Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[C:3]1(NCCN)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.C(O)C.C(=O)([O-])[O-].[K+].[K+].[N+:26](C1C=C([N+]([O-])=O)C=CC=1F)([O-])=O>O.[OH-].[Na+]>[CH:4]1[CH:5]=[CH:6][C:7]2[CH:8]=[C:9]([NH2:26])[CH:10]=[CH:11][C:12]=2[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Reactant: NCCNc1cccc2ccccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: Nc1ccc2ccccc2c1
Temperature: 25 °C

Procedure:
10.0 g (38.6 mmoles) of N-(1-naphthyl)-ethylenediamine dihydrochloride were dissolved in a little water and neutralized with dilute sodium hydroxide solution. After the addition of 120 ml of ethanol and 6.4 g of potassium carbonate (46.3 mmoles), 7.2 g (38.7 mmoles) of 2,4-dinitrofluorobenzene were added dropwise. After refluxing for 1 hour, the whole was cooled to room temperature and the deposit was filtered off under suction and washed with water/ethanol. The intermediate product (2-(2,4-dinitrophenyl)-amino)-ethyl)-naphthylamine was obtained in the form of red crystals with a melting point of 263° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][Si@H:6]1[CH2:11][CH2:10][C@H:9]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=2)[CH2:8][CH2:7]1.[Mg].Cl[C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[C:31]([F:36])[CH:30]=2)=[CH:25][CH:24]=1>[Ni](Cl)Cl.C1(PCCCPC2C=CC=CC=2)C=CC=CC=1.C1(PCCCPC2C=CC=CC=2)C=CC=CC=1.C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][Si@H:6]1[CH2:11][CH2:10][C@H:9]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:23]3[CH:24]=[CH:25][C:26]([C:29]4[CH:34]=[CH:33][C:32]([F:35])=[C:31]([F:36])[CH:30]=4)=[CH:27][CH:28]=3)=[CH:16][CH:15]=2)[CH2:8][CH2:7]1
Reactant: COCCC[Si@H]1CC[C@H](CCc2ccc(Br)cc2)CC1
Reactant: Fc1ccc(-c2ccc(Cl)cc2)cc1F
Agent: Cl[Ni]Cl
Agent: [Mg]
Agent: c1ccc(PCCCPc2ccccc2)cc1
Solvent: C1CCOC1
Product: COCCC[Si@H]1CC[C@H](CCc2ccc(-c3ccc(-c4ccc(F)c(F)c4)cc3)cc2)CC1

Procedure:
35.5 g (100 mmol) of 4-(2-(trans-(4-(3-methoxypropyl)-4-silacyclohexyl))ethyl)phenyl bromide was dripped into a mixture of 2.4 g of magnesium (100 mmol) and 60 ml of THF to obtain a Grignard's reagent. This solution was then dripped into a 300 ml THF solution of 34.5 g of 4-chloro-3',4'-difluorobiphenyl and a catalytic amount of bis (1,3-diphenylphosphinopropane) nickel (II) chloride. After a conventional after treatment, the reaction mixture thus obtained was purified by means of chromatography to obtain 36.3 g (yield 81%) of the target product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:10])=[C:6]([CH:9]=1)[CH:7]=O.Cl.[C:12]([O:16][C:17]([CH:19]1[CH2:22][NH:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.C(Cl)Cl>[C:12]([O:16][C:17]([CH:19]1[CH2:20][N:21]([CH2:7][C:6]2[CH:9]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=2[Cl:10])[CH2:22]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: O=Cc1cc(Br)ccc1Cl
Reactant: CC(C)(C)OC(=O)C1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)C1CN(Cc2cc(Br)ccc2Cl)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 5-bromo-2-chloro-benzaldehyde (2 g, 9.11 mmol) and azetidine-3-carboxylic acid tert-butyl ester hydrochloride (1.765 g, 9.11 mmol) in dichloroethane (50 mL) was stirred at room temperature for 10 minutes. To this mixture was added sodium triacetoxy-borohydride (3.86 g, 18.23 mmol) in 3 portions over a period of 10 minutes and the cloudy mixture was stirred overnight. The reaction mixture was diluted with CH2Cl2 (100 mL) and washed twice with 10% sodium bicarbonate solution, twice with water then brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The crude was purified by chromatography on silica gel (cyclohexane/EtOAc).
Reaction SMILES: [I-].[Na+].C[Si](Cl)(C)C.[O:8]1CCO[CH:9]1[C:13]1[S:17][C:16]([CH:18]([C:20]2[S:21][C:22]([CH3:25])=[CH:23][CH:24]=2)O)=[CH:15][CH:14]=1.[OH-].[Na+].O.O.O.O.O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C.O.C(OCC)(=O)C>[CH3:25][C:22]1[S:21][C:20]([CH2:18][C:16]2[S:17][C:13]([CH:9]=[O:8])=[CH:14][CH:15]=2)=[CH:24][CH:23]=1
Reactant: Cc1ccc(C(O)c2ccc(C3OCCO3)s2)s1
Agent: C[Si](C)(C)Cl
Agent: O=S([O-])([O-])=S
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: Cc1ccc(Cc2ccc(C=O)s2)s1
Yield: 50.2 %

