Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:14])[CH2:12][CH3:13])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[ClH:15].[NH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1.C=O.[C:23](OCC)(=O)C.Cl>C(OCC)(=O)C>[ClH:15].[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11](=[O:14])[CH:12]([CH3:23])[CH2:13][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CCC(=O)c1ccc(CC(C)C)cc1
Reactant: CCOC(C)=O
Reactant: C1CCNC1
Agent: C=O
Agent: Cl
Product: CC(C)Cc1ccc(C(=O)C(C)CN2CCCC2)cc1

Procedure:
A solution of 5.40 g of 4'-isobutylpropiophenone in 15 ml of ethyl acetate, 3.00 g of pyrrolidine hydrochloride, 1.30 g of paraformaldehyde and 0.5 ml of 22% hydrogen chloride-ethyl acetate were treated in the same manner as that described for Example 3 to give 3.53 g of hydrochloride of the desired compound which were recrystallized from methyl ethyl ketone as colorless scales, mp 127°-128°.
Reaction SMILES: [OH:1][C@:2]1([C:12]([OH:14])=[O:13])[CH2:6][CH2:5][C:4]([CH2:8][OH:9])([CH3:7])[C:3]1([CH3:11])[CH3:10].[CH3:15]OCOC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:7][C:4]12[C:3]([CH3:11])([CH3:10])[C@@:2]([C:12]([OH:14])=[O:13])([CH2:6][CH2:5]1)[O:1][CH2:15][O:9][CH2:8]2
Reactant: CC1(CO)CC[C@](O)(C(=O)O)C1(C)C
Reactant: COCOC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CC12CC[C@@](C(=O)O)(OCOC1)C2(C)C
Reaction time: 24 h

Procedure:
A mixture of Example 222A (131.6 mg), dimethoxymethane (0.575 mL) and para-toluenesulfonic acid monohydrate (catalytic) in benzene (15 mL) was stirred and heated to reflux with a Dean-Stark trap overnight. An additional 0.5 mL dimethoxymethane was added and heating continued 24 hours. The reaction mixture was evaporated to dryness and flash chromatographed over silica gel eluting with 10% methanol/CH2Cl2 to afford the title compound. 1H NMR (CDCl3, 300 MHz) δ ppm 0.88 (s, 3H), 0.94 (s, 3H), 1.15 (s, 3H), 1.88-2.05 (m, 3H), 2.7-2.85 (m, 1H), 3.59 (s, 2H), 5.00 (AB q, J=26.3, 7.9 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:17]2[C:12]([CH:13]=[N:14][C:15](OS(C(F)(F)F)(=O)=O)=[N:16]2)=[CH:11][CH:10]=1.C(N(CC)C(C)C)(C)C.[NH2:35][C:36]1[CH:41]=[CH:40][C:39]([CH:42]2[CH2:47][CH2:46][N:45]([CH2:48][C@H:49]([OH:52])[CH2:50][OH:51])[CH2:44][CH2:43]2)=[CH:38][C:37]=1[O:53][CH3:54]>COCC(O)C>[CH3:54][O:53][C:37]1[CH:38]=[C:39]([CH:42]2[CH2:43][CH2:44][N:45]([CH2:48][C@H:49]([OH:52])[CH2:50][OH:51])[CH2:46][CH2:47]2)[CH:40]=[CH:41][C:36]=1[NH:35][C:15]1[N:14]=[CH:13][C:12]2=[CH:11][CH:10]=[C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[N:17]2[N:16]=1
Reactant: COc1cc(C2CCN(C[C@H](O)CO)CC2)ccc1N
Reactant: COc1ccccc1-c1ccc2cnc(OS(=O)(=O)C(F)(F)F)nn12
Solvent: CCN(C(C)C)C(C)C
Solvent: COCC(C)O
Product: COc1cc(C2CCN(C[C@H](O)CO)CC2)ccc1Nc1ncc2ccc(-c3ccccc3OC)n2n1
Temperature: 100 °C
Yield: 26.6 %

