Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[N:7]2[CH2:8][CH2:9][CH:10]([C:12]([O:14]CC)=[O:13])[CH2:11][C:6]2=[N:5][N:4]=1.O[Li].O.Cl>C1COCC1.O>[F:18][C:2]([F:1])([F:17])[C:3]1[N:7]2[CH2:8][CH2:9][CH:10]([C:12]([OH:14])=[O:13])[CH2:11][C:6]2=[N:5][N:4]=1
Reactant: CCOC(=O)C1CCn2c(nnc2C(F)(F)F)C1
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C1CCn2c(nnc2C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine-7-carboxylate (2.28 g, 8.662 mmol) in THF (17 mL) was added 4N LiOH.H2O (726.9 mg, 17.324 mmol) in water (4 mL), then the mixture was stirred at room temperature for 2 h, then acidified with 1N HCl to pH=3. The resulting mixture was extracted with EA and the aqueous phase was directly drying to give 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine-7-carboxylic acid without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:12][C:13]3[O:14][C:15]4[C:20]([C:21](=[O:29])[C:22]=3[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:9]=[C:10](I)[C:3]=12.[CH2:30]([OH:33])[C:31]#[CH:32].ClCCl>C1COCC1.[Cu]I>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:12][C:13]3[O:14][C:15]4[C:20]([C:21](=[O:29])[C:22]=3[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:9]=[C:10]([C:32]#[C:31][CH2:30][OH:33])[C:3]=12
Reactant: Nc1ncnc2c1c(I)nn2Cc1oc2ccccc2c(=O)c1-c1ccccc1
Reactant: C#CCO
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: ClCCl
Product: Nc1ncnc2c1c(C#CCO)nn2Cc1oc2ccccc2c(=O)c1-c1ccccc1
Yield: 76.8 %

Procedure:
To a solution of Example 57a (0.180 g, 0.363 mmoles) in THF (5 ml), propargyl alcohol (0.051 g, 0.436 mmoles) diisopropylamine (0.31 ml, 1.81 mmoles), copper(I) iodide (7 mg, 0.036 mmoles) and) Tetrakis triphenylphosphine Palladium (0.042 g, 0.0363 mmoles) were added and the system is degassed for 30 min and heated to reflux for 4 h. The reaction mixture filtered through celite pad and washed with ethyl acetate. The filtrate was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol: dichloromethane to afford the title compound as brown solid (0.118 g, 77% yield). MP: 171-173° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 8.21(s, 1H), 8.06(dd, J=7.9, 1.6Hz, 1H), 7.77(m, 1H), 7.50(dt, J=8.0, 0.9Hz, 1H), 7.40-7.33(m, 6H), 5.43(s, 2H), 4.33(d, J=6.1z, 2H). Mass: 423.88(M+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:13])[C:10]=1[O:11][CH3:12])[C:5](O)=[O:6].C1(C)C=CC=CC=1.S(Cl)([Cl:23])=O>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:13])[C:10]=1[O:11][CH3:12])[C:5]([Cl:23])=[O:6]
Reactant: COc1c(F)cc(C(=O)O)cc1F
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1c(F)cc(C(=O)Cl)cc1F
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To 3,5-difluoro-4-methoxybenzoic acid (310 mg), toluene (3 mL), N,N-dimethylformamide (1 droplet) and thionyl chloride (0.14 mL) were added to the solution, and then the mixture was stirred at 60° C. for 16 hours. The solvent was distilled off under reduced pressure and then azeotroped with toluene to obtain the title compound (347 mg) as a brown oily substance.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:60][CH3:61])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:24]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:39]5[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][N:46]6[CH2:51][CH2:50][N:49](C(OC(C)(C)C)=O)[C@@H:48]([CH3:59])[CH2:47]6)[CH:40]=5)[CH:36]=[CH:37][CH:38]=4)=[O:30])[CH:26]=[CH:27][CH:28]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:60][CH3:61])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:39]5[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][N:46]6[CH2:51][CH2:50][NH:49][C@@H:48]([CH3:59])[CH2:47]6)[CH:40]=5)[CH:36]=[CH:37][CH:38]=4)=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cccc(-c3cccc(CN4CCN(C(=O)OC(C)(C)C)[C@@H](C)C4)c3)c2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cccc(-c3cccc(CN4CCN[C@@H](C)C4)c3)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.8 %

