Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)C[C@@H](NC(OC(C)(C)C)=O)C(N[C@H](C(=O)NC)C(C)(C)C)=O)C1C=CC=CC=1.[CH3:33][C:34]([CH3:64])([CH3:63])[C@H:35]([NH:38][C:39](=[O:62])[C@H:40]([N:45]1[CH:49]=[CH:48][C:47]([C:50]2[CH:55]=[CH:54][C:53]([C:56]3[CH:61]=[CH:60][N:59]=[CH:58][CH:57]=3)=[CH:52][CH:51]=2)=[CH:46]1)[CH2:41][C:42](O)=[O:43])[CH2:36][OH:37].[O:65]([NH2:83])[Si:66]([C:79]([CH3:82])([CH3:81])[CH3:80])([C:73]1[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=1)[C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CO.C(Cl)Cl>[O:65]([NH:83][C:42](=[O:43])[CH2:41][C@@H:40]([N:45]1[CH:49]=[CH:48][C:47]([C:50]2[CH:51]=[CH:52][C:53]([C:56]3[CH:57]=[CH:58][N:59]=[CH:60][CH:61]=3)=[CH:54][CH:55]=2)=[CH:46]1)[C:39]([NH:38][C@H:35]([CH2:36][OH:37])[C:34]([CH3:33])([CH3:64])[CH3:63])=[O:62])[Si:66]([C:79]([CH3:81])([CH3:80])[CH3:82])([C:73]1[CH:74]=[CH:75][CH:76]=[CH:77][CH:78]=1)[C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1
Reactant: CC(C)(C)[Si](ON)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)[C@@H](CO)NC(=O)[C@@H](CC(=O)O)n1ccc(-c2ccc(-c3ccncc3)cc2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CNC(=O)[C@@H](NC(=O)[C@@H](CC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)C(C)(C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)[C@@H](CO)NC(=O)[C@@H](CC(=O)NO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)n1ccc(-c2ccc(-c3ccncc3)cc2)c1
Yield: 43 %

Procedure:
According to the procedure described in Example 1(b) for the preparation of 3(R)-t- butyloxycarbonylamino-N-(2,2-dimethyl-1(S)-(methylcarbamoyl)propyl)succinamic acid benzyl ester, N-(2,2-dimethyl-1(S)-hydroxymethyl-propyl)-3(R)-[3-[4-(pyridin-4-yl)phenyl]-1H-pyrrol-1-yl]succinamic acid (prepared as described in Example 5(a)) and t-butyldiphenylsiloxyamine were coupled with TBTU. Flash column chromatography with 0-5% MeOH/CH2Cl2 gradient eluant fumished in 43% yield N4-t-butyldiphenylsiloxy-N1-[2,2-Dimethyl-1(S)-(hydroxymethyl)propyl]-2(R)-[3-[4-(pyridin-4-yl)phenyl]-1H-pyrrol-1-yl]succinamide as an amorphous solid. 1H NMR (DMSO-d6): δ 10.73 (s, 1H), 8.59 (d, 2H, J=6.3 Hz), 7.85-7.70 (m, 5H), 7.65-7.56 (m, 6H), 7.45-7.34 (m, 6H), 7.29 (s, 1H), 6.79 (s, 1H), 6.43 (s, 1H), 5.20-5.14 (m, 1H), 4.38-4.36 (m, 1H), 3.54-3.50 (m, 2H), 2.82-2.70 (m, 1H), 0.99 (s, 9H), 0.84 (s, 9H). Anal: Calculated for C41H48N4O4Si•0.4 H2O: C, 70.74; H, 7.07; N, 8.05. Found: C, 70.83; H, 7.04; N, 8.33.
Reaction SMILES: Cl.[CH3:2][C@@H:3]1[C:16](=[O:17])[NH:15][N:14]=[C:13]2[N:4]1[C:5]1[CH:6]=[C:7]3[N:20]([C:21]4([CH3:25])[CH2:24][NH:23][CH2:22]4)[CH:19]=[CH:18][C:8]3=[CH:9][C:10]=1[O:11][CH2:12]2.[C:26](Cl)(=[O:28])[CH3:27]>C(Cl)Cl>[C:26]([N:23]1[CH2:22][C:21]([N:20]2[C:7]3[C:8](=[CH:9][C:10]4[O:11][CH2:12][C:13]5[N:4]([C:5]=4[CH:6]=3)[C@H:3]([CH3:2])[C:16](=[O:17])[NH:15][N:14]=5)[CH:18]=[CH:19]2)([CH3:25])[CH2:24]1)(=[O:28])[CH3:27]
Reactant: CC(=O)Cl
Reactant: C[C@@H]1C(=O)NN=C2COc3cc4ccn(C5(C)CNC5)c4cc3N21
Agent: Cl
Solvent: ClCCl
Product: CC(=O)N1CC(C)(n2ccc3cc4c(cc32)N2C(=NNC(=O)[C@H]2C)CO4)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.1 %

