Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.Br[CH2:10][CH:11]=[CH2:12].C([O-])([O-])=O.[K+].[K+].O>C1COCC1.CCOC(C)=O>[CH2:12]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH:11]=[CH2:10]
Reactant: C=CCBr
Reactant: Nc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: C=CCNc1ccc(F)cc1
Yield: 47 %

Procedure:
A suspension of 4-fluorobenzenamine (25 g, 225 mmol), 3-bromoprop-1-ene (19.0 ml, 225 mmol) and K2CO3 (31.1 g, 225 mmol) was stirred in THF (1 L) for 2 days. Water (20 mL) and EtOAc (1 L) were added into the reaction mixture. The organic layer was separated and washed with brine, dried with Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (20% EtOAc in hexane) to afford the product (16 g, 47.0% yield) as an orange oil.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:11]=[C:10]([N:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([N:21]4[CH:25]=[C:24]([C:26]5[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=5)[N:23]=[CH:22]4)=[C:15]3[C:14]([CH:32]([CH3:34])[CH3:33])=[N:13]2)[CH:9]=[CH:8][C:5]=1[C:6]#[N:7])[CH3:2].[OH:35]O.[OH-].[Na+].O>CS(C)=O>[CH2:1]([NH:3][C:4]1[CH:11]=[C:10]([N:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([N:21]4[CH:25]=[C:24]([C:26]5[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=5)[N:23]=[CH:22]4)=[C:15]3[C:14]([CH:32]([CH3:33])[CH3:34])=[N:13]2)[CH:9]=[CH:8][C:5]=1[C:6]([NH2:7])=[O:35])[CH3:2]
Reactant: CCNc1cc(-n2nc(C(C)C)c3c(-n4cnc(-c5cnn(C)c5)c4)ccnc32)ccc1C#N
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCNc1cc(-n2nc(C(C)C)c3c(-n4cnc(-c5cnn(C)c5)c4)ccnc32)ccc1C(N)=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 90 %

Procedure:
Compound (100b) (1.00 g), copper iodide (0.248 g), cesium carbonate (2.12 g), and 4-bromo-2-(ethylamino)benzonitrile (0.932 g) were suspended in 1,4-dioxane (10 mL), and N,N′-dimethylethylenediamine (0.560 mL) was added to the suspension, followed by stirring at 150° C. for 20 hr. The reaction solution was distributed between chloroform and water. The organic layer was washed with a 2 N aqueous sodium hydroxide solution and dried over magnesium sulfate, and then the solvent was distilled away. The residue was purified by neutral silica gel column chromatography (chloroform/methanol) to obtain 2-(ethylamino)-4-{3-isopropyl-4-(4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzonitrile (1.13 g, 77%) as a white solid. 2-(Ethylamino)-4-{3-isopropyl-4-(4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzonitrile (0.700 g) was dissolved in DMSO (10 mL), and a 30% hydrogen peroxide solution (0.310 mL) and a 4 N aqueous sodium hydroxide solution (1.16 mL) were added to the resulting solution, followed by stirring at room temperature for 10 min. Water was added to the reaction solution, and the precipitate was collected by filtration and was dried under reduced pressure to obtain compound (109) (0.655 g, 90%) as a white solid.
Reaction SMILES: C([O:8][N:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][C:14]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[C:15]([F:20])[CH:16]=2)[NH:11][C:10]1=[O:26])C1C=CC=CC=1.[H][H]>C1COCC1.CO.[Pd]>[F:20][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][C:14]=1[N:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)[NH:11][C:10](=[O:26])[N:9]([OH:8])[C:18]2=[O:19]
Reactant: [H][H]
Reactant: O=c1[nH]c2cc(N3CCCC3)c(F)cc2c(=O)n1OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: O=c1[nH]c2cc(N3CCCC3)c(F)cc2c(=O)n1O
Yield: 113.1 %

