Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[NH2:10].Cl[CH2:12][C:13](Cl)=[O:14].[CH2:16]([NH:19][CH2:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[CH:17]=[CH2:18]>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:13](=[O:14])[CH2:12][N:19]([CH2:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[CH2:16][CH:17]=[CH2:18]
Reactant: O=C(Cl)CCl
Reactant: C=CCNCC1CCCCC1
Reactant: COc1ccc(N)c(Cl)c1
Product: C=CCN(CC(=O)Nc1ccc(OC)cc1Cl)CC1CCCCC1

Procedure:
In a manner similar to Preparation 1 react 2-chloro-4-methoxybenzenamine with chloroacetyl chloride followed by N-(2-propenyl)cyclohexanemethanamine to obtain the title compound.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][C:8]=2[OH:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[Cl-:23].[Cl-:24].[Cl-].[CH3:26][C:27]1[C:31]([Ti+3:33])([CH3:32])[C:30]([CH3:34])=[C:29]([CH3:35])[C:28]=1[CH3:36]>C1(C)C=CC=CC=1>[Cl:23][Ti:33]([Cl:24])([C:31]1([CH3:32])[C:27]([CH3:26])=[C:28]([CH3:36])[C:29]([CH3:35])=[C:30]1[CH3:34])[O:17][C:8]1[CH:9]=[CH:10][C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Oc1ccc2ccccc2c1-c1ccccc1
Reactant: CC1=C(C)C(C)([Ti+3])C(C)=C1C
Reactant: [Cl-]
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: CC1=C(C)C(C)([Ti](Cl)(Cl)Oc2ccc3ccccc3c2-c2ccccc2)C(C)=C1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 58 %

Procedure:
To solution of 1-phenylnaphthalen-2-ol (2.0 g, 9.1 mmol) dissolved in 100 mL of toluene, n-butyllithium (2.5 M in hexane, 3.6 mL) was slowly injected at −78° C. After stirring the mixture at ambient temperature for 12 hours, the reaction mixture was chilled to −78° C., and solution of (pentamethylcyclopentadienyl)titanium(IV) trichloride (2.5 g, 16.3 mmol) dissolved in 60 mL of toluene was slowly added thereto, and the reaction was continued at ambient temperature for 12 hours. When the reaction was completed, the reaction mixture was filtered through celite, and the solvent was removed. Recrystallization from purified toluene and hexane at −35° C., followed by filtration and drying under reduced pressure gave (dichloro) (pentamethylcyclopentadienyl) (1-phenylnaphthalen-2-yloxy)titanium(IV) (2.5 g) (yield: 58.2%) as red solid.
Reaction SMILES: [S-2:1].[Na+].[Na+].[C:4]1([C:10]2[C:11](Cl)=[N:12][S:13][N:14]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N:16]#[C:17]Br>CN(C)C=O.O>[C:4]1([C:10]2[C:11]([S:1][C:17]#[N:16])=[N:12][S:13][N:14]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: N#CBr
Reactant: Clc1nsnc1-c1ccccc1
Reactant: [S-2]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CSc1nsnc1-c1ccccc1
Reaction time: 8 h

