Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:31]=[CH:30][CH:29]=[C:28]([N+:32]([O-:34])=[O:33])[C:5]=1[C:6]([NH:8][C@H:9]([C:11]([N:13]1[CH2:27][CH2:26][CH2:25][C@H:14]1[C:15]([O:17]CC1C=CC=CC=1)=[O:16])=[O:12])[CH3:10])=[O:7])([OH:3])=[O:2].[OH-].[Na+].CO>O>[C:1]([C:4]1[CH:31]=[CH:30][CH:29]=[C:28]([N+:32]([O-:34])=[O:33])[C:5]=1[C:6]([NH:8][C@H:9]([C:11]([N:13]1[CH2:27][CH2:26][CH2:25][C@H:14]1[C:15]([OH:17])=[O:16])=[O:12])[CH3:10])=[O:7])([OH:3])=[O:2]
Reactant: C[C@H](NC(=O)c1c(C(=O)O)cccc1[N+](=O)[O-])C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C[C@H](NC(=O)c1c(C(=O)O)cccc1[N+](=O)[O-])C(=O)N1CCC[C@H]1C(=O)O

Procedure:
The ester product from part (b) (1 g., 2.1 mmole) is stirred in a 10% sodium hydroxide and methanol solution at room temperature for 2.5 hours. The reaction solution is diluted with water and washed with ethyl ether. Upon acidification of the aqueous phase with 10% hydrochloric acid and saturation with sodium chloride, the diacid is extracted via multiple extractions into ethyl acetate. After drying (MgSO4) and evaporating, 0.5 g. of product is obtained as a white solid. In order to remove entrapped solvent, 300 mg. of material is dissolved in water and lyophilized to give pure 1-[N-(2-carboxy-6-nitrobenzoyl)-L-alanyl]-L-proline as a white solid; m.p. 134°-137°. TLC (silica gel Rf =0.28, ethyl acetate:pyridine:acetic acid:water; 45:20:6:11). [α]D =-57.2 (c=1.0, methanol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:34]=[CH:33][C:18]([C:19]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=3)=[O:20])=[C:17]([O:35][CH3:36])[CH:16]=2)[N:10]=1.[C:37]([Cu])#[N:38]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:37]#[N:38])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:34]=[CH:33][C:18]([C:19]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=3)=[O:20])=[C:17]([O:35][CH3:36])[CH:16]=2)[N:10]=1
Reactant: COc1cc(-n2nc(-c3c(Cl)cccc3I)[nH]c2=O)ccc1C(=O)Nc1ccc(F)c(C(F)(F)F)c1
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Product: COc1cc(-n2nc(-c3c(Cl)cccc3C#N)[nH]c2=O)ccc1C(=O)Nc1ccc(F)c(C(F)(F)F)c1

Procedure:
The title compound was prepared by following the procedure as described for Example-62 by using 4-(3-(2-chloro-6-iodophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-2-methoxybenzamide (Intermediate-43, 0.130 g, 0.21 mmol), DMF (4 mL) and CuCN (0.020 g, 0.23 mmol) to afford 0.030 g of crude product which was further purified by column chromatography in basic alumina eluting with 50% methanol:DCM and few drops of 10% ammonia to afford 0.030 g of pure product. 1H NMR (300 MHz, DMSO d6): δ 3.94 (s, 3H), 7.52 (t, 1H), 7.68 (d, J=7.8 Hz, 1H), 7.81 (m, 3H), 8.05-8.12 (m, 3H), 8.26 (s, 1H), 10.40 (s, 1H), 13.01 (br s, 1H); MS (m/z): 532.12 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH2:9])[N:3]=1.CCN(CC)CC.[CH:17]1([CH:20]2[CH2:24][CH2:23][CH2:22][NH:21]2)[CH2:19][CH2:18]1>CC#N>[Cl:8][C:6]1[CH:7]=[C:2]([N:21]2[CH2:22][CH2:23][CH2:24][CH:20]2[CH:17]2[CH2:19][CH2:18]2)[N:3]=[C:4]([NH2:9])[N:5]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: C1CNC(C2CC2)C1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Nc1nc(Cl)cc(N2CCCC2C2CC2)n1
Temperature: 80 °C
Reaction time: 4 h
Yield: 58.6 %

