Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][CH:11]([CH3:13])[CH3:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.ClC(OCC(C)C)=O.[NH2:32][C:33]1[CH:42]=[C:41]2[C:36]([CH:37]=[C:38]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:39](=[O:43])[O:40]2)=[CH:35][CH:34]=1>O1CCCC1>[C:1]([NH:8][C@H:9]([C:14]([NH:32][C:33]1[CH:42]=[C:41]2[C:36]([CH:37]=[C:38]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:39](=[O:43])[O:40]2)=[CH:35][CH:34]=1)=[O:16])[CH2:10][CH:11]([CH3:12])[CH3:13])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1ccc2cc(-c3ccccc3)c(=O)oc2c1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc2cc(-c3ccccc3)c(=O)oc2c1
Reaction time: 0.17 h

Procedure:
To a solution of 1.16 g (5 mmol) of Boc-L-leucine and 0.70 ml (5 mmol) of triethylamine in 12 mL of tetrahydrofuran (dried over sodium/lead alloy) at -15° was added 0.66 mL (5 mmol) of i-butyl chloroformate. After 10 min., 1.19 g (5 mmol) of 7-amino-3-phenylcoumarin suspended in 6 mL of tetrahydrofuran was added. The mixture was stirred at -15° for 30 min. and then overnight at room temperature. The reaction mixture was then reduced to dryness on a rotary evaporator at 1.6 kPa and 60°. The residue was taken up in 100 mL of ethyl acetate, washed twice with 25-mL portions of 1 N aqueous sodium bicarbonate and twice with 25-mL portions of saturated sodium chloride, dried over anhydrous magnesium sulfate, filtered, and evaporated. The residue was dried overnight at room temperature and 3 Pa to yield 1.91 g. (84.8%) of crude product as a yellow foam which was purified by chromatography on a silica gel column eluted first with methylene chloride and then with 5% methanol in methylene chloride. Product recovery was 66.5%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]([N:9]2[CH2:13][CH2:12][S:11][C:10]2=S)=[O:8])=[C:5]([O:17][CH2:18][O:19][CH3:20])[CH:4]=1.[NH2:21]C1SCCN=1.[OH-].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]([NH:9][C:10]2[S:11][CH2:12][CH2:13][N:21]=2)=[O:8])=[C:5]([O:17][CH2:18][O:19][CH3:20])[CH:4]=1
Reactant: COCOc1cc(OC)ccc1C(=O)N1CCSC1=S
Reactant: NC1=NCCS1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COCOc1cc(OC)ccc1C(=O)NC1=NCCS1
Reaction time: 20 h

Procedure:
12.36 g of the thus produced N-(4-methoxy-2-methoxymethoxybenzoyl)thiazolidine-2-thion and 8.36 g of 2-aminothiazoline was dissolved in 150 ml of tetrahydrofuran, and the solution was agitated for 20 hours. To the solution was added 2N aqueous solution of sodium hydroxide. The mixture was extracted with methylene chloride and the extract was dried over anhydrous sodium sulfate. The solvent was distilled off in evacuated atomosphere, and the residue was subjected to column chromatography using silica gel. There was obtained 10.15 g of 2-(4-methoxy-2-methoxymethoxybenzoylamino)thiazoline from fractions eluted with methylene chloride.
Reaction SMILES: Cl.[CH2:2]([S:4][C:5]1[N:6]([C:10]2[CH:15]=[CH:14][C:13](C)=[CH:12][CH:11]=2)[CH:7]=[CH:8][N:9]=1)[CH3:3].Br.C(O)(=[O:20])C>>[CH2:2]([S:4][C:5]1[N:6]([C:10]2[CH:15]=[CH:14][C:13]([OH:20])=[CH:12][CH:11]=2)[CH:7]=[CH:8][N:9]=1)[CH3:3]
Reactant: CCSc1nccn1-c1ccc(C)cc1
Reactant: CC(=O)O
Agent: Br
Agent: Cl
Product: CCSc1nccn1-c1ccc(O)cc1
Yield: 72.5 %