Procedure:
Trifluoro-methanesulfonic acid 7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl ester (320.00 mg, 0.857 mmol), N,N-Diisopropylethylamine (0.779 mL, 4.47 mmol), and (S)-3-[4-(4-Amino-3-methoxy-phenyl)-piperidin-1-yl]-propane-1,2-diol (600.65 mg, 2.142 mmol) were dissolved in 1-methoxy-2-propanol (2.3 mL) and the reaction mixture was heated at 100° C. for 8 h. The reaction mixture was partitioned between dichloromethane and saturated aqueous NaHCO3, and the organic layer was separated and dried over MgSO4, then filtered. The solvent was evaporated under reduced pressure and the product was isolated by column chromatography (ISCO, Silicagel, methanol/dichloromethane 0-10%). The product needed to be further purified by preparative reverse phase HPLC (Gilson, 0.1% TFA water/acetonitrile gradient) followed by neutralization of the resulting TFA salt to afford (S)-3-(4-{3-methoxy-4-[7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-1-yl)-propane-1,2-diol as a light orange solid (115 mg, 27%). MP: 66-80° C.; 1H-NMR (CDCl3) δ 8.69 (s, 1H), 8.29 (d, J=8.0 Hz, 1H), 8.99 (dd, J=8.0, 1.6 Hz, 1H), 7.44 (m, 2H), 7.13 (m, 1H), 7.07 (d, J=8.0 Hz, 1H), 7.02 (d, J=4.7 Hz, 1H), 6.83 (d, J=4.7 Hz, 1H), 6.72 (s, 1H), 6.71 (d, J=8.0 Hz, 1H), 3.90 (s, 3H), 3.86 (m, 1H), 3.85 (s, 3H), 3.77 (m, 1H), 3.55 (m, 1H), 3.22 (d, J=10.6 Hz, 1H), 3.08 (d, J=10.6 Hz, 1H), 2.77 (br s, 2H), 2.69 (m, 1H), 2.48 (m, 3H), 2.20 (m, 1H), 1.85 (m, 4H); LC/MS (ESI+): 504.19 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH3:13])[C:6]([O:8][CH3:9])=[O:7])#[N:2].P(OCC)(OCC)([S-])=[S:15]>C1COCC1.O>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH3:13])[C:6]([O:8][CH3:9])=[O:7])(=[S:15])[NH2:2]
Reactant: CCOP(=S)([S-])OCC
Reactant: COC(=O)c1ccc(C)c(C#N)c1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(C)c(C(N)=S)c1
Reaction time: 3 h
Yield: 80.9 %

Procedure:
A solution of methyl 3-cyano-4-methylbenzoate (compound 1.7, 880 mg, 5.02 mmol, 1.00 equiv) and O,O′-diethyl dithiophosphate (1.41 g, 8.29 mmol, 1.50 equiv) in THF/H2O (40 mL) was stirred at 80° C. (CAUTION: significant gas evolution occurs—this and all other reactions described herein should be carried out in well ventilated fume hoods). After 3 h, the organic solvent was removed under reduced pressure and the residual aqueous phase was extracted with 3×20 mL of ethyl acetate. The combined organic layers were concentrated under reduced pressure to yield 0.85 g (79%) of the title compound as a light yellow solid.
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([CH2:9][CH2:10][C:11]2[CH:36]=[CH:35][N:14]3[C:15](=[O:34])[C:16]([C:20]4[N:24]([CH2:25][C:26]5[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=5)[N:23]=[N:22][N:21]=4)=[C:17]([OH:19])[N:18]=[C:13]3[CH:12]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2].CN(C1C=CC=CN=1)C.C(N(CC)CC)C.[C:53]1([CH3:63])[CH:58]=[CH:57][C:56]([S:59](Cl)(=[O:61])=[O:60])=[CH:55][CH:54]=1>C(Cl)Cl>[CH:1]([C:4]1[N:5]=[C:6]([CH2:9][CH2:10][C:11]2[CH:36]=[CH:35][N:14]3[C:15](=[O:34])[C:16]([C:20]4[N:24]([CH2:25][C:26]5[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=5)[N:23]=[N:22][N:21]=4)=[C:17]([O:19][S:59]([C:56]4[CH:57]=[CH:58][C:53]([CH3:63])=[CH:54][CH:55]=4)(=[O:61])=[O:60])[N:18]=[C:13]3[CH:12]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc(Cn2nnnc2-c2c(O)nc3cc(CCc4nc(C(C)C)cs4)ccn3c2=O)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(Cn2nnnc2-c2c(OS(=O)(=O)c3ccc(C)cc3)nc3cc(CCc4nc(C(C)C)cs4)ccn3c2=O)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 64 %