Procedure:
To 4,6-dichloro-2-pyrimidinamine (95 mg, 0.576 mmol) in CH3CN (5 mL) was added Et3N (0.25 mL, 1.75 mmol) followed by 2-cyclopropylpyrrolidine (74 mg, 0.50 mmol), and the reaction mixture was stirred for 4 hours at 80° C. The reaction was poured onto water (a precipitate was formed), and filtered. Flash chromatography SiO2 (gradient: EtOAc/hexanes) afforded the title compound (70 mg) as a white solid. LC-MS (ES) m/z=239, 241 [M+H]+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.Cl[C:16]1[CH:21]=[CH:20][C:19]([C:22]([O:24][CH3:25])=[O:23])=[CH:18][N:17]=1>CN(C=O)C>[CH3:25][O:24][C:22](=[O:23])[C:19]1[CH:20]=[CH:21][C:16]([NH:1][CH:2]2[CH2:7][CH2:6][N:5]([CH2:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH2:4][CH2:3]2)=[N:17][CH:18]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: COC(=O)c1ccc(Cl)nc1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NC2CCN(Cc3ccccc3)CC2)nc1
Temperature: 75 °C
Reaction time: 12 h
Yield: 45.4 %

Procedure:
4-Amino-1-benzylpiperidine (30 mL, 150 mmol) and N,N'-diisopropylethyl amine (25 mL, 150 mmol) were added sequentially to a solution of methyl 2-chloropyridine-5-carboxylate (5 g, 29.1 mmol) in DMF (20 mL) at 25° C. The mixture was stirred at 75° C. for 12 h. The reaction mixture was then evaporated and diluted with a mixture of sat. NaCl (aq)/EtOAc (100 mL, v/v, 50:50). The aqueous layer was extracted with more EtOAc (3×50 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuc to give a yellow oily residue. Purification of the residue by flash column chromatography (gradient elution 70 to 80% EtOAc/hexanes) provided the title compound (4.3 g, 45.4%): TLC (Rf =0.20; 60% EtOAc/hexanes); 1H NMR (CDCl3) δ 8.73 (d, 1H, J=2.1), 7.95 (m, 1H), 7.30 (m, 5H), 6.32 (d, 1H, J=8.8), 5.01 (d, 1H, J=7.8), 3.85 (s, 3H), 3.71 (m, 1H), 3.52 (s, 2H), 2.85 (m, 2H), 2.18 (m, 2H), 1.20 (m, 2H), 1.57 (m, 2H); 13C NMR (CDCl3) δ 166.4, 160.1, 151.6, 138.3, 129.0, 128.1, 127.6, 127.0, 115.0, 105.8, 63.0, 52.0, 51.4, 48.4, 32.3; HRMS (FAR) m/z 326.1879 (M+H)+ (C19H23N3O2 requires 326.1869).
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[C:9]([C:10](F)=[O:11])=[C:8]([F:13])[C:7]([F:14])=[C:6]([F:15])[C:5]=1[F:16].O.Cl>O1CCOCC1>[F:3][C:4]1[C:9]([CH2:10][OH:11])=[C:8]([F:13])[C:7]([F:14])=[C:6]([F:15])[C:5]=1[F:16]
Reactant: O=C(F)c1c(F)c(F)c(F)c(F)c1F
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: OCc1c(F)c(F)c(F)c(F)c1F
Yield: 211.1 %

