Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]O)=[C:18]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH:17]=1>>[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[C:18]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[CH:17]=1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: OCc1ccc(F)cc1OCc1ccc(F)cc1
Product: N#Cc1ccnc(-n2nccc2OCc2ccc(F)cc2OCc2ccc(F)cc2)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and [4-fluoro-2-[(4-fluorophenyl)methoxy]phenyl]methanol according to the procedure for the preparation of Example 39, part C. [M+H] Calc'd for C23H16F2N4O2,419; Found, 419.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])=[CH:4][CH:3]=1.[Cl:14]N1C(=O)CCC1=O>C(#N)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])=[CH:4][C:3]=1[Cl:14]
Reactant: Nc1ccc(N2CCCC2=O)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: Nc1ccc(N2CCCC2=O)cc1Cl
Yield: 44.7 %

Procedure:
1-(4-Aminophenyl)pyrrolidin-2-one (0.3 g, 1.7 mmol) and N-chlorosuccinimide (0.227 g, 1.7 mmol) were dissolved in acetonitrile (10 ml). The reaction was stirred and heated at reflux for 2 hours. The solvent was removed in vacuum and the residue purified by silica gel column chromatography eluting with 50% ethyl acetate in dichloromethane to afford the title compound as a white powder (0.16 g, 44.6%). 1H-NMR (500 MHz, CDCl3): δ 2.14 (m, 2H), 2.57 (t, J=8.3 Hz, 2H), 3.77 (t, J=7.1 Hz, 2H), 6.75 (d, J=8.7 Hz, 1H), 7.31 (dd, J=2.5 Hz, 8.7 Hz, 1H), 7.48 (d, J=2.5 Hz, 1H), 8.8 (s, 2H).
Reaction SMILES: [N+](C1C=CC(C[O:9][C:10]([C:12]2[N:17]3[C:18](=[O:31])[C@@H:19]([NH:20][C:21](=[O:30])[CH2:22][O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C@H:16]3[S:15][CH2:14][C:13]=2[S:32][CH3:33])=[O:11])=CC=1)([O-])=O.O1CCCC1.CO>[Pd].O1CCCC1.CO>[CH3:33][S:32][C:13]1[CH2:14][S:15][C@@H:16]2[C@H:19]([NH:20][C:21](=[O:30])[CH2:22][O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18](=[O:31])[N:17]2[C:12]=1[C:10]([OH:11])=[O:9]
Reactant: CSC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@@H](NC(=O)COc3ccccc3)[C@H]2SC1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CSC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)COc3ccccc3)[C@H]2SC1
Reaction time: 4 h

Procedure:
A solution of 53 mg of 3-methylthio-7β-phenoxyacetylamino-3-cephem-4-carboxylic acid p-nitrobenzyl ester in 5 ml of a warm 2:1 mixture of tetrahydrofurane and methanol is added to a mixture, which has been prehydrogenated for 30 minutes in a hydrogenation apparatus, of 51 mg of 5% strength palladium-on-charcoal catalyst in 1 ml of tetrahydrofurane/methanol, 1:1, and the mixture is hydrogenated for 4 hours whilst stirring. The solution is filtered, the catalyst is washed with 4 times 6 ml of ethyl acetate and the filtrate and the washing liquid are evaporated in vacuo. The residue is dissolved in methylene chloride and extracted with dilute aqueous sodium bicarbonate solution. The aqueous phase is extracted by shaking three times with methylene chloride and the yellow oil of the intermediate layer is discarded. The aqueous bicarbonate solution is cooled in an ice bath, covered with ethyl acetate and acidified to about pH 2 with 2 N hydrochloric acid. The organic phase is separated off, the yellow oil of the intermediate layer is again discarded and the aqueous phase is extracted with methylene chloride. The combined ethyl acetate and methylene chloride phases are washed with water, dried over sodium sulphate and evaporated in vacuo. The residue is recrystallised from methylene chloride/diethyl ether and gives 3-methylthio-7β-phenoxyacetylamino-3-cephem-4-carboxylic acid of melting point 122°-125° C.; IR spectrum (KBr): characteristic bands at 5.64; 5.95; 6.25; 6.55; 6.70; 8.20; 8.58; 8.94 and 13.25μ.
Reaction SMILES: [F-].[Cs+].[OH:3][C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([O:15][CH3:16])[C:13]=1[OH:14])[C:7]([O:9][CH3:10])=[O:8].Br[CH2:18]Br.CCOCC>CN(C=O)C>[CH2:16]1[O:14][C:13]2[C:4]([O:3][CH3:18])=[CH:5][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:11][C:12]=2[O:15]1
Reactant: COC(=O)c1cc(O)c(O)c(OC)c1
Reactant: BrCBr
Agent: [Cs+]
Agent: [F-]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OC)c2c(c1)OCO2
Temperature: 110 °C
Reaction time: 1 h
Yield: 98.8 %