Procedure:
A mixture of 14 parts of 2-(ethylthio)-1-(4-methylphenyl)-1H-imidazole monohydrochloride and 113 parts of hydrobromic acid solution 48% in glacial acetic acid is stirred and refluxed for 3 hours. The reaction mixture is evaporated and the residue is dissolved in water. The solution is neutralized with sodium hydrogen carbonate. The precipitated product is filtered off and crystallized from 2-propanol, yielding 8.3 parts (72.5%) of 4-[2-(ethylthio)-1H-imidazol-1-yl]phenol; mp. 165.2° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-:23].[K+].[K+]>O1CCOCC1.O>[O:23]=[C:2]1[N:7]=[C:6]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:5]=[CH:4][NH:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccnc(Cl)n2)CC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc[nH]c(=O)n2)CC1
Temperature: 25 °C
Yield: 103.5 %

Procedure:
A mixture of tert-butyl 4-(2-chloropyrimidin-4-yloxy)piperidine-1-carboxylate (341.5 mg, 0.90 mmol), potassium carbonate (225.6 mg, 1.64 mmol, EMD) and 1,4-diazacyclo[2,2,2]octane (48.8 mg, 0.44 mmol, commercially available from Alfa Aesar) in dioxane/H2O (10 mL/10 mL) was heated at 70° C. for 6 h, cooled to room temperature and then evaporated. The residual was purified by flash chromatography (0 to 10% MeOH/CH2Cl2) to yield 275 mg (85%) of the product as an off-white solid.
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.ClC(Cl)C.[CH3:13][C:14](=O)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[I:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH3:13])=[CH:4][CH:3]=1
Reactant: CCCCCCC(C)=O
Reactant: Nc1ccc(I)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CCCCCCC(C)Nc1ccc(I)cc1
Reaction time: 0.17 h
Yield: 88 %

Procedure:
A flask containing 4-iodoaniline (11.0 g, 50.2 mmol)was charged with dry dichloroethane (125 ml), 2-octanone (7.9 ml, 50.0 retool) and sodium triacetoxyborohydride (13.8 g, 65 retool). After stirring for 10 minutes, acetic acid (2.9 ml, 50.7 retool) was added via syringe over a 5 minute period. The reaction was stirred under an N2 atmosphere for 16 hrs. At the end of this period the reaction was quenched by the careful addition of a solution of saturated aqueous ammonium chloride (100 ml). After stirring for 0.5 hr, the reaction was poured over ether (250 ml) andthe layers were separated. The ether layer was washed with saturated aqueous ammonium chloride (100 ml), dried (Na2SO4), filtered and evaporated in vacuo. Flash column chromatography (silica, 1:39; EtOAC:hexanes) provided N-(4'-iodophenyl)-2-amino octane (14.6 g, 88%) as a light yellow oil.
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][CH:9]=[O:10])=[C:6]([Cl:11])[N:5]=[C:4]([NH:12][CH:13]=[O:14])[N:3]=1.[CH3:15][O:16][CH2:17][O:18][CH2:19][CH2:20][CH2:21][O:22][NH2:23].C(N(CC)C(C)C)(C)C>COCCOCCOC>[Cl:11][C:6]1[C:7]([NH:8][CH:9]=[O:10])=[C:2]([NH:23][O:22][CH2:21][CH2:20][CH2:19][O:18][CH2:17][O:16][CH3:15])[N:3]=[C:4]([NH:12][CH:13]=[O:14])[N:5]=1
Reactant: COCOCCCON
Reactant: O=CNc1nc(Cl)c(NC=O)c(Cl)n1
Solvent: COCCOCCOC
Solvent: CCN(C(C)C)C(C)C
Product: COCOCCCONc1nc(NC=O)nc(Cl)c1NC=O
Temperature: 100 °C

