Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[CH:26]([NH:27][C:28](=[O:60])/[C:29](=[N:55]\[O:56][CH2:57][C:58]#[CH:59])/[C:30]3[N:31]=[C:32]([NH:35][C:36]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[S:33][CH:34]=3)[C:25](=[O:61])[N:7]2[C:8]=1[C:9]([O:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].[Na+].[I-:63]>CC(C)=O>[CH2:57]([O:56]/[N:55]=[C:29](/[C:30]1[N:31]=[C:32]([NH:35][C:36]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[S:33][CH:34]=1)\[C:28]([NH:27][CH:26]1[C:25](=[O:61])[N:7]2[C:8]([C:9]([O:11][CH:12]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[O:10])=[C:3]([CH2:2][I:63])[CH2:4][S:5][C@H:6]12)=[O:60])[C:58]#[CH:59]
Reactant: [I-]
Reactant: C#CCO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: [Na+]
Solvent: CC(C)=O
Product: C#CCO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CI)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 1 h
Yield: 100.1 %

Procedure:
A mixture of diphenylmethyl 3-chloromethyl-7-[(Z)-2-propargyloxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]-3-cephem-4-carboxylate (VI-f) (2.0 g, 2.3 mmoles) and NaI (1.04 g, 6.9 mmoles) in acetone (40 ml) was stirred for 1 hour. The mixture was filtered and the filtrate was poured into water and extracted with ethyl acetate. The organic layer was washed with 5% aqueous Na2S2O3, water and a saturated aqueous NaCl, successively. It was then dried over MgSO4 and evaporated to give 2.2 g (98%) of the title compound [VII-f].
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C@H:11]([CH3:12])[O:10]1.[NH:19]1[CH2:24][CH2:23][CH2:22][CH:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[CH2:20]1.O.O.O.Cl([O-])(=O)(=O)=O.[Li+]>C(#N)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:10])([C@H:11]([N:19]1[CH2:24][CH2:23][CH2:22][CH:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[CH2:20]1)[CH3:12])[CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1
Reactant: c1ccc(C2CCCNC2)nc1
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC#N
Solvent: O
Product: C[C@@H](N1CCCC(c2ccccn2)C1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 35.7 %

Procedure:
(2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-ylmethyl)oxirane (0.87 g, 3.5 mmol) and 2-piperidin-3-ylpyridine (2.80 g, 17.26 mmol) were dissolved in acetonitrile (50 ml), and lithium perchlorate trihydrate (1.50 g, 9.3 mmol) was added thereto and refluxed for 40 hours. The solvent was evaporated under a reduced pressure, and the thus obtained residue was dissolved in ethyl acetate and washed with water. The solvent was again evaporated under a reduced pressure, and the residue was purified using a silica gel column to obtain 0.35 g of the intended substance (yield 35.7%).
Reaction SMILES: C([O:8][C:9]1[CH:31]=[CH:30][C:12]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[S:19]2(=[O:21])=[O:20])=[CH:11][CH:10]=1)C1C=CC=CC=1.C1CC=CCC=1>CCO.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[S:19]2(=[O:21])=[O:20])=[CH:30][CH:31]=1
Reactant: O=C1c2ccccc2S(=O)(=O)N1CCCCOc1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: C1=CCC=CC1
Solvent: CCO
Product: O=C1c2ccccc2S(=O)(=O)N1CCCCOc1ccc(O)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 55.1 %

