Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:16]=2)(=[O:14])=[O:13])[C:5]([C:8](O)=[O:9])=[N:6][CH:7]=1.[CH3:26][NH:27][C:28]1[CH:33]=[C:32]([CH3:34])[CH:31]=[CH:30][N:29]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>>[CH3:26][N:27]([C:28]1[CH:33]=[C:32]([CH3:34])[CH:31]=[CH:30][N:29]=1)[C:8]([C:5]1[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:25])([F:23])[F:24])[CH:16]=2)(=[O:13])=[O:14])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)=[O:9]
Reactant: CNc1cc(C)ccn1
Reactant: O=C(O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccnc(N(C)C(=O)c2ncc(Cl)cc2NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)c1

Procedure:
5-Chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)picolinic acid (100 mg, 0.24 mmol), methyl-(4-methyl-pyridin-2-yl)-amine (88 mg, 0.72 mmol), BOP (137 mg, 0.31 mmol) and DIEA (265 μL, 1.44 mmol) were reacted according to the procedure D to provide the title compound. HPLC purification (20→90% gradient of MeCN-water) provided 5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylic acid methyl-(4-methyl-pyridin-2-yl)-amide: MS m/z: 519.0(M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH:11]([CH3:13])[CH3:12])[N:8]=[C:7]2[C:14]1[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=1.B(Br)(Br)Br.C1CCCCC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH:11]([CH3:12])[CH3:13])[N:8]=[C:7]2[C:14]1[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=1
Reactant: COc1ccc(-c2nn(C(C)C)c3c(Cl)cccc23)cc1
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Product: CC(C)n1nc(-c2ccc(O)cc2)c2cccc(Cl)c21
Yield: 29.1 %

Procedure:
Prepared according to Method D step C from 7-chloro-1-isopropyl-3-(4-methoxyphenyl)-1H-indazole (0.093 g, 0.30 mmol), boron tribromide (0.094 mL, 1.0 mmol) and 0.3 mL of cyclohexene to give the product (0.025 g) as an off-white solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.CCN=C=NCCCN(C)C.Cl.[C:27]([C:29]1[C:30]([C:43]([F:46])([F:45])[F:44])=[C:31]2[C:35](=[CH:36][CH:37]=1)[N:34]([CH2:38][C:39](=[NH:42])[NH:40]O)[CH:33]=[CH:32]2)#[N:28]>ClCCCl>[F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4]1[O:6][N:42]=[C:39]([CH2:38][N:34]2[C:35]3[C:31](=[C:30]([C:43]([F:46])([F:44])[F:45])[C:29]([C:27]#[N:28])=[CH:37][CH:36]=3)[CH:32]=[CH:33]2)[N:40]=1
Reactant: N#Cc1ccc2c(ccn2CC(=N)NO)c1C(F)(F)F
Reactant: O=C(O)c1cc(C(F)(F)F)ccc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCCl
Product: N#Cc1ccc2c(ccn2Cc2noc(-c3cc(C(F)(F)F)ccc3F)n2)c1C(F)(F)F
Temperature: 80 °C
Reaction time: 1 h
Yield: 49.6 %

Procedure:
2-Fluoro-5-(trifluoromethyl)benzoic acid (0.016 g, 0.075 mmol) and EDCl (0.015 g, 0.078 mmol) were stirred in DCE (2 mL) for 5 min at rt and then 2-[5-cyano-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide (0.020 g, 0.071 mmol) was added. After 1 h at rt, the reaction was heated to 80° C. for 15 h. Direct purification (SiO2, EtOAc/hexanes) provided the title compound (0.016 g): MS (ESI): m/z 455 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([Cl:9])[C:5]([Cl:10])=[CH:4][N:3]=1.[N:11]1([C:17]2[CH:25]=[CH:24][C:20]([C:21](O)=O)=[CH:19][CH:18]=2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>O=P(Cl)(Cl)Cl>[Cl:10][C:5]1[C:6]([Cl:9])=[C:7]2[NH:8][C:21]([C:20]3[CH:19]=[CH:18][C:17]([N:11]4[CH2:16][CH2:15][O:14][CH2:13][CH2:12]4)=[CH:25][CH:24]=3)=[N:1][C:2]2=[N:3][CH:4]=1
Reactant: Nc1ncc(Cl)c(Cl)c1N
Reactant: O=C(O)c1ccc(N2CCOCC2)cc1
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1cnc2nc(-c3ccc(N4CCOCC4)cc3)[nH]c2c1Cl
Temperature: 105 °C
Yield: 20.5 %

