Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]([OH:16])=O)=[N:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[CH2:49]([O:51][C:52](=[O:55])[CH2:53][NH2:54])[CH3:50]>CN(C=O)C.O>[CH2:49]([O:51][C:52](=[O:55])[CH2:53][NH:54][C:14]([C:11]1[CH:10]=[CH:9][C:8]([NH:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:13][N:12]=1)=[O:16])[CH3:50]
Reactant: O=C(O)c1ccc(Nc2ccccc2)cn1
Reactant: CCOC(=O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CNC(=O)c1ccc(Nc2ccccc2)cn1
Reaction time: 8 h
Yield: 88.4 %

Procedure:
To a stirred solution of 5-phenylamino-pyridine-2-carboxylic acid (0.26 g, 0.00121 mol) in DMF (2 mL) was added DIPEA (0.471 g, 0.00364 mol), HOBt (0.196 g, 0.00145 mol) and EDCI.HCl (0.278 g, 0.00145 mol) at ambient temperature. After 2 minutes glycine ethyl ester hydrochloride (0.203 g, 0.00146 mol) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water. The resulting precipitate was isolated by filtration and purified by column chromatography using silica gel 60-120 mesh (60% ethyl acetate in hexane) to afford 0.32 g (88%) of [(5-phenylamino-pyridine-2-carbonyl)-amino]-acetic acid ethyl ester. LCMS: 300.13 (M+1)+, 97%. To a stirred solution [(5-phenylamino-pyridine-2-carbonyl)-amino]-acetic acid ethyl ester (0.32 g, 0.00107 mol) in a mixture of THF (5 mL), methanol (10 mL) and H2O (2 mL) was added LiOH.H2O (0.134 g, 0.00321 mol) at ambient temperature and the resulting mixture was stirred for 2 hours. Volatiles were then evaporated and the resulting residue was diluted with water, acidified with 10% aqueous HCl solution. The resulting precipitate was isolated by filtration and dried to afford 0.26 g (90%) of [(5-phenylamino-pyridine-2-carbonyl)-amino]-acetic acid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6][C:5]2=[O:18].B.C1COCC1>C1COCC1>[C:12]1([CH:7]2[CH2:6][CH:5]([OH:18])[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([OH:1])[CH:3]=3)[O:8]2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C1CC(c2ccccc2)Oc2ccc(O)cc21
Agent: B
Solvent: C1CCOC1
Product: Oc1ccc2c(c1)C(O)CC(c1ccccc1)O2
Temperature: 25 °C

Procedure:
Into a suspension of 6-hydroxyflavanone (1.0 g) in dry THF (11.5 ml) was added dropwise a solution of borane-THF complex (12.5 ml, 1.0 M in THF) under nitrogen. The reaction mixture was refluxed for 1 hour. After cooling to the room temperature it was poured into an ice-2 M HCl-solution. 2-Phenylchroman-4,6-diol was filtered. 1H NMR (400 MHz, d6-DMSO) δ: 8.83 (s, 1H), 7.45-7.38 (m, 4H), 7.35 (m, 1H), 6.89 (d, 1H, J 2.8 Hz), 6.59 (d, 1H, J 8.7 Hz), 6.54 (dd, 1H, J 8.7, 2.8 Hz), 5.41 (d, 1H, J 7.0 Hz), 5.11 (dd, 1H, J 11.7, 1.2 Hz), 4.87 (m, 1H), 2.26 (m, 1H), 1.90 (m, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:11])[S:3]([N:6]1[CH:10]=[CH:9][CH:8]=[N:7]1)(=[O:5])=[O:4].[Cl:12]C(Cl)(Cl)C(Cl)(Cl)Cl.C([Li])CCC>>[Cl:12][C:8]1[CH:9]=[CH:10][N:6]([S:3]([N:2]([CH3:11])[CH3:1])(=[O:4])=[O:5])[N:7]=1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: CN(C)S(=O)(=O)n1cccn1
Agent: [Li]CCCC
Product: CN(C)S(=O)(=O)n1ccc(Cl)n1