Procedure:
To a mixture of (R)-1-methyl-10-(3-methyl-azetidin-3-yl)-3,5-dihydro-10H-6-oxa-3,4,10,11b-tetraaza-cyclopenta[b]phenanthren-2-one hydrochloric acid (Example #148, 0.4 g, 1.2 mmol) in DCM (15 mL) was added acetyl chloride (0.42 g, 5.35 mmol) and TEA (0.37 g, 3.69 mmol) at 0° C. The reaction mixture was stirred at ambient temperature for 1 h. The mixture was concentrated in vacuo and the residue was purified by prep-HPLC (Table 3, Method 29) to give (R)-10-(1-acetyl-3-methyl-azetidin-3-yl)-1-methyl-3,5-dihydro-10H-6-oxa-3,4,10,11b-tetraaza-cyclopenta[b]phenanthren-2-one (0.146 g, 11%) as a pale yellow solid. 1H NMR (400 MHz, methanol-d4): δ 7.27 (s, 1H), 7.21 (s, 1H), 6.87 (d, J=10.8 Hz, 1H), 6.45 (s, 1H), 5.04 (m, 1H), 4.90 (m, 1H), 4.61 (m, 4H), 4.34 (m, 1H), 2.04 (m, 3H), 1.79 (m, 3H), 1.44 (m, 3H). LC/MS (Table 1, Method 4) Rt=1.836 min.; MS m/z: 368 [M+H]+.
Reaction SMILES: Cl[CH:2]([C:13](=O)[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.[C:20]([NH2:23])(=[S:22])[CH3:21]>>[CH3:21][C:20]1[S:22][C:2]([CH2:3][C:4]2[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=2)=[C:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[N:23]=1
Reactant: CCCCCC(=O)C(Cl)Cc1ccc([N+](=O)[O-])cc1
Reactant: CC(N)=S
Product: CCCCCc1nc(C)sc1Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C

Procedure:
An equimolar mixture (19.6 mmol) of 2-chloro-1-(4-nitrophenyl)octan-3-one and thioacetamide is heated at 60° C. for 24 hours. After cooling to room temperature, the reaction mixture is concentrated and taken up in isopropyl ether to give 1.7 g of 2-methyl-5-(4-nitrobenzyl)-4-pentylthiazole, which is a pale yellow solid melting at 57° C.
Reaction SMILES: CC1(C)C2CC[C@@]1(CS(O)(=O)=O)C(=O)C2.C[O:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:30]3[CH:35]=[CH:34][C:33]([N:36]4[CH:40]=[N:39][N:38]([C@@H:41]([CH3:44])[CH2:42][CH3:43])[C:37]4=[O:45])=[CH:32][CH:31]=3)[CH2:26][CH2:25]2)=[CH:20][CH:19]=1.S([O-])([O-])=O.[Na+].[Na+].Br.C(=O)([O-])[O-].[K+].[K+]>O.ClCCl.C(O)CCC>[OH:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:25][CH2:26][N:27]([C:30]3[CH:31]=[CH:32][C:33]([N:36]4[CH:40]=[N:39][N:38]([C@@H:41]([CH3:44])[CH2:42][CH3:43])[C:37]4=[O:45])=[CH:34][CH:35]=3)[CH2:28][CH2:29]2)=[CH:20][CH:19]=1
Reactant: CC[C@H](C)n1ncn(-c2ccc(N3CCN(c4ccc(OC)cc4)CC3)cc2)c1=O
Agent: Br
Agent: CC1(C)C2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])[O-]
Solvent: CCCCO
Solvent: O
Solvent: ClCCl
Product: CC[C@H](C)n1ncn(-c2ccc(N3CCN(c4ccc(O)cc4)CC3)cc2)c1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 57.5 %