Procedure:
The 8-[2-(4-isopropyl-1,3-thiazol-2-yl)ethyl]-2-hydroxy-3-[(4-methoxybenzyl)-tetrazol-5-yl]-4H-pyrido[1,2-a]pyrimidin-4-one(73 mg) obtained in (A) was dissolved in methylene chloride (2 ml), added with dimethylaminopyridine (5 mg), triethylamine(40 ml) and p-toluenesulfonyl chloride (83 mg) at 0° C., and then the mixture was stirred at room temperature for 6 hours. The reaction solution was directly purified by silica gel column chromatography to obtain the title compound (61 mg, 64%) as pale yellow powder.
Reaction SMILES: CS([Cl:5])(=O)=O.[C:6]([O:10][C:11]([N:13]1[CH2:18][C@H:17]([CH2:19]O)[N:16]([CH2:21][C:22]([N:24]2[C:32]3[CH:31]=[C:30]([CH2:33][C:34]4[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=4[F:41])[N:29]=[CH:28][C:27]=3[C:26]([CH3:43])([CH3:42])[CH2:25]2)=[O:23])[CH2:15][C@H:14]1[CH3:44])=[O:12])([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C>C(Cl)Cl>[C:6]([O:10][C:11]([N:13]1[CH2:18][C@H:17]([CH2:19][Cl:5])[N:16]([CH2:21][C:22]([N:24]2[C:32]3[CH:31]=[C:30]([CH2:33][C:34]4[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=4[F:41])[N:29]=[CH:28][C:27]=3[C:26]([CH3:43])([CH3:42])[CH2:25]2)=[O:23])[CH2:15][C@H:14]1[CH3:44])=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H]1CN(CC(=O)N2CC(C)(C)c3cnc(Cc4ccc(F)cc4F)cc32)[C@@H](CO)CN1C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H]1CN(CC(=O)N2CC(C)(C)c3cnc(Cc4ccc(F)cc4F)cc32)[C@@H](CCl)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.8 %

