Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]2[C:21](Cl)=[N:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:23]1[CH2:28][CH2:27][CH:26]([CH2:29][OH:30])[CH2:25][CH2:24]1.CCN(CC)CC>CS(C)=O.O>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]2[C:21]([N:23]3[CH2:28][CH2:27][CH:26]([CH2:29][OH:30])[CH2:25][CH2:24]3)=[N:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OCC1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CC(c2nc3ccccc3nc2Cl)C1
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC(c2nc3ccccc3nc2N2CCC(CO)CC2)C1
Temperature: 140 °C
Yield: 84 %

Procedure:
To a solution of 3-(3-chloro-quinoxalin-2-yl)-azetidine-1-carboxylic acid tert-butyl ester (46) (638 mg, 2 mmol, Preparation 14) and piperidin-4-yl-methanol (253 mg, 2.2 mmol) in DMSO (10 mL) was added Et3N (404 mg, 4 mmol). The reaction mixture was stirred at 140° C. in microwave heating for 4 h. The reaction mixture was diluted with water, extracted with EtOAc (30 mL×3). The combined organic extracts were washed with water (30 mL) and brine (30 mL), dried over Na2SO4 and filtered. The filtrate was evaporated in vacuo and the residue was purified by flash column chromatography on silica gel to give (47) (670 mg, 1.68 mmol, yield 84.15%). ESI-MS (M+1): 399 calc. for C17H22N4O 398.
Reaction SMILES: Cl.[NH2:2][OH:3].[CH:4]([NH:7][C:8]1[N:13]=[C:12]([C:14](=O)[CH3:15])[CH:11]=[C:10]([CH3:17])[N:9]=1)([CH3:6])[CH3:5].CO>O.[OH-].[Na+]>[CH:4]([NH:7][C:8]1[N:13]=[C:12]([C:14](=[N:2][OH:3])[CH3:15])[CH:11]=[C:10]([CH3:17])[N:9]=1)([CH3:6])[CH3:5]
Reactant: CC(=O)c1cc(C)nc(NC(C)C)n1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(=NO)c1cc(C)nc(NC(C)C)n1
Temperature: 80 °C
Reaction time: 2 h
Yield: 83.6 %

Procedure:
A solution of hydroxylamine hydrochloride (737 mg, 10.6 mmol) in water (3.0 mL) and 1 N aq. NaOH (11 mL) is added to 1-(2-isopropylamino-6-methyl-pyrimidin-4-yl)-ethanone (1.71 g, 8.85 mmol). The solution is stirred at 80° C. for 2 h and MeOH is added to maintain homogeneity of the mixture. The mixture is cooled to rt and the precipitate that forms is collected, washed with water and dried in vacuo to give 1-(2-isopropylamino-6-methyl-pyrimidin-4-yl)-ethanone oxime (1.54 g) as a yellow solid; LC-MS: tR=0.72 min, [M+H]+=209.52; 1H NMR (D6-DMSO): δ 1.15 (d, J=6.5 Hz, 6H), 2.10 (s, 3H), 2.25 (s, 3H), 4.07 (m, 1H), 6.80 (s, 1H), 6.86 (d, J=7.5 Hz, 1H), 11.62 (s, 1H).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[N:7]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([Cl:15])=[CH:10][C:9]=2[CH3:16])=[O:5].[Br:24]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:1][CH2:2][O:3][C:4]([C:6]1[N:7]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([Cl:15])=[CH:10][C:9]=2[CH2:16][Br:24])=[O:5]
Reactant: CCOC(=O)c1cc2cc(Cl)cc(C)c2n1C(=O)OC(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1cc2cc(Cl)cc(CBr)c2n1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 95 %