Procedure:
2,3-Diamino-4,5-dichloropyridine (Example 206a) (0.10 g, 0.56 mmol) and 4-morpholin-4-ylbenzoic acid (0.12 g, 0.56 mmol) were dissolved in POCl3 (5 ml) and heated to 105° C. for 5 h. The excess of POCl3 was evaporated off and the residue was dissolved in EtOAc and aqueous K2CO3. The aqueous phase was extracted three times with EtOAc. The combined organic phases were washed with brine, dried (Na2SO4), evaporated in vacuo and the residue was purified by HPLC-C18. The product crystallized from the chromatography fraction and was filtered off and dried to yield a white powder (0.040 g, 20%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.CC([O:15][C@H:16]1[CH:20]=[CH:19][C@@H:18](O)[CH2:17]1)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:19]2[CH2:20][C@H:16]([OH:15])[CH:17]=[CH:18]2)=[C:4]([Cl:11])[N:3]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: CC(=O)O[C@H]1C=C[C@@H](O)C1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O[C@@H]1C=C[C@H](n2cnc3c(Cl)nc(Cl)nc32)C1
Reaction time: 0.08 h

Procedure:
2,6-Dichloropurine (10 g, 52.90 mmol), (1S,4R)-cis-4-acetoxy-2-cyclopenten-1-ol (10 g, 70.40 mmol), tris(dibenzylideneacetone)dipalladium(0) (3.20 g, 3.50 mmol) and polymer supported triphenylphosphine (3 mmol/g, 11.60 g, 35.00 mmol) are placed in an oven-dried flask under an atmosphere of argon. Dry deoxygenated THF (80 mL) is added and the reaction mixture is stirred gently for 5 minutes. Triethylamine (20 mL) is added and the reaction mixture is stirred at 50° C. The reaction is shown to be complete by LCMS after 1 hour. The reaction mixture is allowed to cool, filtered and the solvent is removed in vacuo. The title compound is obtained after purification by flash column chromatography (silica, dichloromethane/methanol 25:1).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:16]([OH:26])[CH2:17][C:18]3[C:23]([Cl:24])=[CH:22][N:21]=[CH:20][C:19]=3[Cl:25])[CH:9]=[CH:10][C:11]=2[O:12][CH:13]([F:15])[F:14])[CH2:3][CH2:2]1.[CH3:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[CH:35]=[C:34]([C@H:39]([CH3:43])[C:40](O)=[O:41])[CH:33]=[CH:32]2.Cl.C(N=C=NCCCN(C)C)C.O>CN(C=O)C.CN(C)C1C=CN=CC=1>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:16]([O:26][C:40](=[O:41])[CH:39]([C:34]3[CH:33]=[CH:32][C:31]4[C:36](=[CH:37][CH:38]=[C:29]([O:28][CH3:27])[CH:30]=4)[CH:35]=3)[CH3:43])[CH2:17][C:18]3[C:19]([Cl:25])=[CH:20][N:21]=[CH:22][C:23]=3[Cl:24])[CH:9]=[CH:10][C:11]=2[O:12][CH:13]([F:14])[F:15])[CH2:3][CH2:2]1
Reactant: OC(Cc1c(Cl)cncc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2cc(C(C)C(=O)OC(Cc3c(Cl)cncc3Cl)c3ccc(OC(F)F)c(OCC4CC4)c3)ccc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.9 %