Procedure:
To a stirred solution of 83.3 (0.1 g, 0.23 mmol) in EtOH (5 mL) was added 10% Pd/C (0.1 g, 100% w/w) and 1,4-cyclohexadiene (92 mg, 1.15 mmol) and the resulting suspension was stirred vigorously at 50° C. for 2 hours. The reaction mixture was cooled to room temperature, the catalyst was removed by filtration through Celite, and the filtrate was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel (60% diethyl ether-hexane) to give 84 (0.044 g, 56% yield) as a white solid (m p 107-109° C.). 1H NMR (500 MHz, CDCl3) δ 8.06 (d, J=7.0 Hz, 1H), 7.92 (d, J=7.0 Hz, 1H), 7.87 (td, J=7.0 Hz, J=1.2 Hz, 1H), 7.83 (td, J=7.0 Hz, J=1.2 Hz, 1H), 6.79 (d, J=9.0 Hz, 2H), 6.74 (d, J=9.0 Hz, 2H), 4.38 (br s, 1H), 3.96 (t, J=6.4 Hz, 2H), 3.89 (t, J=7.2 Hz, 2H), 2.05 (quintet, J=6.9 Hz, 2H), 1.89 (quintet, J=6.9 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:20])[C:9]=1[C:10]1[S:11][C:12]2[C:13](Cl)=[N:14][CH:15]=[CH:16][C:17]=2[N:18]=1)[C:5]#[N:6].C[Si]([Br:25])(C)C>C(#N)CC>[Br:25][C:13]1[C:12]2[S:11][C:10]([C:9]3[C:8]([F:20])=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=3[Cl:1])=[N:18][C:17]=2[CH:16]=[CH:15][N:14]=1
Reactant: C[Si](C)(C)Br
Reactant: N#Cc1cc(F)c(-c2nc3ccnc(Cl)c3s2)c(Cl)c1
Solvent: CCC#N
Product: N#Cc1cc(F)c(-c2nc3ccnc(Br)c3s2)c(Cl)c1
Yield: 101.7 %

Procedure:
A suspension of 3-chloro-4-(4-chlorothiazolo[5,4-c]pyridin-2-yl)-5-fluorobenzonitrile (0.077 g, 0.24 mmol) and trimethylsilyl bromide (63 μL 0.48 mmol) in propionitrile (2.4 mL) was heated under reflux for 5 hours before further trimethylsilyl bromide (30 μL, 0.24 mmol) was added. The resulting mixture was heated under reflux for a further 16 hours then partitioned between DCM and water. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give the desired compound as an off-white solid (0.090 g, quant. yield). 1H NMR (300 MHz, CDCl3): δ 8.53 (d, J=5.6 Hz, 1H), 8.03 (d, J=5.6 Hz, 1H), 7.72 (t, J=1.4 Hz, 1H), 7.52 (dd, J=8.3; 1.5 Hz, 1H). LCMS (Method D): RT=3.89 min, m/z: 368 [M+H+].
Reaction SMILES: [O:1]1[CH:5]=[N:4][C:3]([C:6]2[CH:10]=[CH:9][S:8][C:7]=2[NH2:11])=[N:2]1.[F:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[F:23])[N:19]([CH2:24][C:25](O)=[O:26])[C:18](=[O:28])[CH:17]=[CH:16]2>>[O:1]1[CH:5]=[N:4][C:3]([C:6]2[CH:10]=[CH:9][S:8][C:7]=2[NH:11][C:25](=[O:26])[CH2:24][N:19]2[C:20]3[C:15](=[CH:14][C:13]([F:12])=[C:22]([F:23])[CH:21]=3)[CH:16]=[CH:17][C:18]2=[O:28])=[N:2]1
Reactant: Nc1sccc1-c1ncon1
Reactant: O=C(O)Cn1c(=O)ccc2cc(F)c(F)cc21
Product: O=C(Cn1c(=O)ccc2cc(F)c(F)cc21)Nc1sccc1-c1ncon1

Procedure:
The title compound was prepared from 3-(1,2,4-oxadiazol-3-yl)thiophen-2-amine (18 mg, 108 umol) and 2-(6,7-difluoro-2-oxoquinolin-1(2H)-yl)acetic acid (32 mg, 134 umol) using protocol A. The crude product was purified by HPLC to yield N-(3-(1,2,4-oxadiazol-3-yl)thiophen-2-yl)-2-(6,7-difluoro-2-oxoquinolin-1(2H)-yl)acetamide. Method [7] retention time 5.34 min by HPLC (M+=389) and (M+Na=411). 1H NMR (300 MHz, CDCl3) δ 11.06 (s, 1H), 8.69 (s, 1H), 7.74 (d, J=9.9 Hz, 1H), 7.42 (m, 2H), 7.35 (m, 1H), 6.98 (d, J=5.4 Hz, 1H), 6.86 (d, J=9.3 Hz, 1H), 5.22 (s, 2H).
Reaction SMILES: [F:1][CH:2]([F:31])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[C:17]([O:25][CH2:26][C:27]([F:30])([F:29])[F:28])[CH:16]=2)[CH:4]=1.[NH2:32][C:33]1[CH:42]=[CH:41][C:36]([C:37]([NH:39][OH:40])=[NH:38])=[CH:35][N:34]=1>>[F:31][CH:2]([F:1])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]3[O:40][N:39]=[C:37]([C:36]4[CH:41]=[CH:42][C:33]([NH2:32])=[N:34][CH:35]=4)[N:38]=3)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[C:17]([O:25][CH2:26][C:27]([F:30])([F:29])[F:28])[CH:16]=2)[CH:4]=1
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)c(OCC(F)(F)F)c3)nc12
Reactant: N=C(NO)c1ccc(N)nc1
Product: Nc1ccc(-c2noc(-c3cnn4c(C(F)F)cc(-c5ccc(C(F)(F)F)c(OCC(F)(F)F)c5)nc34)n2)cn1

