Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:9][C:10]([C:37](=[O:39])N)=[CH:11][C:12]1[N:13]=[C:14]([F:36])[N:15]([C:17]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.CC(C)=[O:43]>>[C:1]([NH:9][C:10]([C:37]([OH:43])=[O:39])=[CH:11][C:12]1[N:13]=[C:14]([F:36])[N:15]([C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:16]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)C(=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1)NC(=O)c1ccccc1
Reactant: CC(C)=O
Agent: Cl
Product: O=C(O)C(=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1)NC(=O)c1ccccc1

Procedure:
The azlactone from Example 67 was suspended in acetone and heated for 10 minutes on a steam bath. Addition of 2N HCl and extractive work-up gave 4-(2-benzoylamino-2-carboxyvinyl)-2-fluoro-1-triphenylmethylimidazole, having the following n.m.r. in CDCl3 : 6.88 (s, 1H); 6.95-7.7 (m, 19H); 8.1-8.3 (m, 2H); 13.09 (br s, 1H).
Reaction SMILES: [NH2:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[NH:6][C:5](=[O:14])[CH2:4][CH:3]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl.[CH3:22][O:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH:26]=O>CO>[C:15]1([CH:3]2[CH:2]([NH:1][CH2:26][C:25]3[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=3[O:23][CH3:22])[CH:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[NH:6][C:5](=[O:14])[CH2:4]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NC1C(c2ccccc2)CC(=O)NC1c1ccccc1
Reactant: COc1ccccc1C=O
Agent: Cl
Solvent: CO
Product: COc1ccccc1CNC1C(c2ccccc2)CC(=O)NC1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.7 %

Procedure:
Under a nitrogen atmosphere in a round bottom flask were placed 500 mg (1.9 mmol) of 5 -amino-4,6-diphenyl-2-oxopiperidine and 5 mL of methanol. To the system was added 1 g of 3 Å molecular sieves, and the pH of the mixture was adjusted to 4.5 using methanol saturated with hydrogen chloride. To this system was added 284 mg (2.1 mmol) of 2-methoxybenzaldehyde, and the mixture was stirred at room temperature overnight. The mixture was filtered through diatomaceous earth (Celite (trademark)), the filter cake was rinsed well with methanol and the filtrate was concentrated with a rotary evaporator. The residue was partitioned between saturated aqueous sodium bicarbonate and chloroform, the layers were separated and the aqueous phase was extracted with three portions of chloroform. The combined chloroform extracts were dried (sodium sulfate) and concentrated, and the residue was subjected to flash column chromatography (30 g of silica gel) using 3:97 methanol/chloroform as the eluant to obtain 115 mg of 4,6-diphenyl-5-(2-methoxybenzylamino)-2-oxopiperidine.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][C:7]([C:15]([NH:17][C@@H:18]([CH2:26][CH:27]4[CH2:32][CH2:31][CH:30]([O:33][C:34]([N:36]([CH3:38])[CH3:37])=[O:35])[CH2:29][CH2:28]4)[C:19]([O:21]C(C)(C)C)=[O:20])=[O:16])([CH2:8]3)[CH2:6]1)[CH2:12]2)=[O:4]>C(O)=O>[CH3:1][O:2][C:3]([C:5]12[CH2:12][CH:11]3[CH2:10][CH:9]([CH2:8][C:7]([C:15]([NH:17][C@@H:18]([CH2:26][CH:27]4[CH2:28][CH2:29][CH:30]([O:33][C:34]([N:36]([CH3:38])[CH3:37])=[O:35])[CH2:31][CH2:32]4)[C:19]([OH:21])=[O:20])=[O:16])([CH2:13]3)[CH2:6]1)[CH2:14]2)=[O:4]
Reactant: COC(=O)C12CC3CC(CC(C(=O)N[C@@H](CC4CCC(OC(=O)N(C)C)CC4)C(=O)OC(C)(C)C)(C3)C1)C2
Solvent: O=CO
Product: COC(=O)C12CC3CC(CC(C(=O)N[C@@H](CC4CCC(OC(=O)N(C)C)CC4)C(=O)O)(C3)C1)C2
Reaction time: 8 h