Procedure:
Chloroacetyl chloride (0.995 mL, 12.0 mmol) was added dropwise to a stirred solution of 6-(2,4-difluoro-benzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine hydrochloride (3.10 g, 10.0 mmol) and triethylamine (4.6 mL, 33.0 mmol) in anhydrous DCM (50 mL) and the mixture was stirred at room temperature for 16 hours. (2R,5R)-5-Hydroxymethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (2.76 g, 12.0 mmol) was added and the mixture was stirred at room temperature for a further 16 hours. Further triethylamine (1 mL) and (2R,5R)-5-hydroxymethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (700 mg) were added and the mixture stirred for a further 16 hours. The mixture was diluted with DCM, washed with water, the organic layer separated and the solvent removed in vacuo. Chromatography (silica, elution with 30-100% ethyl acetate in petroleum ether) afforded (2R,5R)-4-{2-[6-(2,4-difluoro-benzyl)-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-c]pyridin-1-yl]-2-oxo-ethyl}-5-hydroxymethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (4.36 g, 80%) as a pale tan foam. MS: [M+H]+ 545. Methanesulfonyl chloride (0.78 mL, 10.0 mmol) was added dropwise to a stirred solution of (2R,5R)-4-{2-[6-(2,4-difluoro-benzyl)-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-c]pyridin-1-yl]-2-oxo-ethyl}-5-hydroxymethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (4.36 g, 8.0 mmol) and triethylamine (1.67 mL, 12.0 mmol) in anhydrous DCM (40 mL) and the mixture was stirred at room temperature for 16 hours. The mixture was diluted with DCM, washed successively with saturated aqueous sodium hydrogen carbonate and then water. The organic layer was separated and the solvent removed in vacuo to afford the title compound (4.0 g, 71%) as a pale yellow foam. MS: [M+H]+=563, 565.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[C@@H:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:46][CH2:47]OS(C)(=O)=O)=[CH:38][CH:37]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:53][NH2:54]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:18][CH:19]=2)[C@@H:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:46][CH2:47][NH:54][CH3:53])=[CH:38][CH:37]=2)[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CN
Reactant: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)N(CCOS(C)(=O)=O)CCC3)cc1
Product: CNCCN1CCCc2ccc(CO[C@H]3CN(C(=O)OC(C)(C)C)CC[C@@H]3c3ccc(OCCCOCc4ccccc4OC)cc3)cc21

Procedure:
In analogy to the procedure described in example 8(c), the (3R,4R)-3-[1-(2-methanesulfonyloxy-ethyl)-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy]-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester was treated with methylamine to yield the (3R,4R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-3-[1-(2-methylamino-ethyl)-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy]-piperidine-1-carboxylic acid tert-butyl ester as a yellow oil; MS: 674 (M+H)+.
Reaction SMILES: [NH2:1][C:2](=[S:18])[N:3]1[CH2:7][CH:6]2[CH2:8][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][CH:5]2[CH2:4]1.Cl[CH2:20][C:21]([C:23]1[CH2:27][CH:26]([C:28]2[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=2[F:35])[O:25][N:24]=1)=O.N1C=CC=CC=1>C(Cl)(Cl)Cl>[F:35][C:29]1[CH:30]=[CH:31][CH:32]=[C:33]([F:34])[C:28]=1[CH:26]1[O:25][N:24]=[C:23]([C:21]2[N:1]=[C:2]([N:3]3[CH2:7][CH:6]4[CH2:8][N:9]([C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])[CH2:10][CH:5]4[CH2:4]3)[S:18][CH:20]=2)[CH2:27]1
Reactant: O=C(CCl)C1=NOC(c2c(F)cccc2F)C1
Reactant: CC(C)(C)OC(=O)N1CC2CN(C(N)=S)CC2C1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CC2CN(c3nc(C4=NOC(c5c(F)cccc5F)C4)cs3)CC2C1
Temperature: 90 °C

Procedure:
To a stirred solution of 1,1-dimethylethyl 5-(aminothioxomethyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (i.e. the product of Step A) (0.5 g, 18.42 mmol) in chloroform (20 mL) was added 2-chloro-1-[5-(2,6difluorophenyl)-4,5-dihydroisoxazol-3-yl]ethanone (i.e. the product of Step B) (0.478 g, 18.42 mmol) and pyridine (0.29 g, 37.12 mmol) at room temperature. The reaction mixture was heated at 90° C. for 5 h, cooled to room temperature and concentrated under reduced pressure. The resulting material was dissolved in ethyl acetate (100 mL) and washed with water (100 mL) and saturated aqueous sodium chloride solution (100 mL) and concentrated under reduced pressure. The resulting material was purified by column chromatography (1% methanol/chloroform as eluant) to provide the title product as white solid (0.7 g) melting at 78.9-80.2° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][S:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N+:12]=2[O-:17])=[O:10])=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19].C(OO)(=[O:23])C.S(=O)(=O)(O)[O-].[Na+].O>C(O)(=O)C>[N+:18]([C:3]1[CH:4]=[C:5]([CH2:8][S:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N+:12]=2[O-:17])(=[O:23])=[O:10])[CH:6]=[CH:7][C:2]=1[Cl:1])([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1cc(CS(=O)c2cccc[n+]2[O-])ccc1Cl
Reactant: CC(=O)OO
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(CS(=O)(=O)c2cccc[n+]2[O-])ccc1Cl
Temperature: 70 °C

