Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].N1C=CC=CC=1.[Cl:18][C:19]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][C:20]=1[C:21](Cl)=[O:22]>ClCCl>[Cl:18][C:19]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][C:20]=1[C:21]([NH:7][C:6]1[CH:8]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10])=[O:22]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1Cl
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1cc(Cl)ccc1[N+](=O)[O-])c1cc([N+](=O)[O-])ccc1Cl
Temperature: 0 °C
Reaction time: 72 h
Yield: 86.2 %

Procedure:
5-Chloro-2-nitroaniline (1 g; 5.8 mmol) and pyridine (0.64 ml; 8.1 mmol) were dissolved in dichloromethane (10 ml) and cooled to 0° C. This was added drop wise over 5 minutes to a solution of 2-chloro-5-nitrobenzoyl chloride (1.34 g; 6.1 mmol) in dichloromethane (5 ml). The reaction was stirred at room temperature for 72 hours before adding further acid chloride (1.34 g) and pyridine (0.64 ml). After 30 minutes, the solvent was evaporated and the bisacylated residue treated with 1:1 concentrated ammonia/acetonitrile (10 ml). All the solvent was removed after 5 minutes and the residue crystallised from 1:1 chloroform/heptane (30 ml) to give 2-chloro-N-(5-chloro-2-nitro-phenyl)-5-nitro-benzamide (1.78 g, 86%)
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].Cl[C:17]1[N:22]=[CH:21][CH:20]=[CH:19][N:18]=1.[Cl-].[NH4+].C(OCC)(=O)C>C(OCC)(=O)C.ClCCl>[CH2:14]([O:13][C:11]([C:3]1[NH:4][C:5]2[C:10]([C:2]=1[NH:1][C:17]1[N:22]=[CH:21][CH:20]=[CH:19][N:18]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:12])[CH3:15]
Reactant: CCOC(=O)c1[nH]c2ccccc2c1N
Reactant: Clc1ncccn1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1[nH]c2ccccc2c1Nc1ncccn1
Yield: 17.7 %

Procedure:
Heat a mixture of ethyl 3-aminoindole-2-carboxylate (204 mg, 1.0 mmol) and 2-chloropyrimidine (1.2 g, 10.5 mmol) at 100° C. for 16 h. Cool the reaction and add aqueous ammonium chloride and ethyl acetate. Filter off excess 2-chloropyrimidine, separate the organic layer, dry with MgSO4, filter and concentrate to afford a crude mixture. Flash chromatograph the mixture on silica gel eluting with 25% ethyl acetate/dichloromethane to afford 50 mg of the title compound: MS 283 (M+H), TLC (silica gel, 25% ethyl acetate/dichloromethane) Rf=0.44.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:20][C:19]2[CH:21]=[CH:22][C:16]([Cl:15])=[CH:17][CH:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Nc1ccc(Cl)cc1
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(Cl)cc2)CC1

Procedure:
1-(tert-Butoxycarbonyl)-4-piperidone (5.00 g) and 4-chloroaniline (3.05 g) was treated in the same manner as described in Preparation Example 37 to give white powder of the title compound.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]#[N:12])=[CH:6][CH:5]=1.Cl[CH2:14][O:15][CH2:16][CH2:17]Cl.C(OCC)C>CN1CCCC1=O>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:11]#[N:12])[CH2:17][CH2:16][O:15][CH2:14]2)=[CH:6][CH:5]=1
Reactant: ClCCOCCl
Reactant: N#CCc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOCC
Product: N#CC1(c2ccc(Cl)cc2)CCOC1
Temperature: 25 °C

Procedure:
To a solution of the NaH (60% by weight, 4 g, 98 mmol) and 1-methylpyrrolidin-2-one (82.5 mL) at −20° C., was added dropwise a mixture of 2-(4-chlorophenyl)acetonitrile (5 g, 33 mmol) and 2-chloroethyl chloromethyl ether (4 mL, 33 mmol) in diethyl ether (16.5 mL, 33 mmol). The mixture was allowed to warm to room temperature over 24 hours. The reaction was then slowly quenched with ice water and extracted with ether (3×). The organic layers were combined, washed with H2O (3×) and brine, dried over Na2SO4, concentrated in vacuo, and purified by silica flash chromatography (13% EtOAc/hexane) to give the desired compound as a yellow oil. MS m/e=208.0 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][C:12]([C:16]#[C:17][Si](C)(C)C)=[CH:13][CH:14]=2)[C:9]([CH3:23])([CH3:22])[CH2:8][C:7]=1[CH3:24])=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][C:12]([C:16]#[CH:17])=[CH:13][CH:14]=2)[C:9]([CH3:23])([CH3:22])[CH2:8][C:7]=1[CH3:24])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(C)CC(C)(C)c2cc(C#C[Si](C)(C)C)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: C#Cc1ccc2c(c1)C(C)(C)CC(C)=C2C(=O)OCC