Procedure:
Cesium fluoride (26.5 g, 174 mmol) was added quickly to a stirred solution of diol 4 (7.7 g, 39 mmol) in DMF (80 ml) at rt under Ar. After stirring for 1 h, dibromomethane (5.4 ml, 78 mmol) was added dropwise at rt and the mixture heated to 110° C. for 12 h. Upon cooling to rt, ether (300 ml) was added and the mixture washed with cold water (3×50 ml). The combined aqueous phase was then extracted with ether (2×100 ml), dried and concentrated in vacuo. The resultant crude residue was absorbed onto silica gel (gravity) and purified via silica gel chromatography (gravity, 1:5; EtOAc in n-hexane), affording methylenedioxy derivative 5 (8.1 g, 99%) as a colorless powder; m.p. 89–91° C. (mp 89–91° C., Pettit and Singh, 1987); 1H-NMR (300 MHz):3.89 (3H, s, —OCH3), 3.94 (3H, s, —OCH3), 6.05 (2H, s, —OCH2O—), 7.21 (1H, d,J=1.8 Hz, ArH), 7.33 (I H, d, J=1.8 Hz, ArH).
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.Cl.Cl.[C:28]1([CH:34]2[C:39]3[N:40]=[C:41]([NH:43][CH:44]4[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]4)[S:42][C:38]=3[CH2:37][CH2:36][CH2:35]2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(CC)C(C)C)(C)C.Cl[C:60]1[S:64][N:63]=[C:62]([CH3:65])[N:61]=1>O1CCOCC1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:65][C:62]1[N:61]=[C:60]([N:47]2[CH2:46][CH2:45][CH:44]([NH:43][C:41]3[S:42][C:38]4[CH2:37][CH2:36][CH2:35][CH:34]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[C:39]=4[N:40]=3)[CH2:49][CH2:48]2)[S:64][N:63]=1
Reactant: Cc1nsc(Cl)n1
Reactant: c1ccc(C2CCCc3sc(NC4CCNCC4)nc32)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1nsc(N2CCC(Nc3nc4c(s3)CCCC4c3ccccc3)CC2)n1
Temperature: 200 °C

Procedure:
Palladium (II) acetate (3.6 mg, 0.016 mmol) and 2-(dicyclohexylphosphino)biphenyl (11.6 mg, 0.032 mmol) were stirred under nitrogen at room temperature in dioxane (1.8 mL) for 10 minutes. Sodium tert.-butylat (29 mg, 0.3 mmol), (4-phenyl-4,5,6,7-tetrahydro-benzothiazol-2-yl)-piperidin-4-yl-amine dihydrochloride (77.3 mg, 0.2 mmol), N,N-diisopropylethylamine (69 L, 0.4 mmol) and 5-chloro-3-methyl-[1,2,4]thiadiazole (29.6 mg; 0.22 mmol) were added and the reaction was heated to 200° C. for 30 minutes in a microwave oven. The reaction was diluted with water and extracted twice with ethyl acetate. The combined organic layers were washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using heptane/EtOAc 4:1 to 1:4 (v/v) as eluent. The title compound was obtained as a white solid (55 mg, 67%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[N:8]1[CH:13]=[C:12]([CH:14]=O)[CH:11]=[N:10][CH:9]=1>C(Cl)(Cl)Cl>[N:8]1[CH:13]=[C:12]([CH:14]=[N:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:11]=[N:10][CH:9]=1
Reactant: O=Cc1cncnc1
Reactant: Nc1ccccn1
Solvent: ClC(Cl)Cl
Product: C(=Nc1ccccn1)c1cncnc1
Reaction time: 0.25 h
Yield: 99.7 %