Procedure:
The title compound was prepared from 7-difluoromethyl-5-[3-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.14) (228 mg, 0.5 mmol) and 6-amino-N-hydroxy-nicotinamidine (example B.4) (114 mg, 0.75 mmol) according to general procedure II. Obtained after flash chromatography on silica gel (ethyl acetate/heptane) and further purification by crystallization (dichloromethane/hexane) as a yellow solid (125 mg, 44%). MS (ISP) 572.1 [(M+H)+]; mp 285° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30](Br)[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=1B(O)O>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:41]5[CH:40]=[C:39]([F:42])[CH:38]=[CH:37][C:36]=5[Cl:35])[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: OB(O)c1cc(F)ccc1Cl
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Br)n4)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(-c5cc(F)ccc5Cl)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 42, Step 2, using 1-{4′-[4-(6-bromo-pyridin-2-ylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 2-chloro-5-fluoro-phenylboronic acid.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:10](Cl)(=O)[CH2:11][CH3:12]>>[CH2:11]([CH:12]1[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2][CH2:1][NH:9]1)[CH3:10]
Reactant: CCC(=O)Cl
Reactant: NCCc1ccccc1
Product: CCC1NCCc2ccccc21

Procedure:
In accordance with the same procedures as in Steps 1, 2, and 3 of Preparation 21, except for using phenethylamine and propionyl chloride, 1-ethyl-1,2,3,4-tetrahydroisoquinoline was obtained. In accordance with the same procedures as in Preparation 20, the titled compound was obtained as pale yellow oil. (Yield: 78%) The product was used in the subsequent step without further purification.
Reaction SMILES: [OH:1][CH:2]([CH2:20][CH3:21])[C:3]([N:5]1[CH2:10][CH2:9][C:8]2[N:11]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:13][C:7]=2[CH2:6]1)=[O:4].N1C=CN=C1.[C:27]([Si:31](Cl)([CH3:33])[CH3:32])([CH3:30])([CH3:29])[CH3:28].C(Cl)Cl>CN(C=O)C.CN(C1C=CN=CC=1)C>[C:27]([Si:31]([CH3:33])([CH3:32])[O:1][CH:2]([CH2:20][CH3:21])[C:3]([N:5]1[CH2:10][CH2:9][C:8]2[N:11]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:13][C:7]=2[CH2:6]1)=[O:4])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCC(O)C(=O)N1CCc2nc(-c3ccccc3)oc2C1
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCC(O[Si](C)(C)C(C)(C)C)C(=O)N1CCc2nc(-c3ccccc3)oc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
710.00 mg (2.48 mmol) 2-hydroxy-1-(2-phenyl-6,7-dihydro-4H-oxazolo[5,4-c]pyridin-5-yl)-butan-1-one are placed in 10 mL DMF and combined with 340.00 mg (4.99 mmol) imidazole. Then 600.00 mg (3.98 mmol) tert.-butyl-chloro-dimethyl-silane and 30.00 mg (0.25 mmol) DMAP are added and the mixture is stirred overnight at RT. The DMF is eliminated i.V., the residue is added to DCM and extracted 1 time each with H2O, 1N HCl and saturated sodium chloride solution. The solvent of the org. phase is eliminated in vacuo and the residue is purified on silica gel. (Eluant: cyclohexane/EA).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](=[O:12])[CH3:11])=[CH:4][CH:3]=1.[C:13]([Si:17](Cl)([CH3:19])[CH3:18])([CH3:16])([CH3:15])[CH3:14].N1C=CN=C1>CN(C=O)C>[Si:17]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10](=[O:12])[CH3:11])=[CH:6][CH:7]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:19])[CH3:18]
Reactant: CC(=O)CCc1ccc(O)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(=O)CCc1ccc(O[Si](C)(C)C(C)(C)C)cc1