Procedure:
Sodium iodide (6.4 g, 42.6 mmol) and trimethylsilyl chloride (4.6 g, 42.6 mmol) were suspended in acetonitrile (100 mL) on an ice bath, and (5-[1,3]dioxolane-2-ylthiophen-2-yl)-(5-methyl-thiophen-2-yl)-methanol described in Preparation Example 65 (2.0 g, 7.09 mmol) was added dropwise. After dropwise addition was completed, the reaction solution was gradually allowed to room temperature. A solution obtained by dissolving an aqueous solution of 2N sodium hydroxide (10.6 mL) and sodium thiosulfate pentahydrate (530 mg, 2.13 mmol) in water (5 mL) was added to the reaction solution that had been cooled on an ice bath, and the solution was stirred. Water and ethyl acetate were added to the reaction solution, which was then partitioned, and the organic layer was concetrated in vacuo. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:1), and the title compound (790 mg, 3.56 mmol, 50.2%) was obtained as a brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][C:3]=1[F:11].Br[CH2:13][CH2:14]Br.[OH-].[Na+]>C1(C)C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:9]#[N:10])[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:11]
Reactant: N#CCc1ccc(Br)c(F)c1
Reactant: BrCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: N#CC1(c2ccc(Br)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 8.5 h

Procedure:
A solution of 4-bromo-3-fluorophenylacetonitrile (5 g, 23 mmoles) in toluene (20 ml) is added with 35 mmoles of 1,2-dibromoethane, a 50% NaOH aqueous solution (20 ml) and tetrabutylammonium bromide (1.6 g, 5 mmoles). The mixture is kept under stirring at room temperature for 5-12 hours, then diluted with water and extracted with ethyl acetate. The organic phase is washed with 1N HCl, then with brine, finally dried and concentrated under vacuum to give a brown solid, which is subjected to chromatography on a silica gel column (200 g), eluting with hexane-ethyl ether 1-1, to afford the product in the solid form.
Reaction SMILES: [C:1]([C:5]1[CH:31]=[CH:30][C:8]([C:9]([NH:11][C:12]2[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][C:13]=2[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[O:15])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[C:1]([C:5]1[CH:31]=[CH:30][C:8]([C:9]([NH:11][C:12]2[CH:28]=[CH:27][C:26]([NH:29][S:39]([CH3:38])(=[O:41])=[O:40])=[CH:25][C:13]=2[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[O:15])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(NC(=O)c2cc(N)ccc2NC(=O)c2ccc(C(C)(C)C)cc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(NC(=O)c2cc(NS(C)(=O)=O)ccc2NC(=O)c2ccc(C(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 72.9 %