Procedure:
A solution of 2-aminopyridine (11.314 g, 120.3 mmol) and pyrimidine-5-carboxaldehyde (14.0 g, 129.6 mmol) in chloroform (300 mL) was stirred at room temperature for 15 min. The volatiles were then removed under reduced pressure (1 h at 75° C.) to yield a yellow solid. The crude solid was dissolved in chloroform (300 mL) and the solution was stirred for 15 min. The volatiles were then removed under reduced pressure (1 h at 75° C.) to yield a yellow solid. The crude solid was again dissolved in chloroform (300 mL), the solution was stirred for 15 min, and the volatiles were removed under reduced pressure (1 h at 85° C.) to yield a yellow solid. This solid was dried in a vacuum oven overnight at 80° C. to yield 22.090 g (99.8%) of the title compound.
Reaction SMILES: C(OC(=O)[NH:7][C:8]([C:10]1[S:11][C:12]([S:26][CH3:27])=[C:13]([S:15]([C:18]2[CH:19]=[N:20][C:21](Cl)=[C:22]([Br:24])[CH:23]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])(C)(C)C.[NH2:29][CH2:30][C:31]([CH3:35])([CH3:34])[CH2:32][OH:33].C(Cl)Cl.[C:39]([OH:45])([C:41]([F:44])([F:43])[F:42])=[O:40]>C1COCC1>[F:42][C:41]([F:44])([F:43])[C:39]([OH:45])=[O:40].[Br:24][C:22]1[CH:23]=[C:18]([S:15]([C:13]2[CH:14]=[C:10]([C:8]([NH2:7])=[NH:9])[S:11][C:12]=2[S:26][CH3:27])(=[O:17])=[O:16])[CH:19]=[N:20][C:21]=1[NH:29][CH2:30][C:31]([CH3:35])([CH3:34])[CH2:32][OH:33]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cnc(Cl)c(Br)c1
Reactant: CC(C)(CN)CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: C1CCOC1
Product: CSc1sc(C(=N)N)cc1S(=O)(=O)c1cnc(NCC(C)(C)CO)c(Br)c1

Procedure:
The reaction was conducted following the procedure for Example 164: step c, using {[4-(5-bromo-6-chloro-pyridine-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (0.035 g, 0.066 mmol), 3-amino-2,2-dimethylpropanol (0.013 g, 0.133 mmol), THF [2 mL], followed by DCM/TFA (1:1) and reverse-phase HPLC to yield the title compound. ESI-MS (m/z): Calcd. for C17H22BrN3O3S3: 493.48 (M+H); found 493.1, 495.0.
Reaction SMILES: [I-].[CH:2]1([N:6]2[CH2:11][CH2:10][N:9]([C:12](=[O:25])[CH2:13][N+:14]3[CH:19]=[CH:18][C:17]4[N:20]=[C:21]([S:23][CH3:24])[O:22][C:16]=4[CH:15]=3)[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3]1.[BH4-].[Na+]>CO>[CH:2]1([N:6]2[CH2:7][CH2:8][N:9]([C:12](=[O:25])[CH2:13][N:14]3[CH2:19][CH2:18][C:17]4[N:20]=[C:21]([S:23][CH3:24])[O:22][C:16]=4[CH2:15]3)[CH2:10][CH2:11]2)[CH2:5][CH2:4][CH2:3]1
Reactant: CSc1nc2cc[n+](CC(=O)N3CCN(C4CCC4)CC3)cc2o1
Agent: [BH4-]
Agent: [I-]
Agent: [Na+]
Solvent: CO
Product: CSc1nc2c(o1)CN(CC(=O)N1CCN(C3CCC3)CC1)CC2
Temperature: 25 °C