Procedure:
38 g of sodium borohydride in 200 ml of dry dioxane are initially introduced into the apparatus at 20° C. and a solution of 86 g of pentafluorobenzoyl fluoride in 100 ml of dioxane is added dropwise, whilst stirring. When the addition has ended, the mixture is subsequently stirred at 20° C. for 2 hours and at 80° C. for 30 minutes and cooled and 75 ml of water are slowly added dropwise, followed by dilute hydrochloric acid until the mixture has a clearly acid reaction. After extraction with methylene chloride, the organic phase is distilled. 168 g of pentafluorobenzyl alcohol are obtained at a boiling point of 87° C./19 mbars.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[O:6]1[C:11]2[CH:12]=[CH:13][CH:14]=[C:15]([C:16]([OH:18])=[O:17])[C:10]=2[O:9][CH2:8][CH2:7]1>>[Cl:1][S:2]([C:13]1[CH:14]=[C:15]([C:16]([OH:18])=[O:17])[C:10]2[O:9][CH2:8][CH2:7][O:6][C:11]=2[CH:12]=1)(=[O:5])=[O:3]
Reactant: O=C(O)c1cccc2c1OCCO2
Reactant: O=S(=O)(O)Cl
Product: O=C(O)c1cc(S(=O)(=O)Cl)cc2c1OCCO2
Temperature: 55 °C
Yield: 93.4 %

Procedure:
670 g of chlorosulfonic acid were introduced into a balloon flask provided with a condenser and a thermometer. 173 g of 1,4-benzodioxane-5-carboxylic acid were added in portions with the temperature being maintained at 5°-10° C. The mixture was heated at 55° C. and then cooled and poured into ice. The precipitate was dried off, washed and dried again. 250 g of 7-chlorosulfonyl-1,4-benzodioxane-5-carboxylic acid were obtained (M.P.: 210°-215° C.; yield: 93.5%).
Reaction SMILES: Cl[C:2]1[N:22]=[C:5]2[C:6]([C:10]3[C:11]([O:20][CH3:21])=[N:12][CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH:33]([C:36]2[CH:41]=[CH:40][C:39]([NH2:42])=[CH:38][CH:37]=2)[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH:33]([C:36]2[CH:41]=[CH:40][C:39]([NH:42][C:2]3[N:22]=[C:5]4[C:6]([C:10]5[C:11]([O:20][CH3:21])=[N:12][CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=5)=[CH:7][CH:8]=[CH:9][N:4]4[N:3]=3)=[CH:38][CH:37]=2)[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cc2)CC1
Reactant: COc1ncc(C(F)(F)F)cc1-c1cccn2nc(Cl)nc12
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: COc1ncc(C(F)(F)F)cc1-c1cccn2nc(Nc3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cc3)nc12

Procedure:
[4-{4-[8-(2-Methoxy-5-trifluoromethyl-pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-phenyl}-piperidine-1-carboxylic acid tert-butyl ester was prepared from 2-chloro-8-(2-methoxy-5-trifluoromethyl-pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine and 4-(4-amino-phenyl)-piperidine-1-carboxylic acid tert-butyl ester, with 2,2′-bis-dicyclohexylphosphanyl-biphenyl as the ligand in a manner analogous to Example 2d (0.233 g, 41%). MP=142-144° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.75 (s, 1H), 8.80 (d, 1H), 8.65 (s, 1H), 8.55 (s, 1H), 7.85 (d, 1H), 7.55 (d, 2H), 7.02 (m, 3H), 4.05 (m, 2H), 3.90 (s, 3H), 2.6-2.8 (m, 3H), 1.65 (m, 2H), 1.40 (m, 11H). MS=569 (MH)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[N:7]=[CH:8][NH:9][CH:10]=1.[CH3:11][S:12][C:13](=[N:16][C:17]#[N:18])SC>>[C:17]([NH:16][C:13](=[N:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[N:7]=[CH:8][NH:9][CH:10]=1)[S:12][CH3:11])#[N:18]
Reactant: CSC(=NC#N)SC
Reactant: NCCCCc1c[nH]cn1
Product: CSC(=NCCCCc1c[nH]cn1)NC#N

Procedure:
Reaction of 4-(4-aminobutyl)imidazole with dimethylcyanodithioimidocarbonate gives N-cyano-N'-[4-(4-imidazolyl)butyl]-S-methylisothiourea which when reacted by the procedure of Example 12 with the following compounds:
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][C:6]1[N:7]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:8]([CH3:27])=[CH:9][C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:20])=[O:19].ClCCl.C([O-])(O)=O.[Na+]>C(#N)C>[C:1]([C:9]1[C:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[S:18]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)(=[O:20])=[O:19])=[C:6]([CH3:5])[N:7]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:8]=1[CH3:27])(=[O:3])[CH3:2]
Reactant: CCOC(=O)Cn1c(C)cc(Cc2ccccc2S(=O)(=O)c2ccccc2)c1C
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Product: CCOC(=O)Cn1c(C)c(Cc2ccccc2S(=O)(=O)c2ccccc2)c(C(C)=O)c1C
Reaction time: 0.08 h
Yield: 73.5 %