Procedure:
To a solution of 2-(4-tert-butylbenzoylamino)-5-amino-N-(4-methoxyphenyl)benzamide (150 mg, 0.36 mmol) in methylene chloride (5 mL) cooled to 0° C. was added pyridine (32 μl, 0.40 mmol) followed by methanesulfonyl chloride (31 μl, 0.40 mmol). After 5 min, the reaction mixture was allowed to warm to room temperature and stirred for 30 min. The reaction mixture was diluted with methylene chloride and washed twice with water. The organic layer was dried (magnesium sulfate), filtered, and concentrated in vacuo. The residue was chromatographed (silica gel, 30% ethyl acetate/70% methylene chloride) to give 130 mg (73%) of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:40]=[CH:41][CH:42]=1)[C:7]([C:9]1[CH:14]=[C:13]([CH2:15][N:16]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:12]([OH:27])=[C:11]([CH2:28][N:29]([CH2:35][C:36]([O:38][CH3:39])=[O:37])[CH2:30][C:31]([O:33][CH3:34])=[O:32])[CH:10]=1)=[O:8])([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:40]=[CH:41][CH:42]=1)[C:7]([C:9]1[CH:10]=[C:11]([CH2:28][N:29]([CH2:30][C:31]([O:33][CH3:34])=[O:32])[CH2:35][C:36]([O:38][CH3:39])=[O:37])[C:12]([OH:27])=[C:13]([CH2:15][N:16]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH:14]=1)=[O:8]
Reactant: COC(=O)CN(CC(=O)OC)Cc1cc(C(=O)c2cccc([N+](=O)[O-])c2)cc(CN(CC(=O)OC)CC(=O)OC)c1O
Agent: [Pd]
Solvent: CO
Product: COC(=O)CN(CC(=O)OC)Cc1cc(C(=O)c2cccc(N)c2)cc(CN(CC(=O)OC)CC(=O)OC)c1O

Procedure:
Compound 1 (0.89 g, 1.5 mmol) was stirred for 1 h in methanol (50 mL) with 10% Pd/C (90 mg) under hydrogen pressure of 50 psi. The mixture was filtered and evaporated in vacuo. The product was purified by chromatography on silica gel using light petroleum (b.p. 50°-70° C.)/ethyl acetate (2:5) as the eluent. The yield of yellowish oil was 0.40 g (48%). 1H NMR (CDCl3): k 3.56 (1H, s), 3.59 (8H, s), 3.71 (12H, s), 4.01 (6H, broad s), 7.05-7.14 (4H, m), 7.70 (2H, s).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH:9]2[N:19]3[C:20]4[N:11]([C:12](=[O:22])[CH:13]=[CH:14][C:15]=4[CH:16]=[CH:17][C:18]3=[O:21])[CH2:10]2)[CH2:4][CH2:3]1.COC1N=C2C(CCC(=O)N2C[C@@H]2CO2)=CC=1.[S:40]1[C:49]2[CH:48]=[C:47]([CH:50]=O)[N:46]=[CH:45][C:44]=2[O:43][CH2:42]C1>>[S:40]1[C:49]2[CH:48]=[C:47]([CH2:50][NH:1][CH:2]3[CH2:3][CH2:4][N:5]([CH2:8][CH:9]4[N:19]5[C:20]6[N:11]([C:12](=[O:22])[CH:13]=[CH:14][C:15]=6[CH:16]=[CH:17][C:18]5=[O:21])[CH2:10]4)[CH2:6][CH2:7]3)[N:46]=[CH:45][C:44]=2[O:43][CH2:42]1
Reactant: O=Cc1cc2c(cn1)OCCS2
Reactant: NC1CCN(CC2Cn3c(=O)ccc4ccc(=O)n2c43)CC1
Agent: COc1ccc2c(n1)N(C[C@@H]1CO1)C(=O)CC2
Product: O=c1ccc2ccc(=O)n3c2n1CC3CN1CCC(NCc2cc3c(cn2)OCS3)CC1