Procedure:
The solid from Step 1 is dissolved in MeOH and NaBH4 (210 mg, 5.56 mmol) is added to the solution. The solution is heated at reflux for 4 hr, and then cooled to rt. The solvent is removed in vacuo and the residue is partitioned between water (6 mL) and EtOAc (6 mL). The layers are separated and aqueous layer is extracted with EtOAc (6 ml). The combined extracts are washed with brine (5 ml), dried and evaporated. The residue is purified by PTLC to give the title compound as a light yellow oil. MS (M+1): 351.0; 1H NMR (δ, CDCl3): 3.55-3.65 (m, 6H), 3.40 (s, 2H), 2.87 (t, 2H), 2.65-2.76 (m, 1H), 2.54-2.62 (m, 5H), 2.28 (t, 4H), 1.64-2.06 (m, 6H)
Reaction SMILES: Br[C:2]1[C:3]([N:23]2[CH2:27][CH2:26][C@@H:25]([OH:28])[CH2:24]2)=[N:4][CH:5]=[C:6]([CH:22]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([F:21])([F:20])([F:19])([F:18])[F:17])=[CH:12][CH:11]=1)=[O:8].[N:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[N:31][CH:30]=1>>[OH:28][C@@H:25]1[CH2:26][CH2:27][N:23]([C:3]2[C:2]([C:33]3[CH:34]=[N:29][CH:30]=[N:31][CH:32]=3)=[CH:22][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([S:16]([F:20])([F:19])([F:21])([F:17])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:24]1
Reactant: OB(O)c1cncnc1
Reactant: O=C(Nc1ccc(S(F)(F)(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Product: O=C(Nc1ccc(S(F)(F)(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2cncnc2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 151 using (R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(pentafluorosulfanyl)phenyl)nicotinamide (Stage 216.1) and pyrimidin-5-ylboronic acid to afford a solid. UPLC-MS (Condition 3), tR=0.97 min, m/z=488.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6), δ ppm 1.74 (m, 1H) 1.84 (m, J=8.99 Hz, 1H) 2.88 (d, J=10.95 Hz, 1H) 3.18-3.26 (m, 2H) 3.33-3.43 (m, 1H) 4.20 (br. s, 1H) 4.83-4.97 (m, 1H) 7.80-7.88 (m, 2H) 7.91-7.99 (m, 2H) 8.10 (d, J=1.00 Hz, 1H) 8.80 (d, J=1.96 Hz, 1H) 8.88 (s, 2H) 9.18 (s, 1H) 10.36 (br. s, 1H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[NH:5][C:4](=[S:13])[C:3]=1[C:14]([C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)=O.[NH2:23]OS(O)(=O)=O.[OH-].[Li+]>CO>[CH3:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[NH:5][C:4]1[S:13][N:23]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)[C:3]=1[C:2]2=[O:1]
Reactant: NOS(=O)(=O)O
Reactant: Cc1ccc(C(=O)c2c(O)c3cc(C)ccc3[nH]c2=S)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(-c2nsc3[nH]c4ccc(C)cc4c(=O)c23)cc1
Temperature: 25 °C
Reaction time: 30 h
Yield: 55.4 %

Procedure:
To a solution of 13 (80 mg, 0.259 mmol) in 25 mL of methanol was added a solution of hydroxylamine-O-sulfonic acid (102.6 mg, 0.907 mol) and lithium hydroxide (38.1 mg, 0.907 mmol) in 3 mL of methanol and the mixture was stirred at room temperature for 30 hours. The reaction mixture was concentrated under reduced pressure and applied to flash chromatography. Elution with heptane/EtOAc (3:1) gave 19 as a white solid (44 mg, 55%). mp: 330° C.;
Reaction SMILES: [OH:1][C:2]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:20]1[CH:24]=[CH:23]SC=1)[C:3]([O:5][CH2:6][CH:7]1[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]1)=[O:4].O.[C:32]1([CH3:42])[CH:37]=[CH:36][C:35]([S:38]([OH:41])(=[O:40])=[O:39])=[CH:34][CH:33]=1>C(#N)C>[S:38]([C:35]1[CH:36]=[CH:37][C:32]([CH3:42])=[CH:33][CH:34]=1)([OH:41])(=[O:40])=[O:39].[CH:20]1([C:2]([OH:1])([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:3]([O:5][CH2:6][CH:7]2[CH2:8][CH2:9][NH:10][CH2:11][CH2:12]2)=[O:4])[CH2:37][CH2:32][CH2:33][CH2:23][CH2:24]1
Reactant: CC(C)(C)OC(=O)N1CCC(COC(=O)C(O)(c2ccccc2)c2ccsc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC#N
Product: O=C(OCC1CCNCC1)C(O)(c1ccccc1)C1CCCCC1
Temperature: 30 °C
Reaction time: 8 h
Yield: 159.7 %