Procedure:
US 20130288893(A1) describes, inter alia, certain (3-halo-1-(pyridin-3-yl)-1H-pyrazol-4-yl)amides and carbamates and their use as pesticides. The route to prepare such compounds involved the preparation of 3-(3-chloro-1H-pyrazol-1-yl)pyridine by the direct coupling of 3-bromopyridine with 3-chloropyrazole. The 3-chloropyrazole was prepared by a) treating 1H-pyrazole with 2-dimethylsulfamoyl chloride and sodium hydride to provide N,N-dimethyl-1H-pyrazole-1-sulfonamide, b) treating the N,N-dimethyl-1H-pyrazole-1-sulfonamide with perchloroethane and n-butyl lithium to provide 3-chloro-N,N-dimethyl-1H-pyrazole-1-sulfonamide, and c) removing the N,N-dimethylsulfonamide from 3-chloro-N,N-dimethyl-1H-pyrazole-1-sulfonamide with trifluoroacetic acid to give the 3-chloropyrazole.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:24]C(OC(C)(C)C)=O)[C:10](=[O:23])[N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.Cl.CCN(C(C)C)C(C)C.[N:42]1([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[CH2:51][C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH2:44][C@H:43]1[C:52]([OH:54])=O.CCN=C=NCCCN(C)C.CI.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:24][C:52]([C@@H:43]2[CH2:44][C:45]3[C:50](=[CH:49][CH:48]=[CH:47][CH:46]=3)[CH2:51][N:42]2[C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])=[O:54])[C:10](=[O:23])[N:11]2[CH2:12][CH2:13][N:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:15][CH2:16]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ccccc2)CC1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ccccc2)CC1
Yield: 31.7 %

Procedure:
To N-{(1R)-1-[(4-chlorophenyl)methyl]-2-oxo-2-(4-phenylpiperazinyl)ethyl}(tert-butoxy)carboxamide (Step 1) (573 mg, 1.30 mmol) in 50 mL round bottomed flask equipped with magnetic stirring was added 25 mL of EtOAc satd with HCl, and the reaction mixture was stirred for 1 h. The resulting solid was filtered and washed with hexane. The solid was dried further in vacuo and then added to a 50 mL round bottomed flask equipped with magnetic stirring. DMF (10 mL), DIEA (110 μl, 0.631 mmol) (Aldrich), Boc-L-Tic-OH (90 mg, 0.68 mmol) (Peptech), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide methiodide (396 mg, 1.33 mmol), and HOAT (90 mg, 0.661 mmol) were added to the reaction flask. The resulting solution was stirred 2 h then worked up as in Preparation XIX. The resulting crude was purified by flash chromatography (SiO2, 1:1, hexane-EtOAc) to afford tert-butyl 3-(N-{(1R)-1-[(4-chlorophenyl)methyl]-2-oxo-2-(4-phenylpiperazinyl)ethyl}carbamoyl)(3S)-1,2,3,4-tetrahydroisoquinoline-2-carboxylate (130 mg). MS (ESI, pos. ion) m/z: 603 (M+H), (ESI, neg. ion) m/z: 601 (M−H). Calc'd for C34H39ClN4O4: 603.15.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][NH:17][C:16](=[O:20])[CH2:15]3)[C:11]2=[O:21])=[CH:6][CH:5]=1.Br[CH2:25][CH2:26][CH2:27][CH3:28]>>[CH2:25]([N:17]1[CH2:18][CH2:19][C:12]2([C:11](=[O:21])[N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:22])[F:23])=[CH:5][CH:6]=3)[CH2:14][CH2:13]2)[CH2:15][C:16]1=[O:20])[CH2:26][CH2:27][CH3:28]
Reactant: CCCCBr
Reactant: O=C1CC2(CCN1)CCN(c1ccc(OC(F)(F)F)cc1)C2=O
Product: CCCCN1CCC2(CCN(c3ccc(OC(F)(F)F)cc3)C2=O)CC1=O

