Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-].[I-].[CH3:3][N+:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([O:12][C:13]2[CH:30]=[CH:29][C:28]3[C@@H:27]4[C@H:18]([C@H:19]5[C@@:23]([CH2:25][CH2:26]4)([CH3:24])[C@@H:22]([O:31][C:32]([C:34]4[CH:35]=[N+:36]([CH3:40])[CH:37]=[CH:38][CH:39]=4)=[O:33])[CH2:21][CH2:20]5)[CH2:17][CH2:16][C:15]=3[CH:14]=2)=[O:11])[CH:5]=1.C1(CN2C=CC(C(N)=O)=CC2)C=CC=CC=1>C(#N)C.C(Cl)Cl>[CH3:3][N:4]1[CH:9]=[CH:8][CH2:7][C:6]([C:10]([O:12][C:13]2[CH:30]=[CH:29][C:28]3[C@@H:27]4[C@H:18]([C@H:19]5[C@@:23]([CH2:25][CH2:26]4)([CH3:24])[C@@H:22]([O:31][C:32]([C:34]4[CH2:39][CH:38]=[CH:37][N:36]([CH3:40])[CH:35]=4)=[O:33])[CH2:21][CH2:20]5)[CH2:17][CH2:16][C:15]=3[CH:14]=2)=[O:11])=[CH:5]1
Reactant: C[n+]1cccc(C(=O)Oc2ccc3c(c2)CC[C@@H]2[C@@H]3CC[C@]3(C)[C@@H](OC(=O)c4ccc[n+](C)c4)CC[C@@H]23)c1
Agent: NC(=O)C1=CCN(Cc2ccccc2)C=C1
Agent: [I-]
Solvent: CC#N
Solvent: ClCCl
Product: CN1C=CCC(C(=O)Oc2ccc3c(c2)CC[C@@H]2[C@@H]3CC[C@]3(C)[C@@H](OC(=O)C4=CN(C)C=CC4)CC[C@@H]23)=C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
One gram (1.31 mmol) of the product of Example 71 was dissolved in 100 mL of dry acetonitrile. To that solution, which was flushed with nitrogen, 0.28 g (1.31 mmol) of 1-(phenylmethyl)-4-(aminocarbonyl)-1,2-dihydropyridine was added, and the reaction mixture was stirred at 0° C. for 1 hour. Removal of the solvent under reduced pressure afforded a solid, which was suspended in methylene chloride and removed by filtration. The filtrate was chromatographed several times on a neutral alumina column prepared with methylene chloride. Purification and evaporation of the solvent in vacuo gave a solid foam. The product had the formula ##STR104## as confirmed by UV, NMR and elemental analyses.
Reaction SMILES: [I-].[C:2]([C:5]1[CH:10]=[C:9]([I:11])[CH:8]=[CH:7][NH+:6]=1)([OH:4])=O.[N:12]1([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[I:11][C:9]1[CH:8]=[CH:7][N:6]=[C:5]([C:2]([N:15]2[CH2:16][CH2:17][CH2:18][N:12]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:13][CH2:14]2)=[O:4])[CH:10]=1
Reactant: O=C(O)c1cc(I)cc[nH+]1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [I-]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCCN(C(=O)c2cc(I)ccn2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-carboxy-4-iodopyridinium iodide (1 eq) in DMF were added tert-butyl 1-homopiperazinecarboxylate (2.05 eq), HBTU (2.05 eq) and DIPEA (2.05 eq) and the mixture was stirred overnight at RT. The reaction mixture was diluted with DCM and washed with 0.5N HCl solution and brine. The organic phase was dried (Na2SO4) and concentrated under reduced pressure. The resulting crude was used as such in the next step without purification. MS (ES) C16H22IN3O3 requires: 431, found: 432 (M+H)+.
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[C:10]([C:12]([OH:14])=O)[C:9]([C:15]([F:18])([F:17])[F:16])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][O:20][CH2:21][CH2:22][N:23]([CH3:31])[C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][N:25]=1>>[CH3:19][O:20][CH2:21][CH2:22][N:23]([CH3:31])[C:24]1[N:25]=[CH:26][C:27]([NH:30][C:12]([C:10]2[C:9]([C:15]([F:18])([F:17])[F:16])=[N:8][N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:11]=2)=[O:14])=[CH:28][CH:29]=1
Reactant: COCCN(C)c1ccc(N)cn1
Reactant: O=C(O)c1cn(-c2ccccc2)nc1C(F)(F)F
Product: COCCN(C)c1ccc(NC(=O)c2cn(-c3ccccc3)nc2C(F)(F)F)cn1