Procedure:
To a solution of 0.30 g (0.9 mmol) of 5-chloro-7-methyl-indole-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester in CCl4 (10 ml), 016 g N-bromosuccinimide (NBS) and 11 mg of benzoyl peroxide were added. The reaction mixture was heated at reflux for one hour and cooled down to RT. The succinimide was filtered off and the solvent removed under reduced pressure to afford 0.35 g (95%) of 7-bromomethyl-5-chloro-indole-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester as a light brown solid. This product was directly used in the next step (unstable).
Reaction SMILES: [CH3:1][C:2]([CH3:23])([O:4][C:5]([NH:7][C@@H:8]([C:12]12[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:20][C:14]([OH:22])([CH2:15]3)[CH2:13]1)[CH2:19]2)[C:9]([OH:11])=O)=[O:6])[CH3:3].[C@H:24]12[CH2:29][C@H:28]1[CH2:27][C@@H:26]([C:30]([NH2:32])=[O:31])[NH:25]2.CS(O)(=O)=O.Cl.ON1C2C=CC=CC=2N=N1>>[NH2:32][C:30]([C@@H:26]1[CH2:27][C@H:28]2[C@H:24]([CH2:29]2)[N:25]1[C:9](=[O:11])[C@H:8]([C:12]12[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:20][C:14]([OH:22])([CH2:15]3)[CH2:13]1)[CH2:19]2)[NH:7][C:5]([O:4][C:2]([CH3:1])([CH3:3])[CH3:23])=[O:6])=[O:31]
Reactant: NC(=O)[C@@H]1C[C@@H]2C[C@@H]2N1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C12CC3CC(CC(O)(C3)C1)C2
Agent: CS(=O)(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Product: CC(C)(C)OC(=O)N[C@H](C(=O)N1[C@H](C(N)=O)C[C@@H]2C[C@@H]21)C12CC3CC(CC(O)(C3)C1)C2

Procedure:
A coupling reaction is then used to couple (αS)-α[[(1,1-dimethylethoxy)carbonyl]amino]-3-hydroxytricyclo[3.3.1.13,7]decane-1-acetic acid, (Formula VI) to (1S,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carboxamide (Formula J) methanesulfonic acid salt or HCl salt in the presence of 1-hydroxybenzotriazole (HOBT) or other known coupling agent to produce 3-(aminocarbonyl)-(αS)-α-(3-hydroxytricyclo[3.3.1.13,7]dec-1-yl)-β-oxo-(1S,3S,5S)-2-azabicyclo[3.1.0]hexane-2-ethanecarbamic acid, 1,1-dimethylethyl ester (Formula K). Formula K compound is subjected to dehydration by treating compound K with organic base such as pyridine or triethylamine, and trifluoroacetic anhydride or other dehydrating agent such as phosphorus oxychloride (POCl3) or cyanuric chloride, and then subjecting the reaction to hydrolysis by cooling to from about 25 to about 40° C. and treating with sodium hydroxide or other strong base such as KOH or LiOH to form Compound L. 3-cyano-(αS)-α-(3-hydroxytricyclo[3.3.1.13,7]dec-1-yl)-β-oxo-(1S,3S,5S)-2-azabicyclo[3.1.0]hexane-2-ethanecarbamic acid, 1,1-dimethylethyl ester (Formula L), which is then deprotected to form the dipeptidyl peptidase IV inhibitor (1S,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxytricyclo[3.3.1.13,7]dec-1-yl)-1-oxoethyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile (Formula M).
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:14]1[N:15]([CH:20]([CH3:22])[CH3:21])[N:16]=[C:17]([CH3:19])[N:18]=1)[N:7]=3.CC1(C)C(C)(C)OB([C:33]2[CH:34]=[N:35][N:36]([CH2:38][CH2:39][N:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)[CH:37]=2)O1>>[CH:20]([N:15]1[C:14]([C:8]2[N:7]=[C:6]3[C:5]4[CH:23]=[CH:24][C:2]([C:33]5[CH:34]=[N:35][N:36]([CH2:38][CH2:39][N:40]6[CH2:45][CH2:44][O:43][CH2:42][CH2:41]6)[CH:37]=5)=[CH:3][C:4]=4[O:13][CH2:12][CH2:11][N:10]3[CH:9]=2)=[N:18][C:17]([CH3:19])=[N:16]1)([CH3:22])[CH3:21]
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(Br)cc2OCC3)n(C(C)C)n1
Reactant: CC1(C)OB(c2cnn(CCN3CCOCC3)c2)OC1(C)C
Product: Cc1nc(-c2cn3c(n2)-c2ccc(-c4cnn(CCN5CCOCC5)c4)cc2OCC3)n(C(C)C)n1

