Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:42]([OH:44])=O)=[N:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:29])[NH:15][S:16]([C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=3)(=[O:18])=[O:17])=[CH:10][C:9]=2[C:30]([N:32]2[CH2:41][CH2:40][C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH2:33]2)=[O:31])[C:6]=1[CH3:7].[CH2:45]([NH:49][C:50]1[CH:55]=[CH:54][C:53](Cl)=[C:52](Cl)[CH:51]=1)[CH2:46][CH2:47][CH3:48]>>[CH2:45]([N:49]([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[C:42]([C:3]1[C:2]([Cl:1])=[C:6]([CH3:7])[N:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:29])[NH:15][S:16]([C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=3)(=[O:18])=[O:17])=[CH:10][C:9]=2[C:30]([N:32]2[CH2:41][CH2:40][C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH2:33]2)=[O:31])[N:4]=1)=[O:44])[CH2:46][CH2:47][CH3:48]
Reactant: Cc1c(Cl)c(C(=O)O)nn1-c1ccc(C(=O)NS(=O)(=O)c2ccc3ccccc3c2)cc1C(=O)N1CCc2ccccc2C1
Reactant: CCCCNc1ccc(Cl)c(Cl)c1
Product: CCCCN(C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccccc4c3)cc2C(=O)N2CCc3ccccc3C2)c(C)c1Cl)c1ccccc1

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 122G, 4-chloro-5-methyl-1-(4-(naphthalen-2-ylsulfonylcarbamoyl)-2-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-1H-pyrazole-3-carboxylic acid (Intermediate 122F, 50 mg, 0.079 mmol) and N-butyl-3,4-dichloroaniline (Aldrich, 10 mg, 0.046 mmol) were converted to the title compound. 1H NMR (1:1 CD3OD:CDCl3, mixture of amide rotamers) δ 8.73 (s, 1H), 8.12-8.00 (m, 4H), 7.97-7.94 (m, 1H), 7.74-7.66 (m, 2H), 7.57 (br s, 1H), 7.46 (br s, 1H), 7.36 (br s, 1H), 7.26-7.19 (m, 4.5H), 7.12-7.10 (m, 0.5H), 7.00 (br s, 1H), 6.73 (br s, 1H), 6.66 (br s, 0.5H), 6.50 (br s, 0.5H), 4.66 (br s, 0.5H), 4.51 (br s, 0.5H), 4.39 (br s, 0.5H), 4.25 (br s, 0.5H), 3.85 (br s, 2H), 3.58 (br s, 2H), 3.13 (br s, 1H), 2.81 (br s, 1H), 2.20-2.16 (m, 3H), 1.38-1.21 (m, 4H), 0.93-0.83 (m, 3H); MS(ESI+) m/z 760.2 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C([Mg]Cl)CC.[Sn:13](Cl)([CH3:16])([CH3:15])[CH3:14].N#N>C1COCC1>[CH3:14][Sn:13]([CH3:16])([CH3:15])[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Sn](C)(C)Cl
Reactant: Brc1cccnc1
Agent: CCC[Mg]Cl
Agent: N#N
Solvent: C1CCOC1
Product: C[Sn](C)(C)c1cccnc1
Temperature: 10 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
To anhydrous THF (100 ml) containing 3-bromo-pyridine (3.29 g, 20.82 mmol), were added 1.2 eq of /PrMgCl (12.49 ml, 2M in THF) and the resulting mixture was stirred for 2 hours under N2 (10° C.). Subsequently 1.2 eq of (CH3)3SnCl were added and the reaction mixture was stirred for 18 hours at room temperature (under N2). The reaction mixture was quenched with a saturated NH4Cl solution, diluted with ethyl acetate, washed three times with a saturated NaHCO3 solution, dried (Na2SO4), filtered and concentrated. The resulting residue was purified by flash chromatography (diethyl ether/PE 1/1) to afford 3-trimethylstannanyl-pyridine (71) (3.32 g, 66%). LCMS (method A): Rt: 2.09 min, ([M+H]+=242). 1H-NMR (400 MHz, CDCl3): δ 8.62 (bs, 1H), 8.52 (dd, J=5 Hz, 2 Hz, 1H), 7.76 (dt, J=8 Hz, 2 Hz, 1H), 7.25-7.21 (m, 1H), 0.33 (s, 9H), with Sn satellites at 0.41 and 0.27.