl-carbamic acid 4-chloro-phenyl ester was reacted with pyrrolidine in N,N-dimethylacetamide at 50° C. for 2 hours to yield trans-methyl-[4-(4-pyrrolidin-1-yl-butoxymethyl)-cyclohexylmethyl]-carbamic acid 4-chloro-phenyl ester as colorless viscous oil, MS: 437 (MH+, 1Cl).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:6]=1[C:7]([O:9][CH:10]([CH3:12])[CH3:11])=[O:8])(=[O:4])=[O:3].[CH2:18]([N:22]=[C:23]=[O:24])[CH2:19][CH2:20][CH3:21].C([O-])([O-])=O.[K+].[K+]>CC(=O)CC>[CH2:18]([NH:22][C:23]([NH:1][S:2]([C:5]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:6]=1[C:7]([O:9][CH:10]([CH3:12])[CH3:11])=[O:8])(=[O:4])=[O:3])=[O:24])[CH2:19][CH2:20][CH3:21]
Reactant: CC(C)OC(=O)c1ccc(Cl)cc1S(N)(=O)=O
Reactant: CCCCN=C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCNC(=O)NS(=O)(=O)c1cc(Cl)ccc1C(=O)OC(C)C
Temperature: 25 °C
Yield: 49.5 %

Procedure:
A mixture of 1063.4 g of isopropyl 2-(aminosulfonyl)-4-chlorobenzoate, 590.4 g of n-butyl isocyanate and 590.4 g of K2CO3 in 10.8 liters of 2-butanone are heated under reflux overnight. After cooling to room temperature, the reaction mixture is in each case poured into 10 liters of ice-water. The aqueous phase is extracted with 9 liters of methylene chloride. The aqueous phase is acidified to pH 1.0 using concentrated HCl, and the resulting precipitate is filtered off. After drying, 714.6 g of isopropyl 2-[N-(N-butylaminocarbonyl)aminosulfonyl]-4-chlorobenzoate (44% of theory) of melting point 129-132° C. are obtained.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].C([Li])CCC.CN(C)CCN(C)C.[Br:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31]Br)=[C:27]([CH2:33]Br)[CH:26]=1>C1COCC1>[Br:24][C:25]1[CH:26]=[C:27]2[C:28](=[CH:29][CH:30]=1)[CH2:31][C:3]1([C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]1=[O:10])[CH2:33]2
Reactant: O=C1Cc2ccccc2N1
Reactant: BrCc1ccc(Br)cc1CBr
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C1Nc2ccccc2C12Cc1ccc(Br)cc1C2
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of oxindole (363 mg, 2.73 mmol) at −78° C. in THF (15 mL) was added butyllithium (2.5 M in hexanes, 2.29 mL, 5.73 mmol) drop wise, followed by the drop wise addition of tetramethylethylenediamine (0.905 mL, 6.00 mmol). The solution was stirred for 1 h at −78° C., then a solution of 4-bromo-1,2-bis(bromomethyl)benzene [Anderson et al., J. Org. Chem. 1979, 44(9), 1519-1533] (1.87 g, 5.45 mmol) in THF (5 mL) was added drop wise. The reaction solution was stirred at −10 to −20° C. for 2 h and at ambient temperature for 16 h. The reaction mixture was partitioned between saturated NH4Cl (50 mL) and EtOAc (50 mL). The aqueous phase was further extracted with EtOAc (2×50 mL), and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc-100:0 to 50:50, to give the title compound. MS: m/z=315 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:23][CH2:24][CH3:25])[N:14]([CH2:15][C:16]([CH3:22])([CH3:21])[CH2:17][C:18](=O)[CH3:19])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.Cl.[CH3:27][O:28][NH2:29]>>[CH3:27][O:28][N:29]=[C:18]([CH2:17][C:16]([CH3:22])([CH3:21])[CH2:15][N:14]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:1])[C:11]=2[N:12]=[C:13]1[CH2:23][CH2:24][CH3:25])[CH3:19]
Reactant: CON
Reactant: CCCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)CC(C)=O
Agent: Cl
Product: CCCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)CC(C)=NOC