Procedure:
A mixture of 4,6-dichloro-2,5-diformamidopyrimidine (1.75 g, 7.4 mmol), 3-(methoxymethoxy)propoxyamine (1.0 g, 7.4 mmol) and N,N-diisopropylethylamine (2 g, 15.5 mmol) in dry diglyme was heated to 100° C. for 2 hr. The cooled reaction mixture was filtered and the filtrate was evaporated in vacuo. The residue was purified by column chromatography on silica eluting with ethyl acetate:hexane (50:50) then ethyl acetate to give the title compound as a yellow oil which was crystallised from ethyl acetate (1.2 g, 50%) mp 136°-8° C. νmax (KBr) 3240, 2920, 2880, 1705, 1640, 1590, 1565, 1495, 14650, 1410, and 1380 cm-1 ; δH [(CD3)2SO]1.85 (2H, quintet, J=6.3 Hz, CH2CH2CH2), 3.24 (3H, s, OCH3), 3.58 (2H, t, J=6.3 Hz, CH2OCH2OCH3 ), 3.94 (2H, t, J=6.3 Hz, CH2ONH), 4.5 (2H, s, OCH2O), 8.15 (1H, s, NHCHO), 9.26 (1H, d, J=9.6 Hz, collapses to singlet on D2O, NHCHO), 9.4 (1H, s, D2O exchangeable NHOCH2), 10.73 (1H, s, D2O, exchangeable NHCHO), 10.84 (1H, d, J=9.6 Hz, D2O exchangeable, NHCHO).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:14](O)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[CH2:25][N:26]=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1.CN.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:14](=[O:15])[NH:26][CH3:25])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2ccccc2)(C(=O)O)CC1
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)C1(Cc2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.25 h
Yield: 93.6 %

Procedure:
N-tert-butyloxycarbonyl-4-benzylpiperidine-4-carboxylic acid (3.0 g; 9.0 mmol) was dissolved in methylene chloride (25 ml) and EDAC (1.8 g; 9.0 mmol) and HOAt (1.3 g; 9.0 mmol) was added. The mixture was stirred for 15 min, then methyl amine (33% in ethanol; 2.3 ml; 18 mmol) and DIEA (1.6 ml; 9.0 mmol) was added and the mixture was stirred overnight. Methylene chloride (100 ml) was added and the mixture was washed with a saturated aqueous solution of sodium hydrogen carbonate (50 ml) and a aqueous solution of sodium hydrogensulfate (10%, 50 ml), dried (MgSO4) and evaporated in vacuo. The residue was chromatographed on silica (90 g) using a mixture of aqueous ammonia/ethanol/methylene chloride (1:7:92) as eluent to afford 2.8 g of 4-benzyl-4-methylcarbamoylpiperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [Br:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([OH:11])=[C:4]([F:12])[CH:3]=1.[C:13](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[CH3:13][O:11][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([Br:1])=[CH:3][C:4]=1[F:12]
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1cc(O)c(F)cc1Br
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cc([N+](=O)[O-])c(Br)cc1F
Reaction time: 5 h
Yield: 96.6 %