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[Cl:27][C:28]1[C:29]([F:54])=[C:30]([NH:34][C:35]2[C:44]3[C:39](=[CH:40][C:41]([O:52][CH3:53])=[C:42]([O:45][CH:46]4[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]4)[CH:43]=3)[N:38]=[CH:37][N:36]=2)[CH:31]=[CH:32][CH:33]=1.C(N(C(C)C)CC)(C)C.[CH3:64][C:65]1[C:69]([C:70](O)=[O:71])=[CH:68][O:67][N:66]=1>C(Cl)Cl>[Cl:27][C:28]1[C:29]([F:54])=[C:30]([NH:34][C:35]2[C:44]3[C:39](=[CH:40][C:41]([O:52][CH3:53])=[C:42]([O:45][CH:46]4[CH2:47][CH2:48][N:49]([C:70]([C:69]5[C:65]([CH3:64])=[N:66][O:67][CH:68]=5)=[O:71])[CH2:50][CH2:51]4)[CH:43]=3)[N:38]=[CH:37][N:36]=2)[CH:31]=[CH:32][CH:33]=1
Reactant: Cc1nocc1C(=O)O
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCN(C(=O)c2conc2C)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 21.1 %

Procedure:
HATU (0.31 g) was added to a solution of N-(3-chloro-2-fluorophenyl)-7-methoxy-6-(piperidin-4-yloxy)quinazolin-4-amine dihydrochloride (300 mg), diisopropylethylamine (0.45 ml) and 3-methyl-4-isoxazolecarboxylic acid (0.128 g) in methylene chloride (9 ml). The resulting mixture was stirred at room temperature for 2.5 hrs. Methylene chloride (20 ml) was added and the organics washed with aqueous sodium hydroxide (2M, 30 ml) and water (30 ml). The crudes were then purified by flash column chromatography eluting with methanol/methylene chloride (2.5/97.5). Fractions containing the desired product were evaporated to a white foam which was triturated with diethyl ether (20 ml) to give N-(3-chloro-2-fluorophenyl)-7-methoxy-6-({1-[(3-methylisoxazol-4-yl)carbonyl]piperidin-4-yl}oxy)quinazolin-4-amine as a white solid (0.068 g). 1H NMR Spectrum: (DMSO d6 373K) 1.86 (m, 2H), 2.02 (m, 2H), 2.30 (s, 3H), 3.52 (m, 2H), 3.82 (m, 2H), 3.96 (s, 3H), 4.79 (m, 1H), 7.22 (m, 1H), 7.22 (s, 1H), 7.40 (m, 1H), 7.58 (m, 1H), 7.89 (s, 1H), 8.39 (s, 1H), 9.00 (s, 1H), 9.25 (br s, 1H); Mass Spectrum: (M+H)+ 512
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:20])[CH:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:11]([OH:13])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[C:22]([C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1)(=[NH:24])[NH2:23].[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:1]([O:8][C:9](=[O:20])[CH:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:11]([NH:29][C:28]1[CH:30]=[CH:31][C:25]([C:22](=[NH:23])[NH2:24])=[CH:26][CH:27]=1)=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C(C(=O)OCc1ccccc1)c1ccccc1
Reactant: N=C(N)c1ccc(N)cc1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N=C(N)c1ccc(NC(=O)C(C(=O)OCc2ccccc2)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
10 g (37 mmol) phenyl malonic acid monobenzyl ester and 7.7 g (37 mmol) 4-amidino aniline hydrochloride were dissolved in 60 ml DMF and cooled to 0° C. 12.2 g (37 mmol) TOTU and 19 ml (111 mmol) DIPEA were added and the mixture stirred at rt overnight. The solvent was removed, the residue taken up in ethyl acetate, and extracted with 10% sodium carbonate solution and brine. After drying over sodium sulfate, the solution was evaporated to dryness and extracted with diethyl ether twice. The remaining solid product was sufficiently pure.