Procedure:
This material was prepared as a white solid in analogy to example 1 step E) from 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decane-1,7-dione and 1-bromo-butane. MS (ESI): 385.1 (MH+).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[CH3:23])[C:5]([NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:9]=1[O:18][CH3:19])=[O:6].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].Br[C:48]1[CH:49]=[C:50]2[C:55](=[CH:56][CH:57]=1)[C:54]([N:58]1[CH2:63][CH2:62][O:61][CH2:60][CH2:59]1)=[N:53][N:52]=[CH:51]2.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)C>[CH3:19][O:18][C:9]1[CH:10]=[CH:11][C:12]([C:14]([F:17])([F:16])[F:15])=[CH:13][C:8]=1[NH:7][C:5](=[O:6])[C:4]1[CH:20]=[CH:21][C:22]([CH3:23])=[C:2]([C:48]2[CH:49]=[C:50]3[C:55](=[CH:56][CH:57]=2)[C:54]([N:58]2[CH2:59][CH2:60][O:61][CH2:62][CH2:63]2)=[N:53][N:52]=[CH:51]3)[CH:3]=1
Reactant: Brc1ccc2c(N3CCOCC3)nncc2c1
Reactant: COc1ccc(C(F)(F)F)cc1NC(=O)c1ccc(C)c(I)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Pd]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(C(F)(F)F)cc1NC(=O)c1ccc(C)c(-c2ccc3c(N4CCOCC4)nncc3c2)c1
Reaction time: 0.17 h

Procedure:
3-Iodo-N-(2-methoxy-5-(trifluoromethyl)phenyl)-4-methylbenzamide (205 mg, 471 μmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium dichloride (34 mg, 47 μmol), bis(pinacolato)diboron (179 mg, 707 μmol), and potassium acetate (118 μL, 1884 μmol) were dissolved/suspended in dimethylformamide (2.4 mL) and placed in the microwave at 160° C. for 10 min. The reaction mixture was then transferred to another vial containing 6-bromo-1-morpholinophthalazine (125mg, 424 μmol), tetrakis(triphenylphosphine) palladium(0)(54 mg, 47 μmol), potassium carbonate-2 M in water (942 μL, 1884 μmol), and ethanol (2.4 mL). The combined mixture was reacted in a microwave oven at 160° C. for 10 min. The reaction mixture was diluted with 50 mL of EtOAc, added to an addition funnel and partitioned with sodium bicarbonate (saturated, aqueous). The organic layer was washed 3 times with 50 mL of sodium bicarbonate (saturated, aqueous), dried over sodium sulfate, and concentrated via rotovap to give a crude product. The crude product was purified by chromatography to obtain the title compound. Found MS (ES+): 523(M+H)+.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[NH2:9][C:10]1[C:11]([Cl:30])=[C:12]([C:26]([Cl:29])=[CH:27][CH:28]=1)[CH2:13][CH:14]1[CH2:18][CH2:17][N:16]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:15]1=[O:25]>C(Cl)(Cl)(Cl)Cl>[NH2:9][C:10]1[C:11]([Cl:30])=[C:12]([C:26]([Cl:29])=[CH:27][C:28]=1[Br:8])[CH2:13][CH:14]1[CH2:18][CH2:17][N:16]([CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]2)[C:15]1=[O:25]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ccc(Cl)c(CC2CCN(C3CCCCC3)C2=O)c1Cl
Solvent: ClC(Cl)(Cl)Cl
Product: Nc1c(Br)cc(Cl)c(CC2CCN(C3CCCCC3)C2=O)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.4 %

Procedure:
Add NBS (7.82 g, 43.9 mmol) to a solution of 3-(3-amino-2,6-dichlorobenzyl)-1-cyclohexyl-pyrrolidin-2-one (Example 50) (15.0 g, 43.9 mmol) in CCl4 (500 mL). Stir at room temp overnight. Filter the suspension. Concentrate the filtrate. Form a suspension in CH2Cl2 and filter. Dissolve the solid in CH2Cl2 and wash several times with water. Dry, filter and concentrate. Concentrate the filtrate. Purify the combined residue by a plug of silica gel eluting with a mixture of EtOAc and hexanes (20:80) to give the title compound (17.6 g, 96%): Mass spectrum (apci) m/z=421.1 (M+H).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[CH:10]=[C:9]1[C:21](O)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:24]([N:27](CC)C(C)C)(C)[CH3:25].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N)C>CN(C=O)C.CO>[CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[CH:10]=[C:9]1[C:21]([NH:27][CH2:24][CH3:25])=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1nnc2ccc3c(cc(C(=O)O)n3Cc3ccccc3)n12
Agent: CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CO
Product: CCNC(=O)c1cc2c(ccc3nnc(C)n32)n1Cc1ccccc1
Reaction time: 0.03 h