Procedure:
The product from Step C was dissolved in formic acid at room temperature and the reaction mixture was stirred overnight. After evaporation of the solvent under reduced pressure, the title compound was isolated as a solid.
Reaction SMILES: [CH2:1]([N:4]([C:18]1[C:23](Br)=[C:22]([N:25]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[N:21]2[N:42]=[CH:43][C:44]([C:45]3[CH:46]=[N:47][C:48]4[C:53]([CH:54]=3)=[CH:52][C:51]([F:55])=[CH:50][CH:49]=4)=[C:20]2[N:19]=1)[CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].C([O-])([O-])=O.[K+].[K+]>[N+](CCCC)(CCCC)(CCCC)CCCC.[Br-].CN(C=O)C.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:31][Si:30]([CH3:32])([CH3:33])[CH2:29][CH2:28][O:27][CH2:26][N:25]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:39])[CH3:40])[C:22]1[N:21]2[N:42]=[CH:43][C:44]([C:45]3[CH:46]=[N:47][C:48]4[C:53]([CH:54]=3)=[CH:52][C:51]([F:55])=[CH:50][CH:49]=4)=[C:20]2[N:19]=[C:18]2[N:4]([CH:5]3[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:12])[CH2:7][CH2:6]3)[CH:1]=[C:2]([CH3:3])[C:23]=12
Reactant: C=CCN(c1nc2c(-c3cnc4ccc(F)cc4c3)cnn2c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c1Br)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cn(C2CCN(C(=O)OC(C)(C)C)CC2)c2nc3c(-c4cnc5ccc(F)cc5c4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c12
Temperature: 90 °C

Procedure:
A degassed mixture of tert-butyl 4-(allyl(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-bromo-3-(6-fluoroquinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)amino)piperidine-1-carboxylate (163 mg, 0.19 mmol), Pd(OAc)2 (4.3 mg, 0.02 mmol), Bu4NBr (73.6 mg, 0.23 mmol), and K2CO3 (78.7 mg, 0.57 mmol) in DMF (6 mL) was heated at 90° C. for 3 h. After cooling to room temperature, the mixture was diluted with H2O and then extracted with ethyl acetate (×2). The combined organic layers were washed with brine and dried with Na2SO4. Evaporation and purification by column chromatography afforded tert-butyl 4-(8-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(6-fluoroquinolin-3-yl)-7-methyl-5H-pyrazolo[1,5-a]pyrrolo[2,3-d]pyrimidin-5-yl)piperidine-1-carboxylate: LCMS tR=1.96 Min (5 min run, UV254nm), Mass calculated for M+775.4, observed LC/MS m/z 776.0 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:13]2[O:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[CH:20][CH:19]=3)=[N:16][N:17]=2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)([O-])=O.[O:30]1[CH2:35][CH2:34][N:33]([C:36]2[CH:43]=[CH:42][C:39]([CH:40]=O)=[CH:38][CH:37]=2)[CH2:32][CH2:31]1>>[O:27]1[CH2:28][CH2:29][N:24]([C:21]2[CH:22]=[CH:23][C:18]([C:15]3[O:14][C:13]([C:6]4[CH:7]=[CH:8][C:9]5[NH:10][C:40]([C:39]6[CH:38]=[CH:37][C:36]([N:33]7[CH2:34][CH2:35][O:30][CH2:31][CH2:32]7)=[CH:43][CH:42]=6)=[N:1][C:4]=5[CH:5]=4)=[N:17][N:16]=3)=[CH:19][CH:20]=2)[CH2:25][CH2:26]1
Reactant: O=[N+]([O-])c1ccc(-c2nnc(-c3ccc(N4CCOCC4)cc3)o2)cc1[N+](=O)[O-]
Reactant: O=Cc1ccc(N2CCOCC2)cc1
Product: c1cc(N2CCOCC2)ccc1-c1nc2cc(-c3nnc(-c4ccc(N5CCOCC5)cc4)o3)ccc2[nH]1

Procedure:
Compound 428 was prepared according to the procedure similar to that described in Scheme III from 3,4-dinitro-1-(5-(4-morpholinophenyl)-1,3,4-oxadiazol-2-yl)benzene and 4-morpholinobenzaldehyde. [M+H]+ calcd for C29H28N6O3: 590.23; found: 508.98.
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[CH:8][C:9]2[S:13][C:12]([CH2:14][N:15]([CH3:17])[CH3:16])=[N:11][C:10]=2[CH:18]=1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl.Br>O1CCCC1>[NH2:15][CH2:14][CH2:12][S:13][CH2:4][C:6]1[CH:7]=[CH:8][C:9]2[S:13][C:12]([CH2:14][N:15]([CH3:16])[CH3:17])=[N:11][C:10]=2[CH:18]=1
Reactant: CCOC(=O)c1ccc2sc(CN(C)C)nc2c1
Agent: Br
Agent: Cl
Agent: [Al+3]
Solvent: C1CCOC1
Product: CN(C)Cc1nc2cc(CSCCN)ccc2s1