Reaction SMILES: [C:1]([CH2:3][CH:4]([CH:25]1[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]1)[N:5]1[CH:9]=[C:8]([C:10]2[N:15]3[CH:16]=[CH:17][N:18]=[C:14]3[CH:13]=[C:12]([C:19]3[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=3)[N:11]=2)[CH:7]=[N:6]1)#[N:2].C(Cl)[Cl:39].Cl.O1CCOCC1>>[ClH:39].[CH3:24][N:22]1[CH:23]=[C:19]([C:12]2[N:11]=[C:10]([C:8]3[CH:7]=[N:6][N:5]([CH:4]([CH:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)[CH2:3][C:1]#[N:2])[CH:9]=3)[N:15]3[CH:16]=[CH:17][N:18]=[C:14]3[CH:13]=2)[CH:20]=[N:21]1.[CH3:24][N:22]1[CH:23]=[C:19]([C:12]2[N:11]=[C:10]([C:8]3[CH:7]=[N:6][N:5]([CH:4]([CH:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)[CH2:3][C:1]#[N:2])[CH:9]=3)[N:15]3[CH:16]=[CH:17][N:18]=[C:14]3[CH:13]=2)[CH:20]=[N:21]1
Reactant: Cn1cc(-c2cc3nccn3c(-c3cnn(C(CC#N)C4CCN(C(=O)OC(C)(C)C)CC4)c3)n2)cn1
Reactant: ClCCl
Agent: Cl
Solvent: C1COCCO1
Product: Cn1cc(-c2cc3nccn3c(-c3cnn(C(CC#N)C4CCNCC4)c3)n2)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Tert-butyl 4-(2-cyano-1-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)ethyl)piperidine-1-carboxylate (59.4 mg, 0.118 mmol) was dissolved in DCM (592 μL, 0.118 mmol). To this was added 4N HCl in dioxane (296 μL, 1.18 mmol) and stirred at ambient temperature for 1 hour. Complete conversion was observed after 1 hour and the reaction mixture was concentrated to dryness to afford the HCl salt of 3-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)-3-(piperidin-4-yl)propanenitrile (56.0 mg, 99.7% yield). MS (apci) m/z=402.3 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7].C(=O)([O-])[O-].[K+].[K+].[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Cl)=[CH:25][CH:24]=1>CC(C)=O>[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([O:14][CH2:27][C:26]2[CH:29]=[CH:30][C:23]([Cl:22])=[CH:24][CH:25]=2)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: ClCc1ccc(Cl)cc1
Reactant: COC(=O)c1cccc(O)c1C(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cccc(OCc2ccc(Cl)cc2)c1C(=O)OC
Yield: 109.1 %

Procedure:
To a stirred suspension of 3-hydroxyphthalic acid dimethyl ester (1.3 g, 6.3 mmol) in acetone (20 mL) and potassium carbonate (2.6 g, 19 mmol) was added 4-chlorobenzyl chloride (1.1 g, 6.6 mmol) and refluxed overnight. The solvent was evaporated and the residue was partitioned between water (100 mL) and ethyl acetate (150 mL) and washed with water (2×100 mL). The combined organic phases was dried, concentrated and purified by flash column chromatography (EtOAc/Hexane) to give 3-(4-chloro-benzyloxy)-phthalic acid dimethyl ester (2.3 g, 110% crude yield). The product was used in the next step without further purification.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]2[N:18](COCC[Si](C)(C)C)[C:17]([O:27][C@H:28]3[C@H:32]4[O:33][CH2:34][C@@H:35]([OH:36])[C@H:31]4[O:30][CH2:29]3)=[N:16][C:12]2=[N:13][C:14]=1[I:15].CO>ClCCl>[Cl:8][C:9]1[CH:10]=[C:11]2[NH:18][C:17]([O:27][C@H:28]3[C@H:32]4[O:33][CH2:34][C@@H:35]([OH:36])[C@H:31]4[O:30][CH2:29]3)=[N:16][C:12]2=[N:13][C:14]=1[I:15]
Reactant: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2nc(I)c(Cl)cc21