Procedure:
A mixture of 29.4 g of (+)-(S)-2,4-dihydro-4-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-2-(1-methylpropyl)-3H-1,2,4-triazol-3-one (S)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptane-1-methanesulfonate (1:2) (intermediate (5)), 2.0 g of sodium sulfite and 151 ml of a hydrobromic acid solution 48% in water was stirred for 5 hours at reflux temperature. The reaction mixture was cooled to room temperature and water was added. The whole was neutralized with potassium carbonate to pH 7 while stirring in a mixture of dichloromethane and 1-butanol (90:10 by volume). The separated organic layer was dried, filtered and evaporated in vacuo. The residue was triturated in methanol. The precipitated product was filtered off and purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 4-methyl-2-pentanone. The product was filtered off and dried, yielding 10.4 g (77.7%) of (+)-(S)-2,4-dihydro-4-[4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl]-2-(1-methylpropyl)-3H-1,2,4-triazol-3-one; mp. 1 80.6° C.; [α]D20=+4.38° (conc.=1% in methanol) (interm. 7).
Reaction SMILES: [N:1]([CH2:4][C:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:8]=1)=[O:6])=[N+]=[N-].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1.[Pd]>[NH2:1][CH2:4][C:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:8]=1)=[O:6]
Reactant: CC(C)(C)OC(=O)n1cc(C(=O)CN=[N+]=[N-])c2ccccc21
Agent: [Pd]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1cc(C(=O)CN)c2ccccc21

Procedure:
To a stirred solution of 3-azidoacetyl-1-(tert-butoxycarbonyl)-indole (0.01 mol), which may be prepared as described in Step (d) above, in THF is added a reducing agent such as, for example, a catalytic amount (0.0001 to 0.001 mol) of a hydrogenolysis catalyst such as, for example, 10% palladium on carbon, and the mixture is shaken under a hydrogen atmosphere at from atmospheric pressure to about 75 psi. (Alternatively, other reducing agents such as lithium aluminum hydride may be used. Reaction work-up conditions may be modified according to the reduction reaction employed.) Reaction progress may be followed by TLC or HPLC. When a sufficient amount of desired product is formed, the mixture is filtered, optionally through a filter aid such as, for example, CELITE (Celite Products Company, Los Angeles, Calif.), and the filter cake is washed with additional solvent (THF). The filtrate and washings rotary evaporated to give 3-aminoacetyl-1-(tert-butoxycarbonyl)-indole, which may be purified, if needed or desired, by chromatography on silica gel or crystallization. Alternatively, the 3-aminoacetyl-1-(tert-butoxycarbonyl)-indole can be dissolved in ethyl ether, which optionally contains minor amounts (i.e., <50% v/v) of THF, and 1 mol equivalent of a solution of either hydrogen chloride in ethyl ether or concentrated hydrochloric acid is added. The solid 3-aminoacetyl-1-(tert-butoxycarbonyl)-indole hydrochloride which precipitates, or if little or no solid precipitates, the 3-aminoacetyl-1-(tert-butoxycarbonyl)-indole hydrochloride obtained upon rotary evaporation of the mixture, may be purified, if needed or desired, by crystallization.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:7].S([CH2:21][N+:22]#[C-:23])(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CO>[O:7]1[C:6]([C:5]2[CH:4]=[C:3]([CH2:2][OH:1])[CH:10]=[CH:9][CH:8]=2)=[CH:23][N:22]=[CH:21]1
Reactant: O=Cc1cccc(CO)c1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: OCc1cccc(-c2cnco2)c1
Yield: 90.2 %

Procedure:
3-Hydroxymethyl-benzaldehyde (1.14 g, 8.35 mmol), tosylmethyl isocyanide (2.47 g, 12.5 mmol) and potassium carbonate (1.75 g, 12.5 mmol) in methanol (25 ml) were refluxed at 85° C. for 1 h. The reaction was concentrated, residue dissolved in DCM/water and separated using a hydrophobic filter tube. The organic phase was concentrated and purified by silica chromatography using DCM followed by DCM:MeOH (19:1) to yield (3-oxazol-5-yl-phenyl)methanol (1.32 g, 90%) as an orange oil.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[CH3:21][C:22]1([CH3:28])[CH2:27][O:26][CH2:25][CH2:24][NH:23]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][C:22]3([CH3:28])[CH3:21])=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: CC1(C)COCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)COCCN1C(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with 3,3-dimethylmorpholine (CAN 59229-63-9) in the presence of TBTU and DIEA to obtain the title compound as colorless oil; MS (EI): m/e=382.4 [MH+].
Reaction SMILES: [CH2:1]([CH:3]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12](C=O)[CH:11]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].Cl.[NH2:21][OH:22].N1C=CC=CC=1>C(O)C>[CH2:1]([CH:3]([CH2:9][C:10]1[CH2:11][C:12](=[N:21][OH:22])[C:13]([O:16][CH3:17])=[CH:14][CH:15]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]
Reactant: CCOC(=O)C(CC)Cc1ccc(OC)c(C=O)c1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CCOC(=O)C(CC)CC1=CC=C(OC)C(=NO)C1
Yield: 93.3 %