Procedure:
To a mixture of 14.0 g (0.0426 mole) of 2-[[(4-chloro-3-nitrophenyl) methyl]sulfinyl]-pyridine-N-oxide in 35 ml of acetic acid was added 10.1 g of peracetic acid (40% in acetic acid) dropwise over one hour. The temperature of the reaction mixture rose to 27° C. before a water bath was placed on the flask to hold the temperature at 25° C. After addition, the mixture was heated to 70° C. for five hours. The mixture was cooled, and 20 ml additional acetic acid and solid sodium bisulfate and water were added to destroy the excess peracetic acid. The aqueous mixture was neutralized with potassium carbonate and chilled in an ice bath to precipitate an almost white solid. This solid was filtered off, washed with water, dried under vacuum overnight, and had a melting point of 162-164° C. Infrared and NMR spectra were both consistent with the proposed structure. The product was recrystallized from ethanol to give needle-like white crystals having a melting point of 168-170° C. C,H,N calculated for C12H9ClN2O5S: C=43.85%; H=2.76%; N=8.52%. Found: C=43.27% H=2.65%; N=8.21%.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH:3]=[CH:2]1.C1C=C(Cl)C=C(C(OO)=[O:18])C=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.O>[N+:1]1([O-:18])[CH:2]=[CH:3][C:4]2[C:9]=1[NH:8][CH:7]=[CH:6][CH:5]=2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: c1cnc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: [O-][n+]1ccc2ccc[nH]c1-2
Temperature: 25 °C
Reaction time: 14 h
Yield: 58.2 %

Procedure:
7-Azaindole (100 g, 846 mmol) was dissolved in 1 L of ethyl acetate, and an ethyl acetate solution (400 mL) of m-CPBA (65%, 520 g) was dropwise added thereto under ice-cooling over two hours. The resulting mixture was stirred at room temperature for 14 hours. The precipitated solid was collected by filtration under reduced pressure, washed with ethyl acetate, and dried under reduced pressure. Distilled water (600 mL) was added to the obtained solid, and an aqueous solution prepared by dissolving potassium carbonate (125 g, 907 mmol) in water (350 mL) was added thereto while stirring. The resulting solution was cooled at 4° C. for 2 hours to precipitate crystals. The crystals were collected by filtration under reduced pressure, washed with a minimum amount of iced water, and dried under reduced pressure to give 7-azaindole N-oxide (66.0 g) as an off-white solid (yield: 58%).
Reaction SMILES: [NH:1]([C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])[C@H:2]([C:11]([NH:13][C@H:14]([C:19]([NH:21][C@H:22]([C:27](OCC)=[O:28])[CH2:23][CH:24]([CH3:26])[CH3:25])=[O:20])[CH2:15][C:16](=[O:18])[NH2:17])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7](O)=[CH:6][CH:5]=1.[OH2:42].[NH2:43][NH2:44]>CO>[NH:1]([C:32]([O:34][CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)=[O:33])[C@H:2]([C:11]([NH:13][C@H:14]([C:19]([NH:21][C@H:22]([C:27]([NH:43][NH2:44])=[O:28])[CH2:23][CH:24]([CH3:26])[CH3:25])=[O:20])[CH2:15][C:16](=[O:18])[NH2:17])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:42])=[CH:6][CH:5]=1
Reactant: NN
Reactant: CCOC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1
Reactant: O
Solvent: CO
Product: CC(C)C[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1)C(=O)NN
Reaction time: 8 h