Procedure:
To a stirred solution of 3.8 grams(g)(0.05 mole) of sodium sulfide in 100 mL of dimethylformamide was added 8 g(0.041 mole) of 4-Phenyl-3-chloro-1,2,5-thiadiazole. The mixture was stirred overnight (~16 hours), and to the resulting dark green solution was added 6.64 g(1.5 molar equivalents) of cyanogen bromide. This mixture was stirred for about 14 hours and then diluted with 100 mL of water and extracted with 200 mL of methylene chloride. The organic layer was separated and washed with water (2×100 mL), dried and concentrated under reduced pressure. The thus recovered crude material was chromatographed on silica gel with a 10% EtoAc:90% hexane mixture to yield 6.6 g (72 percent of theoretical) as an oil which turned to a white solid melting at 49° C. upon standing; 13C NMR (75 MHz, CDCl3) δ 159.10, 141.78, 130.59, 129.76, 129.06, 127.88, 105.98; MS (EI) m/e 219(M+), 192, 160, 135, 103.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([OH:23])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:10][C:9]=2[C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:4])([CH3:3])[CH3:2].[P:24]([O:27][C:28]1[C:29](=[CH:31][CH:32]=[CH:33][CH:34]=1)[OH:30])(Cl)[OH:25].C(N(CC)CC)C>C1(C)C=CC=CC=1.CC(C)=O>[P:24]([OH:27])([OH:23])[OH:25].[C:1]([C:5]1[C:6]([C:31]2[CH:32]=[CH:33][CH:34]=[C:28]([OH:27])[C:29]=2[OH:30])=[CH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:10][C:9]=2[C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(O)c2c(C(C)(C)C)cc(C(C)(C)C)cc2c1
Reactant: Oc1ccccc1OP(O)Cl
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc(C(C)(C)C)c2cc(-c3cccc(O)c3O)c(C(C)(C)C)cc2c1
Product: OP(O)O
Temperature: 6 °C
Reaction time: 16 h

Procedure:
6.0 weight parts of 3,6,8-tri-t-butylnaphthol was dissolved in 86.7 weight parts of dry toluene and the solution cooled to about 6° C. Under nitrogen, 3.36 weight parts of catechol phosphorochloridite was added to the solution. 1.95 weight parts of triethyl amine was added slowly to the cooled stirred solution. The reaction was allowed to continue for 16 hours at room temperature. 69 weight percent product was obtained. The reaction mixture was filtered, washed twice with water, dried over MgSO4 and rotoevaporated to remove all traces of toluene. An oil was obtained that solidified. This solid was stirred in acetone and a white powder was obtained that had a melting point of 140°-142° C. The expected structure was confirmed by infra red and nuclear magnetic resonance spectra. The molecular weight was confirmed by the field desorption/mass spectrum.
Reaction SMILES: Br.Br[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([NH2:14])[S:12][CH:13]=2)=[CH:5][CH:4]=1.[CH:15]1([NH:18][C:19](=[O:36])[C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[C:22](B3OC(C)(C)C(C)(C)O3)[CH:21]=2)[CH2:17][CH2:16]1>>[NH2:14][C:11]1[S:12][CH:13]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:22]3[C:23]([CH3:26])=[CH:24][CH:25]=[C:20]([C:19]([NH:18][CH:15]4[CH2:17][CH2:16]4)=[O:36])[CH:21]=3)=[CH:4][CH:5]=2)[N:10]=1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Nc1nc(-c2ccc(Br)cc2)cs1
Agent: Br
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(-c2csc(N)n2)cc1

Procedure:
Example 5 was prepared using 4-(4-bromophenyl)-2-thiazolamine monohydrobromide and N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)benzamide (Intermediate 17).
Reaction SMILES: [Br:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([CH2:18][C:19](OC)=[O:20])=[C:8]2[CH3:23])=[CH:4][CH:3]=1.CC(C[AlH]CC(C)C)C.CCOCC.CCCCCC>C(Cl)Cl>[Br:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([CH2:18][CH:19]=[O:20])=[C:8]2[CH3:23])=[CH:4][CH:3]=1
Reactant: COC(=O)Cc1c(C)n(Cc2ccc(Br)cc2)c2ccc(OC)cc12
Agent: CC(C)C[AlH]CC(C)C
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCCCCC
Product: COc1ccc2c(c1)c(CC=O)c(C)n2Cc1ccc(Br)cc1
Temperature: -78 °C
Yield: 87.7 %