Procedure:
With a procedure similar to example 16 above, 1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide was prepared from 1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid and N2-(2-methoxy-ethyl)-N2-methyl-pyridine-2,5-diamine. LCMS calcd for C20H20F3N5O2 (m/e) 419, obsd 420 (M+H). The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[NH:25]1[CH2:30][CH2:29][CH:28]([CH2:31][CH2:32][OH:33])[CH2:27][CH2:26]1>CN(C=O)C.CS(C)=O.CO>[OH:33][CH2:32][CH2:31][CH:28]1[CH2:29][CH2:30][N:25]([C:2]2[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]3[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=3)[CH:3]=2)[CH2:26][CH2:27]1
Reactant: OCCC1CCNCC1
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Solvent: CS(C)=O
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(N3CCC(CCO)CC3)n2n1
Temperature: 25 °C
Yield: 58.4 %

Procedure:
A solution of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2F, 86 mg, 0.25 mmol) and 2-(piperidin-4-yl)ethanol (100 mg, 0.75 mmol) in DMF (1.0 mL) was stirred at 100° C. for 2 h. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC (30-35% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white solid (63.9 mg, 58%). Melting point (234.0-234.1° C.). 1H NMR (DMSO-d6) δ: 10.93 (s, 1H), 8.00 (d, J=8.6 Hz, 2H), 7.61 (d, J=8.6 Hz, 2H), 7.20 (s, 1H), 6.20 (s, 1H), 4.51 (d, J=12.6 Hz, 2H), 3.50 (t, J=6.4 Hz, 2H), 3.07 (t, J=11.5 Hz, 2H), 2.38 (s, 3H), 1.84 (d, J=12.9 Hz, 2H), 1.68-1.81 (m, 1H), 1.46 (s, 6H), 1.41-1.45 (m, 2H), 1.29-1.41 (m, 2H); ESI-MS: m/z 438.3 (M+H)+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH:7]([C:10]1[CH:11]=[C:12]([CH:16]=[C:17]([CH:21]([CH3:23])[CH3:22])[C:18]=1[O:19][CH3:20])[C:13]([OH:15])=O)([CH3:9])[CH3:8].[CH2:24]([C:31]1[S:35][C:34]2[CH:36]=[CH:37][CH:38]=[CH:39][C:33]=2[CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[Sn](Cl)(Cl)(Cl)Cl>ClCCl.O.CN(C=O)C>[CH2:24]([C:31]1[S:35][C:34]2[CH:36]=[CH:37][CH:38]=[CH:39][C:33]=2[C:32]=1[C:13]([C:12]1[CH:16]=[C:17]([CH:21]([CH3:23])[CH3:22])[C:18]([O:19][CH3:20])=[C:10]([CH:7]([CH3:8])[CH3:9])[CH:11]=1)=[O:15])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: c1ccc(Cc2cc3ccccc3s2)cc1
Reactant: COc1c(C(C)C)cc(C(=O)O)cc1C(C)C
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1c(C(C)C)cc(C(=O)c2c(Cc3ccccc3)sc3ccccc23)cc1C(C)C
Temperature: -78 °C