Procedure:
Twenty percent Pd/C (50 mg) was added to a solution of 3-benzyloxy-6-fluoro-7-pyrrolidinyl-1H-quinazoline-2,4-dione (Example 1, 0.21 g, 0.6 mmol) in 100 mL of THF and 100 mL of methanol. The mixture was shaken under 50 PSI of hydrogen for 4.5 hours, filtered, and concentrated to afford 0.18 g of the title compound as a solid, mp >250° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]=1)#[N:2].[CH2:19]([OH:21])[CH3:20].[O:22]1CCCC1>[Pd]>[CH2:20]1[O:22][C:16]2([CH2:17][CH2:18][CH:13]([C:6]3[C:5]4[C:9](=[CH:10][CH:11]=[C:3]([C:1]#[N:2])[CH:4]=4)[N:8]([CH3:12])[CH:7]=3)[CH2:14][CH2:15]2)[O:21][CH2:19]1
Reactant: C1CCOC1
Reactant: Cn1cc(C2=CCCCC2)c2cc(C#N)ccc21
Reactant: CCO
Agent: [Pd]
Product: Cn1cc(C2CCC3(CC2)OCCO3)c2cc(C#N)ccc21
Reaction time: 5 h

Procedure:
A mixture of 4-(5-cyano-1-methyl-3-indolyl)-cyclohex-3-en-isomer ethylene ketal (3.77 g) and 10% palladium on carbon (0.99 g) in ethanol-tetrahydrofuran (200:80 ml) was hydrogenated for 5 hours. The catalyst was filtered off and the solvent was removed under vacuum to afford a white powder which was washed with ethanol-hexanes (1:1) and dried under vacuum for 4 hours (2.75 g): mp 170-172° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH2:7])=[C:3]([NH2:8])[CH:2]=1.[C:9](O)(=[O:13])[C:10](O)=[O:11]>Cl>[NH:7]1[C:10](=[O:11])[C:9](=[O:13])[NH:8][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][C:4]1=2
Reactant: O=C(O)C(=O)O
Reactant: Nc1ccncc1N
Agent: Cl
Product: O=c1[nH]c2ccncc2[nH]c1=O
Temperature: 100 °C
Yield: 107.2 %

Procedure:
Pyridine-3,4-diamine (2.00 g, 18.3 mmol) and oxalic acid (1.96 g, 20.2 mmol) were dissolved in an aqueous hydrochloric acid solution (2.00 M, 20.0 mL) and the mixture was stirred with heat at 100° C. for 24 hours. After the reaction mixture was cooled to room temperature, the precipitate was collected by filtration and dried under reduced pressure. Thus, pyrido[3,4-b]pyrazine-2,3(1H,4H)-dione (3.20 g, 74%) was obtained.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:17])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:2].CN(CCN(C)C)C.[Li]C(CC)C.C1CCCCC1.[CH3:37][Si:38](Cl)([CH3:40])[CH3:39]>C1COCC1>[CH2:1]([NH:3][C:4](=[O:17])[C:5]1[C:10]([Si:38]([CH3:40])([CH3:39])[CH3:37])=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:2]
Reactant: CCNC(=O)c1ccccc1-c1ccccc1
Reactant: C[Si](C)(C)Cl
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: CCNC(=O)c1c(-c2ccccc2)cccc1[Si](C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 39 %

Procedure:
This amide (2.25 g, 10 mmol) and TMEDA (1.2 eq) in THF were mixed and cooled to -78° C. and a 1.3M s-BuLi solution in cyclohexane (2.2 eq) was added dropwise. The resulting reaction mixture was stirred at -78° C. for 30 min and TMSCl (1.2 eq) was added dropwise. The reaction was stirred at -78° C. for 30 min and allowed to warm to -30° C. The reaction was worked up in the usual manner. The crude product was purified by flash chromatography and recrystallization from hexanes to afford the title compound as a white solid (1.15 g, 39%). m.p. 159°-160° C.
Reaction SMILES: [C:1](=[O:12])(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl.[NH2:13][C:14]1[CH:41]=[CH:40][C:17]([C:18]([N:20]2[CH2:25][CH2:24][N:23]([CH2:26][C:27]3[CH:28]=[C:29]([CH:37]=[CH:38][CH:39]=3)[C:30]([NH:32][C@@H:33]([CH2:35][CH3:36])[CH3:34])=[O:31])[CH2:22][CH2:21]2)=[O:19])=[CH:16][C:15]=1[F:42].C(N(C(C)C)C(C)C)C.[CH3:52][C:53]([CH3:57])([CH3:56])[CH2:54][NH2:55]>ClCCl>[C@H:33]([NH:32][C:30](=[O:31])[C:29]1[CH:37]=[CH:38][CH:39]=[C:27]([CH2:26][N:23]2[CH2:24][CH2:25][N:20]([C:18](=[O:19])[C:17]3[CH:40]=[CH:41][C:14]([NH:13][C:1]([NH:55][CH2:54][C:53]([CH3:57])([CH3:56])[CH3:52])=[O:12])=[C:15]([F:42])[CH:16]=3)[CH2:21][CH2:22]2)[CH:28]=1)([CH2:35][CH3:36])[CH3:34]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)CN
Reactant: CC[C@@H](C)NC(=O)c1cccc(CN2CCN(C(=O)c3ccc(N)c(F)c3)CC2)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@@H](C)NC(=O)c1cccc(CN2CCN(C(=O)c3ccc(NC(=O)NCC(C)(C)C)c(F)c3)CC2)c1
Reaction time: 1 h
Yield: 4.8 %