Procedure:
To a solution of ester from Step 2 (16.0 g, 39.8 mmol) in CH2Cl2 (320 mL) at -100° C. was added slowly a solution of DIBAH (1.5M/toluene, 32 mL, 47.7 mmol). The reaction was then stirred for 1-- h at -78° C., before being quenched by the addition of MeOH (3 mL), followed by 25% w/v tartaric acid (100 mL). After stirring overnight at r.t., the product was extracted with CH2Cl2. The organic layer was dried (MgSO4), filtered, and evaporated to give a pale green syrup. This was stirred vigorously with 1:4 Et2O/hexane to give 13 g of the title compound as an off-white solid.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[O:12])[C:10]#[N:11].Cl.[OH2:14]>>[Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[O:12])[C:10]([NH2:11])=[O:14]
Reactant: O
Reactant: N#CC(=O)c1ccccc1CCl
Agent: Cl
Product: NC(=O)C(=O)c1ccccc1CCl
Temperature: 40 °C
Reaction time: 20 h
Yield: 40.2 %

Procedure:
A mixture of 2-(2-chloromethylphenyl)-2-oxoacetonitrile (1.80 g) and 36% hydrochloric acid aqueous solution (10 ml) was stirred at 40° C. for 20 hours. After the mixture was cooled by allowing it to stand, ice-cooled water was added, and the resulting mixture was stirred at room temperature for 30 minutes. The mixture was extracted with ethyl acetate twice. The combined ethyl acetate layer was washed successively with a saturated aqueous solution of sodium bicarbonate and saturated brine, and dried over anhydrous sodium sulfate. Evaporation of the solvent under reduced pressure gave a crude product (0.89 g). The crude product was recrystallized from ethyl acetate-hexane to give the title compound (0.80 g, yield: 40.2%, pale yellow crystals).
Reaction SMILES: [CH3:1][C:2]1O[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:34]=[CH:33][C:18]([CH2:19][O:20]/[N:21]=[C:22]2\[CH2:23][C:24]([CH:28]([CH3:32])C(O)=O)=[CH:25][CH:26]=[CH:27]\2)=[CH:17][CH:16]=1.Cl.C(N=C=NCCCN(C)C)C.C[N:48](C)[CH:49]=[O:50].[OH2:52]>>[CH3:1][C:2]1[O:52][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][O:20]/[N:21]=[C:22](/[C:27]2[CH:32]=[CH:28][CH:24]=[CH:25][CH:26]=2)\[CH2:23][C:49]([NH2:48])=[O:50])=[CH:33][CH:34]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CO/N=C2/C=CC=C(C(C)C(=O)O)C2)cc1
Reactant: CN(C)C=O
Reactant: O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CO/N=C(\CC(N)=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 86 %

Procedure:
A mixture of E-3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-phenylpropionic acid (600 mg), 1-hydroxybenzotriazole ammonia complex (260 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (328 mg) and N,N-dimethylformamide (5 ml) was stirred at room temperature for 15 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed successively with an aqueous solution of potassium carbonate and an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The remaining crystals were recrystallized from tetrahydrofuran-hexane to obtain E-3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-3-phenylpropanamide (512 mg, yield 86%) as colorless crystals. m.p. 164-165° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10]C)=[O:9])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[CH3:21][C:22]1[NH:23][CH:24]=[CH:25][N:26]=1.C(OCC)(=O)C>CN1CCCC1=O>[CH3:21][C:22]1[N:23]([C:2]2[N:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][CH:3]=2)[CH:24]=[CH:25][N:26]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: Cc1ncc[nH]1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nccn1-c1ccc(C(=O)O)cn1
Temperature: 100 °C
Reaction time: 48 h