Procedure:
A drop of DMF was added to a solution of oxalyl chloride (1.4 mL, 16.2 mmmol), 3,5-diisopropyl-4-methoxybenzoic acid (4.0 g, 14.7 mmol) in dichloromethane under a dry nitrogen atmosphere. After 4 h the solvent was removed and the resulting solid was triturated with petroleum ether and dried in vacuo. To this solid was added 2-benzyl-benzo[b]thiophene (3.32 g, 13.4 mmol) and dichloromethane (75 mL). The resulting solution was stirred under a dry nitrogen atmospher and cooled to -78° C. Tin tetrachloride (3.44 mL, 29.48 mmol) was added dropwise over a 20 minute period. The reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was added to water and extracted with ether. The ether extract was washed with water and brine. Silica gel was added and the solvent was removed. The adsorbate was flash chromatographed (gradient, petroleum ether to 95:5 petroleum ether:ethyl acetate). The solvent was removed and the solid was triturated with ether to give the title compound as a a white solid (3.68 g, 62%): mp 124-125° C.; NMR (CDCl3); δ 7.75 (ddd, J=8, 2, 1 Hz, 1H), 7.64 (s, 2H), 7.48 (ddd, J=8, 2, 1, 1H), 7.30-7.19 (m, 7H), 4.22 (s, 2H), 3.80 (s, 3H) 3.35 (septuplet, J=7 Hz, 2H), 1.19 (d, J=7 Hz, 12H); MS (+FAB): 443 (100%, M+H); Anal. Calc. for C29H30O2S: C, 78.69, H, 6.83, N, 0.00. Found: C, 78.57, H, 6.88, N, 0.14.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:20].[N:21]1([C:27]2[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>O1CCCC1>[CH3:19][O:18][C:14]1[CH:13]=[C:12]([C:8]2[CH:7]=[C:6]3[C:11]([C:3](=[CH:2][NH:33][C:30]4[CH:29]=[CH:28][C:27]([N:21]5[CH2:22][CH2:23][O:24][CH2:25][CH2:26]5)=[CH:32][CH:31]=4)[C:4](=[O:20])[NH:5]3)=[CH:10][CH:9]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: COc1cccc(-c2ccc3c(c2)NC(=O)C3=CO)c1
Reactant: Nc1ccc(N2CCOCC2)cc1
Solvent: C1CCOC1
Product: COc1cccc(-c2ccc3c(c2)NC(=O)C3=CNc2ccc(N3CCOCC3)cc2)c1
Temperature: 25 °C

Procedure:
The named compound is prepared by refluxing 0.020 gms E & Z 3-hydroxymethylene-6-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one with 0.020 gms. 4-morpholin-4-yl-phenylamine in tetrahydrofuran (0.33 mL) for 2 days. Following cooling to room temperature, solvent evaporation in vacuo, trituration with isopropanol and filtration the reaction yields the named compound as a solid in the amount of 15.7 mg.
Reaction SMILES: [Cl-].[Cl-].CN([CH:6]=[C:7]([CH:12]=[N+](C)C)[CH:8]=[N+](C)C)C.[NH2:16][C:17]1[CH:18]=[C:19]([NH:23][C:24](=[O:26])[CH3:25])[CH:20]=[CH:21][CH:22]=1.C(O)(=[O:29])C>>[CH:12]([C:7]1[CH:6]=[N:16][C:17]2[C:22]([CH:8]=1)=[CH:21][CH:20]=[C:19]([NH:23][C:24](=[O:26])[CH3:25])[CH:18]=2)=[O:29]
Reactant: CC(=O)Nc1cccc(N)c1
Reactant: CN(C)C=C(C=[N+](C)C)C=[N+](C)C
Reactant: CC(=O)O
Agent: [Cl-]
Product: CC(=O)Nc1ccc2cc(C=O)cnc2c1
Temperature: 140 °C
Reaction time: 1 h
Yield: 86.9 %