Procedure:
To a stirred solution of bis(trichloromethyl) carbonate (0.989 mmol, 0.294 g) in dichloromethane (30 mL) was added (R)-3-((4-(4-amino-3-fluorobenzoyl)piperazin-1-yl)methyl)-N-sec-butylbenzamide (2.91 mmol, 1.2 g) and N-ethyl-N-isopropylpropan-2-amine (6.40 mmol, 1.058 mL, 0.827 g) in dichloromethane (30 mL). The reaction mixture was stirred for 1 hour then 2,2-dimethylpropan-1-amine (3.49 mmol, 0.408 ml, 0.304 g) was added. After 2 hours stirring, the crude material was purified by acidic reverse phase LC/MS then by silica chromatography to give the title compound (25 mg).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([C@@H:25]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][C@H:26]2[OH:38])=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[O:32])[CH2:27][C:26]2=[O:38])=[CH:21][CH:20]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](c2ccc(OCc3ccccc3)cc2)[C@H](O)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCc3ccccc3)cc2)C(=O)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 72.5 %

Procedure:
To a solution of DMSO (3.7 mL, 52 mmol) in 50 mL of DCM under nitrogen at −78° C. was added oxalyl chloride (4.45 mL, 51 mmol). The mixture was stirred for 10 minutes after the completion of the addition. Then a solution of (±)-rel-(3S,4S)-tert-butyl 4-(4-(benzyloxy)phenyl)-3-hydroxypiperidine-1-carboxylate (from Example 50, step D, 6.5 g, 17 mmol) in 50 mL of DCM was added and the mixture was stirred in the cold for a further 90 minutes. The reaction was then quenched by the addition of 11.8 mL of triethylamine (85 mmol) and allowed to warm up to rt. The mixture was then partitioned between 200 mL brine and 200 mL DCM. The layers were separated, and the organic layer was dried over Na2SO4, filtered, and concentrated. The residue was subjected to column chromatography on 48 g of basic alumina eluting with 8% ethyl acetate/hexanes to afford 4.7 g (67%) of racemic tert-butyl 4-(4-(benzyloxy)phenyl)-3-oxopiperidine-1-carboxylate. LCMS (method F) RT 2.376 min, m/z 381.2 (M+); chiral SFC (method G) RT 4.54 min (46.9% AP, 4.93 min (49.7% AP). 1H NMR (400 MHz, DMSO-d6) δ 7.30-7.40 (m, 5H), 7.07 (d, J=7 Hz, 2H) 6.94 (d, J=7), 2H; 5.08 (s, 2H), 4.10 (d, J=17.6, 1H), 3.97 (d, J=17.6, 1H), 3.77 (m, 2H), 3.43 (br s, 1H), 2.16 (m, 2H), 1.42 (s, 9H).
Reaction SMILES: C(OC(=O)[NH:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:20]=1[O:21][CH3:22])[N:17]=[CH:16][CH:15]=[C:14]2[O:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][C:34]2[S:35][CH:36]=[CH:37][N:38]=2)=[O:32])=[C:26]([F:39])[CH:25]=1)C1C=CC=CC=1.FC(F)(F)C(O)=O.C1(SC)C=CC=CC=1>>[NH2:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:20]=1[O:21][CH3:22])[N:17]=[CH:16][CH:15]=[C:14]2[O:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][C:34]2[S:35][CH:36]=[CH:37][N:38]=2)=[O:32])=[C:26]([F:39])[CH:25]=1
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)Nc4nccs4)c(F)c3)c2cc1NC(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CSc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4nccs4)c(F)c3)c2cc1N
Temperature: 60 °C
Reaction time: 2 h