Procedure:
A mixture of 1,1-dimethylethyl (2S)-4-[(3′-{[({3-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]phenyl}-carbonyl)amino]methyl}-3-biphenylyl)methyl]-2-methyl-1-piperazinecarboxylate (33 mg), TFA (0.2 mL) and DCM (1.0 mL) was stirred at room temperature overnight. Then TEA (0.4 mL) was added at −78° C. and the solution was then concentrated. Dilution with MeOH (0.5 mL) followed by separation via a Gilson HPLC (basic conditions) afforded the desired product (13 mg). LC-MS m/z 729 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[N:9][N:10]=2)[CH:7]=1.[NH2:11][C:12]1[C:21]2[C:16](=[C:17](Br)[C:18]([CH3:22])=[CH:19][CH:20]=2)[N:15]=[N:14][C:13]=1[C:24]([NH2:26])=[O:25]>>[N:10]1[N:9]=[CH:8][N:6]2[CH:7]=[C:2]([C:17]3[C:18]([CH3:22])=[CH:19][CH:20]=[C:21]4[C:16]=3[N:15]=[N:14][C:13]([C:24]([NH2:26])=[O:25])=[C:12]4[NH2:11])[CH:3]=[CH:4][C:5]=12
Reactant: Cc1ccc2c(N)c(C(N)=O)nnc2c1Br
Reactant: Brc1ccc2nncn2c1
Product: Cc1ccc2c(N)c(C(N)=O)nnc2c1-c1ccc2nncn2c1

Procedure:
The title compound was prepared in a manner similar to EXAMPLE 96 using 6-bromo-[1,2,4]triazolo[4,3-a]pyridine and 4-amino-8-bromo-7-methylcinnoline-3-carboxamide. 1H NMR (400 MHz, CD3OD) δ ppm 2.45 (s, 3 H), 7.45 (d, J=9.35 Hz, 1 H), 7.78 (d, J=8.84 Hz, 1 H), 7.92 (d, J=9.60 Hz, 1 H), 8.34 (d, J=8.84 Hz, 1 H), 8.56 (s, 1 H), 9.25 (s, 1 H); ESI-MS m/z [M+H]+ 320.1.
Reaction SMILES: BrC1C=CC(O)=C(C2C=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)C=1.[NH2:37][C:38]1[C:43]([Cl:44])=[CH:42][C:41]([C:45](=O)[CH3:46])=[CH:40][C:39]=1[Cl:48].[OH-].[K+]>C(O)C>[NH2:37][C:38]1[C:43]([Cl:44])=[CH:42][C:41]([C:45]2[CH:46]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)=[CH:40][C:39]=1[Cl:48]
Reactant: CC(=O)c1cc(Cl)c(N)c(Cl)c1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(Br)ccc4O)ccc3c1)n2C1CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Nc1c(Cl)cc(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)cc1Cl
Yield: 25 %

Procedure:
Following the procedure and workup for Compound 354, Compound 354e (100 mg, 0.256 mmol) was reacted with 1-(4-amino-3,5-dichloro-phenyl)-ethanone (0.256 mmol) in ethanol (2 mL) using 10% w/v KOH in ethanol (506 μL, 0.64 mmol) to produce the title compound (31 mg, 25% yield).
Reaction SMILES: C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(OC([NH:41][C:42]1[S:46][C:45]([C:47]2[C:52]([F:53])=[CH:51][CH:50]=[CH:49][C:48]=2[F:54])=[N:44][C:43]=1[C:55]([OH:57])=O)=O)(C)(C)C.[NH2:58][C:59]1[CH:60]=[N:61][N:62]([CH3:78])[C:63]=1[N:64]1[CH2:69][CH2:68][N:67](C(OC(C)(C)C)=O)[CH2:66][C@H:65]1[CH3:77].CCN(C(C)C)C(C)C>C(Cl)Cl>[NH2:41][C:42]1[S:46][C:45]([C:47]2[C:48]([F:54])=[CH:49][CH:50]=[CH:51][C:52]=2[F:53])=[N:44][C:43]=1[C:55]([NH:58][C:59]1[CH:60]=[N:61][N:62]([CH3:78])[C:63]=1[N:64]1[CH2:69][CH2:68][NH:67][CH2:66][C@H:65]1[CH3:77])=[O:57]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1c(N)cnn1C
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CNCCN1c1c(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)cnn1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 22 %