Procedure:
To a 6 w/w % acetic acid solution of 2-dimethylaminomethylene-1,3-bis(dimethyliminio)propane dichloride (3.2 mL, 0.75 mmol) was added N-(3-aminophenyl)acetamide (75 mg, 0.5 mmol). The mixture was refluxed at an external bath temperature of 140° C. for 2.5 hours, and the reaction mixture was cooled to room temperature and concentrated under reduced pressure. Water (3.2 mL) was added to the concentrated residue and the resulting mixture was stirred at room temperature for 1 hour. Precipitated crystals were collected by filtration, washed three times with water (1 mL) and dried under reduced pressure to obtain N-(3-formylquinolin-7-yl)acetamide (93 mg, yield: 86.9%) as white crystals.
Reaction SMILES: [Cl:1][CH:2]([C:5]1[NH:13][C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:7]2[N:6]=1)[CH2:3][CH3:4].[C:14]1([P:20]([C:27]2C=C[CH:30]=[CH:29][CH:28]=2)[C:21]2C=C[CH:24]=[CH:23][CH:22]=2)C=C[CH:17]=[CH:16][CH:15]=1>CN(C)C=O.C(#N)C>[Cl-:1].[CH2:27]([P+:20]([CH2:14][CH2:15][CH2:16][CH3:17])([CH2:21][CH2:22][CH2:23][CH3:24])[CH:2]([C:5]1[NH:13][C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:7]2[N:6]=1)[CH2:3][CH3:4])[CH2:28][CH2:29][CH3:30]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CCC(Cl)c1nc2cccnc2[nH]1
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCCC[P+](CCCC)(CCCC)C(CC)c1nc2cccnc2[nH]1
Product: [Cl-]
Temperature: 90 °C

Procedure:
8.66 g of 2-(1-chloropropyl)-3H-imidazo[4,5-b]pyridine (compound B3) are suspended in 18 ml of N,N-dimethylformamide and 61 ml of acetonitrile. 6.3 ml of triphenylphosphine are added at 40° C. and the mixture is heated to 90° C. for 16 h. The mixture is concentrated to dryness to give 11.9 g of the title compound as an oil, which is used as obtained. MS: 362.2 (M+). TLC: Rf=0.2640.43 (dichloromethane/methanol 10:1).
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][CH2:4][CH2:5][CH3:6].C([Li])CCC.[CH2:31]([C:40]1[CH:47]=[CH:46][C:43]([CH:44]=O)=[CH:42][CH:41]=1)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]>O1CCCC1.CCCCCC>[CH2:31]([C:40]1[CH:47]=[CH:46][C:43]([CH:44]=[CH:2][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:42][CH:41]=1)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCCCCCCc1ccc(C=O)cc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCC=Cc1ccc(CCCCCCCCC)cc1
Reaction time: 0.5 h

Procedure:
A suspension of 13.9 g of pentyltriphenylphosphonium bromide in 150 ml of tetrahydrofuran is cooled to -20° under argon, 21.2 ml of 1.6M butyllithium solution in hexane are added within a period of 5 minutes and the whole is stirred for a further 30 minutes at 0°-10°. 6 g of 4-nonylbenzaldehyde in 40 ml of tetrahydrofuran are added dropwise over a period of 30 minutes to the mixture, which has been cooled to from -60° to -70°. The reaction mixture is allowed to warm spontaneously to 0°-10°, stirred at this temperature for a further 45 minutes and concentrated by evaporation. The residue is taken up in hexane/ethyl acetate (1:) and filtered over silica gel. The filtrate is concentrated by evaporation and chromatographed on silica gel with hexane. The title compound (mixture of cis- and trans-isomers) is obtained in the form of a colourless oil, which is used directly in the next stage.
Reaction SMILES: CS(N)(=O)=O.[N:6]1([S:10]([NH2:13])(=[O:12])=[O:11])[CH2:9][CH2:8][CH2:7]1.C(C1(COC2C(C3CC3)=CC(C(O)=O)=C(F)C=2)C2CC3CC(CC1C3)C2)#N.[Cl:41][C:42]1[C:43]([O:52][CH2:53][C:54]2([C:64]#[N:65])[CH:61]3[CH2:62][CH:57]4[CH2:58][CH:59]([CH2:63][CH:55]2[CH2:56]4)[CH2:60]3)=[CH:44][C:45]([F:51])=[C:46]([CH:50]=1)[C:47](O)=[O:48]>>[N:6]1([S:10]([NH:13][C:47](=[O:48])[C:46]2[CH:50]=[C:42]([Cl:41])[C:43]([O:52][CH2:53][C:54]3([C:64]#[N:65])[CH:55]4[CH2:63][CH:59]5[CH2:58][CH:57]([CH2:62][CH:61]3[CH2:60]5)[CH2:56]4)=[CH:44][C:45]=2[F:51])(=[O:12])=[O:11])[CH2:9][CH2:8][CH2:7]1
Reactant: NS(=O)(=O)N1CCC1
Reactant: N#CC1(COc2cc(F)c(C(=O)O)cc2Cl)C2CC3CC(C2)CC1C3
Agent: CS(N)(=O)=O
Agent: N#CC1(COc2cc(F)c(C(=O)O)cc2C2CC2)C2CC3CC(C2)CC1C3
Product: N#CC1(COc2cc(F)c(C(=O)NS(=O)(=O)N3CCC3)cc2Cl)C2CC3CC(C2)CC1C3