Procedure:
The benzothiazole derivative (1 g) was subjected to reduction with lithium aluminum hydride (0.6 g) in anhydrous tetrahydrofuran (15 ml). Then, the product was refluxed by heating for 6 hrs in an aqueous solution (7.2 ml) of cystheamine hydrochloride (0.43 g) and 47% hydrobromide to yield 5-[(2-aminoethyl)thiomethyl]-2-dimethylaminomethylbenzothiazole.2hydrobromide (1.52 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[CH:19]=[N:18][CH:17]=[C:16](Cl)[N:15]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[CH:21]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)=[O:22]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[CH:19]=[N:18][CH:17]=[C:16]([C:26]3[CH:27]=[CH:28][C:23]([CH:21]=[O:22])=[CH:24][CH:25]=3)[N:15]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: COc1cc(Nc2cncc(Cl)n2)cc(OC)c1OC
Product: COc1cc(Nc2cncc(-c3ccc(C=O)cc3)n2)cc(OC)c1OC
Yield: 61.6 %

Procedure:
Using Method C with 200 mg (0.68 mmol) 2a and 123 mg (0.82 mmol) 4-formylphenylboronic acid, 153 mg (61.7%) pure title compound were obtained after preparative HPLC (eluent: AcOEt) purification of the whole batch. Reaction time: 24 hours. 1H-NMR (DMSO), δ (ppm), J (Hz): 3.64 (s, 3H, CH3O(4′)), 3.83 (s, 6H, CH3O(3′+5′)), 7.25 (s, 2H, Harom(2+6)), 8.05 (d, 2H, Harom 2′+6′, J=8.22), 8.23 (s, 1H, HP5), 8.35 (d, 2H, Harom3′+5′), 8.64 (s, 1H, HP3), 9.68 (s, 1H, NHamine), 10.08 (s, 1H, CHO); MS, (C20H19N3O4), m/z: 395 [M++1, 100].
Reaction SMILES: [OH:1][CH2:2][C@H:3]([CH3:8])[C:4]([O:6][CH3:7])=[O:5].[CH3:9][S:10](Cl)(=[O:12])=[O:11].CCN(CC)CC>C(Cl)Cl>[CH3:9][S:10]([O:1][CH2:2][C@H:3]([CH3:8])[C:4]([O:6][CH3:7])=[O:5])(=[O:12])=[O:11]
Reactant: COC(=O)[C@@H](C)CO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](C)COS(C)(=O)=O
Yield: 102.1 %

Procedure:
A solution of methyl 3-hydroxy-2-(S)-methylpropanoate (35 g, 295 mmol) in 830 mL of CH2Cl2, under N2 atmosphere, was cooled to -60° C. With rapid stirring, methanesulfonyl chloride (24 mL, 310 mmol) was added, followed by Et3N (50 mL, 354 mmol) over 90 s. As the addition ended, a heavy white precipitate formed which stopped the magnetic stirring. The cold bath was removed and the reaction allowed to reach r.t. The reaction mixture was poured into aq 25% NH4OAc. After separation, the organic phase was dried over MgSO4 and evaporated to give the title compound as a colorless oil (59.1 g, 102%).
Reaction SMILES: O.[C:2]1([CH:8]([CH3:11])[C:9]#[N:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:12].[H][H]>C(O)C>[ClH:12].[C:2]1([CH:8]([CH3:11])[CH2:9][NH2:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C#N)c1ccccc1
Reactant: [H][H]
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC(CN)c1ccccc1
Temperature: 57 °C
Yield: 76.2 %