Procedure:
In a round-bottomed flask equipped with a magnetic stir bar, acetyl chloride (1.7 μL, 0.024 mmol) was added to a solution of ethyl 2-(2,5-dimethyl-3-(2-(phenylsulfonyl)benzyl)-1H-pyrrol-1-yl)acetate (10 mg, 0.024 mmol) in acetonitrile (0.5 mL) at room temperature. The reaction was stirred for 5 minutes, then dichloromethane (10 mL) and NaHCO3 (sat. aq. 10 mL) were added. The dichloromethane layer was separated and dried over Na2SO4, filtered and concentrated to yield ethyl 2-(3-acetyl-2,5-dimethyl-4-(2-(phenylsulfonyl)benzyl)-1H-pyrrol-1-yl)acetate (8 mgs, 72%).
Reaction SMILES: [CH3:1][NH2:2].F[C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1[N+:14]([O-:16])=[O:15]>CN(C)C=O>[CH3:1][NH:2][C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1[N+:14]([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Reactant: CN
Solvent: CN(C)C=O
Product: CNc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Reaction time: 2 h
Yield: 86 %

Procedure:
A stream of methylamine was bubbled through a solution of 1.3 g (6.2 mmol) 4-fluoro-3-nitrobenzotrifluoride in 25 ml dimethylformamide at 25° C. for 5 min. Stirring was continued at 25° C. for 2 h, and then the reaction mixture was evaporated in vacuo. The residue was stirred with water, and the precipitate was filtered off to give 1.17 g (86%) 4-methylamino-3-nitrobenzotrifluoride. NMR (CDCl3): 8.4 (1H, s), 8.2 (1H, broad s), 7.6 (1H, dd), 6.9 (1H, d), 3.1 (3H, d).
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][N:9]([CH:12]([C:14]3[CH:19]=[C:18]([CH3:20])[C:17]([O:21][CH2:22][CH:23]([F:25])[F:24])=[CH:16][N:15]=3)[CH3:13])[C:10](=[O:11])[C:6]=2[CH:5]=[CH:4][N:3]=1.[CH:26]([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:27]>>[F:24][CH:23]([F:25])[CH2:22][O:21][C:17]1[C:18]([CH3:20])=[CH:19][C:14]([CH:12]([N:9]2[C:10](=[O:11])[C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:26]([O:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:27])[C:7]=3[CH2:8]2)[CH3:13])=[N:15][CH:16]=1
Reactant: O=COc1ccccc1
Reactant: Cc1cc(C(C)N2Cc3c(ccnc3Cl)C2=O)ncc1OCC(F)F
Product: Cc1cc(C(C)N2Cc3c(ccnc3C(=O)Oc3ccccc3)C2=O)ncc1OCC(F)F
Yield: 74 %

Procedure:
The title compound is prepared in 74% yield (91 mg, colorless solid) from 4-chloro-2-(1-(5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (100 mg, 0.27 mmol, Intermediate-76, single enantiomer) and phenyl formate (66 mg, 0.54 mmol) in a similar manner to Intermediate-91.
Reaction SMILES: [C:1](=[N:9][OH:10])([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:11]=[C:12]=[O:13]>>[C:12]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:1](=[N:9][OH:10])[NH2:8])(=[O:13])[NH2:11]
Reactant: NC(=NO)c1ccccc1
Reactant: [N-]=C=O
Product: NC(=O)c1ccccc1C(N)=NO

Procedure:
Alternatively, the benzamide oxime in Reaction 1 above is reacted with the isocyanate to produce the carbamyl benzamidoxime shown below: ##STR9##
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[C:11](Cl)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:19]([Sn](CCCC)(CCCC)CCCC)=[CH2:20]>C1(C)C=CC=CC=1.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>[CH2:1]([O:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[C:11]([CH:19]=[CH2:20])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1OCc1ccccc1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1ccc([N+](=O)[O-])c(OCc2ccccc2)n1
Temperature: 110 °C
Reaction time: 12 h