Procedure:
Following general procedure F and using 2,4,4-trimethyl-6-trimethylsilanylethynyl-3,4-dihydro-naphthalene-1-carboxylic acid ethyl ester (Intermediate 199, 0.31 g, 0.92 mmol), ethanol (2 mL) and potassium carbonate (0.3 g, 2.2 mmol), the title compound was obtained (0.26 g, >100%).
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([CH3:36])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-])=O)=[CH:29][CH:28]=1)([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:9][CH2:8]2)(=[O:3])[CH3:2].CO.[H][H]>[Pd].C1C=CC=CC=1>[C:1]([O:4][C:5]1[C:6]([CH3:36])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([CH2:25][O:26][C:27]1[CH:28]=[CH:29][C:30]([NH2:33])=[CH:31][CH:32]=1)([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:9][CH2:8]2)(=[O:3])[CH3:2]
Reactant: CCCCCCCCC1(COc2ccc([N+](=O)[O-])cc2)CCc2c(C)c(OC(C)=O)c(C)c(C)c2O1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: c1ccccc1
Product: CCCCCCCCC1(COc2ccc(N)cc2)CCc2c(C)c(OC(C)=O)c(C)c(C)c2O1

Procedure:
Using Paar's hydrogenation apparatus, a mixture of 4 g of 6-acetoxy-5,7,8-trimethyl-2-(4-nitrophenoxymethyl)-2-octylchroman (prepared as described in Preparation 16), 0.8 g of 10% w/w palladium-on-carbon, 30 ml of methanol and 10 ml of benzene was stirred for 5 hours under 3-5 atmospheres (about 3-5 bars) pressure or hydrogen. The catalyst was filtered off, and the filtrate was condensed by evaporation under reduced pressure. The crystals thus obtained were washed with hexane to give the title compound, melting at 112°-114° C.
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][CH2:22][CH:23]1[CH2:29][N:28]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:27][CH2:26][CH2:25][O:24]1)=[O:19])C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][CH2:22][CH:23]1[CH2:29][N:28]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:27][CH2:26][CH2:25][O:24]1)=[O:19]
Reactant: CC(C)(C)OC(=O)N1CCCOC(CONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCCOC(CONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3O)C1
Yield: 78 %

Procedure:
To a solution of tert-butyl 2-{[({[(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}-1,4-oxazepane-4-carboxylate 132 (0.32 g, 0.63 mml) in methanol (20 mL) was added 5% Pd/C (0.30 g). The mixture was hydrogenated at 15 psi hydrogen atmosphere at room temperature for 1 h. The catalyst was filtered out through Celite, and the filtrate was evaporated to give tert-butyl 2-{[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}-1,4-oxazepane-4-carboxylate 133 (0.205 g, 78%) as a colorless foam.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][N:3]=1.C([O:11][CH:12]=[C:13]([C:19](OCC)=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15])C.C1(OC2C=CC=CC=2)C=CC=CC=1>>[I:8][C:5]1[CH:6]=[CH:7][C:2]2[N:3]([CH:4]=1)[C:12](=[O:11])[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:19][N:1]=2
Reactant: Nc1ccc(I)cn1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2ccc(I)cn2c1=O
Temperature: 25 °C
Yield: 32 %