Procedure:
To an autoclave hydrogenation apparatus under nitrogen was charged water-wet 5% palladium on carbon (453 g), ethanol (6.36 L), 2-phenylpropionitrile (636 g, 4.85 moles) and finally concentrated (12M) hydrochloric acid (613 g, 5.6 mole). The mixture was stirred rapidly and pressurized to 89.7-92.7 psi (618.46-639.15 kPa) with hydrogen. The mixture was then heated to 50-64° C. for 3 hours. 1H NMR analysis of an aliquot showed less than 5% starting material. The reaction mixture was depressurized and filtered to afford two lots of filtrate that were concentrated under reduced pressure to ˜400 mL each. To each lot was added methyl tert-butyl ether (MTBE) (2.2 L each) and the precipitate solids were allowed to stir overnight. Each lot was filtered and the collected solids were each washed with fresh MTBE (100 mL) and dried overnight. The lots were combined to afford 2-phenyl-1-propylamine HCl (634.4 g, 76.2%) as a white powder.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:8]([CH2:31][O:32][CH2:33][CH2:34][O:35][CH3:36])[S:9]([C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[O:25][CH:26]=[CH:27][N:28]=4)=[CH:20][C:19]=3[CH:29]=[O:30])=[CH:14][CH:15]=[CH:16][CH:17]=2)(=[O:11])=[O:10])=[N:4][O:5][C:6]=1[CH3:7].[BH4-].[Na+]>CO>[CH3:1][C:2]1[C:3]([N:8]([CH2:31][O:32][CH2:33][CH2:34][O:35][CH3:36])[S:9]([C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[O:25][CH:26]=[CH:27][N:28]=4)=[CH:20][C:19]=3[CH2:29][OH:30])=[CH:14][CH:15]=[CH:16][CH:17]=2)(=[O:11])=[O:10])=[N:4][O:5][C:6]=1[CH3:7]
Reactant: COCCOCN(c1noc(C)c1C)S(=O)(=O)c1ccccc1-c1ccc(-c2ncco2)cc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COCCOCN(c1noc(C)c1C)S(=O)(=O)c1ccccc1-c1ccc(-c2ncco2)cc1CO
Reaction time: 2 h
Yield: 92.2 %

Procedure:
To a solution of the title product of Step D of Example 1 (0.37 g, 0.76 mmol) in 10 mL of MeOH at room temperature, sodium borohydride (0.035 g, 0.93 mmol) was added and the mixture stirred for 2 hours. The clear solution was then concentrated to 5 mL and diluted with 100 mL of water and the aqueous solution was extracted with 3×100 mL of EtOAc. The combined organic extracts were then washed once with water and dried and evaporated to provide 0.36 g (95%) of the title product of this step as a colorless gum. Rf (silica gel)=0.32 (5% methanol in CH2Cl2).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:39])[CH2:4][CH2:5][CH2:6]/[CH:7]=[CH:8]\[CH2:9][C@@H:10]1[C@@H:14](/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C@H:13]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:12][C@@H:11]1[O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33].N(C(C)(C)C#N)=NC(C)(C)C#N>C1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:39])[CH2:4][CH2:5][CH2:6]/[CH:7]=[CH:8]/[CH2:9][C@@H:10]1[C@@H:14](/[CH:15]=[CH:16]/[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C@H:13]([O:23][Si:24]([C:27]([CH3:29])([CH3:30])[CH3:28])([CH3:25])[CH3:26])[CH2:12][C@@H:11]1[O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:33])[CH3:34]
Reactant: CCCCCC/C=C\[C@@H]1[C@@H](C/C=C\CCCC(=O)OC)[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H]1O[Si](C)(C)C(C)(C)C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: c1ccccc1
Product: CCCCCC/C=C/[C@@H]1[C@@H](C/C=C/CCCC(=O)OC)[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H]1O[Si](C)(C)C(C)(C)C
Reaction time: 19 h

Procedure:
The compound 116 obtained above (7.27 g, 12.5 mmole) was dissolved in benzene (40 ml), and 5-mercapto-1-methyltetrazole disulfide (2.88 g, 12.5 mmole) and α,α'-azobis-isobutyronitrile (205 mg, 1.25 mmole) were added thereto, and the mixture was refluxed with stirring for 19 hours. Then, the reaction mixture was treated following the procedure similar to that of Example 41, to yield a residue. The residue was chromatographed over silica gel (330 g), eluting with ethyl acetate: n-hexane (1:50), to yield 5.34 g of a mixture of geometrical isomers with respect to the double bond. The material was further chromatographed over 10% silver nitrate--silica gel (500 g), eluting with ether-n-hexane (1:50), to yield 3.64 g of the title compound 117 (yield 50%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH:24]3[CH2:26][CH2:25]3)[N:9]=2)[CH:5]=[N:6][CH:7]=1.[NH2:27][C:28]1[CH:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][N:29]=1>>[CH:24]1([C:10]2[N:9]=[C:8]([C:4]3[CH:5]=[N:6][CH:7]=[C:2]([C:31]4[CH:30]=[N:29][C:28]([NH2:27])=[CH:33][CH:32]=4)[CH:3]=3)[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=2)[CH2:26][CH2:25]1
Reactant: FC(F)(F)c1ccc(-c2cc(-c3cncc(Br)c3)nc(C3CC3)c2)cc1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Nc1ccc(-c2cncc(-c3cc(-c4ccc(C(F)(F)F)cc4)cc(C4CC4)n3)c2)cn1