Procedure:
To a stirred solution of tert-butyl 4-((2-hydroxy-2-phenyl-2-(thiophen-3-yl)acetyloxy)methyl)piperidine-1-carboxylate (0.84 g, 1.94 mmol) in acetonitrile (10 mL), p-toluenesulfonic acid monohydrate (0.55 g, 2.91 mmol) was added. The reaction was stirred at 30° C. overnight and then concentrated under reduced pressure to afford the title compound (1.17 g, >100%) that was used without further purification in the next step.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:15]1([P:21](Cl)(Cl)=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>>[CH:15]1([P:21]2(=[O:22])[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[CH2:1][N:8]2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=P(Cl)(Cl)C1CCCCC1
Reactant: c1ccc(CNc2ccccc2)cc1
Product: O=P1(C2CCCCC2)c2ccccc2CN1c1ccccc1
Yield: 14.5 %

Procedure:
The procedure of Example 1 was employed utilizing N-benzylaniline and cyclohexyl phosphonic dichloride. The crude product produced as a result of the chromatographic separation yielded without additional purification 1-cyclohexyl-2-phenyl-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide (2.7 g, 14.5% yield) as a beige solid having a melting point of 167°-169° C. and the following analysis:
Reaction SMILES: [C:1]1([C:7]2[N:8]=[N:9][NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]Br.C(=O)([O-])[O-]>CC(=O)CC>[Br:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][N:10]1[C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=[N:9]1
Reactant: BrCCCCCCCCBr
Reactant: c1ccc(-c2nn[nH]c2-c2ccccc2)cc1
Agent: O=C([O-])[O-]
Solvent: CCC(C)=O
Product: BrCCCCCCCCn1nnc(-c2ccccc2)c1-c1ccccc1

Procedure:
4,5-Diphenyl-1,2,3-triazole was treated with 1,8-dibromooctane and potassinm carbonate in butanone to give after chromatographic work up the title compound, m.p. 90°-91° C, Found: C, 64.0; H, 6.5; N, 10.1; Br, 19.8%; C22H26BrN3 requires: C, 64.1; H, 6.4; N, 10.2; Br, 19.4%.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)N)=[CH:5][CH:4]=1.[CH3:20][C:21]([CH3:31])([CH2:26][C:27](=O)[CH2:28][CH3:29])[C:22]([O:24]C)=[O:23]>C(O)(C)(C)C>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[C:12]3[C:17](=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[C:28]([CH3:29])=[C:27]2[CH2:26][C:21]([CH3:31])([CH3:20])[C:22]([OH:24])=[O:23])=[CH:5][CH:4]=1
Reactant: COc1ccc(N(N)Cc2ccc(Cl)cc2)cc1
Reactant: CCC(=O)CC(C)(C)C(=O)OC
Agent: Cl
Solvent: CC(C)(C)O
Product: COc1ccc2c(c1)c(C)c(CC(C)(C)C(=O)O)n2Cc1ccc(Cl)cc1

Procedure:
Following the method of Example 2, but using 1-[(4-chlorophenyl)methyl]-1-(4-methoxyphenyl)hydrazine hydrochloride and methyl 2,2-dimethyl-4-oxohexanoate as the starting materials and tert-butanol as the solvent, the title compound was prepared.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]([O-:14])=[O:13])=[N:10][CH:11]=1)[C:2]#[C:3][CH3:4].[OH-].[Li+]>CO.O1CCOCC1.O>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]([OH:14])=[O:13])=[N:10][CH:11]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(C(=O)[O-])nc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CO
Product: CC#CCOc1ccc(C(=O)O)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.7 %