Procedure:
To a solution of 6-benzyl-1-methyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine-7-carboxylic acid (0.0067 g, 0.022 mmol, Example 58, Step 4) in DMF (0.3 mL) was added N,N-diisopropylethylamine (0.015 mL, 0.087 mmol, Aldrich) followed by N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.015 g, 0.039 mmol, Aldrich). After 2 minutes, ethylamine (0.0123 mL, 0.219 mmol, Aldrich) was introduced. When the reaction was determined complete by LCMS, the mixture was diluted with MeOH and purified via preparative HPLC-MS (C18 eluting with a gradient of MeCN and H2O containing 0.15% NH4OH). Yield: (5 mg, 70%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:21][CH3:22])[C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)=[O:10])=[C:4]([F:23])[CH:3]=1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:19]([C:16]1[CH:17]=[CH:18][C:13]([CH2:12][NH:11][C:9](=[O:10])[CH:8]([C:5]2[CH:6]=[CH:7][C:2]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:3][C:4]=2[F:23])[O:21][CH3:22])=[CH:14][CH:15]=1)#[N:20]
Reactant: OB(O)c1ccccc1
Reactant: COC(C(=O)NCc1ccc(C#N)cc1)c1ccc(Br)cc1F
Product: COC(C(=O)NCc1ccc(C#N)cc1)c1ccc(-c2ccccc2)cc1F

Procedure:
In analogy to example 57.1, (RS)-2-(4-bromo-2-fluoro-phenyl)-N-(4-cyano-benzyl)-2-methoxy-acetamide (example 41.2) was reacted with phenylboronic acid to give (RS)-N-(4-cyano-benzyl)-2-(3-fluoro-biphenyl-4-yl)-2-methoxy-acetamide. Light yellow gum.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[C:9]([NH:10][C:11]([C:13]2[C:14]([NH:19][CH:20]3[CH2:22][CH2:21]3)=[N:15][CH:16]=[CH:17][CH:18]=2)=[O:12])=[C:8]([CH3:23])[CH:7]=[CH:6][N:5]=1.[H][H]>COCCOCCOC.O.C(O)(=O)C>[CH3:23][C:8]1[CH:7]=[CH:6][N:5]=[C:4]2[N:19]([CH:20]3[CH2:22][CH2:21]3)[C:14]3[N:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:11](=[O:12])[NH:10][C:9]=12
Reactant: [H][H]
Reactant: Cc1ccnc(Cl)c1NC(=O)c1cccnc1NC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: COCCOCCOC
Product: Cc1ccnc2c1NC(=O)c1cccnc1N2C1CC1
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 96.8 %