Procedure:
A mixture of ethyl 2-ethyl-3-(3-formyl-4-methoxyphenyl)propanoate (1.06 g, 4.01 mmol), hydroxylamine hydrochloride (293 mg, 4.22 mmol), pyridine (1 mL) and ethanol (20 mL) was refluxed for 6 hours. After cooling, the mixture was concentrated and the residue was dissolved in ethyl acetate, which was washed with 1 mol/L hydrochloric acid, saturated aqueous solution of sodium hydrogencarbonate and brine, dried over anhydrous sodium sulfate, and then concentrated. The residue was purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate=6:1 v/v) to afford 1.00 g (89%) of the title compound as a pale yellow oil.
Reaction SMILES: C([Li])CCC.[CH:6]([C@H:9]1[CH2:13][O:12][C:11](=[O:14])[NH:10]1)([CH3:8])[CH3:7].[C:15](Cl)(=[O:24])[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl.[Cl-].[Na+]>O1CCCC1.CCCCCC>[CH:6]([C@@H:9]1[CH2:13][O:12][C:11](=[O:14])[N:10]1[C:15](=[O:24])[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH3:8])[CH3:7]
Reactant: CC(C)[C@H]1COC(=O)N1
Reactant: O=C(Cl)CCc1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)[C@@H]1COC(=O)N1C(=O)CCc1ccccc1
Reaction time: 0.5 h
Yield: 69995.3 %

Procedure:
68.3 ml of butyllithium (as a 1.6M hexane solution) were added dropwise, at -78° C. and under an atmosphere of nitrogen, to a solution of 11.75 g (91.0 mmoles) of 4(S)-isopropyl-2-oxazolidinone in 200 ml of anhydrous tetrahydrofuran. The mixture was stirred for 30 minutes, and then a solution of 18.41 g (0.11 mmoles) of dihydrocinnamoyl chloride in 100 ml of anhydrous tetrahydrofuran was added dropwise over a period of 10 minutes. The mixture was then stirred for a further 1 hour, after which 100 ml of 1N aqueous hydrochloric acid and 100 ml of a saturated aqueous solution of sodium chloride were added to the reaction mixture, which was then extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, the solvent was removed by distillation under reduced pressure, and the residue was purified by medium pressure silica gel column chromatography (using a 1:4 by volume mixture of ethyl acetate and hexane as eluent), followed by recrystallization from diisopropyl ether, to give 20.12 g (yield 85%) of the title compound as white crystals, melting at 62°-63° C.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=O)C=1.[C:12]([O:16][C:17]([O:19][N:20]([CH2:27][CH2:28][CH2:29][CH2:30][N:31]1[C:43]2[C:42]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[N:36]=[CH:35][C:34]=2[N:33]=[C:32]1[CH2:44][CH2:45][CH3:46])[C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])=[O:18])([CH3:15])([CH3:14])[CH3:13].[OH-].[NH4+:48].C1(S(Cl)(=O)=O)C=CC=CC=1>C(Cl)(Cl)Cl>[NH2:48][C:35]1[C:34]2[N:33]=[C:32]([CH2:44][CH2:45][CH3:46])[N:31]([CH2:30][CH2:29][CH2:28][CH2:27][N:20]([O:19][C:17]([O:16][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:18])[C:21](=[O:26])[C:22]([CH3:24])([CH3:23])[CH3:25])[C:43]=2[C:42]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[N:36]=1
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCCN(OC(=O)OC(C)(C)C)C(=O)C(C)(C)C
Reactant: [NH4+]
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=S(=O)(Cl)c1ccccc1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCCc1nc2c(N)nc3ccccc3c2n1CCCCN(OC(=O)OC(C)(C)C)C(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
mCPBA (75% purity, 4.03 g, 17.5 mmol) was added to a solution of N-[(tert-butoxycarbonyl)oxy]-2,2-dimethyl-N-[4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]propanamide (5.00 g, 10.0 mmol) in chloroform (975 mL). The reaction mixture was stirred at room temperature for 1.5 hours. The mixture was cooled to 0° C. and concentrated ammonium hydroxide (20 mL) was added, followed by benzene sulfonyl chloride (2.49 mL, 19.5 mmol). The reaction mixture was stirred for 2 hours at room temperature, then was transferred to a separatory funnel. The layers were separated and the organic layer was washed with saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, eluted with 5% methanol in dichloromethane) to afford 3.35 g of N-[4-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-N-[(tert-butoxycarbonyl)oxy]-2,2-dimethylpropanamide.
Reaction SMILES: [CH3:1][C:2]([CH3:24])([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([N:13]([CH3:23])[C:14]2[C:19]([N+:20]([O-])=O)=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])[CH3:3]>CO.[Pd]>[CH3:3][C:2]([CH3:24])([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([N:13]([CH3:23])[C:14]2[C:19]([NH2:20])=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])[CH3:1]
Reactant: CN(c1ncccc1[N+](=O)[O-])C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Pd]
Solvent: CO
Product: CN(c1ncccc1N)C1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 2 h