Procedure:
The title compound was prepared from 1-[(4-amino-1-piperidinyl)methyl]-1,2-dihydro-4H,9H-imidazo[1,2,3-ij]-1,8-naphthyridine-4,9-dione (2:1 mixture of S:R prepared analogously to Example 11(a-d)) but using 7-(methyloxy)-1-[(2R)-2-oxiranylmethyl]-3,4-dihydro-1,8-naphthyridin-2(1H)-one (for a synthesis see example 5(f)) and 2,3-dihydro[1,4]oxathiino[2,3-c]pyridine-7-carbaldehyde (for a synthesis see WO2004058144, Example 60) according to the general method of Example 12.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([NH2:8])=[NH:7])[CH3:2].Cl[C:14]1[C:19]([C:20](OCC)=[O:21])=[CH:18][N:17]=[C:16]([S:25][CH3:26])[N:15]=1.C(N(CC)CC)C>C(#N)C>[CH3:26][S:25][C:16]1[N:17]=[C:18]2[N:7]=[C:6]([C:5]3[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=3[O:3][CH2:1][CH3:2])[NH:8][C:20](=[O:21])[C:19]2=[CH:14][N:15]=1
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Reactant: CCOc1ccccc1C(=N)N
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOc1ccccc1-c1nc2nc(SC)ncc2c(=O)[nH]1
Temperature: 2 °C
Reaction time: 1 h

Procedure:
2-Ethoxybenzamidine (from sodium, 0.08 g, in ethanol, 10 ml, and 2-ethoxybenzamidine hydrochloride, 0.70 g) was dissolved in acetonitrile (10 ml) and the resulting cooled (2° C.) solution was added to a cooled (2° C.) suspension of ethyl 4-chloro-2-methylthio-5-pyrimidine carboxylate (0.81 g) in acetonitrile (10 ml). The reaction mixture was stirred at 2° C. for one hour. Triethylamine (0.35 g) was added and the reaction mixture was stirred at ambient temperature for 21 hours to yield a white precipitate, 0.22 g, which was collected by filtration. The filtrate was reduced in volume under reduced pressure to yield a second crop of solid, 0.41 g. The products were combined and recrystallised from ethanol to yield the title compound, 0.30 g, m.p. 224.5°-225.5° C.
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][CH2:26][N:27]4[CH2:33][C:32](=O)[C:29]5([CH2:31][CH2:30]5)[CH2:28]4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][CH:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:35])[NH:6]2.Br[Zn][CH2:38][Zn]C[Zn]Br.C1OCCC1>O1CCCC1>[F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][CH2:26][N:27]4[CH2:33][C:32](=[CH2:38])[C:29]5([CH2:30][CH2:31]5)[CH2:28]4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][CH:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:35])[NH:6]2
Reactant: Br[Zn]C[Zn]C[Zn]Br
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ccnc2cc1OCCN1CC(=O)C2(CC2)C1
Solvent: C1CCOC1
Product: C=C1CN(CCOc2cc3nccc(Oc4ccc5[nH]c(C)cc5c4F)c3cc2OC)CC12CC2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The above product from Example 2 (50 mg) was dissolved into anhydrous tetrahydrofuran (5 ml) and Nysted reagent (1.5 eq, 20% solution) was added to the reaction. The reaction was stirred at RT for two days and quenched with NH4Cl solution and extracted with EtOAc followed by washing with water, then brine and dried over Na2SO4 and purified with silica gel column to give the titled compound. Mass: (M+1), 474
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([OH:25])[C:15]3[N:11]([CH:12]=[N:13][CH:14]=3)[C@@H:10]([C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][C:17]=3[F:24])[CH2:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1>COCCOC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:24][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:16]=1[C@@H:10]1[N:11]2[CH:12]=[N:13][CH:14]=[C:15]2[C@@:8]([OH:25])([C:5]2[CH:6]=[CH:7][C:2]([C:37]3[CH:38]=[CH:39][C:34]([O:33][CH3:32])=[CH:35][CH:36]=3)=[CH:3][CH:4]=2)[CH2:9]1)[C:20]#[N:21]
Reactant: N#Cc1ccc([C@H]2C[C@](O)(c3ccc(Br)cc3)c3cncn32)c(F)c1
Reactant: COc1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(-c2ccc([C@@]3(O)C[C@H](c4ccc(C#N)cc4F)n4cncc43)cc2)cc1
Temperature: 120 °C
Yield: 48.5 %