Procedure:
2.78 Grams of Z-Tyr-Asn-Leu-OEt was dissolved in 30 ml of methanol, further 1.21 ml of hydrazine hydrate was added to the solution and the mixture was allowed to stand overnight, the crystals formed were collected by filtration, then washed with a small amount of methanol to obtain 3.10 g of Z-Tyr-Asn-Leu-NHNH2.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][C@:10]([CH:15]3[CH2:17][CH2:16]3)([C:13]#[N:14])[C:9]2=[O:18])[CH:5]=[CH:4][N:3]=1.[NH2:19][C:20]1[CH:21]=[N:22][N:23]([C:25]2([CH2:29][OH:30])[CH2:28][CH2:27][CH2:26]2)[CH:24]=1.C(O)(=O)C>CC(O)C>[CH:15]1([C@:10]2([C:13]#[N:14])[CH2:11][CH2:12][N:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:19][C:20]4[CH:21]=[N:22][N:23]([C:25]5([CH2:29][OH:30])[CH2:28][CH2:27][CH2:26]5)[CH:24]=4)[N:7]=3)[C:9]2=[O:18])[CH2:17][CH2:16]1
Reactant: N#C[C@@]1(C2CC2)CCN(c2ccnc(Cl)n2)C1=O
Reactant: Nc1cnn(C2(CO)CCC2)c1
Solvent: CC(=O)O
Solvent: CC(C)O
Product: N#C[C@@]1(C2CC2)CCN(c2ccnc(Nc3cnn(C4(CO)CCC4)c3)n2)C1=O
Yield: 62.6 %

Procedure:
A solution of (3S)-1-(2-chloropyrimidin-4-yl)-3-cyclopropyl-2-oxopyrrolidine-3-carbonitrile (150 mg) obtained in Step E of Example 103, (1-(4-amino-1H-pyrazol-1-yl)cyclobutyl)methanol (95 mg) obtained in Step C of Example 127 and acetic acid (34 mg) in propan-2-ol (4.0 mL) was stirred in a microwave reactor at 160° C. for 1 hr. The reaction mixture was concentrated under reduced pressure, the residue was poured into saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate), and recrystallized (diisopropyl ether/ethyl acetate) to give the title compound (140 mg).
Reaction SMILES: Cl.[CH:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH:3]1[NH2:12])[CH2:9]2.CCN(C(C)C)C(C)C.C1N=CN([C:27](N2C=NC=C2)=[O:28])C=1.[NH:34]1[CH2:39][CH2:38][C:37]2([C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[N:41]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:40]2)[CH2:36][CH2:35]1>C(Cl)Cl>[CH:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH:3]1[NH:12][C:27]([N:34]1[CH2:35][CH2:36][C:37]3([C:47]4[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=4)[N:41]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:40]3)[CH2:38][CH2:39]1)=[O:28])[CH2:9]2
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NC1C2CC3CC(C2)CC1C3
Reactant: CC(C)(C)OC(=O)N1CC2(CCNCC2)c2ccccc21
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC2(CCN(C(=O)NC3C4CC5CC(C4)CC3C5)CC2)c2ccccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 25 %