Procedure:
The title compound was prepared as described in General Method 5 using 10 g (60.9 mmol) of 4-(4-hydroxyphenyl)-2-butanone, 10.1 g (67 mmol) of tert-butyldimethyl silyl chloride, 4.56 g (67 mmol) of imidazole and 150 mL of DMF. The crude product was carried on "as is" to the next step (see Example KK).
Reaction SMILES: [C:1]([C:4]1[N:5]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)[C:6]2[C:11]([C:12]=1[C:13]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[C:19]([F:24])[CH:18]=1)=[O:14])=[CH:10][CH:9]=[C:8]([O:25][CH:26]([CH3:28])[CH3:27])[CH:7]=2)(=O)[CH3:2].[OH:36][NH2:37].Cl.N1C=CC=CC=1>CO>[F:24][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][C:20]=1[F:23])[CH2:16][NH:15][C:13]([C:12]1[C:11]2[C:6](=[CH:7][C:8]([O:25][CH:26]([CH3:27])[CH3:28])=[CH:9][CH:10]=2)[N:5]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)[C:4]=1/[C:1](=[N:37]/[OH:36])/[CH3:2])=[O:14]
Reactant: CC(=O)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(OC(C)C)cc2n1Cc1ccccn1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: C/C(=N\O)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(OC(C)C)cc2n1Cc1ccccn1
Temperature: 65 °C
Reaction time: 20 h

Procedure:
General Procedure Q. To a solution of 2-acetyl-N-(3,4-difluorobenzyl)-6-isopropoxy-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide (Compound 109, 18 mg, 0.038 mmol) in MeOH (3 ml) was added HONH2.HCl (8.0 mg, 0.11 mmol) and pyridine (30 μl, 0.38 mmol). The reaction was stirred at 65° C. for 20 h and the solvent was removed in vacuo. The residue was purified by PTLC (75% EtOAc-hexanes) to yield the title compound.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C(N(C(C)C)CC)(C)C.Cl[CH2:26][CH2:27][CH2:28][C:29]([N:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:33][CH2:32]1)=[O:30].O>CN(C)C=O>[Cl:2][C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[N:10]1[CH2:15][CH2:14][N:13]([CH2:26][CH2:27][CH2:28][C:29]([N:31]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH2:33][CH2:32]2)=[O:30])[CH2:12][CH2:11]1
Reactant: O=C(CCCCl)N1CCc2ccccc21
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCCN1CCN(c2cccc(Cl)c2Cl)CC1)N1CCc2ccccc21
Temperature: 45 °C
Yield: 113.5 %

Procedure:
A mixture of 1-(2,3-dichlorophenyl)piperazine, hydrochloride (8.0 g) and diisopropylethylamine (10 mL) in dimethyl formamide (50 mL) was heated to 45° C. followed by the addition of 4-chloro-1-(2,3-dihydro-1H-indol-1-yl)butan-1-one (6.7 g). The resulting mixture was heated at 100° C. for 6 h, cooled to room temperature and poured into water. The aqueous phase was extracted with diethyl ether, and the combined organic phases were dried (MgSO4), filtered and evaporated in vacuo to give a black oil (14.2 g). The oil was crystallised from acetone, and the formed crystals were recrystallised from ethanol to give a white crystalline material (3.8 g). Mp 134–136° C. 1H NMR (CDCl3): 1.90–2.05 (m, 2H); 2.45–2.60 (m, 4H); 2.65 (s, 4H); 3.00 (s, 4H); 3.20 (t, 2H); 4.10 (t, 2H); 6.90 (d, 1H); 7.00 (t, 1H); 7.05–7–25 (m, 4H); 8.25 (d, 1H). MS m/z: 418 (MH+), 299, 228, 188.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[S:12][CH:13]=[CH:14][N:15]=3)=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28](B(O)O)[CH:27]=1.C(#N)C.C([O-])(O)=O.[Na+]>C(OCC)(=O)C>[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:2]2[CH:3]=[C:4]3[C:10]([C:11]4[S:12][CH:13]=[CH:14][N:15]=4)=[CH:9][NH:8][C:5]3=[N:6][CH:7]=2)[CH:27]=1
Reactant: OB(O)c1cccnc1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3nccs3)c3cc(Br)cnc32)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: c1cncc(-c2cnc3[nH]cc(-c4nccs4)c3c2)c1
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 76.1 %