Procedure:
A 500 ml 4NRB flask with stirrer, temperature controller thermocouple, addition funnel and condenser with an oil bubbler to exclude air was inserted with nitrogen and charged with 15.00 g of 60% sodium hydride in a mineral oil slurry and 120 ml of diglyme. The mixture was heated to 130° C. and treated dropwise with a solution of 41.7 g (0.138 mol) of N-(2-chloro-4-methyl-3-pyridinyl)-2-(cyclopropylamino)-3-pyridinecarboxamide, from example 4, in 70 ml of diglyme at 80 ° C. The reaction mixture was heated at 130° C. until hydrogen evolution ceased. The mixture was cooled to ambient temperature and water (6.75 g) was added dropwise cautiously. When hydrogen evolution ceased, an additional 100 ml of water was added. Acetic acid (20 ml) was added to reduce the pH of the mixture from 11-13 to about 7. An additional 100 ml of water was added and the reaction mixture stirred under ambient conditions for 30 minutes while the product crystallized. The solid product was collected by filtration and the filter cake rinsed with 100 ml of water followed by 50 ml of cyclohexane to remove any residual mineral oil from the mineral oil-sodium hydride slurry. The wet cake was dried in a vacuum oven at 50° C. for 18 hours to obtain 35.58 g of nevirapine.
Reaction SMILES: [CH:1]1([C:4]2[C:13]3[C:12](=[O:14])[CH2:11][CH2:10][C:9]([CH3:16])([CH3:15])[C:8]=3[CH:7]=[C:6](OS(C(F)(F)F)(=O)=O)[CH:5]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.O1CCCC1.[CH3:37][Si:38]([C:41]#[CH:42])([CH3:40])[CH3:39]>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C>[CH:1]1([C:4]2[CH:5]=[C:6]([C:42]#[C:41][Si:38]([CH3:40])([CH3:39])[CH3:37])[CH:7]=[C:8]3[C:13]=2[C:12](=[O:14])[CH2:11][CH2:10][C:9]3([CH3:16])[CH3:15])[CH2:3][CH2:2]1
Reactant: CC1(C)CCC(=O)c2c(C3CC3)cc(OS(=O)(=O)C(F)(F)F)cc21
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: CC1(C)CCC(=O)c2c(C3CC3)cc(C#C[Si](C)(C)C)cc21

Procedure:
Following General Procedure B and using trifluoro-methanesulfonic acid 4-cyclopropyl-8,8-dimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalen-2yl ester (Intermediate 158, 1.09 g, 3 mmol), triethyl amine (5 mL), tetrahydrofuran (5 mL), copper(I)iodide (0.12 g, 0.6 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.42 g, 0.6 mmol) and (trimethylsilyl)acetylene (2.2 mL, 15 mmol) followed by flash column chromatography over silica gel (230–400 mesh) using 7% ethyl acetate in hexane as the eluent, the title compound was obtained as an orange oil (1.05 g, quantitative).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:42])[C@@H:4]([NH:32][C@H:33]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:34][CH3:35])[CH2:5][C:6]1[CH:31]=[CH:30][C:9]2[O:10][C@@H:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=4)=[CH:16][CH:15]=3)[CH2:12][O:13][C:8]=2[CH:7]=1.C=O.F[C:46](F)(F)C(O)=O.C([O-])(O)=O.[Na+]>O1CCOCC1>[CH3:1][O:2][C:3]([C@@H:4]1[CH2:5][C:6]2[CH:7]=[C:8]3[O:13][CH2:12][C@H:11]([C:14]4[CH:15]=[CH:16][C:17]([O:20][CH2:21][C:22]5[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=5)=[CH:18][CH:19]=4)[O:10][C:9]3=[CH:30][C:31]=2[CH2:46][N:32]1[C@H:33]([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[CH2:34][CH3:35])=[O:42]
Reactant: CC[C@H](N[C@@H](Cc1ccc2c(c1)OC[C@H](c1ccc(OCc3ccc(Cl)c(Cl)c3)cc1)O2)C(=O)OC)c1ccccc1
Reactant: O=C(O)C(F)(F)F
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)OC)OC[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Temperature: 25 °C
Reaction time: 12 h