Procedure:
To a solution of 4-[(5R,7S)-7-(4-bromo-phenyl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl]-3-fluoro-benzonitrile (25 mg, 63 μmol) in DME:H2O (4:1, 1 ml) were added Na2CO3 (10 mg, 94 μmol) and 4-methoxyphenylboronic acid (10.5 mg, 69 μmol). To this stirred mixture, PdCl2(dppf).CH2Cl2 complex (1.03 mg, 1.26 μmol) was added. The reaction was carried out under sealed-vessel microwave heating at 120° C. for 10 minutes using a Biotage Initiator™ (pre-stirring: 10 s, absorption level: very high). Upon completion, the mixture was allowed to cool to room temperature, the Pd catalyst was filtered off and the solvent was removed. The crude product obtained was purified using preparative LC-MS and lyophilized to give 3-fluoro-4-[(5R,7S)-7-hydroxy-7-(4′-methoxy-biphenyl-4-yl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl]-benzonitrile (13 mg, >95% purity). MS 426.0 (M+H), LCMS condition C, retention time 2.06 min. 1H NMR (600 MHz, DMSO-d6) δ ppm 2.90 (dd, 1H), 3.43-3.48 (m, 1H), 3.78 (s, 3H), 6.17 (dd, 1H), 6.59 (br. s., 1H), 7.01-7.03 (m, 2H), 7.33 (t, 1H), 7.53 (d, 2H), 7.60-7.62 (m, 2H), 7.63-7.65 (m, 2H), 7.78 (dd, 1H), 8.02 (dd, 1H), 8.94 (br. s., 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:25][CH3:26])[C:10]([N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][C@H:13]1[C:21](OC)=[O:22])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:27][CH2:28][CH2:29][CH2:30][NH2:31]>CO>[OH:27][CH2:28][CH2:29][CH2:30][NH:31][C:21]([C@@H:13]1[CH2:14][C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:12]1[C:10](=[O:11])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:25][CH3:26])=[O:22]
Reactant: NCCCO
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)N1c2ccccc2C[C@H]1C(=O)OC
Solvent: CO
Product: CC[C@H](NC(=O)OC(C)(C)C)C(=O)N1c2ccccc2C[C@H]1C(=O)NCCCO
Temperature: 50 °C
Reaction time: 3 h

Procedure:
Methyl 1-(N-t-butoxycarbonyl-2(S)-aminobutyryl)indoline-2(S)-carboxylate (0.36 g, 1 mmol) was dissolved in methanol (10 ml) and treated, under nitrogen and at 50° C., with 3-hydroxypropylamine (10 ml). The mixture was stirred at 50° C. for 3 h and the solvent was evaporated off. The residue was dissolved in methylene chloride (30 ml) and washed with 1M KHSO4. The organic phase was dried (Na2SO4) and evaporated. The residue was purified by column chromatography in order to give the product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:13])([CH3:12])[CH2:7][CH2:6][CH2:5]2.[Li]CCCC.C([O:22][B:23](OC(C)C)[O:24]C(C)C)(C)C>C1(C)C=CC=CC=1.Cl>[CH3:12][C:8]1([CH3:13])[CH2:7][CH2:6][CH2:5][C:4]2[CH:3]=[C:2]([B:23]([OH:24])[OH:22])[CH:11]=[CH:10][C:9]1=2
Reactant: CC1(C)CCCc2cc(Br)ccc21
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: CC1(C)CCCc2cc(B(O)O)ccc21
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
To a cold (−78° C.) solution of 2.02 g (8.4 mmol) of 6-bromo-1,2,3,4-tetrahydro-1,1-dimethylnaphthalene in 11.0 mL of toluene, was added 4.6 g (6.8 mL, 10.9 mmol, 1.6 M in hexane) of n-BuLi. The resulting solution was stirred at −78° C. for 45 min. and then 2.40 g (3.0 mL, 12.7 mmol) of triisopropylborate was dropwise added and the reaction stirred at room temperature for 12 h. The reaction was then diluted with 10% HCl, and extracted with ether (2×). The combined organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo to give an oil. Recrystallization from hexane afforded the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([NH:26][C:27]([C:29]4[S:30][CH:31]=[CH:32][CH:33]=4)=[O:28])[CH:22]=[CH:23][C:24]=3[CH3:25])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:38].Cl.Cl.[NH:41]1[CH:45]=[CH:44][N:43]=[C:42]1[CH2:46][NH2:47]>>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:47][CH2:46][C:42]3[NH:41][CH:45]=[CH:44][N:43]=3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([NH:26][C:27]([C:29]4[S:30][CH:31]=[CH:32][CH:33]=4)=[O:28])[CH:22]=[CH:23][C:24]=3[CH3:25])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:38]
Reactant: Cc1ccc(NC(=O)c2cccs2)cc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: NCc1ncc[nH]1
Agent: Cl
Product: Cc1ccc(NC(=O)c2cccs2)cc1-c1nc(NCc2ncc[nH]2)nc2c1ccc(=O)n2-c1c(F)cccc1F