Procedure:
A mixture of 2-(5-bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridine-3-yl)thiazole (75 mg, 0.17 mmol), pyridine-3-ylboronic acid (27 mg, 0.22 mmol) 1,1′-bis(diphenylphosphino)ferrocenepalladium(II)-dichloride dichloromethane adduct (6.9 mg, 0.009 mmol), acetonitrile (1 mL) and saturated aqueous NaHCO3 (1 mL) were stirred in a sealed microwave tube at 140° C. for 30 minutes. The mixture was then cooled to room temperature, diluted with ethyl acetate, washed with brine and concentrated to dryness. Silica gel chromatography afforded 2-(5-(pyridine-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl)thiazole (36 mg, 76% yield) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 7.47 (m, 1H), 7.56 (d, J=3.5 Hz, 1H), 7.81 (d, J=3.5 Hz, 1H), 8.10 (m, 1H), 8.24 (s, 1H), 8.55 (dd, J=2.0, 5.0 Hz, 1H), 8.61 (d, J=2.5 Hz, 1H), (d, J=2.0 Hz, 1H), 8.89 (m, 1H), 12.37 (s, 1H). MS: m/z 279.0 (M+H+)
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].C1(C)C=CC=CC=1.[CH2:14]([O:25][C:26]1[CH:34]=[CH:33]C(C(O)=O)=[CH:28][CH:27]=1)[CH2:15][CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>CN(C=O)C.C(Cl)Cl>[CH2:14]([O:25][C:26]1[CH:27]=[CH:28][C:1]([C:2]([Cl:4])=[O:3])=[CH:33][CH:34]=1)[CH2:15][CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCCCC/C=C\CCCOc1ccc(C(=O)O)cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCCCCC/C=C\CCCOc1ccc(C(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
1 mL of oxalyl chloride (11.5 mmol) and two drops of anhydrous DMF are added under argon to 101 mg of toluene-dried acid 34 (348 μmol) dissolved in 18 mL of anhydrous DCM. The medium is stirred at room temperature for two hours and then concentrated to give 107 mg of a yellow oil, i.e. a yield of 99%.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH:11]1(B(O)O)[CH2:13][CH2:12]1.C1(C)C(C)=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>CCCCCC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OC(=O)C)C>[CH:11]1([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH2:13][CH2:12]1
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: OB(O)C1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1C
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cnccc1C1CC1
Temperature: 130 °C
Yield: 736.3 %

Procedure:
4-Chloro-3-nitropyridine (100 mg, 0.630 mmol) and cyclopropyl boronic acid (10.0 mg, 0.091 mmol) were added to a solution of xylene (3 mL) previously purged with argon (10 minutes). The reaction mixture was purged with argon for a further 15 minutes, followed by the addition of potassium carbonate (174.35 mg, 1.26 mmol) and Pd(PPh3)4 (34.5 mg, 0.063 mmol). The resulting mixture was heated to reflux at 130° C. overnight. The reaction was monitored by TLC (30% ethylacetate in hexane). The reaction mixture was cooled and concentrated to afford the crude product. Purification by column chromatography on silica gel (15% ethyl acetate in hexane) afforded 110 mg of the product (100% yield). LCMS Purity: 99%, m/z=165 (M+1)
Reaction SMILES: [Na][Na].[OH2:3].OCC[N:7]([CH2:11][P:12](=[O:15])([OH:14])[OH:13])[CH2:8][CH2:9][OH:10].[OH-].[K+]>>[P:12]([CH2:11][NH:7][CH2:8][C:9]([OH:3])=[O:10])([OH:13])([OH:14])=[O:15].[NH2:7][CH2:11][P:12](=[O:13])([OH:15])[OH:14]
Reactant: O=P(O)(O)CN(CCO)CCO
Reactant: O
Agent: [K+]
Agent: [Na][Na]
Agent: [OH-]
Product: NCP(=O)(O)O
Product: O=C(O)CNCP(=O)(O)O
Yield: 12.6 %
Yield: 60 %