Procedure:
Compound (3) (12.0 g) was dissolved in DMF (100 ml) then (S)-2-(6-methoxy-naphthalen-2-yl)-propionic acid (7.5 g), 4-dimethylaminopyridine (3.6 g), and 1-ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride (5.7 g) was added. After stirring at rt for 4 hours, water (1000 ml) is added. The mixture was extracted with EtOAc (500 ml×2), the combined organic layers are dried over sodium sulphate, and the solvent was removed by evaporation under reduced pressure to afford 17.0 g of an oil which is crystallized from EtOH thus obtaining 11.5 g of the title compound as mixture of diastereomers (11) and (13),
Reaction SMILES: [F:1][C:2]1[C:7]([NH:8][CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[C:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)[C:11]=2[F:25])=[C:6]([F:26])[CH:5]=[CH:4][C:3]=1[OH:27].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37].O>CN(C=O)C>[F:1][C:2]1[C:7]([NH:8][CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[C:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)[C:11]=2[F:25])=[C:6]([F:26])[CH:5]=[CH:4][C:3]=1[O:27][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37]
Reactant: CCOC(=O)CBr
Reactant: COc1cc(CNc2c(F)ccc(O)c2F)c(F)c(-c2cccc(F)c2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1ccc(F)c(NCc2cc(OC)cc(-c3cccc(F)c3)c2F)c1F
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 67.4 %

Procedure:
To a stirred solution of 2,4-difluoro-3-[[2-fluoro-3-(3-fluorophenyl)-5-methoxy-phenyl]methylamino]phenol (180 mg, 0.48 mmol, 1.0 eq) in DMF (4 mL) was added Cs2CO3 (233 mg, 0.72 mmol, 1.5 eq). The resulting mixture was stirred for 40 min at room temperature then ethyl bromoacetate (96 mg, 0.57 mmol, 1.2 eq) was added. The resulting mixture was stirred at room temperature for 2 h then water added and the aqueous layer extracted with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The crude residue was purified by chromatography (EtOAc:petroleum ether, 0:1 to 1:10) to give the title compound as an oil (150 mg, 68%).
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:10]=[C:11]([CH:24]=[CH:25][C:26]=1[F:27])[CH2:12][C:13]([N:15]([CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[CH2:16][CH3:17])=[O:14].[CH:28]([C@@H:30]1[C@@H:34]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:33][N:32]([C@H:41]([CH:54]2[CH2:59][CH2:58][CH2:57][CH2:56][CH2:55]2)[C:42]([O:44]CC2C=CC(OC)=CC=2)=[O:43])[CH2:31]1)=O>>[F:8][C:9]1[CH:10]=[C:11]([CH:24]=[CH:25][C:26]=1[F:27])[CH2:12][C:13]([N:15]([CH:18]1[CH2:23][CH2:22][N:21]([CH2:28][C@@H:30]2[C@@H:34]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH2:33][N:32]([C@H:41]([CH:54]3[CH2:59][CH2:58][CH2:57][CH2:56][CH2:55]3)[C:42]([OH:44])=[O:43])[CH2:31]2)[CH2:20][CH2:19]1)[CH2:16][CH3:17])=[O:14]
Reactant: CCN(C(=O)Cc1ccc(F)c(F)c1)C1CCNCC1
Reactant: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](c3ccccc3)[C@@H](C=O)C2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCN(C(=O)Cc1ccc(F)c(F)c1)C1CCN(C[C@H]2CN([C@@H](C(=O)O)C3CCCCC3)C[C@@H]2c2ccccc2)CC1
Yield: 54.4 %

Procedure:
The title compound was prepared from 4-(N-((3,4-difluorobenzyl)carbonyl)-N-ethylamino)piperidine trifluoroacetate (40 mg, 0.1 mmol, from Step A) and 2-(R)-(3-(R)-formyl-4-(S)-phenyl-pyrrolidin-1-yl)-2-(cyclohexyl)acetic acid, 4-(methoxy)benzyl ester (25 mg, 0.06 mmol, Aldehyde 5) according to the method described in Example 1, Step C to give 19 mg (54%) of the title compound. ESI-MS: 582.5 (M+H); HPLC A: 2.35 min.
Reaction SMILES: [C:1]([C:5]1[O:6][C:7]([CH3:12])=[C:8]([CH2:10]Cl)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[OH:13][C:14]1[C:22]2[CH:21]=[CH:20][S:19][C:18]=2[C:17]([CH:23]=[O:24])=[CH:16][CH:15]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CC(C)=O>[C:1]([C:5]1[O:6][C:7]([CH3:12])=[C:8]([CH2:10][O:13][C:14]2[C:22]3[CH:21]=[CH:20][S:19][C:18]=3[C:17]([CH:23]=[O:24])=[CH:16][CH:15]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=Cc1ccc(O)c2ccsc12
Reactant: Cc1oc(C(C)(C)C)nc1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: Cc1oc(C(C)(C)C)nc1COc1ccc(C=O)c2sccc12
Yield: 85.6 %