Procedure:
A solution of 4-bromo-2-fluoro-5-nitrophenol (25 g, 106 mmol) in DMF (200 mL) was treated with potassium carbonate (28.9 g, 212 mmol) and methyl iodide (12.8 mL, 212 mmol). The reaction mixture was stirred at 60 C for 5 hours and evaporated in vacuo. The mixture was partitioned between water and ethyl acetate. The organic layer was dried over magnesium sulfate and evaporated under vacuum to afford the product (25.6 g, 97%) as a yellow solid. LC-MS (ES) (M+H)+ m/z=251.
Reaction SMILES: CO.[CH:3]([C@@H:5]1[C@@H:14]2[C@@H:8]([O:9][CH2:10][C@@H:11]([CH2:15][CH2:16][CH2:17][C:18]([O:20][CH:21](C)C)=[O:19])[CH2:12][CH2:13]2)[CH2:7][C@H:6]1[O:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][O:26]1)=O.[C:31](=O)([O-])[O-].[K+].[K+].C/C(/[O-])=C(/P(OC)(OC)=O)\[N+]#N>C(OCC)(=O)C>[C:3]([C@@H:5]1[C@@H:14]2[C@@H:8]([O:9][CH2:10][C@@H:11]([CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH2:12][CH2:13]2)[CH2:7][C@H:6]1[O:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][O:26]1)#[CH:31]
Reactant: O=C([O-])[O-]
Reactant: CC(C)OC(=O)CCC[C@H]1CC[C@@H]2[C@@H](C=O)[C@H](OC3CCCCO3)C[C@@H]2OC1
Agent: COP(=O)(OC)/C([N+]#N)=C(/C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: C#C[C@@H]1[C@H]2CC[C@H](CCCC(=O)OC)CO[C@H]2C[C@H]1OC1CCCCO1
Temperature: 25 °C
Reaction time: 6 h
Yield: 28.4 %

Procedure:
To a methanol solution (2.3 mL) of the compound (180 mg) produced in Example 13, potassium carbonate (94 mg) and a Bestmann reagent (dimethyl-1-diazo-2-oxopropyl phosphonate) (105 mg) were added, followed by stirring at room temperature for 6 hours. Further, potassium carbonate (47 mg) and the Bestmann reagent (53 mg) were added, followed by stirring at room temperature overnight. The reaction mixture was cooled to 0° C.; diluted with ethyl acetate; and then separated by adding water. The organic layer was washed with water and a saturated saline; dried with magnesium sulfate; then filtered; and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=97:3→65:35) to obtain a titled compound (47 mg) having the following physical property values.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:6]([C:8]1[CH:13]=[CH:12][C:11](OC)=[C:10](OC)[CH:9]=1)=[O:7].[C:23]1(OC)[C:24](=CC=[CH:29][CH:30]=1)OC.[Cl-].[Al+3].[Cl-].[Cl-].C1(C(Cl)=O)C2C(=CC=CC=2)C=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:6]([C:8]1[C:9]2[C:10](=[CH:24][CH:23]=[CH:30][CH:29]=2)[CH:11]=[CH:12][CH:13]=1)=[O:7]
Reactant: COc1ccc(C(=O)c2ccc(OC)c(OC)c2)cc1OC
Reactant: COc1ccccc1OC
Agent: O=C(Cl)c1cccc2ccccc12
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc(C(=O)c2cccc3ccccc23)cc1OC

Procedure:
1-(3,4-Dimethoxybenzoyl)naphthalene was prepared analogously to 3,4,3′,4′-tetramethoxybenzophenone using veratrole (1.3 mL, 10 mmol), aluminum chloride (1. 5 g, 11 mmol) and 1-naphthoyl chloride (1.5 mL, 10 mmol) with a reaction time of 24 hours at room temperature. The crude product was purified by flash column chromatography (silica gel, 2.5% ethyl acetate/methylene chloride) to afford 1.85 g (63%) of the product as a white solid: mp 92.5-94.5° C.; 1H NMR (CDCl3) δ 8.06-7.84 (m, 3 H), 7.80-7.39 (m, 5 H), 7.31-7.21 (m, 1 H), 6.84-6.74 (m, 1 H), 3.94 (s, 3 H), 3.91 (s, 3 H); 13C NMR (CDCl3) δ 196.6, 153.5, 149.0, 136.8, 133.6, 131.1, 130.9, 130.5, 128.2, 126.9, 126.7, 126.3, 126.3, 125.6, 124.3, 111.3, 109.7, 56.0, 55.9; Anal. Calcd for C19H16O3. Theoretical: C, 78.06; H, 5.52. Found: C, 77.97; H, 5.66.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=3[OH:22])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[F:23][C:24]1[CH:25]=[CH:26][C:27]([OH:33])=[C:28](B(O)O)[CH:29]=1>>[F:23][C:24]1[CH:29]=[CH:28][C:27]([OH:33])=[C:26]([C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]4[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=4[OH:22])[N:9]=3)[CH:5]=[CH:4][CH:3]=2)[CH:25]=1
Reactant: OB(O)c1cc(F)ccc1O
Reactant: COc1ccc(O)c(-c2cccc(-c3cccc(Br)n3)n2)c1
Product: COc1ccc(O)c(-c2cccc(-c3cccc(-c4cc(F)ccc4O)n3)n2)c1
Yield: 50 %