Procedure:
In a 3-necked round-bottom connected to a Dean-Stark trap, a solution of 2-amino-5-iodopyridine (Preparation 1, 500 mg) and diethyl ethoxymethylenemalonate (0.92 mL) is heated at 130° C. for 2 h. The reaction is cooled to room temperature. Diphenyl ether (5 mL) is added and the reaction is heated at 250° C. for 1 h. Upon cooling the mixture to room temperature, a solid precipitates and is filtered and washed with hexanes. The crude solid is adsorbed onto silica and chromatographed eluting with CH2Cl2 (2 L). Product-containing fractions are combined and concentrated to afford a solid. The crude product is recrystallized from CH2Cl2/hexanes to yield 251 mg (32%) of the title compound as a yellow solid. Physical characteristics: m.p. 166-168° C.; 1H NMR (300 MHz, DMSO-d6) δ 9.24, 8.85, 8.38, 7.62, 4.27, 1.30; IR (drift) 1747, 1611, 1558, 1506, 1473, 1355, 1345, 1291, 1266, 1258, 1152, 1140, 1118, 840, 796 cm−1; MS (ESI+) m/z 345; Anal. found: C, 38.37; H, 2.48; N, 8.11.
Reaction SMILES: [OH-].[Na+].O.[C:4]1([C:10]2([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C@@H:18]3[C@@H:14]([CH2:15][N:16]([C:19](=[O:31])[C@@H:20]([O:27]C(=O)C)[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:17]3)[C@@:13]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[O:39][CH3:40])([OH:32])[CH2:12][CH2:11]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(O)C>[C:41]1([C:10]2([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=3)[C@@H:18]3[C@@H:14]([CH2:15][N:16]([C:19](=[O:31])[C@@H:20]([OH:27])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:17]3)[C@@:13]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[O:39][CH3:40])([OH:32])[CH2:12][CH2:11]2)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: COc1ccccc1[C@]1(O)CCC(c2ccccc2)(c2ccccc2)[C@H]2CN(C(=O)[C@@H](OC(C)=O)c3ccccc3)C[C@H]21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccccc1[C@]1(O)CCC(c2ccccc2)(c2ccccc2)[C@H]2CN(C(=O)[C@@H](O)c3ccccc3)C[C@H]21
Yield: 80.9 %

Procedure:
1.4 cm 3 of an aqueous 1N solution of sodium hydroxide and then 10 cm3 of water are added to a solution of 0.8 g of (3aS,4S,7aS)-7,7-diphenyl-4-(2- methoxyphenyl)-2-[(S)-2-acetyloxy-2-phenylacetyl]perhydroisoindol-4-ol in 30 cm3 of ethanol. The reaction mixture is refluxed for 1 hour and concentrated to dryness under reduced pressure (2.7 kPa), and the residue is taken up in 50 cm3 of water and then 1.5 cm3 of an aqueous 1N solution of hydrochloric acid and extracted with 40 cm3 of ethyl acetate (3 times). The organic phases are combined, washed with 50 cm3 of water, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a Merck silica gel column (particle size 0.04-0.06 mm, diameter 2.5 cm, height 27 cm) by eluting under a pressure of 0.4 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (50/50 by volume) and collecting fractions of 30 cm3. Fractions 2 to 5 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue is triturated in isopropyl ether. 0.6 g of (3aS,4S,7aS)-7,7-diphenyl-4-(2-methoxyphenyl)-2-[(S)-2-hydroxy-2-phenylacetyl]perhydroisoindol-4-ol is obtained in the form of white crystals which melt at 256° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH2:7][CH2:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:20]4=[N:21][S:22](=[O:26])(=[O:25])[CH2:23][CH2:24][N:19]4[CH:18]=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)=[CH:4][CH2:3]1.CC(O)=O>C1COCC1.[Pt](=O)=O>[CH3:1][C:2]1([CH3:27])[CH2:7][CH2:6][CH:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]3[C:20]4=[N:21][S:22](=[O:26])(=[O:25])[CH2:23][CH2:24][N:19]4[CH2:18][CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[CH2:4][CH2:3]1
Reactant: CC1(C)CC=C(Oc2ccc(C3=CC=CN4CCS(=O)(=O)N=C34)cc2)CC1
Agent: O=[Pt]=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC1(C)CCC(Oc2ccc(C3CCCN4CCS(=O)(=O)N=C34)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.9 %