Procedure:
The title compound was prepared as described in Example 1 d from N-{3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylphenyl}-2-thiophenecarboxamide and (1H-imidazol-2-ylmethyl)amine dihydrochloride: LC-MS m/z 570 (M+H)+, 1.70 min (ret time).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[NH:9][CH:10]=1)=[O:5])C.[OH-].[Na+].Cl>CO>[F:20][C:17]([F:18])([F:19])[C:14]1[CH:13]=[CH:12][C:11]([C:8]2[NH:9][CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=2)=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1c[nH]c(-c2ccc(C(F)(F)F)cc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1c[nH]c(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 80 °C
Reaction time: 6.5 h
Yield: 52.1 %

Procedure:
To a solution of 2-[4-(trifluoromethyl)phenyl]-1H-imidazole-4-carboxylic acid ethyl ester (300 mg) in methanol (4 ml) was added 1 N aqueous solution of sodium hydroxide (4 ml) at room temperature, and stirred at 80° C. for 6.5 hours. After completion of the reaction, 1 N hydrochloric acid aqueous solution (4 ml) was added thereto, and the solvent was evaporated. The obtained residue was washed with water, and dried in vacuo to give the titled compound (141 mg) as a pale brown solid.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([C:18]3[S:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)=[CH:21][CH:22]=3)(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH2:29][CH2:30][CH:31]([C:33]1[CH:34]=[CH:35][C:36]([OH:44])=[C:37]([NH:39][S:40]([CH3:43])(=[O:42])=[O:41])[CH:38]=1)[OH:32]>>[OH:32][CH:31]([C:33]1[CH:34]=[CH:35][C:36]([OH:44])=[C:37]([NH:39][S:40]([CH3:43])(=[O:42])=[O:41])[CH:38]=1)[CH2:30][NH:29][CH:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][S:15]([C:18]3[S:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)=[CH:21][CH:22]=3)(=[O:17])=[O:16])=[CH:12][CH:13]=2)[CH2:6][CH2:7]1
Reactant: CS(=O)(=O)Nc1cc(C(O)CN)ccc1O
Reactant: O=C1CCN(c2ccc(NS(=O)(=O)c3ccc(-c4ccccn4)s3)cc2)CC1
Product: CS(=O)(=O)Nc1cc(C(O)CNC2CCN(c3ccc(NS(=O)(=O)c4ccc(-c5ccccn5)s4)cc3)CC2)ccc1O