Procedure:
Similarly to as described in General Procedure C, 8-Bromo-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene was reacted with 4-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethyl)morpholine. Purification of the crude reaction mixture by reverse phase HPLC gave 210. LCMS: 489.2
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5]([NH:6][CH:7]=[N:8][C:9]=2[Cl:11])=[N:4][CH:3]=1.O[CH:13]1[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[Br:1][C:2]1[C:10]2[C:9]([Cl:11])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH:13]2[CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16]2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Reactant: Clc1nc[nH]c2ncc(Br)c1-2
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(n2cc(Br)c3c(Cl)ncnc32)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To a solution of 5-bromo-4-chloro-1H-pyrrolo[2,3-d]pyrimidine (400 mg, 1.721 mmol), 1,1-dimethylethyl 3-hydroxy-1-azetidinecarboxylate (894 mg, 5.16 mmol) and triphenylphosphine (903 mg, 3.44 mmol) in Tetrahydrofuran (THF) (10 mL) was added dropwise DEAD (545 μl, 3.44 mmol). The solution was let stir at room temp. After 1 hr the reaction observed 10% product and the reaction was heated at 60° C. After 1 hr observed 80% desired product. Additional 100 mg of the 5-bromo-4-chloro-1H-pyrrolo[2,3-d]pyrimidine was added and heating was continued. The reaction was concentrated then loaded on to a 25 g SNAP column with 0 to 35% EtOAc in Hexane gradient over 30 minutes to give 1,1-dimethylethyl 3-(5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-azetidinecarboxylate (624 mg, 94% yield) as a white solid. LC-MS (ES) m/z=386.9, 389.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.69 (s, 1H), 8.38 (s, 1H), 5.53-5.62 (m, 1H), 4.33 (d, J=8.34 Hz, 4H), 1.43 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].[I:10]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCOCC1.N1C=CC=CC=1>[I:10][C:7]1[CH:6]=[C:5]([CH3:9])[C:3]([NH2:4])=[C:2]([CH3:1])[CH:8]=1
Reactant: Cc1cccc(C)c1N
Reactant: II
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: Cc1cc(I)cc(C)c1N
Temperature: 0 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a solution of 2,6-dimethyl aniline (50 gm) in 1,4-dioxane (400 ml) and pyridine (40 ml) was added iodine (157.3 gm) slowly at 0° C. The solution was stirred for 1 hour at 0° C. and the temperature was raised to room temperature. The solution was stirred for 1 hour at room temperature and then added a saturated solution of sodium thiosulfate. The layers were separated and the aqueous layer was extracted with methylene chloride. The combined organic layers were dried with anhydrous sodium sulfate and the solvent was evaporated in vacuum to obtain 91.8 gm of 4-iodo-2,6-dimethyl benzenamine.
Reaction SMILES: [CH3:1][C@@:2]1([C:7]([OH:9])=[O:8])[CH2:6][CH2:5][CH2:4][NH:3]1.[C:10](Cl)(=[O:12])[CH3:11].C(N(CC)C(C)C)(C)C>CN(C)C(=O)C>[C:10]([N:3]1[CH2:4][CH2:5][CH2:6][C@@:2]1([CH3:1])[C:7]([OH:9])=[O:8])(=[O:12])[CH3:11]
Reactant: C[C@@]1(C(=O)O)CCCN1
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CC(=O)N1CCC[C@@]1(C)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.3 %

Procedure:
To a solution of (S)-2-methyl-pyrrolidine-2-carboxylic acid (50.0 mg, 0.387 mmol) dissolved in N,N-dimethylacetamide (1.5 mL, 16 mmol) was added a solution of acetyl chloride (31.9 mg, 0.406 mmol) dissolved in N,N-dimethylacetamide (0.5 mL), and then N,N-diisopropylethylamine (1 mL, 6 mmol) was added and the reaction mixture stirred at room temperature for 30 minutes. The reaction mixture was concentrated to produce the title compound as a light brown oil (30 mg, 40% yield). (m/z): [M+H]+ calcd for C8H13NO3 172.10 found 172.2.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[C:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][C:12]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25].[Mg]>CO>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[C@H:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])[CH2:13][C@H:12]1[C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCOC(=O)C1=C(c2ccncc2OCOC)CCN(C(=O)OC(C)(C)C)C1
Agent: [Mg]
Solvent: CO
Product: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1c1ccncc1OCOC