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2nc(I)c(Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Trifluoroacetic acid (70.0 ml, 909 mmol) was added to a stirred solution of (3R,3aR,6R,6aR)-6-[6-chloro-5-iodo-1-(2-trimethylsilylethoxymethyl)imidazo[4,5-b]pyridin-2-yl]oxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol (14.99 g, 27.1 mmol) in dichloromethane (70 ml). The reaction mixture was an amber solution that was stirred at room temperature. After 3 hours, the reaction mixture was concentrated under reduced pressure to give an amber oil. Methanol (50 ml) was added and the resulting solution was stirred at room temperature. After about 5 minutes, the product crystallized and precipitated to give a white suspension. Dichloromethane (50 ml) was added to the reaction mixture. The crystalline product was collected from the reaction mixture by vacuum filtration and was dried overnight under vacuum to give the title compound as a crystalline white solid. LC-MS: calculated for C12H11ClIN3O4 422.95 observed m/e: 424.0 (M+H)+ (Rt 0.92/2 min).
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1)[CH3:2].[N+:10]([O-])([OH:12])=[O:11]>C(OC(=O)C)(=O)C>[CH2:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1)[CH3:2]
Reactant: CCc1ccc(N)cc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Product: CCc1ccc(N)c([N+](=O)[O-])c1
Temperature: 10 °C

Procedure:
To acetic anhydride (160 ml) at room temperature was added 4-ethylaniline (30 g) over 15 minutes with stirring. The mixture was cooled to 10° C. and concentrated nitric acid (45 ml) was added very slowly, keeping the reaction temperature to below 14° C. The mixture was warmed to room temperature over one hour, poured into ice-water and the resultant yellow solid was filtered off and dried. This was added to dioxan (100 ml), followed by 6M hydrochloric acid (100ml), the solution heated to 70° C. for 3 hr, poured into water, and 1M sodium hydroxide added until pH 10. The product was extracted into ethyl acetate which was then washed with water, brine, dried over magnesium sulphate and solvent removed under vacuum to give 4-ethyl-2-nitroaniline (28.4 g). δ (60 MHz CDCl3) 1.2 (3H, t, CH3), 2.5 (2H, q, CH2). 6.3 (2H. bs, NH2 ) and 6.6 to 7.8 (3H, m, ArH).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)[CH2:2][CH3:3].[NH2-:10].[Na+].C1(C)C(C)=CC=CC=1>O>[NH2:10][C:6]1[CH:5]=[C:4]([CH2:1][CH2:2][CH3:3])[CH:9]=[CH:8][N:7]=1
Reactant: [NH2-]
Reactant: CCCc1ccncc1
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: O
Product: CCCc1ccnc(N)c1

Procedure:
75 g (0.62M) of 4-n-propylpyridine and 28 g (0.73M) of sodium amide were added to 250 ml of xylene, and the mixture was heated under reflux for 10 hr. Water was added in small portions to the reaction mixture under ice cooling to decompose excess sodium amide, and the reaction mixture was extracted with ethyl acetate, dried over magnesium sulfate and then purified by column chromatography (dichloromethanemethanol 50:1→20:1). The yield was 33 g. (blackish purple