Procedure:
After adding {4-[3-fluoro-4-(3-(thiazol-2-yl)ureido)phenoxy]-7-methoxyquinolin-6-yl}carbamic acid benzyl ester (100 mg) to a mixture of trifluoroacetic acid (3 ml) and thioanisole (0.1 ml), the mixture was heated and stirred at 60° C. for 2 hours.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:22])[C:5](C(O)=O)=[N:6][N:7]([C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:18]=2[N:17]=[CH:16][CH:15]=[CH:14]3)[CH:8]=1.C1C=CC(P([N:37]=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.CCN(CC)CC.[OH-].[Na+]>C1(C)C=CC=CC=1.CN(C=O)C>[NH2:37][C:5]1[C:4](=[O:22])[C:3]([O:2][CH3:1])=[CH:8][N:7]([C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:18]=2[N:17]=[CH:16][CH:15]=[CH:14]3)[N:6]=1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: COc1cn(-c2cccc3cccnc23)nc(C(=O)O)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1cn(-c2cccc3cccnc23)nc(N)c1=O
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 20.5 %

Procedure:
A mixture of 5-methoxy-4-oxo-1-quinolin-8-yl-1,4-dihydropyridazine-3-carboxylic acid (2.59 g, 8.71 mmol), DPPA (2.81 mL, 13.1 mmol) and Et3N (1.82 mL, 13.1 mmol) in toluene (26 mL) was heated to reflux for 1 h. To the suspension were added DMF (52 mL), DPPA (2.81 mL, 13.1 mmol) and Et3N (1.82 mL, 13.1 mmol) at room temperature. The mixture was heated to 100° C. for 1.5 h. To the mixture was added 8 M NaOH aqueous solution (10.9 mL) at 0° C. The mixture was stirred at room temperature for 1.5 h, extracted with EtOAc, dried over Na2SO4, filtered, concentrated in vacuo, purified by column chromatography on basic silica gel (hexane/EtOAc=50/50 to 0/100 and EtOAc/MeOH=100/0 to 80/20) and on silica gel (EtOAc/MeOH=100/0 to 50/50) and triturated with EtOAc/hexane to yield the title compound (479 mg, 20% yield) as a pale yellow solid: 1H NMR (DMSO-d6, 300 MHz): δ ppm 3.75 (3H, s), 6.11 (2H, s), 7.67 (1H, dd, J=8.5, 4.4 Hz), 7.72-7.80 (1H, m), 7.99 (1H, dd, J=7.6, 1.5 Hz), 8.12 (1H, dd, J=8.3, 1.1 Hz), 8.48-8.61 (2H, m), 8.99 (1H, dd, J=4.4, 1.7 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:18])=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH3:17])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1O.[C:19](=[O:22])([O-])[O-].[K+].[K+].O.[C:26]1([CH3:32])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C=O)C>[Cl:1][C:2]1[C:3]([F:18])=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH3:17])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[O:22][CH2:19][C@H:29]1[CH2:30][CH2:31][C@H:26]([CH2:32][CH2:3][CH2:2][CH2:7][CH3:6])[CH2:27][CH2:28]1
Reactant: Cc1ccccc1
Reactant: CCCc1ccc(-c2ccc(O)c(Cl)c2F)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCC[C@H]1CC[C@H](COc2ccc(-c3ccc(CCC)cc3)c(F)c2Cl)CC1
Temperature: 70 °C
Reaction time: 6 h