Procedure:
Following the procedure as described in Example 332 Step 7 and making non-critical variations to replace methanesulfonamide with azetidine-1-sulfonamide and to replace 4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid with 5-chloro-4-((2-cyanoadamantan-2-yl)methoxy)-2-fluorobenzoic acid, the title compound was obtained following purification by reverse-phase HPLC as a colorless powder (0.037 g, 18%): 1H NMR (300 MHz, DMSO-d6) δ 11.86 (br s, 1H), 7.78 (d, J=7.4 Hz, 1H), 7.41 (d, J=12.2 Hz, 1H), 4.54 (s, 2H), 4.02 (t, J=7.7, 7.7 Hz, 4H), 2.17-2.07 (m, 6H), 1.98-1.78 (m, 6H), 1.70-1.61 (m, 4H); MS (ES−) m/z 480.1, 482.1 (M−1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2/[CH:14]=[CH:15]/[C:16]([NH:18][C:19]2[CH:33]=[CH:32][C:22]([CH2:23][C:24]3[S:25][CH:26]=[C:27]([C:29]([OH:31])=O)[N:28]=3)=[CH:21][CH:20]=2)=[O:17])=[CH:4][CH:3]=1.Cl.C([N:37]=C=NCCCN(C)C)C.CN(C)C=O>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2/[CH:14]=[CH:15]/[C:16]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([CH2:23][C:24]3[S:25][CH:26]=[C:27]([C:29]([NH2:37])=[O:31])[N:28]=3)=[CH:32][CH:33]=2)=[O:17])=[CH:4][CH:3]=1
Reactant: Cn1ncc(/C=C/C(=O)Nc2ccc(Cc3nc(C(=O)O)cs3)cc2)c1-c1ccc(F)cc1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ncc(/C=C/C(=O)Nc2ccc(Cc3nc(C(N)=O)cs3)cc2)c1-c1ccc(F)cc1
Yield: 87.7 %

Procedure:
A mixture of 2-[4-({(2E)-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]prop-2-enoyl}amino)benzyl]-1,3-thiazole-4-carboxylic acid (0.24 g), a 1-hydroxy-1H-1,2,3-benzotriazole ammonia complex (0.12 g), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.15 g) and N,N-dimethylformamide (5 mL) was stirred at room temperature for 3 days. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 0.1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give 2-[4-({(2E)-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]prop-2-enoyl}amino)benzyl]-1,3-thiazole-4-carboxamide as colorless crystals (0.21 g, yield 88%). Recrystallization thereof from acetone-hexane gave colorless prism crystals. melting point: 159-160° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][C:15]2[O:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:18][N:19]=2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:34]2[CH:39]=[CH:38][C:37]([C:40]3([C:43]([NH:45][S:46]([CH3:49])(=[O:48])=[O:47])=[O:44])[CH2:42][CH2:41]3)=[CH:36][CH:35]=2)O1>>[CH3:13][C:10]1[C:9]([NH:14][C:15]2[O:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:18][N:19]=2)=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:34]3[CH:35]=[CH:36][C:37]([C:40]4([C:43]([NH:45][S:46]([CH3:49])(=[O:48])=[O:47])=[O:44])[CH2:42][CH2:41]4)=[CH:38][CH:39]=3)=[CH:3][CH:4]=2)[O:12][N:11]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1Nc1nnc(-c2ccccc2)o1
Reactant: CC1(C)OB(c2ccc(C3(C(=O)NS(C)(=O)=O)CC3)cc2)OC1(C)C
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)NS(C)(=O)=O)CC4)cc3)cc2)c1Nc1nnc(-c2ccccc2)o1