Procedure:
6-(5-Fluoro-2-hydroxyphenyl)-6′-(2-hydroxy-5-methoxyphenyl)-2,2′-bipyridine was prepared from 6-bromo-6′-(2-hydroxy-5-methoxyphenyl)-2,2′-bipyridine and 5-fluoro-2-hydroxyphenylboronic acid in 50% yield using method F; δH [2H6]-DMSO 13.09,(1H, b), 12.63,(1H, b), 8.36,(2H, m), 8.22,(4H, m), 7.99,(1H, d), 7.64,(1H, s), 7.22,(1H, t), 7.05-6.91,(3H, m), 3.80,(3H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[SH:9].[N:10]1[CH:15]=[CH:14][C:13]([CH:16]=O)=[CH:12][CH:11]=1>>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]2[S:9][C:16]([C:13]3[CH:14]=[CH:15][N:10]=[CH:11][CH:12]=3)=[N:1][C:2]=2[CH:7]=1
Reactant: Nc1cc(Cl)ccc1S
Reactant: O=Cc1ccncc1
Product: Clc1ccc2sc(-c3ccncc3)nc2c1
Yield: 18.2 %

Procedure:
2-Amino-4-chlorothiophenol (6.5 g, 0.04 mol) and 4-pyridine carboxaldehyde (4.4. g, 0.04 mol) were reacted as exemplified in Example 7 step 1, to afford the title compound as a brown solid (1.8 g, 20%). δH (CDCl3), 7.44 (1H, m, ArH), 7.86 (1H, m, ArH), 7.92 (2H, m, ArH), 8.08 (1H, s, ArH), 8.78 (2H, m, ArH). m/z (ES+) 247 (M+1)+.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)=[C:15]3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1.[C:34](Cl)(=[O:36])[CH3:35]>>[C:34]([NH:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)=[C:15]3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1)(=[O:36])[CH3:35]
Reactant: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ccnc2c1C(=O)N[C@H]1CC[C@@H](N)CC1
Reactant: CC(=O)Cl
Agent: Cl
Product: CC(=O)N[C@H]1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(F)ccc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-5-fluorophenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f9) and commercially acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:6]([C:8]([S:11][C:12]([F:15])([F:14])[F:13])=[CH:9][N:10]=2)[CH:7]=1.[NH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>C(#N)C>[N:16]1([C:2]2[N:3]=[CH:4][C:5]3[N:6]([C:8]([S:11][C:12]([F:15])([F:14])[F:13])=[CH:9][N:10]=3)[CH:7]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1
Reactant: FC(F)(F)Sc1cnc2cnc(Cl)cn12
Reactant: C1CNCCN1
Solvent: CC#N
Product: FC(F)(F)Sc1cnc2cnc(N3CCNCC3)cn12