Procedure:
To a solution of 5-(but-2-yn-1-yloxy)picolinate (72 mg, 0.35 mmol) in methanol (1 ml), dioxane (1 ml) and water (0.1 ml) was added lithium hydroxide (31 mg, 1.3 mmol). The reactions were stirred at ambient temperature for 2 h. The solvents were removed in vacuo. The residue from the reaction was triturated with 0.5 mL 1 N aqueous HCl. The tan precipitate was collected by vacuum filtration, washed with water, and dried in vacuo to generate 5-(but-2-yn-1-yloxy)picolinic acid (56 mg, 0.293 mmol, 83% yield) as a tan powder. LC/MS (ESI+) m/z=192 (M+H).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[N:16]=[C:17]([N:24]4[CH2:29][CH2:28][CH2:27][C@@H:26]([NH:30][C:31]([N:33]5[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]5)=[O:32])[CH2:25]4)[N:18]=[N:19][C:20]=3[C:21]([NH2:23])=[O:22])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[C:48](Cl)(=[O:51])[CH:49]=[CH2:50]>CN(C=O)C>[N:33]1([C:31]([NH:30][C@@H:26]2[CH2:27][CH2:28][CH2:29][N:24]([C:17]3[N:18]=[N:19][C:20]([C:21]([NH2:23])=[O:22])=[C:15]([NH:14][C:11]4[CH:12]=[CH:13][C:8]([CH:5]5[CH2:6][CH2:7][N:2]([C:48](=[O:51])[CH2:49][CH3:50])[CH2:3][CH2:4]5)=[CH:9][CH:10]=4)[N:16]=3)[CH2:25]2)=[O:32])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: NC(=O)c1nnc(N2CCC[C@@H](NC(=O)N3CCCCC3)C2)nc1Nc1ccc(C2CCNCC2)cc1
Reactant: C=CC(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCC(=O)N1CCC(c2ccc(Nc3nc(N4CCC[C@@H](NC(=O)N5CCCCC5)C4)nnc3C(N)=O)cc2)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
(R)-5-(4-(Piperidin-4-yl)phenylamino)-3-(3-(piperidine-1-carboxamido)piperidin-1-yl)-1,2,4-triazine-6-carboxamide hydrochloride (494) (60 mg, 0.11 mmol) was dissolved in 3 mL DMF. To it were added DIEA (190 μL, 1.10 mmol) and then acryloyl chloride (30 mg, 0.33 mmol). The mixture was stirred at RT for 20 min, quenched with 0.3 mL TFA, and directly subjected to reverse phase prep HPLC to isolate the title compound, (R)-3-(3-(piperidine-1-carboxamido)piperidin-1-yl)-5-(4-(1-propionylpiperidin-4-yl)phenylamino)-1,2,4-triazine-6-carboxamide (499), as HCl salt (35 mg). LC-MS (ESI): m/z (M+1) 562.3. UV: λ=258, 329, 337 nm.
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]1([CH3:20])[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[OH:13])[CH:5]1[N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.[Br:21][CH2:22][CH2:23][CH2:24]Br>C(Cl)Cl.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC>[Br:21][CH2:22][CH2:23][CH2:24][O:13][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[CH2:12][C:4]([CH3:20])([CH3:3])[CH:5]2[N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CC1(C)Cc2c(O)cccc2C1N1CCCCC1
Reactant: BrCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [K+]
Solvent: ClCCl
Product: CC1(C)Cc2c(OCCCBr)cccc2C1N1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Potassium hydroxide (1.44 g) is added to a stirred solution of the 4-hydroxy compound of Step 4. above (5 g) in methylene chloride (44 ml) and stirring is continued under N2 for 30 min. 1,3-Dibromopropane (20.7 ml) and tetrabutyl ammonium chloride (0.63 g) are added and the mixture is stirred at RT for about 70 hours. The reaction mixture is diluted with methylene chloride, washed with H2O, dried, filtered and the filtrate evaporated in vacuo. The residue is chromatographed (silica gel, hexane/ether) affording the purified desired product as an oil.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:23]=3Br)[CH:15]=2)=[CH:9][C:8]=1[CH3:33])C.[C:35]1([CH3:42])[C:40]([OH:41])=[CH:39][CH:38]=[CH:37][CH:36]=1>>[CH3:33][C:8]1[CH:9]=[C:10]([O:13][C:14]2[CH:15]=[C:16]([O:21][C:22]3[CH:23]=[CH:24][C:25]([C:28]([F:30])([F:31])[F:29])=[CH:26][C:27]=3[O:41][C:40]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH3:42])[CH:17]=[C:18]([CH3:20])[CH:19]=2)[CH:11]=[CH:12][C:7]=1[CH2:6][CH2:5][C:4]([OH:34])=[O:3]
Reactant: Cc1ccccc1O
Reactant: CCOC(=O)CCc1ccc(Oc2cc(C)cc(Oc3ccc(C(F)(F)F)cc3Br)c2)cc1C
Product: Cc1cc(Oc2ccc(CCC(=O)O)c(C)c2)cc(Oc2ccc(C(F)(F)F)cc2Oc2ccccc2C)c1