Procedure:
Platinum(IV) oxide (40 mg) was added to a solution of 9-{4-[(4,4-dimethylcyclohex-1-en-1-yl)oxy]phenyl}-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (340 mg) in THF (dry) (30 mL), NeOH (30 mL) and AcOH (10 mL). The mixture was stirred at room temperature under hydrogen overnight. Activated carbon was added and the insoluble solid was removed by filtration through silica gel/Celite pad (eluted with EtOAc, to remove catalytic poison). Platinum(IV) oxide (40 mg) was added and the mixture was stirred at 50° C. under hydrogen for 6 hr. Platinum(IV) oxide was added and the mixture was stirred 50° C. under hydrogen for 12 hr. The insoluble solid was removed by filtration through silica gel/Celite pad (eluted with EtOAc) and the filtrate was concentrated in vacuo with silica-gel. The mixture supported on silica-gel was purified by column chromatography (silica gel, eluted with MeOH in EtOAc) and concentrated in vacuo. The residue was crystallized from EtOAc/hexane. This was dissolved in THF, silica-gel was added to the solution and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (silica gel, eluted with MeOH in EtOAc). The residue was crystallized from THF-EtOAc/IPE to give the title compound (37.6 mg) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][N:5]=[C:4]2[N:11]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH:12]=[CH:13][C:3]=12.[H][H]>C1COCC1.CCO.[Pd]>[CH3:1][C:2]1[C:7]([NH2:8])=[CH:6][N:5]=[C:4]2[N:11]([S:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)(=[O:16])=[O:15])[CH:12]=[CH:13][C:3]=12
Reactant: [H][H]
Reactant: Cc1c([N+](=O)[O-])cnc2c1ccn2S(=O)(=O)c1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(N)cnc2c1ccn2S(=O)(=O)c1ccccc1
Yield: 99.8 %

Procedure:
To a mixture of 4-methyl-5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine, (410 mg, 1.29 mmol) in THF (15 mL) and EtOH (10 mL) was added 10% palladium on carbon (10 wt % of Pd/C; 45 mg) under argon. The mixture was hydrogenated using a hydrogen balloon at room temperature for 16 hours. The reaction mixture was flushed with nitrogen and filtered through a plug of Celite® and concentrated in vacuo. The crude material was purified by flash column chromatography on silica gel using hexane:EtOAc (4:6) to get 4-methyl-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-amine, (370 mg). 1H NMR (300 MHz, CD3OD) δ: 7.96-8.04 (m, 2H), 7.83 (s, 1H), 7.53-7.64 (m, 2H), 7.42-7.52 (m, 2H), 6.65 (d, J=4.1 Hz, 1H), 2.26 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1ccc(OCc2ccccc2)cc1

Procedure:
A mixture of 40 g. of 4-benzyloxyphenol, 45.8 g. of ethyl bromoacetate, 40.0 g. of potassium carbonate, 2 g. of potassium iodide and 400 ml. of acetone was heated at reflux for 24 hours. The reaction mixture was filtered and concentrated in vacuo, and the residue was recrystallized from an ether-petroleum ether mixture to give 50 g. of ethyl 4-benzyloxyphonoxyacetate, m.p. 72°-73° C.
Reaction SMILES: C[O:2][C:3](=[O:52])[C@@H:4]([NH:21][C:22]([C@@H:24]1[CH2:33][C:32]2[CH:31]=[C:30]3[O:34][CH2:35][C@H:36]([C:38]4[CH:43]=[CH:42][C:41]([O:44][CH2:45][CH:46]5[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]5)=[CH:40][CH:39]=4)[O:37][C:29]3=[CH:28][C:27]=2[CH2:26][NH:25]1)=[O:23])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[C:15]([CH3:19])[C:14]=2[CH3:20])=[CH:8][CH:7]=1.[N:53]([C:56]([CH3:59])([CH3:58])[CH3:57])=[C:54]=[O:55]>C(Cl)Cl>[C:56]([NH:53][C:54]([N:25]1[C@H:24]([C:22]([NH:21][C@@H:4]([CH2:5][C:6]2[CH:7]=[CH:8][C:9]([O:12][C:13]3[CH:18]=[CH:17][N:16]=[C:15]([CH3:19])[C:14]=3[CH3:20])=[CH:10][CH:11]=2)[C:3]([OH:2])=[O:52])=[O:23])[CH2:33][C:32]2[CH:31]=[C:30]3[O:34][CH2:35][C@H:36]([C:38]4[CH:43]=[CH:42][C:41]([O:44][CH2:45][CH:46]5[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51]5)=[CH:40][CH:39]=4)[O:37][C:29]3=[CH:28][C:27]=2[CH2:26]1)=[O:55])([CH3:59])([CH3:58])[CH3:57]
Reactant: CC(C)(C)N=C=O
Reactant: COC(=O)[C@H](Cc1ccc(Oc2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCC2CCCCC2)cc1)CO3
Solvent: ClCCl
Product: Cc1nccc(Oc2ccc(C[C@H](NC(=O)[C@@H]3Cc4cc5c(cc4CN3C(=O)NC(C)(C)C)O[C@@H](c3ccc(OCC4CCCCC4)cc3)CO5)C(=O)O)cc2)c1C
Reaction time: 1 h