Procedure:
(S)-3-{(S)-2-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2,3-dihydro-benzo[1,4]dioxin-6-yl}-2-((S)-1-phenyl-propylamino)-propionic acid methyl ester (893 mg) was dissolved in 80 mL dry dioxane and 133 mg paraformaldehyde and 20 mL trifluoroacetic acid were added. The reaction stirred 12 h at rt, then 66 mg more paraformaldehyde was added while stirring at rt. After 3 h aqueous NaHCO3 was added until a pH of 7 was achieved, then the mixture was extracted with EtOAc. The organic extract was washed with brine and dried over Na2SO4 and evaporated. The residue was purified by silica gel flash chromatography (9:1 to 8:2 hexanes/EtOAc) to give 872 mg desired product after drying. 1H NMR (400 MHz, acetone-d6): 7.72 (d, 1H), 7.62 (d, 1H), 7.51-7.43 (m, 3H), 7.38-7.25 (m, 5H), 7.10 (m, 2H), 6.67 (s, 1H), 6.60 (s, 1H), 5.20 (s, 2H), 5.09 (m, 1H), 4.30 (m, 1H), 4.13 (m, 2H), 3.99 (m, 1H), 3.92 (m, 1H), 3.59 (m, 1H), 3.52 (s, 3H), 2.96-2.78 (m, 2H), 2.16 (m, 1H), 1.68 (m, 1H), 0.65 (t, 3H).
Reaction SMILES: [NH2:1][C@@H:2]([CH3:36])[C:3]([NH:5][C@H:6]1[CH2:12][O:11][C:10]2[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=2[N:8]([CH2:17][C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]#[N:34])[N:19]=2)[C:7]1=[O:35])=[O:4].[CH3:37][C:38]1([CH3:41])[CH2:40][O:39]1>CCO>[C:33]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[N:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18]([CH2:17][N:8]2[C:7](=[O:35])[C@@H:6]([NH:5][C:3](=[O:4])[C@@H:2]([NH:1][CH2:37][C:38]([OH:39])([CH3:41])[CH3:40])[CH3:36])[CH2:12][O:11][C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]2=3)=[N:19]1)#[N:34]
Reactant: CC1(C)CO1
Reactant: C[C@H](N)C(=O)N[C@H]1COc2ccccc2N(Cc2nn(-c3ccccc3C#N)c3ccccc23)C1=O
Solvent: CCO
Product: C[C@H](NCC(C)(C)O)C(=O)N[C@H]1COc2ccccc2N(Cc2nn(-c3ccccc3C#N)c3ccccc23)C1=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 59.1 %

Procedure:
(S)-2-Amino-N-((S)-5-((1-(2-cyanophenyl)-1H-indazol-3-yl)methyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)propanamide (50 mg, 104 μmol, Eq: 1.00), LiClO4 (11.1 mg, 4.56 μl, 104 μmol, Eq: 1.00) and 2,2-dimethyloxirane (1 mL) were mixed with EtOH (7 mL) in a microwave reaction vial, the vial was sealed and heated in the microwave at 100° C. After 2 h, 20 eq of 2,2-dimethyloxirane were added and heating was continued under microwave at 100° C. for 3 h. The mixture was concentrated and the residue was purified by preparative TLC to give the title compound (34 mg, 59.1%) as a solid. MS m/z 553 (MH+)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20](F)=[CH:19][CH:18]=3)[O:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[NH2:24][C@H:25]1[CH2:29][CH2:28][C@@H:27]([C:30]([OH:32])=[O:31])[CH2:26]1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>CS(C)=O.CC#N>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([NH:24][C@H:25]4[CH2:29][CH2:28][C@@H:27]([C:30]([OH:32])=[O:31])[CH2:26]4)=[CH:19][CH:18]=3)[O:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: N[C@H]1CC[C@@H](C(=O)O)C1
Reactant: CC(C)Oc1ccc(-c2noc(-c3ccc(F)cc3)n2)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: CC(C)Oc1ccc(-c2noc(-c3ccc(N[C@H]4CC[C@@H](C(=O)O)C4)cc3)n2)cc1Cl
Temperature: 160 °C
Yield: 44.4 %