Procedure:
The title compound was prepared from 5-pyridin-2-yl-thiophene-2-sulfonic acid [4-(4-oxo-piperidine-1-yl)-phenyl]-amide (which was obtained in Example 227) and N-[5-(2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 9) according to the procedure of Example 278 as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.20-1.40 (m, 2H), 1.80-1.90 (m, 2H), 2.45-2.75 (m, 5H), 2.91 (s, 3H), 3.40-3.60 (m, 2H), 4.47 (dd, J=8.0, 4.1 Hz, 1H), 6.80 (d, J=8.3 Hz, 1H), 6.82 (d, J=8.0 Hz, 2H), 6.95 (d, J=8.0 Hz, 2H), 7.00 (dd, J=8.3, 2.0 Hz, 1H), 7.17 (d, J=2.0 Hz, 1H), 7.37 (dd, J=4.8, 1.7 Hz, 1H), 7.40 (d, J=3.9 Hz, 1H), 7.75 (d, J=3.9 Hz, 1H), 7.88 (dd, J=8.0, 1.7 Hz, 1H), 7.98 (d, J=8.0 Hz, 1H), 8.54 (brd, J=4.8 Hz, 1H); MS (ES) m/z: 644.1 (MH+); HRMS Calcd. for C29H34N5O6S3 (MH+): 644.1671. Found: 644.1663.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]=[CH:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12].[C-]#N.[Na+].CS(C)=O.C(Cl)(Cl)Cl>O>[C:4]1([CH:9]=[CH:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])[CH:3]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COc1ccccc1C=CC(=O)c1ccccc1
Agent: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(C=Cc1ccccc1)c1ccccc1

Procedure:
10 g of methoxy chalcone and 2.05 g of sodium cyanide are dissolved into 100 ml of dimethyl-sulfoxide, and then reacted for 24 hours. After the reaction, the reacted solution is mixed with chloroform and agitated together with distilled water so as to extract impurities. After removing the solution phase, the solution is decompressed at a room temperature in order to eliminate chloroform. After recrystallization of the remained solid phase in methanol, the solution is dried under vacuum, thus obtaining 4-hydroxychalcone for photoreaction.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([S:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:33]1[N:41]=[CH:40][N:39]=[C:38]2[C:34]=1[NH:35][CH:36]=[N:37]2.C(NC(C)C)(C)C.O>C(#N)C>[C:1]1([C:7]2[N:8]=[C:9]([S:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]([C:33]3[N:41]=[CH:40][N:39]=[C:38]4[C:34]=3[NH:35][CH:36]=[N:37]4)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[NH:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCCCCCNCCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Reactant: Clc1ncnc2nc[nH]c12
Solvent: CC(C)NC(C)C
Solvent: CC#N
Solvent: O
Product: CCCCCCCN(CCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1)c1ncnc2nc[nH]c12

Procedure:
A solution of N-[5-(4,5-diphenyl-1H-imidazol-2-ylthio)pentyl]-heptanamine (5.30 g, 12.2 mmol), 6-chloropurine (1.90 g, 12.3 mmol), and diisopropylamine (3.00 mL, 17.2 mmol) in acetonitrile (50 mL) was heated to mild reflux for 18 hours, and then cooled and poured into water (200 mL). This was extracted with methylene chloride (2×200 mL), and the extracts were combined, dried over anhydrous potassium carbonate, filtered and evaporated. The residue was separated by flash chromatography (ethyl acetate) to afford the title product as a solid, m.p. 58°-60° C. 1H NMR (CDCl3): 10.66 (2H, br s); 8.30 (1H, s); 7.83 (1H, s); 7.67-7.18 (10H, m); 4.10 (4H, br); 3.08 (2H, t, J=7.1 Hz); 1.80-1.20 (16 H, m); 0.89 (3H, t, J=6.6 Hz). High-resolution mass spectrum: calc. for C32H39N7S 554.3066, obs. 554.3053, diff. 2.3 ppm.
Reaction SMILES: [NH2:1][C:2]([CH3:8])([CH3:7])[C:3](OC)=[O:4].[CH2:9]([NH2:12])[CH2:10][CH3:11]>CO>[CH2:9]([NH:12][C:3](=[O:4])[C:2]([NH2:1])([CH3:8])[CH3:7])[CH2:10][CH3:11]
Reactant: COC(=O)C(C)(C)N
Reactant: CCCN
Solvent: CO
Product: CCCNC(=O)C(C)(C)N

Procedure:
To a solution of 26.3 parts of methyl 2-amino-2-methylpropionate in methanol is added 70 parts of n-propylamine. The mixture is placed in a bomb and left at a temperature of 100° C. for one week. The solvents are then stripped off under reduced pressure. Distillation of the residual oil affords N1 -propyl-2-amino-2-methylpropionamide, boiling at 58° C. at 0.1 mm pressure.