Procedure:
The title compound was prepared from 5′-bromo-6-cyclopropyl-4-(4-trifluoromethylphenyl)-[2,3′]bipyridinyl (example E.25) (0.15 g, 0.36 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.087 g, 0.40 mmol) according to the general procedure VI. Obtained as a white solid (0.080 g, 51%). MS (ISP) 433.3 [(M+H)+]; mp 207-209° C.
Reaction SMILES: CC1(C)[O:6][C@H:5]([CH2:7][N:8]2[CH2:17][CH2:16][C:15]3[C:14]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][C@@H:19]4[CH3:24])=[N:13][C:12]([C:25]4[CH:30]=[CH:29][C:28]([NH:31][C:32]([NH:34][CH2:35][CH3:36])=[O:33])=[CH:27][CH:26]=4)=[N:11][C:10]=3[CH2:9]2)[CH2:4][O:3]1.Cl>O>[OH:6][C@@H:5]([CH2:4][OH:3])[CH2:7][N:8]1[CH2:17][CH2:16][C:15]2[C:14]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][C@@H:19]3[CH3:24])=[N:13][C:12]([C:25]3[CH:30]=[CH:29][C:28]([NH:31][C:32]([NH:34][CH2:35][CH3:36])=[O:33])=[CH:27][CH:26]=3)=[N:11][C:10]=2[CH2:9]1
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(C[C@@H]2COC(C)(C)O2)C3)cc1
Agent: Cl
Solvent: O
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(C[C@@H](O)CO)C3)cc1
Yield: 59.5 %

Procedure:
A solution of 1-(4-(7-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-4-((S)-3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)-3-ethylurea (jz) (50 mg, 0.10 mmol), 1 N HCl (0.20 mL, 0.2 mmol) and water (0.5 mL) was maintained at rt for 24 h. The mixture was purified by RPHPLC to afford 28 mg (60%) of the title compound ka as a colorless solid: LC-MS: m/z=+471 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[O:12][N:11]=[C:10]2[C:15]2[N:16]=[N:17][S:18][C:19]=2[CH2:20][O:21][Si](C(C)C)(C(C)C)C(C)C)[CH:5]=[CH:6][C:7]=1[F:8].CO.Cl>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[O:12][N:11]=[C:10]2[C:15]2[N:16]=[N:17][S:18][C:19]=2[CH2:20][OH:21])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)[Si](OCc1snnc1-c1noc(=O)n1-c1ccc(F)c(Cl)c1)(C(C)C)C(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: O=c1onc(-c2nnsc2CO)n1-c1ccc(F)c(Cl)c1
Temperature: 70 °C
Yield: 87.9 %

Procedure:
Into a round bottom flask was added 4-(3-chloro-4-fluorophenyl)-3-(5-[(triisopropylsilyl)-oxy]methyl-1,2,3-thiadiazol-4-yl)-1,2,4-oxadiazol-5(4H)-one (89 mg, 0.18 mmol), anhydrous MeOH (1.5 mL), and hydrogen chloride in 1,4-dioxane (1.5 mL, 4.0 M). The reaction was heated to 70° C. for 2.5 h. The reaction was concentrated in vacuo and the crude purified by flash chromatography to give the desired product (52 mg, 86%). MF═C11H6ClFN4O3S; LCMS calculated for C11H7ClFN4O3S (M+H)+: m/z=329.0.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[N:6]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=2)[C:13]([O:15][CH3:16])=[O:14])[CH:7]=[CH:8][CH:9]=1)[CH3:3].Cl.ClS([N:25]=[C:26]=O)(=O)=O.[OH-].[Na+]>ClCCl.C(OCC)(=O)C.O.CN(C)C=O>[C:26]([C:7]1[N:6]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=2)[C:13]([O:15][CH3:16])=[O:14])[C:5]([CH2:4][N:2]([CH3:3])[CH3:1])=[CH:9][CH:8]=1)#[N:25]
Reactant: COC(=O)c1cccc(-n2cccc2CN(C)C)c1
Reactant: O=C=NS(=O)(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(-n2c(C#N)ccc2CN(C)C)c1
Reaction time: 0.08 h