Procedure:
Prepared according to the procedure described in Example 94, Step 3, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-(5-phenyl-[1,3,4]oxadiazol-2-yl)-amine and N-{1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarbonyl}-methanesulfonamide.
Reaction SMILES: [CH:1](=O)[CH3:2].C(O)(=O)C.[NH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15](=[O:39])[C@@H:16]([N:18]2[CH2:22][CH2:21][C@H:20]([NH:23][S:24]([C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[C:32]([Cl:37])[CH:33]=4)[CH:28]=3)(=[O:26])=[O:25])[C:19]2=[O:38])[CH3:17])[CH2:10]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.C([N+](CC)(CC)CC)C>C(Cl)Cl>[Cl:37][C:32]1[CH:33]=[C:34]2[C:29](=[CH:30][CH:31]=1)[CH:28]=[C:27]([S:24]([NH:23][C@H:20]1[CH2:21][CH2:22][N:18]([C@@H:16]([CH3:17])[C:15]([N:11]3[CH2:12][CH2:13][CH2:14][CH:9]([NH:8][CH2:1][CH3:2])[CH2:10]3)=[O:39])[C:19]1=[O:38])(=[O:26])=[O:25])[CH:36]=[CH:35]2
Reactant: C[C@@H](C(=O)N1CCCC(N)C1)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC[N+](CC)(CC)CC
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCNC1CCCN(C(=O)[C@H](C)N2CC[C@H](NS(=O)(=O)c3ccc4cc(Cl)ccc4c3)C2=O)C1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
To a solution of acetaldehyde (0.041 ml from a stock solution made up from 0.0127 l acetaldehyde dissolved in 1 ml DCM)) in dry DCM (0.4 ml) treated with acetic acid (0.1 ml from a stock solution made up from 0.0054 ml acetic acid dissolved in 1 ml DCM) was added N-{(3S)-1-[(1S)-2-(3-aminopiperidin-1-yl)-1-methyl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-6-chloronaphthalene-2-sulfonamide [Example 365] (0.045 g) followed by tetraethylammonium triacetoxyborohydride (0.005 g). The mixture was stirred at room temperature, under nitrogen, for 60 h. DCM (1 ml) was added and the resultant solution washed with saturated sodium bicarbonate (1 ml) in a hydrophobic frit. The solvent was concentrated under reduced pressure and the residue purified by mass directed preparative h.p.l.c. to give the title compound (0.8 mg) as an oil.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][NH:10][CH:11]=[O:12])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[CH3:13][O:14][C:15](=[O:18])[CH2:16]Cl>>[CH3:13][O:14][C:15](=[O:18])[CH2:16][N:10]([CH2:9][P:4]([O:3][CH2:1][CH3:2])([O:5][CH2:6][CH3:7])=[O:8])[CH:11]=[O:12]
Reactant: CCOP(=O)(CNC=O)OCC
Reactant: COC(=O)CCl
Product: CCOP(=O)(CN(C=O)CC(=O)OC)OCC

Procedure:
The process in the third step of the process of the invention comprises reacting diethyl-N-(formyl)aminomethylphosphonate with methylchloroacetate in the presence of a proton-extracting base and a suitable solvent to produce N-(diethylphosphonomethyl)-N-(formyl)glycine methyl ester.
Reaction SMILES: II.C(O[C@@H:7]1[O:19][C@H:18]([CH2:20][O:21]C(=O)C)[C@@H:13]([O:14]C(=O)C)[C@H:8]1[O:9]C(=O)C)(=O)C.[NH:25]([C:32]1[CH:37]=[C:36]([Cl:38])[N:35]=[C:34]2[NH:39][CH:40]=[N:41][C:33]=12)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CO>[NH:25]([C:32]1[CH:37]=[C:36]([Cl:38])[N:35]=[C:34]2[N:39]([C@@H:7]3[O:19][C@H:18]([CH2:20][OH:21])[C@@H:13]([OH:14])[C@H:8]3[OH:9])[CH:40]=[N:41][C:33]=12)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: Clc1cc(Nc2ccccc2)c2nc[nH]c2n1
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: II
Solvent: CO
Product: OC[C@H]1O[C@@H](n2cnc3c(Nc4ccccc4)cc(Cl)nc32)[C@H](O)[C@@H]1O
Temperature: 155 °C
Reaction time: 2 h
Yield: 20 %