Procedure:
To a solution of (S)-2-{[(3S,8S)-3-(4-cyclohexylmethoxy-phenyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yloxy)-phenyl]-propionic acid methyl ester (25 mg) in DCM was added 2-isocyanato-2-methyl-propane (5 eq.) and the reaction stirred was at room temperature for 1 hour. The reaction mixture was directly purified over silica (hexanes to 1:1 hexanes EtOAc to 1:1 hexanes EtOAc+1% MeOH to 1:1 hexanes EtOAc+2% MeOH to 1:1 hexanes EtOAc+3% MeOH). The resulting compound was hydrolyzed according to General Procedure B to give the title compound. LCMS (m/z): 792.
Reaction SMILES: C([BH3-])#N.[CH3:4][C:5]1([N:11]2[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[NH2:18][C:19]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:20]=1[OH:29].C(O)(=O)C>C(Cl)Cl>[CH3:4][C:5]1([N:11]2[CH2:16][CH2:15][CH:14]([NH:18][C:19]3[CH:24]=[C:23]([C:25]([F:26])([F:27])[F:28])[CH:22]=[CH:21][C:20]=3[OH:29])[CH2:13][CH2:12]2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1
Reactant: Nc1cc(C(F)(F)F)ccc1O
Reactant: CC1(N2CCC(=O)CC2)CCOCC1
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC1(N2CCC(Nc3cc(C(F)(F)F)ccc3O)CC2)CCOCC1
Temperature: 100 °C
Yield: 59.1 %

Procedure:
Polymer supported cyanoborohydride (191 mg, 0.82 mmol) was added to a solution of 1-(4-methyltetrahydro-2H-pyran-4-yl)-4-piperidinone (D12, 87 mg, 0.44 mmol), 2-amino-4-(trifluoromethyl)phenol (D7, 74 mg, 0.42 mmol, 4.3 mmol/g) and acetic acid (0.12 mL, 2.09 mmol) in DCM (2.5 mL). The mixture was heated by microwave at 100° C. for 10 min before being filtered and concentrated by rotary evaporation to give a yellow oil, which was purified via flash column chromatography (silica, DCM to 0.5% NH3/9.5% MeOH/90% DCM) to give 2-{[1-(4-methyltetrahydro-2H-pyran-4-yl)-4-piperidinyl]amino}-4-(trifluoromethyl)phenol (D14, 89 mg, 60%) as an off-white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:18])OC2C=CC=CC=2)[CH:5]=[C:6]([F:8])[CH:7]=1.O.[NH2:20][NH2:21]>>[F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:18])[NH:20][NH2:21])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: NN
Reactant: O=C(Nc1cc(F)cc(F)c1)Oc1ccccc1
Solvent: O
Product: NNC(=O)Nc1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solid 100 mg of O-phenyl 3,5-difluorophenylcarbamate 0.7 mL of hydrazine monohydrate was added. After stirring for 3 h at room temperature a white solid is collected by filtration, washed with water and ether. Removal of traces of the solvents in vacuo gives 4-(3,5-difluorophenyl)-semicarbazide: m.p. 177°-179° C.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]1[CH:12]=[C:11]([CH2:13][OH:14])[CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[Ca+2].[Br-:21].[Br-].[Br-].C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1>C(Cl)Cl.CO>[Br:21][C:10]1[C:11]([CH2:13][OH:14])=[CH:12][C:3]([N:2]([CH3:1])[CH3:15])=[C:4]([CH:9]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: [Br-]
Reactant: COC(=O)c1ccc(CO)cc1N(C)C
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1cc(Br)c(CO)cc1N(C)C
Yield: 83.5 %