Procedure:
6-Chloro-3-trifluoromethylthioimidazo[1,2-a]pyrazine from Step A is reacted with piperazine (2 g) in efluxing acetonitrile for 24 hours. The mixture is cooled, concentrated under vacuum, and the esidue partitioned between dilute sodium hydroxide and chloroform. The chloroform extract is dried over sodium sulfate, filtered and concentrated under vacuum to the crude base which is purified by chromatography on silica gel and converted to 6-(1-piperazinyl)-3-trifluoromethylthioimidazo[1,2-a]pyrazine hydrochloride with ethanolic hydrogen chloride.
Reaction SMILES: [CH2:1]([C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=O)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br-].C(C1C=CC(C[P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1)(O)=O.C(C1C=CC=CC=1CC[CH2:63][C:64]1[CH:73]=[CH:72][C:67]([C:68]([O:70][CH3:71])=[O:69])=[CH:66][CH:65]=1)CC1C=CC=CC=1>>[CH2:1]([C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11][CH2:63][C:64]1[CH:73]=[CH:72][C:67]([C:68]([O:70][CH3:71])=[O:69])=[CH:66][CH:65]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(CCCc2ccccc2CCc2ccccc2)cc1
Reactant: O=Cc1ccccc1CCc1ccccc1
Agent: O=C(O)c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Product: COC(=O)c1ccc(CCc2ccccc2CCc2ccccc2)cc1

Procedure:
Methyl 4-[2-(phenethyl)phenethyl]benzoate was prepared from 2-phenethylbenzaldehyde and 4-carboxybenzyltriphenylphosphonium bromide using a similar method to the described in Example 24 for the preparation of methyl 4-[3-(2-(phenethyl)phenyl)propyl]benzoate.
Reaction SMILES: [CH:1]1([N:4]2[C:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:7][N:6]([CH2:15][C:16]([OH:18])=O)[C:5]2=[O:19])[CH2:3][CH2:2]1.[CH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:21]=1[CH:30]([NH2:32])[CH3:31].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[CH:1]1([N:4]2[C:8]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)=[CH:7][N:6]([CH2:15][C:16]([NH:32][CH:30]([C:21]3[CH:22]=[CH:23][C:24]4[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:20]=3)[CH3:31])=[O:18])[C:5]2=[O:19])[CH2:2][CH2:3]1
Reactant: CC(N)c1ccc2ccccc2c1
Reactant: O=C(O)Cn1cc(-c2ccccc2)n(C2CC2)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(NC(=O)Cn1cc(-c2ccccc2)n(C2CC2)c1=O)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
40 mg (0.155 mmol) of (3-cyclopropyl-2-oxo-4-phenyl-2,3-dihydro-1H-imidazol-1-yl)-acetic acid from Example 128A, 29.2 mg (0.17 mmol) of 1-(2-naphthyl)ethylamine, 38.6 mg (0.20 mmol) of EDC hydrochloride and 25.1 mg (0.19 mmol) of HOBt are dissolved in 1.5 ml of dry DMF and stirred overnight at RT. The crude product is purified by preparative HPLC [Method 10, with addition of 0.01 M hydrochloric acid in the water]. The target compound is obtained in a yield of 41 mg (63% of theory).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]([CH3:33])[CH2:26][CH2:27][C:28]([O:30]CC)=[O:29])=[O:24])=[CH:19][CH:18]=3)[CH2:12][CH:13]([CH3:15])[CH3:14])=[C:8]([CH3:34])[C:7]=2[CH:35]=1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([C:23]([N:25]([CH3:33])[CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[O:24])=[CH:21][CH:22]=3)[CH2:12][CH:13]([CH3:15])[CH3:14])=[C:8]([CH3:34])[C:7]=2[CH:35]=1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(CC(C)C)c2oc3ccc(OC)cc3c2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc2oc(C(CC(C)C)Nc3ccc(C(=O)N(C)CCC(=O)O)cc3)c(C)c2c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 93.5 %