Procedure:
A mixture of methyl 6-chloropyridine-3-carboxylate (0.75 g), N,N-diisopropyl-ethyl-amine (1.75 mL) and 2-methyl-1H-imidazole (0.58 g) in N-methylpyrrolidone (6 mL) is heated to 100° C. overnight. Additional 2-methyl-1H-imidazole (0.58 g) is added and the reaction continues at 100° C. for two days. Ethyl acetate is added and the mixture is washed with saturated ammonium chloride. The organic phase is dried over MgSO4 and concentrated in vacuo. The crude ester is dissolved in MeOH (4 mL) and KOH (1.5 g) in water (2 mL) is added and kept at room temperature for 2 h. The MeOH is removed in vacuo and the aqueous phase is acidified with 1N HCl and extracted with dichloromethane. The organic phase is dried over MgSO4 and concentrated to afford the title compound. LC (method 20): tR=0.51 min; Mass spectrum (APCI): m/z=204 [M+H]+.
Reaction SMILES: C[N:2]1CCN(C2C=CC(NC3C4N(N=CN=4)C(C4C=C(C(N)=O)SC=4)=CN=3)=CC=2)CC1.Br[C:33]1[N:38]2[N:39]=[CH:40][N:41]=[C:37]2[C:36]([NH:42][C:43]2[CH:48]=[CH:47][C:46]([N:49]3[CH2:54][CH2:53][O:52][CH2:51][CH2:50]3)=[CH:45][CH:44]=2)=[N:35][CH:34]=1.CC1(C)C(C)(C)OB([C:63]2[CH:64]=[C:65]([C:68]([NH2:70])=[O:69])[O:66][CH:67]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[NH3:2].[O:52]1[CH2:53][CH2:54][N:49]([C:46]2[CH:47]=[CH:48][C:43]([NH:42][C:36]3[C:37]4[N:38]([N:39]=[CH:40][N:41]=4)[C:33]([C:63]4[CH:64]=[C:65]([C:68]([NH2:70])=[O:69])[O:66][CH:67]=4)=[CH:34][N:35]=3)=[CH:44][CH:45]=2)[CH2:50][CH2:51]1
Reactant: CC1(C)OB(c2coc(C(N)=O)c2)OC1(C)C
Reactant: Brc1cnc(Nc2ccc(N3CCOCC3)cc2)c2ncnn12
Reactant: CN1CCN(c2ccc(Nc3ncc(-c4csc(C(N)=O)c4)n4ncnc34)cc2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: N
Product: NC(=O)c1cc(-c2cnc(Nc3ccc(N4CCOCC4)cc3)c3ncnn23)co1
Yield: 65 %

Procedure:
This compound may be prepared using methods as described for Compound 6, step 4, using (5-bromo-[1,2,4]triazolo[1,5-a]pyrazin-8-yl)-(4-morpholin-4-yl-phenyl)-amine (78 mg, 0.16 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-furan-2-carboxylic acid amide (100 mg, 0.34 mmol), and Pd(PPh3)4 (60 mg, 0.052 mmol) in 1.5M Na2CO3 (aq) (1.1 mL, 1.68 mmol), and dioxane (3 mL). The reaction mixture is partitioned between water and ethyl acetate, the title compound precipitates and is collected by filtration. Purification of the solid by silica gel column chromatography, eluting with DCM and 95:5 DCM:NH3 (7M in MeOH), affords the title compound (42 mg, 65%). Conversion into the mesylate salt using 0.1M methanesulfonic acid (0.82 mL) gives a solid which is triturated with diethyl ether to afford the title compound (30.5 mg). 1H-NMR (400 MHz, d6-DMSO) δ (ppm) 2.19 (3H, s, MsOH), 3.03-3.07 (4H, m), 3.67 (4H, m), 6.99 (2H, br s), 7.43 (1H, d), 7.74-7.82 (4H, m), 8.06 (1H, br s), 8.59 (1H, br s), 8.64 (1H, s), 9.91 (1H, br s). LCMS: Rt 2.64 min (98.1%), m/z (APCI) 406 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[C:4]1=[O:18])[CH3:2].[O:19]=[S:20]1(=[O:35])[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[C:22](=[O:29])[N:21]1[CH2:30][CH2:31][CH2:32][CH2:33]Br.C(OCC)C>O>[O:19]=[S:20]1(=[O:35])[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[C:22](=[O:29])[N:21]1[CH2:30][CH2:31][CH2:32][CH2:33][N:15]1[CH2:16][CH2:17][CH:12]([N:5]2[C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:3]([CH2:1][CH3:2])[C:4]2=[O:18])[CH2:13][CH2:14]1
Reactant: CCn1c(=O)n(C2CCNCC2)c2ccccc21
Reactant: O=C1c2ccccc2S(=O)(=O)N1CCCCBr
Solvent: CCOCC
Solvent: O
Product: CCn1c(=O)n(C2CCN(CCCCN3C(=O)c4ccccc4S3(=O)=O)CC2)c2ccccc21