Procedure:
4.0 g of the compound (b67) obtained in the second step was dissolved in 20 mL of N,N,-dimethylformamide. After suspending 2.5 g of potassium carbonate in the solution, 5.6 g of the compound (b68) was added thereto, followed by stirring for 6 hours at 70° C. After completing the reaction, water and toluene were added to the reaction mixture, followed by mixing. Thereafter, the mixture was left at rest to separate into an organic layer and an aqueous layer, followed by extracting to the organic layer. The resulting organic layer was washed sequentially with water, a 2N sodium hydroxide aqueous solution, a saturated sodium chloride aqueous solution and water, and then concentrated under reduced pressure to obtain a residue. 7.7 g of the residue was purified by a preparative column chromatography using a mixed solvent of heptane and toluene (heptane/toluene=3/1 by volume) as a developing solvent and silica gel as a mediator, and further purified by repeating recrystallization from a mixed solvent of heptane and Solmix A-11 (heptane/Solmix A-11=2/1 by volume) to obtain 3-chloro-2-fluoro-4-(trans-4-pentyl-cyclohexylmethoxy)-4′-propylbiphenyl (C264) as colorless crystals. The yield was 89.5% based on the compound (b67).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:10])=O)=[CH:4][C:3]=1[N:11]1[C:15]([CH:16]2[CH2:18][CH2:17]2)=[C:14]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:13]=[N:12]1.[CH3:24][NH2:25]>S(Cl)(Cl)=O.C(Cl)Cl.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:25][CH3:24])=[O:10])=[CH:4][C:3]=1[N:11]1[C:15]([CH:16]2[CH2:17][CH2:18]2)=[C:14]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:13]=[N:12]1
Reactant: CN
Reactant: CCOC(=O)c1cnn(-c2cc(C(=O)O)ccc2Cl)c1C1CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1cnn(-c2cc(C(=O)NC)ccc2Cl)c1C1CC1
Reaction time: 6 h
Yield: 77.1 %

Procedure:
A solution of ethyl 1-(2-chloro-5-hydroxycarbonylphenyl)-5-cyclopropyl-1H-pyrazole-4-carboxylate (1.32 g, 3.73 mmol) in thionyl chloride (7.5 mL) was heated at reflux for 2 h under a nitrogen atmosphere. The resulting solution was concentrated in vacuo. A solution of the residue in anhydrous CH2Cl2 (10 mL) under a nitrogen atmosphere was treated with methylamine (2 M solution in THF, 9.33 mL, 18.7 mmol) followed by a catalytic amount of 4-dimethylaminopyridine. The resulting mixture was stirred for 6 h and partitioned between ethyl acetate and HCl (1 M aq). The organic layer was washed with brine, NaHCO3 (sat aq sol), and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash 40M™ chromatography (75:25 ethyl acetate/hexanes) to afford 1.00 g (77% yield) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[N:6][CH:7]=1.OS(O)(=O)=O.C([O-])(O)=O.[Na+].[CH2:22](O)[CH3:23]>>[CH2:22]([O:10][C:9](=[O:11])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([NH2:1])=[CH:7][N:6]=1)[CH3:23]
Reactant: CCO
Reactant: Nc1ccc(CC(=O)O)nc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)Cc1ccc(N)cn1
Temperature: 25 °C
Reaction time: 16.5 h

Procedure:
To a solution of (5-amino-2-pyridinyl)acetic acid (1.46 g, 9.6 mmol, Daisley; R. W.; Hanbali, J. R., Synthetic Communications., 1981, 11 (9), 743.) in ethanol was added conc. H2SO4 and stirred for 16.5 h under hydrogen atmosphere at room temperature. The mixture was neutralized with saturated NaHCO3 aqueous solution and the solvent was removed. The mixture was diluted with water and extracted with ethyl acetate (5×20 ml). The organic layer was washed with brine, dried (MgSO4) and concentrated to give 1.2 g of title compound as brown oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([OH:19])=O)[CH:15]=3)[NH:10][N:9]=2)=[CH:4][CH:3]=1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH2:43]([CH2:45][NH2:46])[OH:44]>O1CCCC1.O.CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH:46][CH2:45][CH2:43][OH:44])=[O:19])[CH:15]=3)[NH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Reactant: NCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(NCCO)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.9 %