Procedure:
0.600 g of 2-tert-butyl-4-chloromethyl-5-methyl-oxazole (example 1, step b], 3.197 mmol) was dissolved in 12 ml of acetone and treated successively with 0.570 g of 4-hydroxy-benzo[b]thiophene-7-carbaldehyde (3.197 mmol), 1.146 g of Cs2CO3 (3.517 mmol), and 0.0265 g of KI (0.16 mmol). The mixture was then refluxed under an atmosphere of Ar. After cooling, the reaction mixture was poured onto crashed ice, extracted twice with AcOEt, the organic layer washed with water, dried over magnesium sulfate, and the solvents removed i.V. Flash chromatography (SiO2, hexane/AcOEt=8/2) yielded 0.901 g of the title compound as white crystals of mp. 119–200.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[CH2:7][N:8]=[C:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].C1COCC1.CN1C(=O)N(C)CCC1.[Li+].CC([N-]C(C)C)C.Br[CH2:46][C:47]1[CH:52]=[C:51]([O:53][CH3:54])[CH:50]=[CH:49][C:48]=1[F:55]>C1COCC1>[C:1]([O:5][C:6](=[O:22])[CH:7]([N:8]=[C:9]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH2:46][C:47]1[CH:52]=[C:51]([O:53][CH3:54])[CH:50]=[CH:49][C:48]=1[F:55])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CN=C(c1ccccc1)c1ccccc1
Reactant: COc1ccc(F)c(CBr)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: COc1ccc(F)c(CC(N=C(c2ccccc2)c2ccccc2)C(=O)OC(C)(C)C)c1
Yield: 80 %

Procedure:
t-Butylglycinate Schiff base 3 (136 mg, 0.46 mmol) in a mixture of dry THF-DMPU 60:40 (2.5 mL) at −78° C. was treated with a 2.0 M LDA solution (0.23 mL, 0.46 mmol) and the mixture was stirred for one h at the same temperature. 2-Fluoro-5-methoxybenzyl bromide (35, 100 mg, 0.46 mmol) in dry THF (2.5 mL) was added dropwise at −78° C. and then the mixture was stirred overnight at room temperature. The reaction was quenched with saturated aqueous ammonium chloride (10 mL), and the product was extracted with diethyl ether (2×15 mL). The combined organic layers were washed with saturated aqueous ammonium chloride (4×10 mL), dried over sodium sulfate, filtered and evaporated to give 40 as a crude yellow oil (110%). When examined, the pure product 40 was made in 80% yield (175 mg).
Reaction SMILES: [N+]([C:4]1[CH:21]=[C:20]([NH:22][CH2:23][C:24]2[N:35]=[C:34]3[C:27]([N:28]=[C:29]([NH:31][C:32]3=[O:33])[NH2:30])=[N:26][CH:25]=2)[CH:19]=[CH:18][C:5]=1[C:6](=[O:17])[NH:7][C@H:8]([C:14]([OH:16])=[O:15])[CH2:9][CH2:10][C:11]([OH:13])=[O:12])([O-])=O.NC1C=CC(C(O)=O)=C([F:46])C=1>>[F:46][C:4]1[CH:21]=[C:20]([NH:22][CH2:23][C:24]2[N:35]=[C:34]3[C:27]([N:28]=[C:29]([NH:31][C:32]3=[O:33])[NH2:30])=[N:26][CH:25]=2)[CH:19]=[CH:18][C:5]=1[C:6](=[O:17])[NH:7][C@H:8]([C:14]([OH:16])=[O:15])[CH2:9][CH2:10][C:11]([OH:13])=[O:12]
Reactant: Nc1nc2ncc(CNc3ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)c([N+](=O)[O-])c3)nc2c(=O)[nH]1
Reactant: Nc1ccc(C(=O)O)c(F)c1
Product: Nc1nc2ncc(CNc3ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)c(F)c3)nc2c(=O)[nH]1