Procedure:
A solution of PyBOP (313 mg, 0.60 mmol) and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid from Example 25 (153 mg, 0.43 mmol) in DCM (10 mL) was stirred at room temperature for 30 min. A solution of (R)-tert-butyl 4-(4-amino-1-methyl-1H-pyrazol-5-yl)-3-methylpiperazine-1-carboxylate (133 mg, 0.45 mmol) and DIPEA (0.12 mL, 0.68 mmol) in DCM (10 mL) were added and the mixture stirred at room temperature for 16 hr. The mixture was diluted with DCM (50 mL) and washed with water (20 mL). The organic layer was separated, passed through a phase separation cartridge and concentrated under reduced pressure. The isolated intermediate was re-dissolved in DCM (6 mL) and TFA (2 mL) added. The mixture was stirred at room temperature for 4 hr. The mixture was concentrated under reduced pressure and the residue re-dissolved in DCM (50 mL) and washed with saturated aqueous NaHCO3 (2×10 mL). The organic layer was separated, passed through a phase separation cartridge and concentrated under reduced pressure. Purification by preparative HPLC gave 112 as a white solid (41 mg, 22% over two steps). 1H NMR (400 MHz, CDCl3) δ 8.66 (s, 1H), 7.92 (s, 1H), 7.38-7.25 (m, 1H), 7.03 (t, J=9.0 Hz, 2H), 6.20 (s, 2H), 3.77 (s, 3H), 3.27-3.15 (m, 2H), 3.10-2.93 (m, 4H), 2.59 (dd, J=12.5, 9.5 Hz, 1H), 0.88 (d, J=6.3 Hz, 3H). Alkyl NH not observed. LCMS (ES+) m/z 434 (M+1).
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11].C(N(C(F)([F:26])C1C=CC=C(C)C=1)CC)C>CCCCCCC>[F:26][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11]
Reactant: C=CCCCCCCCCCO
Reactant: CCN(CC)C(F)(F)c1cccc(C)c1
Solvent: CCCCCCC
Product: C=CCCCCCCCCCF
Yield: 91 %

Procedure:
In the same apparatus as that used in Example 14, 10-undecene-1-ol (10 mmole; 1.7 g) as the substrate and N,N-diethyl-α,α-difluoro(3-methyl)benzylamine (12 mmole; 2.56 g) as the fluorinating agent were added to heptane as the solvent. While the resultant mixture was stirred at the room temperature, the mixture was irradiated with microwave for 10 minutes. As the product, 1-fluoro-10-undecene was obtained at a yield of 91%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([CH2:15][C:16](O)=[O:17])[CH:9]=2)=[CH:4][C:3]=1[F:19].S(Cl)([Cl:22])=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([CH2:15][C:16]([Cl:22])=[O:17])[CH:9]=2)=[CH:4][C:3]=1[F:19]
Reactant: Cc1ccc(-c2ccc(Cl)c(F)c2)cc1CC(=O)O
Reactant: O=S(Cl)Cl
Product: Cc1ccc(-c2ccc(Cl)c(F)c2)cc1CC(=O)Cl
Temperature: 80 °C
Reaction time: 1 h

Procedure:
10.00 g (35.88 mmol) of (4′-chloro-3′-fluoro-4-methylbiphenyl-3-yl)acetic acid (Example 1A) were dissolved in 24.33 g (204.51 mmol) of thionyl chloride. The reaction mixture was stirred at 80° C. for one hour and then concentrated under reduced pressure. Drying under fine vacuum gave 10.54 g (99% of theory) of the title compound as a brownish oil.
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=O)O.N[C@H:12](C(O)=O)CC(=O)O>>[NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[C@H:3]([CH2:4][CH3:5])[CH3:12]
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Reactant: N[C@@H](CC(=O)O)C(=O)O
Product: CC[C@H](C)[C@H](N)C(=O)O

Procedure:
A8, Glu or Asp;
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:12]([NH:14][N:15]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]2[C:21]([O:23]C)=O)=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH3:25]>O.CCOC(C)=O>[Cl:20][C:17]1[CH:18]=[CH:19][N:15]2[C:16]=1[C:21]([OH:23])=[N:25][C:12]([C:9]1([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:11][CH2:10]1)=[N:14]2
Reactant: COC(=O)c1c(Cl)ccn1NC(=O)C1(NC(=O)OC(C)(C)C)CC1
Reactant: N
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)NC1(c2nc(O)c3c(Cl)ccn3n2)CC1
Temperature: 110 °C
Yield: 46.3 %