Procedure:
To a mixture of 1-(1,1-dimethylethoxycarbonyl)-4-[N-methyl-N-(3-nitro-2-pyridinyl)amino]piperidine (International Publication No. WO 91/09849, PREPARATION 125, 5.17 g) in methanol (250 ml) under nitrogen is added palladium black (1.0 g), and the mixture is stirred under a hydrogen atmosphere (balloon) for 2 hrs, palladium black (1.0 g) being added after 1 hr. The mixture is then filtered and concentrated under reduced pressure to give 1-(1,1-dimethylethoxycarbonyl)-4-[N-methyl-N-(3-amino-2-pyridinyl)amino]piperidine. The concentrate is dissolved in absolute ethanol (50 ml) and treated with acetone (17 ml) and sodium cyanoborohydride (950 mg). The pH is adjusted to 5 with glacial acetic acid as measured on moistened pH test paper. The mixture is stirred at 20°-25° for 24 hrs during which additional sodium cyanoborohydride (300 mg) is added, the pH being adjusted after the addition. The mixture is then adjusted to pH 3.5 with 10% aqueous hydrochloric acid, neutralized with aqueous sodium hydroxide (5%) and concentrated to remove ethanol. The residue is diluted with methylene chloride (200 ml) and water (75 ml), the layers are separated, and the organic phase is washed with saturated aqueous potassium carbonate (75 ml) and saline (75 ml), dried over sodium sulfate, and concentrated to give the crude product which is chromatographed (silica gel, 70-230 mesh, 400 g; eluting with a gradient of methanol/chloroform (0.5/95.5-2/98)) to give the title compound, C,H,N: Anal. Calcd for C19H32N4O2 : C=65.49, H=9.26, N=16.08-found: C=65.34, H=9.34, N=15.98.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:30]([CH3:31])=[CH:29][C:15]2[N:16]=[C:17]([C:19]3[CH:28]=[CH:27][C:22]4[N:23]([CH3:26])[N:24]=[N:25][C:21]=4[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.CCO>[C:1]([O:5][C@@H:6]([C:12]1[C:30]([CH3:31])=[CH:29][C:15]2[N:16]=[C:17]([C:19]3[CH:28]=[CH:27][C:22]4[N:23]([CH3:26])[N:24]=[N:25][C:21]=4[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:32]1[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][CH:37]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4c(c3)nnn4C)sc2c1-c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc2nc(-c3ccc4c(c3)nnn4C)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 50 °C