Procedure:
From 4-(3-ethyl-2-oxo-1-benzimidazolinyl)piperidine and 1,1-dioxido-2-(4-bromobutyl)-1,2-benzisothiazol-3(2H)-one (prepared as shown in Example 21) using the procedures described in Example 1 there was obtained a white solid as the freebase (from diethyl ether), melting point 124-25° C. Analysis calculated for C25H30N4O4S.0.4 H2O: C, 61.30; H, 6.34; N, 11.44; found: C, 61.34; H, 6.18; N, 11.47. The NMR was consistent with the structure.
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:20]([F:23])([F:22])[F:21])[CH:9]=[C:10]([C:11]3[CH:16]=[C:15]([F:17])[C:14]([F:18])=[C:13]([F:19])[CH:12]=3)[C:4]=2[N:3]=1.[CH3:24][C@H:25]1[CH2:30][NH:29][CH2:28][CH2:27][NH:26]1>>[CH3:24][C@@H:25]1[NH:26][CH2:27][CH2:28][N:29]([C:2]2[NH:3][C:4]3[C:10]([C:11]4[CH:16]=[C:15]([F:17])[C:14]([F:18])=[C:13]([F:19])[CH:12]=4)=[CH:9][C:8]([C:20]([F:23])([F:22])[F:21])=[CH:7][C:5]=3[N:6]=2)[CH2:30]1
Reactant: C[C@H]1CNCCN1
Reactant: Fc1cc(-c2cc(C(F)(F)F)cc3[nH]c(Cl)nc23)cc(F)c1F
Product: C[C@H]1CN(c2nc3cc(C(F)(F)F)cc(-c4cc(F)c(F)c(F)c4)c3[nH]2)CCN1

Procedure:
2-Chloro-6-(trifluoromethyl)-4-(3,4,5-trifluorophenyl)-1H-benzoimidazole (350 mg, 1 mmol, Example 51b) reacted with (S)-(+)-2-methylpiperazine (150 mg. 1.5 mmol, Aldrich) under the conditions of Example 3c to give the title compound as a light-brown solid. MS (ESI, pos. ion) m/z: 415 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:32])[CH2:10][C@@H:11]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:12]([NH:14][C@H:15]([C:20](=[O:23])NC)C(C)(C)C)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl.N[C@H](CO)[CH2:37][C:38]1[N:42]=[CH:41][NH:40][CH:39]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>>[CH2:1]([O:8][C:9](=[O:32])[CH2:10][C@@H:11]([NH:24][C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])[C:12]([NH:14][C@@H:15]([CH2:37][C:38]1[N:42]=[CH:41][NH:40][CH:39]=1)[CH2:20][OH:23])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNC(=O)[C@@H](NC(=O)[C@@H](CC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)C(C)(C)C
Reactant: N[C@H](CO)Cc1c[nH]cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Product: CC(C)(C)OC(=O)N[C@H](CC(=O)OCc1ccccc1)C(=O)N[C@H](CO)Cc1c[nH]cn1
Yield: 92 %