Procedure:
A stirred solution of methyl 1-(1-((tert-butoxycarbonyl)amino)cyclopropanecarboxamido)-3-chloro-1H-pyrrole-2-carboxylate (500 mg, 1.40 mmol) in water (12 mL) was purged with NH3 gas for 5 minutes. The sealed pressure tube was heated at 110° C. for 12 h. The reaction mixture was dissolved in EtOAc (100 mL) and washed with water (50 mL). The organic layer was separated, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified using CombiFlash ISCO (REDISEP®, SiO2, 12 g, 50% EtOAc/petroleum ether) to give tert-butyl (1-(5-chloro-4-hydroxypyrrolo[2,1-f][1,2,4]triazin-2-yl)cyclopropyl)carbamate (210 mg, 46.3%) as a off-white solid. LCMS Condition B-16: retention time 0.91 min, [M+1]=325.1. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.06-1.10 (m, 2H), 1.37-1.45 (m, 2H), 1.41 (s, 9H), 6.57 (d, J=2.4 Hz, 1H), 7.31 (br s, 1H), 7.51 (d, J=2.4 Hz, 1H), 11.32 (br s, 1H).
Reaction SMILES: Cl.[CH2:2]([O:9][NH2:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:11]1[CH:20]=[C:19]2[C:21]([O:23][C:24](=O)[C:17]3=[C:18]2[C:13](=[C:14]([Br:26])[CH:15]=[CH:16]3)[CH:12]=1)=[O:22]>N1C=CC=CC=1>[CH2:2]([O:9][N:10]1[C:24](=[O:23])[C:17]2[CH:16]=[CH:15][C:14]([Br:26])=[C:13]3[C:18]=2[C:19](=[CH:20][CH:11]=[CH:12]3)[C:21]1=[O:22])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: NOCc1ccccc1
Reactant: O=C1OC(=O)c2ccc(Br)c3cccc1c23
Agent: Cl
Solvent: c1ccncc1
Product: O=C1c2cccc3c(Br)ccc(c23)C(=O)N1OCc1ccccc1
Yield: 87.2 %

Procedure:
O-Benzyl hydroxylamine hydrochloride (2.0 g, 12.5 mmol) and 4-bromo-1,8-naphthalic anhydride (2.9 g, 10.5 mmol) were reacted in pyridine (50 mL) following the procedure of Example D to give 3.5 g of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH:4]=[O:5].C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>ClCCl>[CH3:18][S:19]([O:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][S:19]([CH3:18])(=[O:21])=[O:20])=[CH:6][C:3]=1[CH:4]=[O:5])(=[O:21])=[O:20]
Reactant: O=Cc1cc(O)ccc1O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)Oc1ccc(OS(C)(=O)=O)c(C=O)c1
Reaction time: 0.5 h

Procedure:
To a solution of 2,5-dihydroxybenzaldehyde (8.22 g, 59.5 mmol) in 100 mL of dichloromethane at 0° C. was added triethylamine (24.8 mL, 178 mmol), followed by dropwise addition of methanesulfonyl chloride (10.1 mL, 130 mmol). After 30 minutes, the solution was concentrated in vacuo, then partitioned between EtOAc and saturated NaHCO3 solution. The organic layer was washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The product was isolated as a brown oil which was used without further purification.
Reaction SMILES: Cl[O-].[Na+].[CH2:4]([O:11][C:12]1[CH:13]=[C:14](/[CH:18]=[N:19]/[OH:20])[CH:15]=[CH:16][CH:17]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:21]=[C:22]([CH2:27][C:28]([O:30]C)=[O:29])[C:23]([O:25]C)=[O:24].[OH-].[Na+]>C1COCC1.CO>[CH2:4]([O:11][C:12]1[CH:13]=[C:14]([C:18]2[CH2:21][C:22]([CH2:27][C:28]([OH:30])=[O:29])([C:23]([OH:25])=[O:24])[O:20][N:19]=2)[CH:15]=[CH:16][CH:17]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: C=C(CC(=O)OC)C(=O)OC
Reactant: O/N=C/c1cccc(OCc2ccccc2)c1
Agent: [Na+]
Agent: [O-]Cl
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CC1(C(=O)O)CC(c2cccc(OCc3ccccc3)c2)=NO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.9 %