Procedure:
To a vial was dissolved (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)benzo[d]thiazol-6-yl)acetate (100 mg, 0.182 mmol) in THF (3 mL) and EtOH (1.5 mL). 1M NaOH (1.5 mL) was added, and the mixture was heated to 50° C. overnight. The reaction was cooled to 23° C., and filtered (0.45 micron teflon syringe filter). The filtrate was purified by reverse phase HPLC, eluting with 5-100% acetonitrile in H2O with 0.1% TFA to give the desired product. LCMS-ESI+: calc'd for C27H26ClN4O3S: 521.0 (M+H+); Found: 521.2 (M+H+). 1H NMR (400 MHz, CD3OD) δ 8.60 (s, 1H), 8.26 (dd, J=8.8, 1.5 Hz, 1H), 7.87 (d, J=9.0 Hz, 2H), 7.70 (dd, J=7.4, 2.4 Hz, 1H), 7.65-7.56 (m, 3H), 5.26 (s, 1H), 4.35 (s, 3H), 2.62 (s, 3H), 0.98 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][C:9](=O)[CH2:8][CH2:7]2.C([O-])(=O)C.[Na+].C([BH3-])#N.[Na+].Cl.[CH3:23][NH:24][CH3:25]>C(#N)C>[CH3:23][N:24]([CH3:25])[CH:9]1[CH2:8][CH2:7][C:6]2[C:11](=[C:2]([Br:1])[CH:3]=[CH:4][CH:5]=2)[CH2:10]1
Reactant: O=C1CCc2cccc(Br)c2C1
Reactant: CNC
Agent: CC(=O)[O-]
Agent: Cl
Agent: [BH3-]C#N
Solvent: CC#N
Product: CN(C)C1CCc2cccc(Br)c2C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 29.5 %

Procedure:
To a solution of 8-bromo-2-tetralone (4.5 gm, mMol) in acetonitrile (100 mL) were added sodium acetate (9.9 gm, 120 mMol), sodium cyanoborohydride (880 mg, 120 mMol), dimethylamine hydrochloride (9.8 gm, 120 mMol) and 4A sieves (2.0 gm). The mixture was stirred at room temperature for 3 days. The reaction mixture was then filtered through a bed of celite, and the filtrate was poured into a slurry of ice and water. The solution was made acidic (HC1) and extracted well with diethyl ether. The remaining aqueous was made basic (NH4OH) and extracted well with dichloromethane. These organic phases were combined, dried (Na2SO4), and concentrated in vacuo to give a dark oil. Purification by flash chromatography (5% methanol in dichloromethane+tr. NH4OH) gave the title compound as a yellow oil (1.5 gm, 30%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=O)[CH2:8][CH2:9][O:10]2)=[CH:5][CH:4]=1.C[Si]([C:18]#[N:19])(C)C>CC#N>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:18]#[N:19])=[CH:8][CH2:9][O:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)OCCC2=O
Reactant: C[Si](C)(C)C#N
Solvent: CC#N
Product: COc1ccc2c(c1)OCC=C2C#N

Procedure:
7-Methoxy-4-chromanone (7 g) was added to trimethylsilyl cyanide (TMSCN) (7 ml), CH3CN (10 ml) and a catalytic amount of ZnIhd 2 and refluxed for 2 hrs. The reaction was cooled, evaporated to dryness, then isopropyl alcohol saturated with HCl(g) (100 ml) was added and this solution refluxed 2 hrs. The reaction was cooled, evaporated to dryness, and saturated aqueous NaCl added. This was then extracted with CH2Cl2, the organic layer separated, dried (Na2SO4), filtered and evaporated affording 7.1 g of product IR(CHCl3) 2218 cm-1 :
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9](=[O:11])[N:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:7]([C@@H:18]([NH:20][C:21]1[C:22]3[C:29]([S:30][C:31]4[CH:36]=[CH:35][C:34]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])=[CH:33][CH:32]=4)=[CH:28][N:27](COCC[Si](C)(C)C)[C:23]=3[N:24]=[CH:25][N:26]=1)[CH3:19])=[N:6]2.FC(F)(F)C(O)=O.N>>[CH3:1][C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9](=[O:11])[N:8]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:7]([C@@H:18]([NH:20][C:21]1[C:22]3[C:29]([S:30][C:31]4[CH:32]=[CH:33][C:34]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])=[CH:35][CH:36]=4)=[CH:28][NH:27][C:23]=3[N:24]=[CH:25][N:26]=1)[CH3:19])=[N:6]2
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Sc3ccc(NS(C)(=O)=O)cc3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: N
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(Sc5ccc(NS(C)(=O)=O)cc5)c34)n(-c3ccccc3)c(=O)c12
Yield: 42.6 %

Procedure:
(S)—N-(4-((4-((1-(5-Methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)thio)phenyl)methanesulfonamide (15 mg, 0.02 mmol) was treated with trifluoroacetic acid (2 ml, 25 mmol) and a solution of ammonia (7N in methanol, 2 ml, 120 mmol) according to the method described in Example 27 to give 5 mg (40% yield) of the title compound as a white solid. Purity 99%.