Procedure:
After a crystal of iodine was added to an intimate mixture of 1,2,3,5-tetra-O-acetyl-β-D-ribofuranose (5.2 g, 16 mMol) and 7-anilino-5-chloro-3H-imidazo[4,5-b]pyridine (4.0 g, 16 mMol), the mixture was heated in vacuo at 155° C. After 2 hours, the cooled reaction mixture was suspended in methanol and filtered to remove the unreacted heterocycle (2.29 g). The filtrate was taken to dryness in vacuo and treated with an excess of methanol previously saturated with ammonia. Purification by flash chromatography on silica gel (the residue was adsorbed onto silica gel and placed on the top of the column), elution with chloroform/methanol (20:1 v/v), and removal of the solvent gave 1.22 g (3.2 mMol) of 7-anilino-5-chloro-3-β-D-ribofuranosyl-3H-imidazo[4,5-b]pyridine; yield 46.8%; m.p. 157°-160° C. UV max (nm) at pH 1, 307 (ε15,700); pH 13, 250 sh (ε9,900), 300 ε19,400); NMR (DMSO-d6): 9.42 d (s, 1H, NH); 8.50 (s, 1H, H2); 7.43-7.12 (m, 5H, Phenyl); 6.71 (s, 1H, H5); 5.93 (d, 1H, J=5.97 Hz, H1').
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:10])[C:7]=1[CH2:8]O.[Br:11]P(Br)Br>ClCCl>[BrH:11].[Br:11][CH2:8][C:7]1[C:2]([Cl:1])=[CH:3][N:4]=[CH:5][C:6]=1[Cl:10]
Reactant: BrP(Br)Br
Reactant: OCc1c(Cl)cncc1Cl
Solvent: ClCCl
Product: Br
Product: Clc1cncc(Cl)c1CBr
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 156.7 %

Procedure:
To a solution of (3,5-dichloropyridin-4-yl)methanol (1.9 g, 10.7 mmol) in anhydrous dichloromethane (75 mL) was added tribromophosphane (1.1 mL, 11.5 mmol). The mixture was stirred at room temperature for 1.5 hours. Dichloromethane was evaporated, and the mixture was co-evaporated with toluene (2×20 mL). The residue was dried in vacuo, affording 4-(bromomethyl)-3,5-dichloropyridine hydrobromide (2.9 g, 98% yield), which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].Cl[C:11]1[NH:12][C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=1.Cl>C(O)C>[ClH:1].[NH:12]1[C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=[C:11]1[NH:4][C:3]1[C:5]([CH3:9])=[CH:6][CH:7]=[CH:8][C:2]=1[Cl:1]
Reactant: Cc1cccc(Cl)c1N
Reactant: Clc1nc2ccccc2[nH]1
Agent: Cl
Solvent: CCO
Product: Cc1cccc(Cl)c1Nc1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.5 %

Procedure:
2-Chloro-6-methylaniline (0.46 g) and 2-chlorobenzimidazole (0.5 g) were mixed in a flask and then kept at 170° C. for 30 min. After cooling, the residue was dissolved out of the flask with 1 N HCl and 10% ethanol at boiling heat. The material dissolved out was then stirred at RT for 30 min, then the insoluble material was filtered off with suction and the filtrate was evaporated. The residue was purified by means of preparative HPLC on RP-18 using acetonitrile/water (0.05% TFA). The clean fractions were combined, the acetonitrile was stripped off, the residue was adjusted to pH 10 with potassium carbonate solution, extracted three times with EA, and then the combined phases were dried, filtered, and concentrated. The residue was taken up using HCl/water and freeze-dried. 227 mg of the title compound were obtained.