Procedure:
The synthesis was done in analogy to the synthesis of 2′-nitrofolic acid following examples 1 to 4. In example 1 4-amino-2-fluoro-benzoic acid was used instead of 4-amino-2-nitrobenzoic acid. (HPLC purity: 97.5% area, m/z=460 [M+1]+, 1H-NMR (200 MHz, DMSO-d6) [ppm]: 8.65 (s, C(7)-H, 1H); 7.75 (t, N(8′)-H, 1H, exchangeable with D2O); 7.51 (t, C(3′H), 1H); 7.20 (t, N(10)-H, 1H, exchangeable with D2O); 7.03 (bs, NH2, 2H, exchangeable with D2O); 6.50 (m, C(5′)-H, (C(6′)-H, 2H); 4.48 (d, C(6)H2, 2H); 4.31 (m, C(α)-H, 1H); 2.28 (m, C(β)-H2, 2H); 1.96 (m, C(γ)-H2, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:13])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[C:14]1([CH3:23])[CH:19]=[CH:18][CH:17]=[C:16](B(O)O)[CH:15]=1.C([O-])([O-])=O.[K+].[K+].CCO>[Pd].O>[F:10][C:9]([F:12])([F:11])[CH:8]([C:5]1[CH:6]=[CH:7][CH:2]=[CH:3][C:4]=1[C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([CH3:23])[CH:15]=1)[OH:13]
Reactant: OC(c1ccc(Br)cc1)C(F)(F)F
Reactant: Cc1cccc(B(O)O)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: Cc1cccc(-c2ccccc2C(O)C(F)(F)F)c1
Temperature: 80 °C
Yield: 71.5 %

Procedure:
1-(4-Bromophenyl)-2,2,2-trifluoroethanol (0.13 g, 0.525 mmol), m-tolylboronic acid (0.1 g, 0.736 mmol), Fibercat (4.28% Pd, 47 mgs, 0.0157 mmol Pd), K2CO3 (0.22 g, 1.576 mmol), EtOH (3 mls), and H2O (0.5 mls) were combined and heated at 80° C. for 4 hours. The reaction was shown complete by TLC(CH2Cl2). The mixture was cooled, filtered, concentrated, slurried in CH2Cl2, and chromatographed over silica gel (CH2Cl2) to give 0.1 g of 2,2,2-trifluoro-1-(3′-methylbiphenyl-2-yl)ethanol. Yield: 72%.
Reaction SMILES: [CH2:1]([P:3]([O:10]CCCC)([CH2:5][CH2:6][C:7]([OH:9])=[O:8])=[O:4])[CH3:2].O>C(O)CCC.O>[CH2:1]([P:3]([OH:10])([CH2:5][CH2:6][C:7]([OH:9])=[O:8])=[O:4])[CH3:2]
Reactant: CCCCOP(=O)(CC)CCC(=O)O
Solvent: O
Solvent: CCCCO
Product: CCP(=O)(O)CCC(=O)O
Reaction time: 4 h
Yield: 93 %

Procedure:
444 g (2 mol) of 3-(ethylbutoxyphosphinyl)propionic acid (produced as in Example 13) are initially charged in a 1 l five-neck flask equipped with thermometer, reflux condenser, high-performance stirrer and dropping funnel. At 160° C., during 4 h, 500 ml of water are metered in and a butanol-water mixture is distilled off. The solid residue is recrystallized from acetone to obtain 309 g (93% of theory) of 3-(ethylhydroxyphosphinyl)propionic acid as colorless solid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20]([NH2:23])(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1.[C:34](OC(=O)C)(=[O:36])[CH3:35]>C(O)(=O)C.CCOC(C)=O>[C:34]([NH:23][S:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:10]2[N:9]=[C:8]([C:6]3[CH:5]=[C:4]([C:24]4[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:26][CH:25]=4)[CH:3]=[C:2]([CH3:1])[N:7]=3)[CH:13]=[CH:12][CH:11]=2)[CH:15]=1)(=[O:21])=[O:22])(=[O:36])[CH3:35]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(N)(=O)=O)c3)n2)n1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(=O)NS(=O)(=O)c1cccc(-c2cccc(-c3cc(-c4ccc(C(F)(F)F)cc4)cc(C)n3)n2)c1
Temperature: 130 °C
Reaction time: 72 h
Yield: 88.7 %