Procedure:
By the general method of Part F in Example 30, 5-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)-4,4-dimethylpentan-2-one was reacted with O-methylhydroxylamine hydrochloride to provide 5-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)-4,4-dimethylpentan-2-one O-methyloxime as about a 49 to 1 mixture of E and Z isomers as a yellow solid after recrystallization from aqueous methanol, mp 196-198° C. MS (APCI) m/z 368 (M+H)+; Anal. calcd for C21H29N5O: C, 68.63; H, 7.95; N, 19.06. Found: C, 68.69; H, 7.66; N, 19.04.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:21])[CH2:10][O:11][C:12]1[CH:16]=[C:15]([C:17]([O:19][CH3:20])=[O:18])[NH:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([N:14]1[C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:16][C:12]([O:11][CH2:10][C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH3:21])=[N:13]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)c1cc(OC[C@H](C)NC(=O)OC(C)(C)C)n[nH]1
Reactant: BrCc1ccccc1
Product: COC(=O)c1cc(OC[C@H](C)NC(=O)OC(C)(C)C)nn1Cc1ccccc1

Procedure:
Using methyl 3-({(2S)-2-[(tert-butoxycarbonyl)amino]propyl}oxy)-1H-pyrazole-5-carboxylate and (bromomethyl)benzene, and in the same manner as in Example 1, step A (reaction temperature was room temperature), the title compound was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH:7]=[CH:8][O:9][C:4]=2[CH:3]=1.Br[CH2:14][CH2:15][CH2:16][Cl:17].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:17][CH2:16][CH2:15][CH2:14][O:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH:7]=[CH:8][O:9][C:4]=2[CH:3]=1
Reactant: ClCCCBr
Reactant: O=c1ccoc2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=c1ccoc2cc(OCCCCl)ccc12

Procedure:
A mixture of 7-hydroxy-4H-1-benzopyran-4-one, VII (40.5 g; 0.25 mole; prepared according to G. N. Dorafeenko and V. V. Tkachenko, Chem. Heterocyclic Compounds, 1972 (8) 935), 1-bromo-3-chloropropane (78.5 g; 0.50 mole) and anhydrous potassium carbonate (49 g; 0.50 mole) in 1000 ml of acetone was heated at reflux for 16 hours. The mixture was filtered through celite and concentrated in vacuo. The thick red oil which remained was triturated with ether, upon which 57.8 g (97%) of the title compound was obtained, mp 72°-73° C.
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([Cl:10])[C:7]([F:11])=[CH:6][C:3]=1[C:4]#[N:5].[NH2:12][C:13]1[CH:14]=[C:15]([CH:21]=[CH:22][C:23]=1[CH3:24])[C:16]([NH:18][O:19][CH3:20])=[O:17].C(N(CC)CC)C>C(#N)C>[C:4]([C:3]1[C:2]([NH:12][C:13]2[CH:14]=[C:15]([CH:21]=[CH:22][C:23]=2[CH3:24])[C:16]([NH:18][O:19][CH3:20])=[O:17])=[N:9][C:8]([Cl:10])=[C:7]([F:11])[CH:6]=1)#[N:5]
Reactant: N#Cc1cc(F)c(Cl)nc1Cl
Reactant: CONC(=O)c1ccc(C)c(N)c1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CONC(=O)c1ccc(C)c(Nc2nc(Cl)c(F)cc2C#N)c1
Temperature: 70 °C
Yield: 20.5 %

Procedure:
A mixture of 2,6-dichloro-5-fluoro-nicotinonitrile (830 mg, 4.34 mmol), 3-amino-N-methoxy-4-methyl-benzamide (576 mg, 3.2 mmol) and triethylamine (0.5 mL) in acetonitrile (10 mL) was heated to 70° C. overnight. Then the solvent was removed under reduced pressure and the reaction mixture was partitioned between water and ethyl acetate. The organic layer was dried (sodium sulfate) and concentrated under reduced pressure. The product (220 mg, 21%) was isolated after purification by silica gel chromatography. C15H12ClFN4O2 MS m/e=335 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]([CH:10]([CH3:12])[CH3:11])[C:7](=O)[NH:8][C:4]=2[CH:3]=1.P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:7]1[N:6]([CH:10]([CH3:12])[CH3:11])[C:5]2[CH:13]=[CH:14][C:2]([Cl:1])=[CH:3][C:4]=2[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)n1c(=O)[nH]c2cc(Cl)ccc21
Product: CC(C)n1c(Cl)nc2cc(Cl)ccc21
Temperature: 0 °C
Yield: 82.9 %