Procedure:
The disodium salt of [bis(2hydroxyethyl)amino]methylphosphonic acid monohydrate (4.0 g, 0.016 mol) was heated with 85% potassium hydroxide (15.0 g, 0.23 mol) at 250° C. for 75 minutes. Product isolation gave N-phosphonomethylglycine (0.31 g, 12.6%) and aminomethylphosphonic acid (1.0 g, 60.0%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1.[CH3:8][Si:9]([C:12]#[CH:13])([CH3:11])[CH3:10]>C(N(CC)CC)C.[Cu]I>[CH3:8][Si:9]([C:12]#[C:13][C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1)([CH3:11])[CH3:10]
Reactant: Brc1cncnc1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cncnc1
Reaction time: 0.25 h

Procedure:
Dissolve 5-bromopyrimidine (50.0 g, 314.4 mmol) in triethylamine (400 mL), add copper (1) iodide (1.20 g, 6.2 mmol) and stir mixture under nitrogen. After 15 min., add trimethylsilyl acetylene (53.3 mL, 377.3 mmol), followed by dichlorobis(triphenyl-phosphine) palladium (11) (8.82 g, 12.5 mmol) and stir at RT. After 3 h, filter the solution through Celite®, rinsing with ether. Concentrate the filtrate under reduced pressure. Purification by flash chromatography on silica gel eluting first with hexanes (100%), then with hexanes:EtOAc (3:1) gives the title compound: 1H NMR (300 MHz, CDCl3) δ 9.10 (s, 1H), 8.77 (s, 2H), 0.27 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:65]([O:67][C:68](=[O:76])[C:69]1[CH:74]=[CH:73][C:72]([NH2:75])=[CH:71][CH:70]=1)[CH3:66]>C(Cl)Cl>[CH2:65]([O:67][C:68](=[O:76])[C:69]1[CH:74]=[CH:73][C:72]([NH:75][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:25])[CH3:26])[NH:10]2)=[O:29])=[CH:71][CH:70]=1)[CH3:66]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (100 mg, 0.17 mmol) in methylene chloride (10 mL), HATU (Aldrich, 98 mg, 0.26 mmol) was added followed by the addition of DIPEA (90 uL, 0.52 mmol) and 4-amino benzoic acid ethyl ester (43 mg, 0.26 mmol). The mixture was stirred at rt overnight. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (40 g column, eluent, 20% EtOAc/hexanes) to give a white solid. 37 mg.
Reaction SMILES: O=[C:2]([CH2:8][C:9](=O)[CH3:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C([O-])(=O)C.[NH4+].Cl.[NH:18]([CH2:20][C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[NH2:19]>C(O)C>[CH2:6]([O:5][C:3]([C:2]1[CH:8]=[C:9]([CH3:10])[N:18]([CH2:20][C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[N:19]=1)=[O:4])[CH3:7].[CH2:6]([O:5][C:3]([C:2]1[N:18]([CH2:20][C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[N:19]=[C:9]([CH3:10])[CH:8]=1)=[O:4])[CH3:7]
Reactant: CCOC(=O)C(=O)CC(C)=O
Reactant: NNCC(=O)OCc1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)c1cc(C)n(CC(=O)OCc2ccccc2)n1
Product: CCOC(=O)c1cc(C)nn1CC(=O)OCc1ccccc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 31 %
Yield: 51 %

Procedure:
To a mixture of ethyl 2,4-dioxopentanoate (1.74 g, 11.0 mmol), ammonium acetate (1.16 g, 15.0 mmol) and ethanol (20 mL) was added benzyl hydrazinoacetate hydrochloride (2.17 g, 10.0 mmol), and the mixture was stirred at room temperature for 1 hr and at 80° C. for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (carrier: silica gel, eluent: hexane-ethyl acetate) to give benzyl [3-(ethoxycarbonyl)-5-methyl-1H-pyrazol-1-yl]acetate (0.95 g, 31%) and benzyl [5-(ethoxycarbonyl)-3-methyl-1H-pyrazol-1-yl]acetate (1.56 g, 51%). To a solution of benzyl [3-(ethoxycarbonyl)-5-methyl-1H-pyrazol-1-yl]acetate (0.95 g, 3.14 mmol) in ethanol (10 mL) was added 5% palladium/carbon (0.30 g), and the mixture was stirred under a hydrogen stream for 21 hr. The insoluble material was filtered off, and the filtrate was concentrated. The residue was recrystallized from ethyl acetate-hexane to give the title compound (0.59 g, 88%).