solid)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([OH:17])=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:18]([C:20]1[CH:34]=[CH:33][C:23]([O:24][C:25]2[CH:26]=[C:27]([NH2:32])[CH:28]=[C:29]([OH:31])[CH:30]=2)=[CH:22][CH:21]=1)#[N:19]>>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]1[CH2:10][CH2:11][C@H:12]([C:15](=[O:17])[NH:32][C:27]2[CH:28]=[C:29]([OH:31])[CH:30]=[C:25]([O:24][C:23]3[CH:22]=[CH:21][C:20]([C:18]#[N:19])=[CH:34][CH:33]=3)[CH:26]=2)[CH2:13][CH2:14]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: N#Cc1ccc(Oc2cc(N)cc(O)c2)cc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C(=O)O)CC1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C(=O)Nc2cc(O)cc(Oc3ccc(C#N)cc3)c2)CC1

Procedure:
Following the procedure of Example 9(e) Trans-4-tert-butoxycarbonylamino-cyclohexanecarboxylic acid 0.72 g (2.96 mmol) and [3-(4-cyano-phenoxy)-5-hydroxy-phenyl]-amine (0.67 g, 2.96 mmol) were used to afford 1.0 g of the required product. Percentage purity (LCMS): 73.5%, (M+1)=451.5+1.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][C:11]([F:14])([F:13])[F:12].[CH3:16][O:17][C:18](=[O:22])[CH2:19][C:20]#[N:21].C[O-].[Na+]>CO>[NH2:21][C:20]1[O:1][N:2]=[C:3]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[O:10][C:11]([F:14])([F:13])[F:12])[C:19]=1[C:18]([O:17][CH3:16])=[O:22]
Reactant: COC(=O)CC#N
Reactant: ON=C(Cl)c1ccccc1OC(F)(F)F
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1c(-c2ccccc2OC(F)(F)F)noc1N
Yield: 89.9 %

Procedure:
In a similar manner as described in Preparation Example 17, by using methanol (160 mL), N-hydroxy-2-(trifluoromethoxy)benzimidoylchloride (8.00 g, 33.39 mmol), methylcyanoacetate (4.31 g, 43.41 mmol) and sodium methoxide (3.61 g, 66.78 mmol), a white solid required compound (9.07 g, 30.02 mmol, 90%) was obtained.
Reaction SMILES: Br[CH:2]([CH3:21])[C:3]([NH:5][C:6]1[CH2:10][CH2:9][N:8]([C:11]2[CH:12]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:15][CH:16]=2)[N:7]=1)=[O:4].[CH3:22][NH:23][CH3:24]>C1C=CC=CC=1>[CH3:22][N:23]([CH3:24])[CH:2]([CH3:21])[C:3]([NH:5][C:6]1[CH2:10][CH2:9][N:8]([C:11]2[CH:12]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:15][CH:16]=2)[N:7]=1)=[O:4]
Reactant: CNC
Reactant: CC(Br)C(=O)NC1=NN(c2cccc(C(F)(F)F)c2)CC1
Solvent: c1ccccc1
Product: CC(C(=O)NC1=NN(c2cccc(C(F)(F)F)c2)CC1)N(C)C

Procedure:
A 1.0 g. amount of 2-bromo-N-[1-(α,α,α-trifluoro-m-tolyl)-2-pyrazolin-3-yl]propionamide (Example 12) is dissolved in 50 ml. of benzene in a pressure bottle, then 2.0 ml. of dimethylamine is added and the bottle is sealed for 1/2 hour at room temperature with the separation of crystals. The mixture is heated on a steam bath for 6 hours, then is cooled. The reaction mixture is partitioned between water and benzene. The benzene layer is dried over anhydrous magnesium sulfate and evaporated to a dark gum. The gum is dissolved in hexane and filtered through a hydrous magnesium silicate. The filtrate is evaporated to a gum (0.9 g.). A 210 mg. amount of this gum is chromatographed by thick layer chromatography on one mm Silica Gel G plates using the upper phase of a mixture of 2 parts benzene, 1 part acetone and 2 parts water to give 180 mg. of the desired product as a light yellow gum.