Procedure:
5-Chloro-1-isopropylbenzimidazol-2-one (81 g) in phosphorus oxychloride (207 g) was refluxed for 1 hour. The mixture was left to stand for cooling and then the reaction mixture was poured into ice-water and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous sodium hydroxide solution, water and dried over anhydrous magnesium sulfate and then the solvent was distilled off under reduced pressure. To the residue was added acetonitrile (400 ml) and the insoluble material was removed by filtration and the solvent was distilled off under reduced pressure to give 2,5-dichloro-1-isopropylbenzimidazole (73 g). A part of the obtained product was subjected to silica gel column chromatography [eluted with chloroform] and recrystallized from hexane, which showed the following physical properties:
Reaction SMILES: [Br:1][C:2]1[C:3]([O:20][CH3:21])=[CH:4][C:5]([Cl:19])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH3:18])=[CH:12][CH:11]=2)=O)[CH:7]=1.[C:22](#N)[CH3:23].C([SiH](CC)CC)C.B(F)(F)F.CCOCC>ClCCl>[CH2:21]([O:20][C:3]1[CH:4]=[C:5]([Cl:19])[C:6]([CH2:8][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH3:18])=[CH:12][CH:11]=2)=[CH:7][C:2]=1[Br:1])[CH:22]=[CH2:23]
Reactant: CC#N
Reactant: CCOc1ccc(C(=O)c2cc(Br)c(OC)cc2Cl)cc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: C=CCOc1cc(Cl)c(Cc2ccc(OCC)cc2)cc1Br
Temperature: 0 °C

Procedure:
To a stirred −10° C. solution of (5-Bromo-2-chloro-4-methoxyphenyl)(4-ethoxyphenyl)methanone (54.3 mmol) from Step 4 in dichloromethane (150 mL)/acetonitrile (150 mL) was added triethylsilane (20 mL, 109 mmol) followed by boron trifluoride diethyl etherate (16 mL, 109 mmol) at −10° C. The solution was allowed to warm to 0° C. over 2 h prior to quenching with saturated sodium carbonate solution. After removal of organic volatiles under reduced pressure, the residue was partitioned between ethyl acetate and water. Following extraction of the aqueous layer with ethyl acetate, the combined organic layers were washed with water prior to drying over magnesium sulfate. Filtration and concentration under reduced pressure yielded the title compound as a yellowish solid which was used without further purification.
Reaction SMILES: [C:1]([O:5][CH:6]([C:10]1[C:19]([CH3:20])=[CH:18][C:17]2[C:12](=[CH:13][C:14]([C:21]#[C:22][CH:23]3[CH2:25][CH2:24]3)=[CH:15][CH:16]=2)[C:11]=1[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]>CC#N.O>[C:1]([O:5][CH:6]([C:10]1[C:19]([CH3:20])=[CH:18][C:17]2[C:12](=[CH:13][C:14]([CH2:21][CH2:22][CH:23]3[CH2:25][CH2:24]3)=[CH:15][CH:16]=2)[C:11]=1[C:26]1[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc2ccc(C#CC3CC3)cc2c(-c2ccc(Cl)cc2)c1C(OC(C)(C)C)C(=O)O
Solvent: O
Solvent: CC#N
Product: Cc1cc2ccc(CCC3CC3)cc2c(-c2ccc(Cl)cc2)c1C(OC(C)(C)C)C(=O)O