Procedure:
To a MeOH solution (0.09 M) of 1-(1,1-dimethylethyl) 3-ethyl 3′-{[(methyloxy)methyl]oxy}-5,6-dihydro-4,4′-bipyridine-1,3(2H)-dicarboxylate (1 eq.) from the previous step was added magnesium turnings (3.3 eq.). The suspension was evacuated and back-filled with N2. Finally, the reaction mixture was sonicated at RT for 1.5 h during which the magnesium turnings disappeared. The reaction was then quenched with the addition of EtOAc and 1 N aq. NaOH. The aqueous layer was separated and back-extracted with EtOAc. The combined organic extracts were washed further with water and brine, dried over Na2SO4 and filtered. Concentration of the filtrate in vacuo afforded the title compound as a pale yellow oil.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[N:25]1([S:31]([C:34]2[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=2)[C:37](O)=[O:38])(=[O:33])=[O:32])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>C(Cl)(Cl)Cl.ClCCl>[CH2:1]([NH:8][C:37](=[O:38])[C:36]1[CH:40]=[CH:41][CH:42]=[C:34]([S:31]([N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)(=[O:33])=[O:32])[CH:35]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCCCC2)c1
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: O=C(NCc1ccccc1)c1cccc(S(=O)(=O)N2CCCCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.1 %

Procedure:
Benzylamine (12 mg), triethylamine (0.047 mL) and 25% dichloromethane solution of 2-chloro-1,3-dimethylimidazolinium chloride (0.11 mL) were added in that order to a chloroform (0.30 mL) solution of 3-(piperidin-1-ylsulfonyl)benzoic acid (30 mg), and stirred at room temperature for 1 hour. The reaction liquid was concentrated and purified through reversed-phase HPLC (0.1% TFA acetonitrile/H2O=from 10% to 95%, gradient) to give the entitled compound (26 mg, 65%) as a white crystal.
Reaction SMILES: C(CC[O:5][C:6]([C:8]1[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[C:12]([C:21](=[O:38])[NH:22][CH2:23][CH2:24][CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:11]([CH2:39][O:40][CH2:41][CH2:42][N:43]=[N+:44]=[N-:45])[NH:10][C:9]=1[CH3:46])=[O:7])#N.[OH-].[Na+].Cl.O>CO>[N:43]([CH2:42][CH2:41][O:40][CH2:39][C:11]1[NH:10][C:9]([CH3:46])=[C:8]([C:6]([OH:7])=[O:5])[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[C:12]=1[C:21](=[O:38])[NH:22][CH2:23][CH2:24][CH:25]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[N+:44]=[N-:45]
Reactant: CC1=C(C(=O)OCCC#N)C(c2cccc(Cl)c2)C(C(=O)NCCC(c2ccccc2)c2ccccc2)=C(COCCN=[N+]=[N-])N1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1=C(C(=O)O)C(c2cccc(Cl)c2)C(C(=O)NCCC(c2ccccc2)c2ccccc2)=C(COCCN=[N+]=[N-])N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
250 mg (0.390 mmol) of 6-(2-azidoethoxy) methyl-4-(3-chlorophenyl)-5-(3,3-diphenylpropylcarbamoyl)-2-methyl-1,4-dihydropyridine-3-carboxylic acid (2-cyanoethyl) ester was dissolved in 2 ml of methanol. 0.70 ml of 1 N aqueous sodium hydroxide solution was added and stirred at room temperature for 8 hours. After adding 1 N hydrochloric acid and water, precipitates thus formed were taken by the filtration and dried under reduced pressure to obtain the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=O)[CH2:22][CH2:23][C:24]([O:26]CC)=O)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[NH2:31][NH2:32]>CC(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH2:22][CH2:23][C:24](=[O:26])[NH:32][N:31]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)CCC(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: NN
Solvent: CC(C)O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C3=NNC(=O)CC3)cc2)CC1
Temperature: 120 °C
Reaction time: 8 h
Yield: 88.3 %

Procedure:
To 4-[4-(3-ethoxycarbonyl-propionyl)-phenoxy]-piperidine-1-carboxylic acid tert-butyl ester (2.68 g, 6.61 mmol) in 2-propanol (25 mL) was added hydrazine monohydrate (0.662 g, 13.2 mmol). After overnight stirring at 120° C., the reaction was concentrated down, partitioned between dichloromethane/water, washed with brine, dried over sodium sulfate, and concentrated under vacuum to obtain 2.18 g product (88%); MS m/z 374 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C@:12]23[CH2:21][CH2:20][C@H:19]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:18][C@H:13]2OC(=S)O3)=[CH:8][CH:7]=1)[CH3:2]>C(OP(OCC)OCC)C>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH2:21][CH2:20][C@@H:19]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:18][CH:13]=2)=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc([C@]23CC[C@H](C(C)(C)C)C[C@H]2OC(=S)O3)cc1
Agent: CCOP(OCC)OCC
Product: CCOC(=O)Cc1ccc(C2=CC[C@H](C(C)(C)C)CC2)cc1
Yield: 60.3 %