Procedure:
To the mixture of methyl 3-(2-dimethylaminomethyl-pyrrol-1-yl)benzoate (1.0 g) in dichloromethane (15 ml) was added 4N-hydrogen chloride in ethyl acetate solution (0.97 ml) under ice-cooling and the mixture was stirred for 5 minutes at the same temperature. To the mixture was added dropwise chlorosulfonyl isocyanate (0.4 ml) under ice-cooling and the mixture was stirred for 1 hour at the same temperature. To the mixture was added dropwise N,N-dimethylformamide (3.0 ml) under ice-cooling and the mixture was stirred for 1 hour at the same temperature. The reaction mixture was poured into a mixture of dichloromethane and water, and the separated aqueous layer was adjusted to pH 12 with 5N-sodium hydroxide solution. The aqueous layer was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated in vacuo to give methyl 3-(2-cyano-5-dimethylaminomethylpyrrol-1-yl)benzoate (1.1 g) as an oil.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Se](=O)=[O:16].C.[BH4-].[Na+].[Cl-].[NH4+]>C(O)C.CO.O1CCCC1.C(OCC)C>[OH:16][CH2:1][C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: Cc1ccnc2c([N+](=O)[O-])cccc12
Reactant: O=[Se]=O
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: CO
Solvent: CCOCC
Product: O=[N+]([O-])c1cccc2c(CO)ccnc12
Yield: 21.9 %

Procedure:
A mixture of 4-methyl-8-nitroquinoline (2.80 g) and selenium(IV) oxide (1.82 g) in ethanol (45 ml) was refluxed for 4 hours. The mixture was treated with active charcoal and filtered through Celite pad. The filtrate was concentrated in vacuo to afford a brown solid. This residue was dissolved in a mixture of methanol (10 ml) and tetrahydrofuran (10 ml) and cooled in an ice bath. To this solution was added sodium borohydride (170 mg) and stirred at the same temperature for half an hour. To this mixture was added saturated ammonium chloride solution and extracted with methylene chloride. The organic layer was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by a flash chromatography on silica gel using methylene chloride then 3% methanol in methylene chloride as the eluent to give a solid. This solid was solidified with diethyl ether to afford 4-hydroxymethyl-8-nitroquinoline (665 mg) as a brown solid.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[C:25][Si](C)(C)C)[CH:19]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:30]([F:33])([F:32])[F:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>CO.C(OCC)(=O)C>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[CH:25])[CH:19]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:30]([F:33])([F:32])[F:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)C#Cc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: C#Cc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Yield: 140.4 %

Procedure:
A solution of the above oil, 3-benzyl-8-trifluoromethyl-4-(3-trimethylsilanylethynylphenyl)-quinoline (730 mg, 1.6 mmol) and potassium carbonate (220 mg, 1.6 mmol) in methanol (30 mL) is stirred at ambient temperature for 3 h. The reaction mixture is stripped to dryness and the residue taken up in ethyl acetate and washed with 30 mL (1N HCl). The organic layer is dried and concentrated in vacuo to provide after chromatography 870 mg (80%) of the title compound: MS (ESI) m/z 388.
Reaction SMILES: [C:1]([C:4]([CH:17]1[CH2:21][CH2:20][NH:19][CH2:18]1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2].[CH3:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[CH2:26][CH2:27]Br.C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[C:1]([C:4]([CH:17]1[CH2:21][CH2:20][N:19]([CH2:27][CH2:26][C:25]2[CH:29]=[CH:30][CH:31]=[C:23]([CH3:22])[CH:24]=2)[CH2:18]1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2]
Reactant: NC(=O)C(c1ccccc1)(c1ccccc1)C1CCNC1
Reactant: Cc1cccc(CCBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cc1cccc(CCN2CCC(C(C(N)=O)(c3ccccc3)c3ccccc3)C2)c1
Temperature: 25 °C

Procedure:
A mixture containing 3-(R,S)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine (0.5 g--see Preparation 8), 3-methylphenethylbromide (0.36 g--see J. Ind. Chem. Sac., 40, 327, (1963)) , anhydrous potassium carbonate (0.5 g) and acetonitrile (10 ml) was heated under reflux for 4 hours. On cooling to room temperature, water (60 ml) was added and the mixture was extracted with dichloromethane (3×50 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give an oil which was purified by column chromatography on silica eluting with dichloromethane containing methanol (2% up to 4%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as an oil, yield, 0.17 g.