Procedure:
A mixture of 3-[6′-methyl-4′-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl-6-yl]-benzenesulfonamide (example 266) (300 mg, 0.639 mmol) and acetic anhydride (2.42 mL, 25.6 mmol) in acetic acid (5 mL) was stirred at 130° C. for 3 days. Cooled to rt, diluted with EtOAc, extracted with sat. NaHCO3-sol., dried over Na2SO4, filtered off and evaporated totally to give a crude product, which was purified by silica gel column chromatography with n-heptane/ethyl acetate followed by trituration with diethyl ether/n-heptane to give the title compound (290 mg, 88%) as a white solid. MS (ISP) 512.0 [(M+H)+]; mp 244° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]=[N:13][N:14]([CH:15]4[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]4)[C:5]=3[C:4]=2[N:3]=1.Cl[CH2:22][C:23]([N:25]([CH3:27])[CH3:26])=[O:24].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]=[N:13][N:14]([CH:15]4[CH2:20][CH2:19][N:18]([CH2:22][C:23]([N:25]([CH3:27])[CH3:26])=[O:24])[CH2:17][CH2:16]4)[C:5]=3[C:4]=2[N:3]=1
Reactant: CN(C)C(=O)CCl
Reactant: Clc1ccc2ncc3nnn(C4CCNCC4)c3c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)C(=O)CN1CCC(n2nnc3cnc4ccc(Cl)nc4c32)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 8-chloro-1-(piperidin-4-yl)-1H-[1,2,3]triazolo[4,5-c][1,5]naphthyridine (100 mg, 0.35 mmol), 2-chloro-N,N-dimethylacetamide (46 mg, 0.38 mmol), and K2CO3 (97 mg, 1.04 mmol) in DMF (5 mL) was stirred at r.t. overnight. The solvent was removed, and the residue was extracted with EtOAc (3×10 mL). The combined organic layers were dried over Na2SO4, and concentrated to afford crude 2-(4-(8-chloro-1H-[1,2,3]triazolo[4,5-c][1,5]naphthyridin-1-yl)piperidin-1-yl)-N,N-dimethylacetamide, which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:13])[CH2:10][CH2:11][CH3:12])[CH:5]=[CH:6][CH:7]=1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18](O)=[O:19].C1C=CC2N(O)N=NC=2C=1.C(Cl)Cl>CC#N.C(Cl)Cl>[C:9]([NH:8][C:4]1[CH:3]=[C:2]([NH:1][C:18](=[O:19])[C:17]2[CH:21]=[CH:22][CH:23]=[C:15]([Cl:14])[CH:16]=2)[CH:7]=[CH:6][CH:5]=1)(=[O:13])[CH2:10][CH2:11][CH3:12]
Reactant: CCCC(=O)Nc1cccc(N)c1
Reactant: O=C(O)c1cccc(Cl)c1
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: ClCCl
Product: CCCC(=O)Nc1cccc(NC(=O)c2cccc(Cl)c2)c1

Procedure:
N-(3-Aminophenyl)butyramide (30 mg, 0.168 mmol), 3-chlorobenzoic acid (39.5 mg, 0.252 mmol), HOBt (28.4 mg, 0.185 mmol), and silica-supported DCC (from Silicycle Inc., 362 mg, 0.337 mmol) were added to a 13×100 mm test tube with stir bar. The tube was sealed with a rubber septum and dry DCM (3 mL) was added, then the reaction was stirred for 15 h. 50% CH3CN/DCM (4 mL) was then added, followed by silica-supported trimethylammonium carbonate (from Silicycle Inc., 534 mg, 0.337 mmol). The mixture was stirred for 1 h, then filtered through Celite and washed with 50% CH3CN/DCM (4 mL) and concentrated. The crude solid was redissolved with DCM and purified by column chromatography (EtOAc/hexanes gradient) to yield a white solid after precipitating from hexanes (39 mg, 73%). LRMS (ESI+) (M+H): 317.22.
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:3]=1[C:4]([NH:6][CH2:7][C:8]([NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]1)=[O:9])=[O:5].Cl>CO.O1CCOCC1>[NH2:1][C:2]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:3]=1[C:4]([NH:6][CH2:7][C:8]([NH:10][CH2:11][CH:12]1[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]1)=[O:9])=[O:5]
Reactant: CC(C)(C)OC(=O)N1CCC(CNC(=O)CNC(=O)c2cc(Cl)ccc2N)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Nc1ccc(Cl)cc1C(=O)NCC(=O)NCC1CCNCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 95.4 %