Procedure:
An aqueous sodium hypochlorite solution (5%, 1081 g) was added dropwise to a solution of (E)-1-(3-(benzyloxy)phenyl)-N-hydroxymethanimine (150 g) and dimethyl 2-methylenesuccinate (104 g) in THF (1500 mL) at 5 C (internal temperature: 30 C or lower) over 1 hour, and then, the obtained mixture was stirred at 5 C for 1 hour. To the reaction mixture, methanol (750 mL) was added, and then, a 2 M aqueous sodium hydroxide solution (750 mL) was added dropwise at 5 C (internal temperature: 20 C or lower) over 40 minutes. The obtained mixture was gradually warmed to room temperature and stirred overnight at room temperature. The reaction mixture was concentrated into half the volume under reduced pressure, and then, water (5000 mL) and ethyl acetate (1500 mL) were added to the residue. The aqueous layer was washed with ethyl acetate (1500 mL), then 6 M hydrochloric acid (250 mL) was added thereto, and the obtained mixture was subjected to extraction with ethyl acetate (1500 mL×2). The extract was washed with brine (1500 mL) and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The residue was washed with diethyl ether (10 mL) and hexane (1000 mL) to obtain the title compound (217 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5]1[CH:10]=[CH:9][C:8]([N:11]=[CH:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:7][CH:6]=1)[CH3:2].O.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[CH:46](=[O:50])[CH:47]([CH3:49])[CH3:48].O>O1CCCC1>[CH2:1]([O:3][C:4]([C:5]1[CH:10]=[C:9]2[C:8](=[CH:7][CH:6]=1)[NH:11][CH:12]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[C:47]([CH3:49])([CH3:48])[CH:46]2[OH:50])=[O:19])[CH3:2]
Reactant: CCOC(=O)c1ccc(N=Cc2cccnc2)cc1
Reactant: CC(C)C=O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1ccc2c(c1)C(O)C(C)(C)C(c1cccnc1)N2
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.9 %

Procedure:
To a mixture of 4-[(pyridin-3-ylmethylene)-amino]-benzoic acid ethyl ester (51 g, 200 mmol) and Ytterbium(III) triflate hydrate (12.4 g, 20 mmol) in dry tetrahydrofuran (200 mL) at 25° C. was added isobutyraldehyde (18.2 mL, 200 mmol) and water (3.6 mL, 200 mmol) dropwise. The reaction mixture was stirred at 25° C. for 16 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×200 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 4-hydroxy-3,3-dimethyl-2-pyridin-3-yl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (65.2 g, quant.) as a light yellow oil which was used for next step without further purification: LC/MS m/e calcd for C19H22N2O3 (M+H)+: 327.40, observed: 309.0.
Reaction SMILES: O.[NH2:2][NH2:3].[CH3:4][C:5]([CH3:12])([CH3:11])[C:6](=O)[CH2:7][C:8]#[N:9]>CCO>[C:5]([C:6]1[CH:7]=[C:8]([NH2:9])[N:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[N:2]=1)([CH3:12])([CH3:11])[CH3:4]
Reactant: NN
Reactant: CC(C)(C)C(=O)CC#N
Solvent: CCO
Solvent: O
Product: CCCCCn1nc(C(C)(C)C)cc1N
Temperature: 85 °C
Reaction time: 20 h
Yield: 117.3 %

Procedure:
To a solution of Example 99A (10.0 g, 41.3 mmol) in EtOH (85 mL) was added hydrazine hydrate (3.02 mL, 61.9 mmol). The mixture was warmed to reflux (85° C.) and was allowed to stir for 20 hours. The mixture was cooled to ambient temperature then 4,4-dimethyl-3-oxopentanenitrile (7.78 g, 61.9 mmol) was added and the mixture was again warmed to reflux (85° C.) and was allowed to stir for 4 hours then the mixture was concentrated under reduced pressure and the residue was dissolved in CH2Cl2 (100 mL) and saturated aqueous NaHCO3 (50 mL) was added slowly. The layers were separated and the aqueous phase was extracted with CH2Cl2 (3×10 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by column chromatography (SiO2, 50% hexanes/EtOAc) provided the title compound (7.6 g, 36.3 mmol, 88% yield). MS (DCI/NH3) m/z 210 (M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Cl[CH2:10][C:11]([O:13][CH3:14])=[O:12].C(=O)(O)[O-].[Na+].C(OCC)(=O)C>C(#N)C>[CH3:14][O:13][C:11](=[O:12])[CH2:10][NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[C:2]([I:1])[CH:3]=1
Reactant: COC(=O)CCl
Reactant: Nc1cccc(I)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)CNc1cccc(I)c1
Yield: 150.5 %