Procedure:
3-(3-Chloro-4-isopropoxyphenyl)-5-(4-fluorophenyl)-1,2,4-oxadiazole (360 mg, 1.082 mmol), (1R,3S)-3-aminocyclopentanecarboxylic acid (154 mg, 1.190 mmol), potassium carbonate (329 mg, 2.380 mmol) and DMF (2 ml) was heated with cooling at 160° C. on the Biotage microwave for 30 minutes. The mixture was diluted with DMSO (6 ml) and MeCN (8 ml), filtered and divided into 8 aliquots for purification by molecular ion directed LCMS. The fractions were combined and evaporated to afford a pale brown solid that was dried in vacuo at about 60° C. for about 3 hours. This gave (1R,3S)-3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)phenylamino)cyclopentanecarboxylic acid (212 mg, 0.480 mmol, 44.3% yield) as a pale brown solid. LCMS (Table 1, Method a) Rt=3.49 min, m/z 440.20 (M−H)−. 1H NMR (400 MHz, DMSδ ppm 4.81 (s, 1H), 3.96-3.76 (m, 1H), 2.78 (s, 1H), 2.42-2.25 (m, 1H), 2.12-1.95 (m, 1H), 1.89 (d, J=7.72 Hz, 2H), 1.73-1.61 (m, 1H), 1.61-1.48 (m, 1H), 1.39-1.30 (m, 7H), 12.22-12.07 (m, 1H), 6.73 (d, J=8.82 Hz, 2H), 6.87-6.79 (m, 1H), 7.36 (d, J=8.63 Hz, 1H), 7.87 (d, J=8.59 Hz, 2H), 7.98 (ddd, J=9.78, 1.97, 1.06 Hz, 2H).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:14])[O:12][CH3:13])=[C:6]([CH3:15])[CH:5]=1.[F:16][C:17]1[CH:31]=[CH:30][C:20]2[N:21]=[C:22]([CH2:24]OS(C)(=O)=O)[S:23][C:19]=2[CH:18]=1.[Cl-].[NH4+]>CN(C)C=O>[F:16][C:17]1[CH:31]=[CH:30][C:20]2[N:21]=[C:22]([CH2:24][O:3][C:4]3[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:14])[O:12][CH3:13])=[C:6]([CH3:15])[CH:5]=3)[S:23][C:19]=2[CH:18]=1
Reactant: CS(=O)(=O)OCc1nc2ccc(F)cc2s1
Reactant: COC(=O)Nc1ccc(O)cc1C
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COC(=O)Nc1ccc(OCc2nc3ccc(F)cc3s2)cc1C
Reaction time: 0.17 h
Yield: 34.6 %

Procedure:
15.2 mg of sodium hydride (as a 60% w/w dispersion in mineral oil) were added to a solution of 62.6 mg of methyl N-(4-hydroxy-2-methylphenyl)carbamate [prepared as described in step (a) above] in 4 ml of dimethylformamide with cooling in an ice-water bath. The resulting mixture was stirred at the same temperature for 10 minutes, and then 100.0 mg of 6-fluoro-2-methanesulfonyloxymethylbenzothiazole [prepared as described in Example 5(c)] were added to the reaction mixture. The temperature of the resulting mixture was elevated to room temperature and the mixture was stirred for 3 hours. At the end of this time a saturated aqueous ammonium chloride solution was added to the reaction mixture and the resulting mixture was extracted with ethyl acetate. The resulting extract was washed with water and then dried over anhydrous sodium sulfate. The solvent was then removed by evaporation under reduced pressure to give a crude crystalline product which was purified by column chromatography through silica gel using a 3:1 by volume mixture of hexane and ethyl acetate as the eluent, to give a crystalline solid which was washed with diethyl ether and then dried in vacuo to give 41.4 mg (yield 35%) of the title compound as a solid having a melting point of 149°-151° C.
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)(O)[O-].[Na+].[O:9]=[C:10]1[C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([C:20]#[N:21])[C:14]=2[CH:13]=[CH:12][NH:11]1>C(O)C>[OH:3][NH:2][C:20]([C:15]1[C:14]2[CH:13]=[CH:12][NH:11][C:10](=[O:9])[C:19]=2[CH:18]=[CH:17][CH:16]=1)=[NH:21]
Reactant: N#Cc1cccc2c(=O)[nH]ccc12
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: N=C(NO)c1cccc2c(=O)[nH]ccc12
Reaction time: 48 h
Yield: 59.1 %

Procedure:
Hydroxylamine hydrochloride (3.18 g) and sodium bicarbonate (5.7 g) were added to a suspension of 1-oxo-1,2-dihydro-5-isoquinolinecarbonitrile (Journal of Organic Chemistry (1964), 29(9), 2534-42; 3.9 g) in ethanol (600 ml) at room temperature. The reaction mixture was heated to reflux and stirred for 48 hours. After cooling, the suspension was filtered. The solid was collected, washed with water (2×100 ml) and ethanol (100 ml) to give the title compound (2.75 g).