Reaction SMILES: [CH3:1][C:2]1[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:3]=1[C:4]([C:6]1[N:10]([CH3:11])[C:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=2)=[CH:8][CH:7]=1)=[O:5]>C(OCC)(=O)C.[Pd]>[CH3:1][C:2]1[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:3]=1[C:4]([C:6]1[N:10]([CH3:11])[C:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)=[CH:8][CH:7]=1)=[O:5]
Reactant: Cc1ccc(C(=O)c2ccc(Cc3ccc([N+](=O)[O-])cc3)n2C)c(C)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)c2ccc(Cc3ccc(N)cc3)n2C)c(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.5 %

Procedure:
4-[5-(2,4-Dimethylbenzoyl)-1-methylpyrrol-2-ylmethyl)nitrobenzene (923 mg, 2.52 mmol) [prepared as described in Example 6, Step(e)], was dissolved in ethyl acetate (10 ml). 10% Pd/C (92 mg) was added, and the reaction mixture was vigorously stirred under hydrogen atmosphere at ambient temperature and atmospheric pressure for 2 h. The mixture was filtered through Celite®, and the filtrate was evaporated to dryness to give 4-[5-(2,4-dimethylbenzoyl)-1-methylpyrrol-2-yl-methyl)aniline (718 mg, 85%) as pale yellow crystals, mp 107.6-108.5° C.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:11]=[CH:10][C:9]([CH2:12][N:13]([CH3:15])[CH3:14])=[CH:8][C:7]=2[CH3:16])[CH2:2]1.[C:17]1([C:23]2[O:27][C:26]([C:28](OCC)=[O:29])=[N:25][N:24]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CCO>[CH3:14][N:13]([CH3:15])[CH2:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH:3]2[CH2:2][N:1]([C:28]([C:26]3[O:27][C:23]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)=[N:24][N:25]=3)=[O:29])[CH2:4]2)=[C:7]([CH3:16])[CH:8]=1
Reactant: CCOC(=O)c1nnc(-c2ccccc2)o1
Reactant: Cc1cc(CN(C)C)ccc1OC1CNC1
Solvent: CCO
Product: Cc1cc(CN(C)C)ccc1OC1CN(C(=O)c2nnc(-c3ccccc3)o2)C1
Temperature: 120 °C
Reaction time: 0.25 h
Yield: 58.6 %

Procedure:
Intermediate 16B (0.25 g, 1.13 mmol) was mixed with ethyl 5-phenyl-1,3,4-oxadiazole-2-carboxylate (0.27 g, 1.25 mmol) in a microwave vial, which then was sealed. The mixture was melted in a preheated oil bath and then stirred at 120° C. for 15 min using the oil bath. EtOH (0.2 mL) was added to the reaction mixture via a syringe and the mixture was stirred at 120° C. for another 3 h. To the mixture was added EtOH (5 mL) and the precipitate was stirred at rt for 20 min. The precipitate was filtered, washed with EtOH (20 mL) and then with Et2O (3 mL). The product was dried in vacuo. There was obtained 0.26 g (57%) of 16 as a solid. 1H NMR (500 MHz, CDCl3): δ 2.23 (s, 6H), 2.35 (s, 3H), 3.32 (s, 2H), 4.29-4.37 (m, 1H), 4.60-4.69 (m, 1H), 4.71-4.79 (m, 1H), 5.02-5.17 (m, 2H), 6.52-6.57 (m, 1H), 6.61 (s, 1H), 7.17 (d, 1H), 7.50-7.62 (m, 3H), 8.17 (d, 2H), MS (APCI+) m/z 393 [M+H]+, LC purity: 98%.