Procedure:
To a stirred mixture of (2-(benzyloxy)-6-chloro-3-nitropyridine (3.2 g, 0.0123 mol) in toluene (32.5 mL) in a 250 mL sealed tube, were added Pd(PPh3)4 (426 mg, 0.000369 mol, Aldrich) and vinyl tributyltin (3.90 g, 0.0123 mol). The tube was purged with the argon gas for 10 min, capped and stirred for 12 h at 110° C. After completion of the reaction (monitored by TLC, 10% EtOAc in hexane), the reaction mixture was quenched with water (20 mL) and extracted with EtOAc (50 mL×3). The organic layers were combined, dried over anhydrous sodium sulfate, and purified by column chromatography, silica gel (60-120 mesh) using 5-7% EtOAc in petroleum ether as an eluent to afford the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ: 8.47 (d, J=8.1 Hz, 1H), 7.52 (d, J=6.9 Hz, 1H), 7.43-7.27 (m, 3H), 7.20 (br. s., 2H), 6.92-6.83 (m, 1H), 6.49 (dd, J=17.4, 1.5 Hz, 1H), 5.74 (dd, J=10.5, 1.5 Hz, 1H), 5.59 (s, 2H). MS (ESI, positive ion) m/z: 257 (M+H).
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(CC[OH:28])C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCOCC1>[C:14]1([P:7](=[O:28])([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: OCCc1ccccc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: C1COCCO1
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Triphenylphosphine (1.2 g, 5.4 mmol) and 2-phenylethanol (0.65 g, 5.4 mmol) were sequentially added to a solution of tri-N2,1,2′-O-acetyl-L-biopterin (1.5 g, 4.21 mmol) in 1,4-dioxane (7 ml). To this mixture diisopropylazodicarboxylate (1.05 ml, 5.4 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 18 h. Evaporation and column chromatography on silica gel eluting with AcOEt (1:2) followed by AcOEt gave the expected product together with triphenylphosphine oxide.
Reaction SMILES: [SH:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[CH3:10][O:11][C:12]([C:14]1[C:19]([F:20])=[CH:18][C:17](Br)=[C:16]([NH2:22])[N:15]=1)=[O:13].CCOC(C)=O>CN(C=O)C>[CH3:10][O:11][C:12]([C:14]1[C:19]([F:20])=[CH:18][C:17]([S:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])=[C:16]([NH2:22])[N:15]=1)=[O:13]
Reactant: COC(=O)c1nc(N)c(Br)cc1F
Reactant: CCOC(=O)CS
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CSc1cc(F)c(C(=O)OC)nc1N