Procedure:
The title compound is prepared by reacting the compound of 3-{4-[3-(2-bromo-4-trifluoromethyl-phenoxy)-5-methyl-phenoxy]-2-methyl-phenyl}-propionic acid ethyl ester with o-cresol as in Example 45 to afford 0.038 g (25%). 1H NMR (400 MHz, CDCl3); HRMS (ES+) 71 m/Z exact mass calculated for C31H27O5F3 537.1888, found 537.1893.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4](I)[C:3]=1[OH:10].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]#[CH:20])=[CH:15][CH:14]=1.O>CN(C=O)C.C(NCC)C>[Cl:8][C:6]1[CH:7]=[C:2]([Cl:1])[C:3]2[O:10][C:19]([C:16]3[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=3)=[CH:20][C:4]=2[CH:5]=1
Reactant: Oc1c(Cl)cc(Cl)cc1I
Reactant: C#Cc1ccc(OC)cc1
Solvent: O
Solvent: CCNCC
Solvent: CN(C)C=O
Product: COc1ccc(-c2cc3cc(Cl)cc(Cl)c3o2)cc1
Reaction time: 1 h
Yield: 39.6 %

Procedure:
A solution of 2,4-Dichloro-6-iodo-phenol [2040-83-7] (2.0 g, 6.9 mmol), 4-Methoxyphenylacetylene (0.91 g, 6.9 mmol), PdCl2P(PH3)2 (0.15 g), and Cul (50 mg) in DMF/Diethylamine (26 ml) was heated to 60° C. After 1 hr, the reaction was cooled and poured into water which was extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated to give a solid which was triturated with MeOH, filtered to give 85 as a solid (0.80 g, 42%): Mp=1.72–174° C.; 1H NMR (CDCl3) δ 7.82 (d, 2 H, J=8.1 Hz), 7.41 (d, 1 H, J=1.8 Hz), 7.24 (d, 1 H, J=1.9 Hz), 7.00 (d, 2 H, J=8.8 Hz), 6.84 (s, 3 H), 3.87 (s, 3 H); MS 293/295 [M+H]+
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:14][C:15]([C:17]2[CH:18]=[N:19][CH:20]=[N:21][CH:22]=2)=[O:16])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[Cl:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[C:26]([F:33])[CH:25]=1>>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]2[CH:3]=[C:4]([NH:14][C:15]([C:17]3[CH:18]=[N:19][CH:20]=[N:21][CH:22]=3)=[O:16])[CH:5]=[N:6][C:7]=2[O:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[C:26]([F:33])[CH:25]=1
Reactant: O=C(Nc1cnc(OCC(F)(F)F)c(Br)c1)c1cncnc1
Reactant: OB(O)c1ccc(Cl)cc1F
Product: O=C(Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2F)c1)c1cncnc1

Procedure:
The title compound was synthesized in analogy to Example 39, using pyrimidine-5-carboxylic acid[5-bromo-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-yl]-amide (example 52 a) and B-(4-chloro-2-fluorophenyl)-boronic acid (CAN 160591-91-3) as starting materials; LC-MS (UV peak area/ESI) 92.2%, 425.0446 (M−H)−.