Procedure:
After dissolving methyl 2-(dimethylamino)-4-(hydroxymethyl)benzoate (1.023 g, 4.9 mmol) in a methylene chloride (15 ml) and methanol (6 ml) mixed solvent, calcium carbonate (2 g) was added, the mixture was stirred, and then benzyltrimethylammonium tribromide (2.100 g, 5.4 mmol) was gradually added and the mixture was stirred at room temperature for 50 minutes. The reaction mixture was filtered and the solvent was distilled off under reduced pressure. Water was added to the residue, extraction was performed with ethyl acetate and the ethyl acetate layer was washed with water and brine. The aqueous layer was then extracted with a methylene chloride and methanol mixed solvent, combined with the ethyl acetate layer, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (1.179 g) as a white solid. (84% yield)
Reaction SMILES: [NH2:1][C@H:2]([C:9]([OH:11])=[O:10])[CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1.C(=O)([O-])[O-].[Na+].[Na+].C(N1[C:27](=[O:28])[C:26]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:25]2[C:24]1=[O:33])(OCC)=O>O>[C:24]1(=[O:33])[N:1]([CH:2]([CH2:3][C:4]2[N:8]=[CH:7][NH:6][CH:5]=2)[C:9]([OH:11])=[O:10])[C:27](=[O:28])[C:26]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:25]12
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: N[C@@H](Cc1c[nH]cn1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)C(Cc1c[nH]cn1)N1C(=O)c2ccccc2C1=O
Reaction time: 1.5 h
Yield: 64 %

Procedure:
To a stirred solution of histidine (3.17 g, 20.0 mmol) and sodium carbonate (2.23 g, 21 mmol) in 50 mL of water is added N-carboethoxyphthalimide (4.52 g, 20.0 mmol). After 1.5 hour, the reaction slurry is filtered. The filtrate is stirred and the pH adjusted to 1-2 with 4N hydrochloric acid. The resulting slurry is filtered and the solid washed with water and dried in vacuo (60° C., <1 mm) to afford 3.65 g (64%) of 2-phthalimido-3-(imidazol-4-yl)propionic acid as a white powder: mp 280°-285° C.; 1H NMR (DMSO-d6, 250 M Hz) δ 12.5 (br s, 1H), 7.90-7.60 (m, 6H), 6.80(s, 1H), 4.94 (t, 1H, J=7.8), 3.36 (d, 2H, J=7.8); 13C NMR (DMSO-d6) δ 170.1, 167.1, 134.8, 134.6, 133.2, 131.1, 123.2, 116.3, 52.4, 25.8; Anal. Calculated for C14H11N3O4. Theoretical: C, 58.95; H, 3.89; N, 14.73. Found: C, 58.80; H, 3.88; N, 14.66.
Reaction SMILES: C([NH:8][CH2:9][C:10](=[O:22])[CH2:11][CH2:12][C:13]([O:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[O:14])(OC(C)(C)C)=O.[ClH:23]>C(OCC)C>[ClH:23].[NH2:8][CH2:9][C:10](=[O:22])[CH2:11][CH2:12][C:13]([O:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[O:14]
Reactant: CC(C)(C)OC(=O)NCC(=O)CCC(=O)OCCCC(=O)O
Agent: Cl
Solvent: CCOCC
Product: NCC(=O)CCC(=O)OCCCC(=O)O
Reaction time: 8 h
Yield: 57 %

Procedure:
This compound was prepared from the product of 5b (4.20 g; 13.2 mmol), 2 M HCl in diethyl ether (7.5 mL; 15 mmol), and diethyl ether (50 mL) as described in Example 1 b. After evaporation of the solvent, the oily residue was triturated with diethyl ether (4×10 mL) and kept overnight in a freezer until it solidified into a pale tan solid. 1.90 g (57%) product was obtained after drying at 12 mm Hg and ambient temperature.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([O:9][CH3:10])=[O:8].[Br:11]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:11][C:6]1[N:2]([CH3:1])[C:3]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][CH:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cccn1C
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(Br)n1C
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of methyl 1-methyl-1H-pyrrole-2-carboxylate (100 mg, 0.719 mmol) in CHCl3 (5 mL) at 0° C. was added N-bromosuccinimide (128 mg, 0.719 mmol). The reaction was stirred at 0° C. for 5 min. The reaction was allowed to warm to room temperature and stirred overnight. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by preparative TLC (1000 μm, hexanes/EtOAc (9:1)) to give methyl 5-bromo-1-methyl-1H-pyrrole-2-carboxylate. 1H NMR (500 MHz, CDCl3): δ 6.94 (d, J=4.2 Hz, 1H); 6.21 (d, J=4.1 Hz, 1H); 3.94 (s, 3H); 3.82 (s, 3H).