Procedure:
To a mixture of ethyl 3-{[(4-{[1-(5-methoxy-3-methyl-1-benzofuran-2-yl)-3-methylbutyl]amino}phenyl)carbonyl](methyl)amino}propanoate (350 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (2.00 mL), and the mixture was stirred at room temperature for 5 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (2.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (308 mg, 94%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[C:20]3[C:19]4[CH:21]=[C:22]([NH2:25])[CH:23]=[CH:24][C:18]=4[O:17][C:16]=3[C:15]([O:26][CH3:27])=[CH:14][CH:13]=2)=[O:11])=[CH:5][CH:4]=1.[C:28](Cl)(=[O:30])[CH3:29].N1C=CC=CC=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[C:20]3[C:19]4[CH:21]=[C:22]([NH:25][C:28](=[O:30])[CH3:29])[CH:23]=[CH:24][C:18]=4[O:17][C:16]=3[C:15]([O:26][CH3:27])=[CH:14][CH:13]=2)=[O:11])=[CH:5][CH:4]=1
Reactant: CC(=O)Cl
Reactant: COc1ccc(NC(=O)c2ccc(OC)c3oc4ccc(N)cc4c23)cc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1ccc(NC(=O)c2ccc(OC)c3oc4ccc(NC(C)=O)cc4c23)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
N1-(4-methoxyphenyl)-4-methoxy-8-amino-dibenzo[b,d]furan-1-carboxamide (90 mg, 0.248 mmol) (step 2) was treated with acetyl chloride (1.1 eq.) in THF (10 ml) containing pyridine (1.1 eq) at 0° C. and allowed to warm to room temperature. The reaction was stirred at room temperature for 16 h. THF was evaporated and the residue was washed ethanol to obtain 40 mg of N1-(4-methoxyphenyl)-4-methoxy-8-acetamido-dibenzo[b,d]furan-1-carboxamide as white solid; mp: 285° C.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=O)[CH:11]=[C:10]3[CH3:18])[CH:5]=[CH:4][N:3]=[CH:2]1.P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:12]1[CH:11]=[C:10]([CH3:18])[C:9]2[C:14](=[CH:15][CH:16]=[C:7]([CH2:6][N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)[CH:8]=2)[N:13]=1
Reactant: Cc1cc(=O)[nH]c2ccc(Cn3ccnc3)cc12
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cc(Cl)nc2ccc(Cn3ccnc3)cc12
Yield: 12.5 %

Procedure:
A solution of 13 parts of 6-(1H-imidazol-1-ylmethyl)-4-methyl-2(1H)-quinolinone in 55 parts of phosphoryl chloride was stirred for 1 hour at room temperature. After evaporation, the residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of acetonitrile and 2,2'-oxybispropane. The product was filtered off and dried, yielding 1.75 parts (12.5%) of 2-chloro-6-(1H-imidazol-1-ylmethyl)-4-methylquinoline; mp. 120.6° C. (compound 24).
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH3:12][C:13]1[S:14][C:15]2[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=2[N+:17]=1[CH2:18][CH3:19].C(N(CC)CC)C.[Cl:31][C:32]([Cl:37])([Cl:36])[C:33](Cl)=[O:34]>C1(C)C=CC=CC=1>[Cl:31][C:32]([Cl:37])([Cl:36])[C:33]([CH:12]=[C:13]1[N:17]([CH2:18][CH3:19])[C:16]2[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=2[S:14]1)=[O:34]
Reactant: CC[n+]1c(C)sc2ccccc21
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCN1C(=CC(=O)C(Cl)(Cl)Cl)Sc2ccccc21
Reaction time: 3 h

Procedure:
10 g (28.6 mmol) of 2-methyl-3-ethyl-benzothiazolium p-toluenesulfonate are suspended in 150 ml of toluene, 6.8 g (67.2 mmol) of triethylamine are added and, at 5°-10° C. 6 g (33 mmol) of trichloroacetyl chloride, dissolved in a minor amount of toluene, are added dropwise. After three hours at room temperature, the ammonium salts are filtered off with suction, and the reaction solution is washed with water, dried over sodium sulfate and concentrated in vacuo. The product is caused to crystallize from the diisopropyl ether.