Procedure:
A solution of ethyl mercaptoacetate (1.15 ml) in DMF (40 ml) was ice-cooled under argon, treated with sodium hydride (420 mg of a 60% dispersion in oil) and stirred until all was in solution (about 1 hour). The ester (a) (2.48 g) was added, the mixture allowed to warm to room temp. and stirred overnight. EtOAc (150 ml) was added, the solution washed with water (3×150 ml), dried and evaporated. Chromatography of the residue (40% EtOAc in hexane) gave an oil (1.7 g).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([C:14]2[N:18]3[N:19]=[CH:20][C:21]([C:23]4[CH:24]=[N:25][N:26]([CH:28]([CH3:32])[C:29](O)=[O:30])[CH:27]=4)=[CH:22][C:17]3=[N:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1)=[O:6].[CH3:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[CH3:32][CH:28]([N:26]1[CH:27]=[C:23]([C:21]2[CH:20]=[N:19][N:18]3[C:14]([C:10]4[CH:9]=[C:8]([NH:7][C:5]([NH:4][CH2:3][C:2]([F:34])([F:1])[F:33])=[O:6])[CH:13]=[CH:12][CH:11]=4)=[CH:15][N:16]=[C:17]3[CH:22]=2)[CH:24]=[N:25]1)[C:29]([N:39]1[CH2:40][CH2:41][N:36]([CH3:35])[CH2:37][CH2:38]1)=[O:30]
Reactant: CC(C(=O)O)n1cc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cn1
Reactant: CN1CCNCC1
Product: CC(C(=O)N1CCN(C)CC1)n1cc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cn1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 54, Step 3 starting from 2-(4-{3-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}amino)phenyl]imidazo[1,2-b]pyridazin-7-yl}-1H-pyrazol-1-yl)propanoic acid and 1-methylpiperazine. LCMS (M+H)+: m/z=556.3.
Reaction SMILES: F[B-](F)(F)F.[CH3:6][O+:7]([CH3:9])C.C(N(CC)C(C)C)(C)C.[C:19]([C:21]1[CH:26]=[CH:25][C:24]([CH:27]([C:42]2C(=O)[CH2:46][CH2:45][CH2:44][C:43]=2[OH:49])[NH:28][C:29]([NH:31][C:32]2[CH:37]=[CH:36][N:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[CH:33]=2)=[O:30])=[CH:23][CH:22]=1)#[N:20]>ClCCl>[C:19]([C:21]1[CH:26]=[CH:25][C:24]([CH:27]([C:42]2[C:43](=[O:49])[CH2:44][CH2:45][CH2:46][C:6]=2[O:7][CH3:9])[NH:28][C:29]([NH:31][C:32]2[CH:37]=[CH:36][N:35]=[C:34]([C:38]([F:39])([F:41])[F:40])[CH:33]=2)=[O:30])=[CH:23][CH:22]=1)#[N:20]
Reactant: N#Cc1ccc(C(NC(=O)Nc2ccnc(C(F)(F)F)c2)C2=C(O)CCCC2=O)cc1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC1=C(C(NC(=O)Nc2ccnc(C(F)(F)F)c2)c2ccc(C#N)cc2)C(=O)CCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trimethyloxonium tetrafluoroborate (47 mg, 0.318 mmol) is added to a solution of N,N-diisopropylethylamine (72 μL, 0.412 mmol) and 1-((4-cyanophenyl)(2-hydroxy-6-oxocyclohex-1-enyl)methyl)-3-(2-(trifluoromethyl)pyridin-4-yl)urea (intermediate 26, 90 mg, 0.209 mmol) in dichloromethane (10 mL). The mixture is stirred at room temperature for 1 h and extracted three times with water. The organic phase is dried over Na2SO4 and concentrated under reduced pressure. Yield: 100 mg; ESI mass spectrum [M+H]+=445, Retention time HPLC: 1.05 min (V012_S01).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2(O)[CH2:12][N:11]([CH:13]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:10]2)=[CH:5][CH:4]=1.C(C1C=CC(C2([Cl:56])CN(C(C3C=CC=CC=3)C3C=CC=CC=3)C2)=CC=1)(C)(C)C>>[Cl:56][C:9]1([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:28])([F:27])[F:1])=[CH:4][CH:5]=2)[CH2:12][N:11]([CH:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10]1
Reactant: OC1(c2ccc(C(F)(F)F)cc2)CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CC(C)(C)c1ccc(C2(Cl)CN(C(c3ccccc3)c3ccccc3)C2)cc1
Product: FC(F)(F)c1ccc(C2(Cl)CN(C(c3ccccc3)c3ccccc3)C2)cc1

Procedure:
This compound was prepared from compound (30) using the procedure described for compound (10).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:20](=[O:21])[N:19]([CH3:22])[C:12]2[N:13]=[C:14](SC)[N:15]=[CH:16][C:11]=2[CH:10]=1.[NH2:23][CH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:20](=[O:21])[N:19]([CH3:22])[C:12]2[N:13]=[C:14]([NH:23][CH2:24][CH2:25][CH2:26][N:27]3[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH2:32]3)[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: CSc1ncc2cc(-c3c(Cl)cccc3Cl)c(=O)n(C)c2n1
Reactant: CN1CCN(CCCN)CC1
Product: CN1CCN(CCCNc2ncc3cc(-c4c(Cl)cccc4Cl)c(=O)n(C)c3n2)CC1
Temperature: 160 °C
Reaction time: 3 h