Procedure:
A stirred solution of 2-adamantanamine hydrochloride (81.1 mg, 0.432 mmol) and DIEA (557 mg, 4.32 mmol) in anhydrous CH2Cl2 (5 mL) was cooled to 0° C. and CDI (84 mg, 0.52 mmol) was added. The mixture was stirred for 1 h at 0° C. and tert-butyl spiro[indoline-3,4′-piperidine]-1-carboxylate (140 mg, 0.43 mmol) in anhydrous CH2Cl2 (5 mL) was added. The reaction mixture was allowed to warm to rt and stirred overnight. The reaction mixture was concentrated and the residue was purified by preparative TLC to provide tert-butyl 1′-((2-adamantyl)carbamoyl)spiro[indoline-3,4′-piperidine]-1-carboxylate as a white solid (50 mg, 25%). 1H NMR (CD3OD, 400 MHz): δ=1.58˜2.01 (m, 28H), 2.92 (t, 2H), 3.91 (d, 2H), 4.09 (d, 2H), 5.85 (d, 1H), 6.95˜7.85 (m, 4H); MS: 466 (M++1); LC-MS (4 min) tR=2.70 min, m/z=466.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:17]=[CH:18][CH:19]=1)[CH2:8]C1C=CC=CC=1C#N)([CH3:4])([CH3:3])[CH3:2].[OH-:20].[Na+].[OH2:22]>>[C:1]([C:5]1[CH:6]=[C:7]([CH:17]=[CH:18][CH:19]=1)[C:8]([OH:22])=[O:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cccc(Cc2ccccc2C#N)c1
Reactant: O
Reactant: [OH-]
Agent: [Na+]
Product: CC(C)(C)c1cccc(C(=O)O)c1
Yield: 83 %

Procedure:
To a suspension of 3-tert-butylbenzylbenzonitrile (4.13 g, 21.9 mmol) in water (80 ml) was added sodium hydroxide (2.19 g, 54.8 mmol) and the mixture was heated under reflux overnight. After completion of the reaction, the mixture was diluted with water, and the aqueous layer was washed with ether. The aqueous layer was then acidified with 6N hydrochloric acid, and extracted with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give 3-tert-butylbenzoic acid (3.23 g, 83% in 2 steps) as colorless crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[N+:11]([C:14]1[CH:19]=[CH:18][C:17](O)=[CH:16]C=1)([O-])=O.N1CC[CH2:24][CH2:23][CH2:22]1.Cl.CNC>>[N:11]1([CH2:22][CH2:23][CH2:24][O:10][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[NH2:1])[CH2:14][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: C1CCNCC1
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: CNC
Agent: Cl
Product: Nc1cccc(OCCCN2CCCCC2)c1

Procedure:
The title compound was prepared by a method similar to that described in Example 154 above, wherein 3-nitrophenol was substituted for 4-nitrophenol in Step 1 and piperidine for dimethylamine hydrochloride in Step 2. MS (m/z)=235.2 (M+H+); Calc'd for C14H23N2O=234.34.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[C:9](\[CH3:13])/[C:10](O)=[O:11])=[CH:4][CH:3]=1.Cl.[CH3:15][NH:16][O:17][CH3:18].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[C:9](\[CH3:13])/[C:10]([N:16]([O:17][CH3:18])[CH3:15])=[O:11])=[CH:4][CH:3]=1
Reactant: C/C(=C\c1ccc(F)cc1)C(=O)O
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CON(C)C(=O)/C(C)=C/c1ccc(F)cc1
Yield: 84.6 %

Procedure:
A mixture of Example 1B (16.1 g, 89.4 mmol), N,O-dimethylhydroxylamine hydrochloride (9.15 g, 93.9 mmol), 1-hydroxybenzotriazole hydrate (12.7 g, 93.9 mmol), 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (17.9 g, 93.9 mmol), and diisopropylethyl amine (47.4 g, 370 mmol) was stirred in DMF (400 mL) at ambient temperature overnight. The solution was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated sodium bicarbonate solution, 1N HCl, water, brine, dried over Na2SO4, and evaporated in vacuo. The resulting material was chromatographed (SiO2, 20% ethyl acetate/hexanes to 50% ethyl acetate/hexanes) to yield the title compound (16.89 g, 58% yield) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ ppm 7.33 (dd, J=8.82, 5.43 Hz, 2H), 7.00-7.14 (m, 2H), 6.79 (s, 1H), 3.70 (s, 3H), 3.29 (s, 3H), 2.11 (s, 3H). MS (DCI+) 224 (M+H).