Reaction SMILES: [CH2:1]([O:3][C@@H:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][OH:19])=[CH:13][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:2].[CH3:20][S:21]([O:24][C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=1)(=[O:23])=[O:22]>C1COCC1>[CH2:1]([O:3][C@@H:4]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][O:19][C:28]2[CH:27]=[CH:26][C:25]([O:24][S:21]([CH3:20])(=[O:22])=[O:23])=[CH:30][CH:29]=2)=[CH:15][CH:16]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:2]
Reactant: CS(=O)(=O)Oc1ccc(O)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(CCO)cc1)OCC
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](Cc1ccc(CCOc2ccc(OS(C)(=O)=O)cc2)cc1)OCC
Temperature: 150 °C
Yield: 41.6 %

Procedure:
A solution of cyanomethylenetri-N-butylphosphorane (0.663 g, 2.75 mmol) in THF (1.5 mL) was added to a solution of ethyl(2S)-2-ethoxy-3-[4-(2-hydroxyethyl)phenyl]-propanoate (0.244 g, 0.92 mmol) and 4-hydroxyphenyl methanesulfonate (0.172 g, 0.92 mmol) in THF (1.5 mL). The reaction mixture was heated at 150° C. in a microwave oven for 10 minutes. The solvent was removed under reduced pressure. The crude product was purified by flash chromatography (silica, heptane/ethyl acetate 3:1 as the mobile phase) affording 0.167 g (42%) of the title compound.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH:18]=1)[C:12](OC)=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].ClCCl.CO.O>CCOCC>[Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:21])[CH3:22])[CH:18]=1)[CH2:12][OH:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COC(=O)c1cc(O[Si](C)(C)C(C)(C)C)cc(O[Si](C)(C)C(C)(C)C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)[Si](C)(C)Oc1cc(CO)cc(O[Si](C)(C)C(C)(C)C)c1
Temperature: 10 °C
Yield: 93 %

Procedure:
Methyl 3,5-di-tert-butyldimethylsilyloxybenzoate (170 g, 0.429 mole) was dissolved in ether (800 ml) and cooled to 10° C. Lithium aluminum hydride (14.2 g, 0.374 mole) was added in small portions. After 0.5 h TLC revealed complete conversion (dichloromethane:methanol 95:5), and water (20 ml) was added dropwise to destroy the excess of lithium aluminum hydride. Water/formic acid 4:1 (500 ml) was added to dissolve the aluminum salts, the organic layer was separated, and the aqueous layer was extracted with ether. The combined ether layers were washed with 0.4M sodium hydroxide, water, and brine. After drying (sodium sulfate), the ether was removed in vacuo to yield 147 g of the benzyl alcohol (0.399 mole, 93%).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][CH2:7][CH2:8][CH2:9][OH:10])[C:3]([OH:5])=[O:4].[ClH:11].[CH3:12]O>>[ClH:11].[NH2:1][C@@H:2]([CH2:6][CH2:7][CH2:8][CH2:9][OH:10])[C:3]([O:5][CH3:12])=[O:4]
Reactant: N[C@@H](CCCCO)C(=O)O
Reactant: CO
Agent: Cl
Product: COC(=O)[C@@H](N)CCCCO
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A slurry of (S)-2-amino-6-hydroxyhexanoic acid (2.42 g., 16.4 mmole) in dry methanol (60 ml.) was treated with gaseous hydrogen chloride until the mixture began to reflux. The homogeneous solution was then stirred at room temperature for 2.5 hours. The solvent was stripped and the residue azeotroped three times with toluene to give crude (S)-2-amino-6-hydroxyhexanoic acid, methyl ester, hydrochloride salt as an oil. This oil was dissolved in dimethylformamide (20 ml.) and methylene chloride (50 ml.) and treated with 4-methyl morpholine (3.20 ml., 2.94 g., 29.1 mmole). This mixture was cooled to 0° C. and treated with (S)-2-phthalimido-4-pentenoic acid [obtained from 7.0 g., 16.4 mmole of the salt product from part (a) by partitioning between 10% potassium bisulfate and ethyl acetate] in methylene chloride (10 ml.), followed by solid hydroxybenzotriazole (2.22 g., 16.4 mmole) and ethyl-3-(3-dimethylamino)propyl carbodiimide, hydrochloride salt (3.458 g., 18.0 mmole). After stirring at 0° C. for 0.5 hour and at room temperature for 2 hours, the reaction was partitioned between ethyl acetate and 0.5N hydrochloric acid. The ethyl acetate extract was washed successively with water, 50% saturated sodium bicarbonate, and brine, then dried (sodium sulfate), filtered and stripped. The residue was flash chromatographed (Merck silica gel, ethyl acetate) to give pure title compound as an oil which solidified upon standing. The solid was triturated with ethyl ether and hexane and collected by filtration to give 5.149 g. of analytically pure title product; m.p. 90°-92° C.; [α]D =+25.6 (c=1.1, chloroform). TLC (ethyl acetate) Rf =0.36.