Procedure:
To a solution of 4-[{(N-(2-amino-5-chlorobenzoyl)glycyl)amino}methyl]-1-(tert-butoxycarbonyl)piperidine (1.63 g, 3.84 mmol) in methanol (20 mL) was added 4 N HCl in dioxane (9.5 mL). The solution was stirred at room temperature for 6 h. The reaction mixture was concentrated and 2 N aqueous NaOH solution (20 mL) was added. The mixture was extracted with dichloromethane (20 mL×3), and the combined extracts were dried over sodium sulfate, filtered and concentrated to give 4-[{(N-(2-amino-5-chlorobenzoyl)glycyl)amino}methyl]piperidine (1.19 g, 95%): 1H NMR (CDCl3, 270 MHz) δ 1.10-1.76 (m, 4 H), 2.55 (td, J=2.4 and 12.2 Hz, 2 H), 3.00-3.10 (m, 2 H), 3.17 (t, J=6.2 Hz, 2 H), 3.48 (s, 2 H), 4.03 (d, J=4.9 Hz, 2 H), 5.50 (br. s, 2 H), 6.11-6.23 (m, 1 H), 6.60 (d, J=8.8 Hz, 1 H), 6.85-7.02 (m, 1 H), 7.15 (dd, J=2.7 and 8.8 Hz, 1 H), 7.38 (d, J=2.4 Hz, 1 H); ESI/MS m/e 325.2 (C15H21ClN4O2).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[C:6](=[O:22])[CH2:5]1)(=[O:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1.[C:38](OCC)(=[O:44])[C:39](OCC)=[O:40]>CN(C=O)C>[F:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][N:7]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[N:4]3[C:1](=[O:3])[CH:2]=[C:38]([OH:44])[C:39]([OH:40])=[C:5]3[C:6]2=[O:22])=[CH:20][CH:19]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)N1CC(=O)N(Cc2ccc(F)cc2)c2ccccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=c1c2c(O)c(O)cc(=O)n2c2ccccc2n1Cc1ccc(F)cc1
Reaction time: 0.5 h

Procedure:
To a cold (0° C.) solution of 4-acetyl-1-(4-fluorobenzyl)-3,4-dihydro-quinoxalin-2(1H)-one (0.15 g, 0.52 mmol) in DMF (5 mL) under an atmosphere of nitrogen, a solution of lithium bis(trimethylsilyl)amide in THF (0.57 mL, 0.57 mmol) was added and stirred at the temperature for 30 min. The resultant solution was treated with diethyl oxalate (0.078 mL, 0.57 mmol), and stirred at room temperature overnight. The resultant mixture was then treated with additional lithium bis(trimethylsilyl)amide in THF (1.6 mL, 1.6 mmol) and stirred at room temperature for 6 h. The product mixture was concentrated under vacuum, and the residue partitioned between aqueous HCl and dichloromethane. The organic extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to HPLC purification on C-18 stationary phase eluted with water/acetonitrile/TFA mobile phase. Collection and lyophilization of appropriate fractions provided the title compound as white solid.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N+:2]=1[O-].P([C:20]#[N:21])(=O)(OCC)OCC>C(#N)C>[C:1]1([C:20]#[N:21])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: CCOP(=O)(C#N)OCC
Reactant: [O-][n+]1ccc2ccccc2c1
Solvent: CC#N
Product: N#Cc1nccc2ccccc12

Procedure:
To a stirred solution of isoquinoline 2-oxide (2-Im-9, 5.8 g) in 140 mL of acetonitrile, diethyl phosphoro-cyanidate (1.5 eq) was added under argon followed by slow addition of TEA (3.0 eq). The mixture was refluxed for 18 h and then extracted with DCM. The organic layer was concentrated and purified by silica column chromatography to give isoquinoline-1-carbonitrile (3-Im-9).