Procedure:
A solution of [4-((3aR,6S,7aR)-6-tert-Butyl-2-thioxo-tetrahydro-benzo[1,3]dioxol-3a-yl)-phenyl]-acetic acid ethyl ester (297 mg, 0.80 mmol) in triethylphosphite (3 mL) was slowly added to a solution of triethylphosphite (10 mL) heated to reflux—rate of addition was such that the reaction temperature exceeded 150. After refluxing overnight, the solvent was removed under vacuum and the crude reaction mixture was loaded on top of a silica column and eluted with an ethyl acetate/hexanes gradient to afford 145 mg of the title compound. 1H NMR (500 MHz, CDCl3): 7.32 (d, J=8 Hz, 2 H), 7.20 (d, J=8 Hz, 2 H), 6.10 (m, 1 H), 4.12 (q, J=7 Hz, 2 H), 3.57 (s, 2 H), 2.52-2.32 (m, 2 H), 2.26-2.18 (m, 1 H), 2-1.9 (m, 2 H), 1.38-1.2 (m, 5 H), 0.91 (s, 9 H).
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1[O:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]2[S:21][CH:22]=[C:23]([CH3:25])[N:24]=2)[CH:14]=1.[CH3:26][N:27]([CH3:31])[CH2:28][CH2:29][NH2:30]>>[ClH:1].[ClH:1].[CH3:26][N:27]([CH3:31])[CH2:28][CH2:29][NH:30][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:3]([CH3:2])=[C:4]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[S:21][CH:22]=[C:23]([CH3:25])[N:24]=3)[CH:14]=2)[CH:5]=1
Reactant: CN(C)CCN
Reactant: Cc1csc(Nc2cc(Oc3cc(C(=O)O)ccc3C)ccn2)n1
Agent: Cl
Product: Cc1csc(Nc2cc(Oc3cc(C(=O)NCCN(C)C)ccc3C)ccn2)n1

Procedure:
The title compound was prepared according to the method of Example 107 from 4-methyl-3-(2-(4-methylthiazol-2-ylamino)pyridin-4-yloxy)benzoic acid hydrochloride (Example 108) and N,N-dimethylethylenediamine. Yield: 0.065 g, 25%. 1H NMR (CDCl3), 8.84 (bs, 1H), 8.16 (d, 1H), 7.90 (d, 1H), 7.86 (bs, 1H), 7.37 (d, 1H), 6.80 (bs, 1H), 6.71 (dd, 1H), 6.38 (s, 1H), 3.89 (m, 2H), 3.35 (m, 2H), 2.91 (s, 6H), 2.37 (s, 3H), 2.22 (s, 3H).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([C:9]([OH:13])(O)[C:10](=[O:11])[C:4]2=[CH:3][CH:2]=1)=[O:8].[OH:14][C:15]1[CH:16]=[C:17]([C:21](=[O:23])[CH3:22])[CH:18]=[CH:19][CH:20]=1>C(O)(=O)C.C(Cl)Cl>[C:21]([C:17]1[CH:18]=[CH:19][C:20]([C:9]2([OH:13])[C:10](=[O:11])[C:4]3[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=3)[C:7]2=[O:8])=[C:15]([OH:14])[CH:16]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)c1cccc(O)c1
Reactant: O=C1c2ccccc2C(=O)C1(O)O
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(=O)c1ccc(C2(O)C(=O)c3ccccc3C2=O)c(O)c1
Temperature: 110 °C
Yield: 79.4 %

Procedure:
To a solution of ninhydrin (1.00 g, 5.61 mmol) in acetic acid (20 ml) was added 1-(3-hydroxy-phenyl)-ethanone (0.76 g, 5.61 mmol), followed by heating for 3 hrs at 110° C. The reaction mixture was diluted with methylene chloride, extracted with 2N NaOH aqueous solution, and the concentrated organic layer was purified using column chromatography (ethylacetate:hexane=1:2) to afford the title compound (White, 1.32 g, 79%).
Reaction SMILES: [CH:1](OCC)=[O:2].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[CH:9][CH:8]=1.C[O-].[Na+].Cl>CCOCC>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH2:14][CH:1]=[O:2])=[CH:9][CH:8]=1
Reactant: CC(=O)c1ccc(Cl)cc1
Reactant: CCOC=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Product: O=CCC(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.2 %