Procedure:
According to the procedure described in Example 1(b) for the preparation of 3(R)-t-butoxycarbonylamino-N-(2,2-dimethyl-1(S)-(methylcarbamoyl)propyl)succinamic acid benzyl ester, N-t-butoxycarbonyl-D-aspartic acid β-benzyl ester and L-histidinol dihydrochloride were coupled with TBTU to furnish 410 mg(92%) of 3(R)-(t-butoxycarbonylamino)-N-[2-hydroxy-1(S)-[(1H-imidazol-4-yl)methyl]ethyl]succinamic acid benzyl ester as a solid which was used without further purification.
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[N:25]=[C:24]([CH3:26])[CH:23]=[C:22]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([CH3:34])[CH:28]=4)[N:21]=3)[CH:15]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([C:22]2[CH:23]=[C:24]([CH3:26])[N:25]=[C:20]([C:16]3[CH:15]=[C:14]([C:11]4[S:10][C:9]([S:6]([NH2:5])(=[O:7])=[O:8])=[CH:13][CH:12]=4)[CH:19]=[CH:18][CH:17]=3)[N:21]=2)=[CH:28][C:29]=1[CH3:34]
Reactant: Cc1cc(-c2ccc(Cl)c(C)c2)nc(-c2cccc(-c3ccc(S(=O)(=O)NC(C)(C)C)s3)c2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2ccc(Cl)c(C)c2)nc(-c2cccc(-c3ccc(S(N)(=O)=O)s3)c2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 25.8 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-5-{3-[6-(4-chloro-3-methyl-phenyl)-4-methyl-pyrimidin-2-yl]-phenyl}-thiophene-2-sulfonic acid amide (0.405 g) in dichloromethane (6 ml) was added TFA (6 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (5 ml), diethylether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration and further purified by flash chromatography (heptane/ethyl acetate) and crystallization (diethyl ether/heptane) to yield the title compound as an off-white solid (0.093 g, 20%). MS (ISP) 456.1 [(M+H)+]; mp 240° C.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][C:6](O[Si](C)(C)C)=[C:5](O[Si](C)(C)C)[CH2:4]1)[CH3:2].[ClH:19].Cl.[NH2:21][CH2:22][C:23]([NH2:25])=[NH:24]>>[ClH:19].[ClH:19].[NH2:25][C:23]1[N:24]=[C:6]2[CH2:7][CH2:8][N:3]([CH2:1][CH3:2])[CH2:4][C:5]2=[N:21][CH:22]=1
Reactant: CCN1CCC(O[Si](C)(C)C)=C(O[Si](C)(C)C)C1
Reactant: N=C(N)CN
Agent: Cl
Product: CCN1CCc2nc(N)cnc2C1

Procedure:
This compound was prepared analogous to Example 22 from 1-ethyl-1,2,5,6-tetrahydro-3,4-bis(trimethylsilyloxy)pyridine and α-amino-acetamidine dihydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([O:14]CC)=O)=[C:5]2[OH:17].[NH2:18][C:19]1[S:20][CH2:21][CH2:22][N:23]=1>>[ClH:1].[S:20]1[CH2:21][CH2:22][N:23]=[C:19]1[NH:18][C:12]([C:6]1[CH:7]=[N:8][C:9]2[C:4]([C:5]=1[OH:17])=[CH:3][C:2]([Cl:1])=[CH:11][CH:10]=2)=[O:14]
Reactant: NC1=NCCS1
Reactant: CCOC(=O)c1cnc2ccc(Cl)cc2c1O
Product: Cl
Product: O=C(NC1=NCCS1)c1cnc2ccc(Cl)cc2c1O

Procedure:
Using the procedure of Example 2, ethyl 6-chloro-4-hydroxy-3-quinoline-carboxylate and 2-amino-thiazoline were reacted at reflux for 48 hours and the product was crystallized from acetic acid to obtain N-(4,5-dihydro-thiazol-2-yl)-6-chloro-4-hydroxy-3-quinoline-carboxamide hydrochloride melting at >260° C.
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[OH:22])[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2].CN(C)C1C=CC=CC=1.[Br:32][CH:33]([CH3:37])[C:34](Br)=[O:35].C(OCC)(=O)C>ClCCl>[CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[O:22][C:34](=[O:35])[CH:33]([Br:32])[CH3:37])[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2]
Reactant: CC(Br)C(=O)Br
Reactant: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1O
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CN(C)c1ccccc1
Product: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)C(C)Br