Procedure:
A mixture of 0.152 g (0.43 nmmol) of 6-(2,6-dichlorophenyl)-8-methyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one of Example 37 and 1.0 g (6.40 mmol) of 1-(3-aminopropyl)-4-methylpiperazine was heated with stirring in a 170° C. oil bath (pot T=ca. 160° C.) for 3 hours. The excess amine was evaporated at reduced pressure. Water (5 mL) was added, and the separated gum was extracted into 50 mL of 10% methylene chloride-ether. The organic phase was washed three times with 10 mL of water, dried (potassium carbonate), charcoaled, filtered, and concentrated. The remaining gum was dissolved in 3 mL of ether. The crystals that separated on inducement were filtered and washed with ether; wt 0.033 g; mp 170-172° C.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[C:5]([Cl:12])[C:3]=1N.C(O)(C)C>O>[Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[C:5]([Cl:12])[CH:3]=1
Reactant: Nc1c(Cl)cc([N+](=O)[O-])cc1Cl
Solvent: O
Solvent: CC(C)O
Product: O=[N+]([O-])c1cc(Cl)cc(Cl)c1
Yield: 98 %

Procedure:
207 parts of 2,6-dichloro-4-nitroaniline is introduced into 300 parts of isopropanol and 9 parts of water; 200 parts of concentrated (98 wt%) sulfuric acid is then added to the mixture. At 50° C., 170 parts of isopropyl nitrite is run in, nitrogen being evolved. The mixture is cooled, 800 parts of water is added, and suction filtration carried out. There is obtained 188 parts (98% of theory) of 3,5-dichloronitrobenzene, m.p.: 59° - 62° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:7][CH2:6][C:5]([C:8]2[C:13]([NH2:14])=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH2:3]1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[K+].[C:41]([C:43]1[N:44]=[C:45]([C:56]([O-])=[O:57])[N:46]([CH2:48][O:49][CH2:50][CH2:51][Si:52]([CH3:55])([CH3:54])[CH3:53])[CH:47]=1)#[N:42].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:1][C:2]1([CH3:15])[CH2:7][CH2:6][C:5]([C:8]2[C:13]([NH:14][C:56]([C:45]3[N:46]([CH2:48][O:49][CH2:50][CH2:51][Si:52]([CH3:55])([CH3:54])[CH3:53])[CH:47]=[C:43]([C:41]#[N:42])[N:44]=3)=[O:57])=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH2:3]1
Reactant: CC1(C)CC=C(c2ncccc2N)CC1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1(C)CC=C(c2ncccc2NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 53.3 %

Procedure:
A solution of 80.0 mg (0.395 mmol) of 2-(4,4-dimethyl-cyclohex-1-enyl)-pyridin-3-ylamine (as prepared in the previous step) in CH2Cl2 (10 mL) was treated with 277 mg (0.593 mmol) of PyBroP, 133 mg (0.435 mmol) of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate potassium salt (as prepared in Example 11, step (d)), and 207 μL (1.19 mmol) of DIEA. The mixture was stirred at RT for 17 h, diluted with CH2Cl2 (20 mL) and washed with water (1×10 mL). The aqueous layer was extracted with CH2Cl2 (1×10 mL), and the combined organic layers were dried (MgSO4) and concentrated in vacuo. Silica gel chromatography of the residue on a 10-g Isolute SPE column with 25% EtOAc-hexane afforded 95 mg (53%) of the title compound as a white solid: 1H-NMR (CDCl3; 400 MHz): δ 9.92 (br s, 1H), 8.72 (dd, 1H, J=8.0, 1.6 Hz), 8.37 (dd, 1H, J=4.4, 1.6 Hz), 7.77 (s, 1H), 7.23-7.18 (m, 1H), 6.00-5.94 (m, 1H), 5.93 (s, 2H), 3.70-3.63 (m, 2H), 2.51-2.43 (m, 2H), 2.18-2.11 (m, 2H), 1.61 (t, 2H, J=6.4 Hz), 1.12 (s, 6H), 1.00-0.94 (m, 2H), 0.00 (s, 9H).