Procedure:
A mixture of 3-iodoaniline (40.0 g), methyl chloroacetate (37.12 g) and sodium bicarbonate (30.75 g) was heated in acetonitrile (400 ml) at reflux for 2 days under nitrogen. Ethyl acetate (250 ml) was then added and the mixture was washed with water (2×250 ml) dried and evaporated to give an oil (ca. 80 g), a sample of which (1.2 g) was purified by FCC eluting with ether-petroleum ether (7-3) to give the title compound (Intermediate 27; 0.8 g) as a solid, m.p. 83°.
Reaction SMILES: [CH2:1]([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]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][O:22][C@H:23]1[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:1]([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:21][O:22][C@H:23]1[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24]1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN1CC[C@H](ON)C1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CN1CC[C@H](ONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.2 %

Procedure:
To a mixture of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.25 g, 0.90 mmol, US2005/20572 A1, 2005) in DCM (20 mL) was added (3S)-3-(aminooxy)-1-methylpyrrolidine 109 (0.32 g, 1.39 mmol, J. Med. Chem., 2008, 51, 4601-4608), 1-hydroxybenzotriazole (0.18 g, 1.33 mmol), and 1-ethyl-(3-dimethylamino propyl)carbodiimide hydrochloride (0.26 g, 1.36 mmol) sequentially at room temperature. The mixture was stirred at room temperature overnight, then concentrated in vacuo to provide a residue, which was subjected to chromatography to give 110 (0.26 g, 77%) as a yellow foam.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([CH2:16][C:17]3[CH:21]=[CH:20][S:19][CH:18]=3)[CH:8]=2)[CH2:3][CH2:2]1.C[O:23][C:24](=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31]Br)[CH:26]=1>>[S:19]1[CH:20]=[CH:21][C:17]([CH2:16][N:9]2[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:7]([CH:4]3[CH2:5][CH2:6][N:1]([CH2:31][C:27]4[CH:26]=[C:25]([CH:30]=[CH:29][CH:28]=4)[C:24]([OH:33])=[O:23])[CH2:2][CH2:3]3)=[CH:8]2)=[CH:18]1
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: c1ccc2c(c1)c(C1CCNCC1)cn2Cc1ccsc1
Product: O=C(O)c1cccc(CN2CCC(c3cn(Cc4ccsc4)c4ccccc34)CC2)c1

Procedure:
This compound was prepared following the procedure described in example 117 (part C) starting with 0.1 g (0.38 mmol) of 3-piperidin-4-yl-1-thiophen-3-ylmethyl-1H-indole and 0.1 g (0.48 mmol) of 3-bromomethyl-benzoic acid methyl ester. The crude mixture was purified by HPLC-MS using a C-18 column, and 0.005 g (98% of purity) of the expected acid were isolated.
Reaction SMILES: [Br-].[CH2:2]([Zn+])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.I[C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([C:18]2[N:19]=[C:20]([NH:23][C:24](=[O:31])[C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)[S:21][CH:22]=2)=[C:13]([CH3:32])[CH:12]=1.C([O-])(O)=O.[Na+]>C1COCC1>[CH2:2]([C:11]1[CH:12]=[C:13]([CH3:32])[C:14]([C:18]2[N:19]=[C:20]([NH:23][C:24](=[O:31])[C:25]3[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=3)[S:21][CH:22]=2)=[C:15]([CH3:17])[CH:16]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Cc1cc(I)cc(C)c1-c1csc(NC(=O)c2ccncc2)n1
Reactant: [Zn+]Cc1ccccc1
Agent: O=C([O-])O
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(Cc2ccccc2)cc(C)c1-c1csc(NC(=O)c2ccncc2)n1

Procedure:
A THF solution of benzylzinc(II) bromide (4.0 mL, 2.0 mmol) was added to a degassed solution of N-(4-(4-iodo-2,6-dimethylphenyl)thiazol-2-yl)isonicotinamide (435 mg, 1.0 mmol) and tetrakistriphenylphosphine palladium (57.8 mg, 0.10 mmol) in THF (5.0 mL). The reaction mixture was heated at reflux for 16 h under N2 and then poured into saturated aqueous NaHCO3. The mixture was extracted with ethyl acetate, washed with brine, dried MgSO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give N-(4-(4-benzyl-2,6-dimethylphenyl)thiazol-2-yl)isonicotinamide: 1H NMR (500 MHz, CDCl3) δ 8.70 (d, J=4.9 Hz, 2H), 7.67 (d, J=4.9 Hz, 2H), 7.33 (d, J=8.6 Hz, 2H), 7.10-7.26 (m, 3H), 6.80 (s, 1H), 6.24 (s, 1H), 3.86 (s, 2H), 2.04 (s, 6H); ESI-MS: m/z 399.9 (M+H)+.