Procedure:
2-tert-Butoxy-2-(1-(4-chlorophenyl)-7-(2-cyclopropylethyl)-3-methylnaphthalen-2-yl)acetic acid (92) was prepared using the procedure of Example 87 from 2-tert-butoxy-2-(1-(4-chlorophenyl)-7-(cyclopropylethynyl)-3-methylnaphthalen-2-yl)acetic acid. 1H-NMR: 400 MHz, (CD3OD) δ: 7.73 (d, J=9 Hz, 1H), 7.67 (s, 1H), 7.60 (m, 3H), 7.35 (m, 2H), 7.06 (s, 1H), 5.21 (s, 1H), 2.72 (t, J=7 Hz, 2H), 2.62 (s, 3H), 1.48 (m, 2H), 0.94 (s, 9H), 0.65 (m, 1H), 0.37 (m, 2H), 0.01 (m, 2H). HPLC (Kinetex 2.6u, 50×4.6 mm, 2-100% MeCN/H2O+0.05% HOAc, 5.0 min run): tR (min)=4.02.
Reaction SMILES: Cl[C:2]1[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=[C:6]([Cl:8])[N:7]=1.[NH3:11]>O1CCOCC1>[NH2:11][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=[C:6]([Cl:8])[N:7]=1
Reactant: N
Reactant: Cn1cc(Cl)nc(Cl)c1=O
Solvent: C1COCCO1
Product: Cn1cc(Cl)nc(N)c1=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 3,5-dichloro-1-methyl-2(1H)-pyrazinone (7.16 g, 0.040 mol) in dioxane (120 mL) was treated with a concentrated aqueous solution of ammonia (28%, 16 mL, 0.24 mol). After stirring at room temperature for three days a suspension of solid had formed. The solid was collected, rinsed with a little water, ether, and hexanes and air dried. The product, 3-amino-5-chloro-1-methyl-2(1H)-pyrazinone, was obtained as a white crystalline powder (4.81 g) melting above 250° C.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:27])=[C:8]2[C:16]([Cl:17])=[C:15]([Cl:18])[N:14]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])C.[NH2:28][CH2:29][C:30]([OH:32])=[O:31].C[O-].[Na+].CO>>[Cl:18][C:15]1[N:14]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=[C:6]([C:4]([NH:28][CH2:29][C:30]([OH:32])=[O:31])=[O:5])[C:7]([OH:27])=[C:8]2[C:16]=1[Cl:17]
Reactant: CCOC(=O)c1nc(C#N)c2c(c1O)c(Cl)c(Cl)n2Cc1cccc(F)c1
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2c(Cl)c(Cl)n(Cc3cccc(F)c3)c12

Procedure:
Prepared in analogy to that of Example 1(e) from 2,3-dichloro-7-cyano-1-(3-fluoro-benzyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, glycine and NaOMe/HOMe. The title compound, ESI MS (m/z): 437 (M+H)+.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18]([C:23](O)=[O:24])=[C:17]2[S:26]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)(=[O:28])=[O:27].[NH2:35][CH2:36][CH2:37][C:38]1[N:42]=[CH:41][NH:40][CH:39]=1>O>[NH:40]1[CH:39]=[C:38]([CH2:37][CH2:36][NH:35][C:23]([C:18]2[NH:19][C:20]3[C:16]([C:17]=2[S:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=[O:28])=[O:27])=[CH:15][C:14]([Cl:13])=[CH:22][CH:21]=3)=[O:24])[N:42]=[CH:41]1
Reactant: O=C(O)c1[nH]c2ccc(Cl)cc2c1S(=O)(=O)c1ccccc1
Reactant: NCCc1c[nH]cn1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Product: O=C(NCCc1c[nH]cn1)c1[nH]c2ccc(Cl)cc2c1S(=O)(=O)c1ccccc1
Reaction time: 0.5 h

Procedure:
Carbonyldiimidazole (180 mg, 1.11 mmol) was added to a solution of 5-chloro-3-phenylsulfonylindole-2-carboxylic acid (Example 27, Step A) (336 mg, 0.5 mmol) cooled in an ice bath under an inert atmosphere. After 0.5 hours, histamine (125 mg, 1.12 mmol) was added to the yellow solution. After 5 hours the reaction was diluted with water and the product extracted into ethyl acetate. This organic layer was washed with dilute aq. NaHCO3, dried (Na2SO4), filtered through charcoal and the solvents evaporated. Trituration of this residue with methylene chloride gave the crude product. Crystallization from hot ethyl acetate gave analytically pure product, mp 220°-221.5° C.
Reaction SMILES: O[CH:2]([C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[C:24]#[N:25])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5](/[CH:9]=[CH:10]/[C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=2)[CH:4]=1.[ClH:29]>ClCCl.O.C(=O)(O)[O-].[Na+]>[Cl:29][CH:2]([C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[C:24]#[N:25])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5](/[CH:9]=[CH:10]/[C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=2)[CH:4]=1
Reactant: Cl
Reactant: N#Cc1cccc(C(O)c2cccc(/C=C/c3ccc4ccccc4n3)c2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: N#Cc1cccc(C(Cl)c2cccc(/C=C/c3ccc4ccccc4n3)c2)c1

Procedure:
A suspension of the 3-[α-hydroxy-3-{2(E)-(quinolin-2-yl)ethenyl}benzyl]benzonitrile (1.4 g, 3.87 mmol) in dichloromethane (75 ml) was stirred with concentrated hydrochloric acid (75 ml) for 3 hours, diluted with water and neutralised with saturated sodium bicarbonate solution. The aqueous layer was extracted with further dichloromethane and the combined solvent was dried and evaporated to a pale solid.