Procedure:
Ethyl formate (8.15 g, 0.11 mol) and 4′-chloroacetophenone (15.4 g, 0.1 mol) were stirred in ether (150 mL) at room temperature. Sodium methoxide (25%) (23.77 g, 0.11 mol) was added dropwise. The mixture was stirred at room temperature for 16 hours and was then treated with 150 mL of 1N hydrochloric acid. The phases were separated and the ethereal solution washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to afford 18.3 g of a yellow oil. The resulting crude mixture was used directly in the next step without purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C@H:10]([CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1)[C:11](O)=[O:12])[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[C:47]([O:50][C:51]([CH3:67])([CH3:66])[CH2:52][NH:53][C:54](=[O:65])[C@H:55]([NH:63][CH3:64])[CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)(=[O:49])[CH3:48].C(N(C(C)C)C(C)C)C>CN(C)C=O.ClCCl.C(OCC)(=O)C>[C:47]([O:50][C:51]([CH3:67])([CH3:66])[CH2:52][NH:53][C:54](=[O:65])[C@H:55]([N:63]([C:11](=[O:12])[C@H:10]([N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH3:9])[CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1)[CH3:64])[CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)(=[O:49])[CH3:48]
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccc2ccccc2c1)C(=O)O
Reactant: CN[C@H](Cc1ccccc1)C(=O)NCC(C)(C)OC(C)=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OC(C)(C)CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 88 %

Procedure:
(2R)-2-(N-(tert-Butoxycarbonyl)-N-methylamino)-3-(2-naphthyl)propionic acid (373 mg, 1.13 mmol) was dissolved in N,N-dimethylformamide (2 ml) and dichloromethane (2 ml). 1-Hydroxy-7-azabenzotriazole (153 mg, 1.13 mmol) was added. The solution was cooled to 0° C. N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (217 mg, 1.13 mmol) was added. The reaction mixture was stirred for 10 min at 0° C. 1,1-Dimethyl-2-((2R)-2-methylamino-3-phenylpropionylamino)-ethyl acetate (301 mg, 1.03 mmol) was dissolved in is dichloromethane (2 ml) and added. Ethyldiisopropylamine (0.18 ml, 1.03 mmol) was added. The reaction mixture was stirred for 20 h, while it was warming up to room temperature. It was diluted with ethyl acetate (100 ml) and washed with 1 N hydrochloric acid. The aqueous phase was extracted with ethyl acetate (3×30 ml). The combined organic layers were washed with saturated sodium hydrogen carbonate solution (100 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (85 g), using ethyl acetate/heptane (1:1) as eluent, to give 547 mg of 2-((2R)-2-(N-((2R)-2-(N-tert-butoxycarbonyl-N-methylamino)-3-(2-naphthyl)propionyl)-N-methylamino)-3-phenylpropionylamino)-1,1-dimethylethyl acetate.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH2:12][N:13]2[C:17](=[O:18])[N:16]([CH2:19][CH:20]([OH:25])[C:21]([F:24])([F:23])[F:22])[C:15]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)=[N:14]2)[CH:3]=1.[F:33][C:34]([F:45])([F:44])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1B(O)O>>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([C:15]2[N:16]([CH2:19][CH:20]([OH:25])[C:21]([F:24])([F:22])[F:23])[C:17](=[O:18])[N:13]([CH2:12][C:4]3[CH:3]=[C:2]([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=4[C:34]([F:45])([F:44])[F:33])[CH:11]=[CH:10][C:5]=3[C:6]([O:8][CH3:9])=[O:7])[N:14]=2)=[CH:27][CH:28]=1
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: COC(=O)c1ccc(Br)cc1Cn1nc(-c2ccc(Cl)cc2)n(CC(O)C(F)(F)F)c1=O
Product: COC(=O)c1ccc(-c2ccccc2C(F)(F)F)cc1Cn1nc(-c2ccc(Cl)cc2)n(CC(O)C(F)(F)F)c1=O

Procedure:
Analogously to the preparation of Example 122, 265 mg (0.50 mmol) of the compound from Example 104A were reacted with 149 mg (0.74 mmol) of 2-(trifluoromethyl)phenylboronic acid. This gave 113 mg (38% of theory) of the target compound of a purity of 100% and 101 mg (28% of theory) of a purity of 81%.