Procedure:
In 70 ml of dichloromethane are dissolved 3.0 g of 16β-ethyl-17β-hydroxy-4-estren-3-one and 1.6 ml of N,N-dimethylaniline and, with stirring, 1.2 ml of α-bromopropionyl bromide is added to the above solution. The mixture is stirred at room temperature (15°-25° C.) for 30 hours followed by addition of 300 ml of ethyl acetate. The mixture is washed with 10% sulfuric acid and saturated aqueous sodium chloride solution in that order and dried over anhydrous magnesium sulfate. The solvent is then distilled off under reduced pressure and the residue is subjected to column chromatography. Following passage of 300 ml of diisopropyl ether-n-hexane (1:1), elution is carried out with 600 ml of diisopropyl ether. The eluate is evaporated under reduced pressure to remove the solvent, giving 2.7 g of the above-identified compound as a light-yellow viscous oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH2:9])[CH:3]=1.[CH2:10](OC=C(C#N)C#N)C>C(O)(C)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][CH:10]=[N:9][C:4]=2[CH:3]=1
Reactant: CCOC=C(C#N)C#N
Reactant: Nc1ccc(F)cc1N
Solvent: CC(C)O
Product: Fc1ccc2[nH]cnc2c1
Yield: 83.4 %

Procedure:
A solution of 4-fluoro-1,2-phenylenediamine (2.0 g) and ethoxymethylenemalononitrile (2.9 g) in isopropanol (80 mL) was heated to reflux overnight. The volatiles were removed in vacuo to yield 5-fluoro-1H-benzimidazole (1.8 g). ESI-MS (m/z) 137 [M+H]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:13]4[S:18][C:17]([C:19](O)=[O:20])=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[OH:28][C:29]1[CH:30]=[C:31]([CH:33]=[CH:34][CH:35]=1)[NH2:32]>>[OH:28][C:29]1[CH:30]=[C:31]([NH:32][C:19]([C:17]2[S:18][C:13]3[C:12]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[N:11][C:10]([C:5]4[CH:6]=[CH:7][CH:8]=[C:9]5[C:4]=4[CH:3]=[N:2][NH:1]5)=[N:15][C:14]=3[CH:16]=2)=[O:20])[CH:33]=[CH:34][CH:35]=1
Reactant: O=C(O)c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1
Reactant: Nc1cccc(O)c1
Product: O=C(Nc1cccc(O)c1)c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1

Procedure:
2-(1H-Indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6-carboxylic acid 13 (30 mg) was coupled to 3-hydroxyaniline via General Procedure B. The product was purified via reverse phase HPLC to give 7.7 mg of 246. MS (Q1) 472.7 (M)+
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)[CH:13]=[CH:12]2.[H-].[Na+].[CH3:27][CH2:28]OCC.O.[CH3:33][N:34]([CH:36]=O)C>>[CH:36]1([N:34]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH:13]=[CH:12]3)[CH3:33])[CH2:28][CH2:27]1
Reactant: CCOCC
Reactant: CN(C)C=O
Reactant: Fc1ccc(-n2ccc3cc(OCCCCCCBr)ccc32)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CN(CCCCCCOc1ccc2c(ccn2-c2ccc(F)cc2)c1)C1CC1
Yield: 73 %

Procedure:
195 mg (0.5 mmol) 5-(6-Bromo-hexyloxy)-1-(4-fluoro-phenyl)-1H-indole in 2.5 ml DMF were treated with 185 mg (1 mmol) cyclopropyl-methyl amine·CF3CO2H and 96 mg (2 mmol, 50% in mineral oil) NaH at RT for 2 h and at 60° C. for 3 h. At RT, ether and water were added and the inorganic phase was extracted with ether. The combined organic phases were washed with water, dried over Na2SO4 and evaporated. Purification on silica gel with hexane/ether 1:1 yielded 140 mg (73%) Cyclopropyl-{6-[1-(4-fluoro-phenyl)-1H-indol-5-yloxy]-hexyl}-methyl-amine as light yellow oil, MS: 381 (MH+).