Procedure:
The title compound was prepared as described in Example 76. To a solution of 3-(4-fluorophenyl)-1H-indazole-5-carboxylic acid (0.200 g, 0.781 mmol) in tetrahydrofuran (5 mL) was added 1-hydroxybenzotriazole hydrate (0.316 g, 2.34 mmol) followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.449 g, 2.34 mmol), ethanolamine (0.141 mL, 2.34 mmol) and N,N-dimethylformamide (2 mL). The solution was stirred for 16 h at room temperature. Water (40 mL) was added and the solid was filtered and dried in a vacuum oven which gave the title compound (0.161 g, 69% yield): 1H NMR (DMSO-d6) δ 13.45 (s, 1H), 8.61 (t, 1H), 8.56 (s, 1H), 8.08 (AB quartet, 2H), 7.93 (dd, 1H), 7.62 (d, 1H), 7.40 (t, 2H), 4.76 (t, 1H), 3.54 (q, 2H), 3.80 (q, 2H); ES-MS (m/z) 300 [M+1]+.
Reaction SMILES: [NH:1]([C:3]1[NH:8][C:7](=[O:9])[N:6]([CH3:10])[C:5](=[O:11])[CH:4]=1)[NH2:2].[C:12]1([CH:22]=O)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1>CN(C=O)C>[CH3:10][N:6]1[C:5](=[O:11])[CH:4]=[C:3]([NH:1][N:2]=[CH:22][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)[NH:8][C:7]1=[O:9]
Reactant: Cn1c(=O)cc(NN)[nH]c1=O
Reactant: O=Cc1cccc2ccccc12
Solvent: CN(C)C=O
Product: Cn1c(=O)cc(NN=Cc2cccc3ccccc23)[nH]c1=O
Temperature: 25 °C

Procedure:
A solution of 84 mg (0.54 mmol) 6-hydrazino-3-methylpyrimidine-2,4(1H,3H)-dione and 84 mg (0.54 mmol) 1-naphthaldehyde in 3 mL DMF was heated to 70° C. for 30 min before cooling to room temperature affording a solution of 1-naphthaldehyde (1-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)hydrazone. Isonicotinaldehyde (110 mg, 1.0 mmol) and piperidine (50 μL, 0.6 mmol) were added, and the mixture was heated at 70° C. for 20 h. 1,1,1-trifluoro-2-iodoethane (130 μL, 1.3 mmol) and DBU (200 μL, 1.3 mmol) were added, and the mixture was heated at 90° C. for 20 h. Solvent was removed and the residue was purified by preparative reverse phase HPLC (30%-60% gradient of CH3CN-water with 0.1% TFA) to afford the title compound as the trifluoroacetate salt.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[NH2:11][C:12]1[N:17]=[C:16]([NH2:18])[CH:15]=[CH:14][N:13]=1>CC(C)=O>[C:5]1([C:3]2[N:11]=[C:12]3[N:17]=[C:16]([NH2:18])[CH:15]=[CH:14][N:13]3[CH:2]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: Nc1ccnc(N)n1
Reactant: O=C(CBr)c1ccccc1
Solvent: CC(C)=O
Product: Nc1ccn2cc(-c3ccccc3)nc2n1
Reaction time: 0.25 h

Procedure:
Bromoacetophenone (2.71 g, 14 mmol) was added to a solution of 2,4-diaminopyrimidine (1.00 g, 9 mmol) in acetone (40 ml), and the mixture was heated to reflux for 5 h. The cooled suspension was filtered, the precipitate was washed (acetone), and then stirred for 15 min in a mixture of 10 ml water and 15 ml NH4OH (25%). The suspension was filtered, washed (water), and dried under vacuum. The crude product (1.9 g, quant.) was used in the next step without further purification.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][OH:6])[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:14][S:15](Cl)(=[O:17])=[O:16].O>C(OCC)(=O)C>[CH3:14][S:15]([O:6][CH2:5][CH2:4][CH:1]1[CH2:3][CH2:2]1)(=[O:17])=[O:16]
Reactant: CS(=O)(=O)Cl
Reactant: OCCC1CC1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCC1CC1

Procedure:
A 0.5 g quantity of 2-cyclopropylethanol and 3.1 ml of triethylamine were dissolved in 10 ml of ethyl acetate, and 0.75 ml of methanesulfonyl chloride was added with ice-cooling and stirring. After stirring for 30 minutes, water was added to the reaction mixture and extraction was performed. The organic layer was washed with water twice and concentrated by removing the solvent under reduced pressure to give 1 g of pale yellow oily 2-cyclopropylethyl methanesulfonate.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[CH2:10][C@H:9]1[C:24]([OH:26])=O)=[O:7])(C)(C)C.[C:27]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:32]=[CH:31][C:30](C(O)=O)=[CH:29][CH:28]=1.[CH2:42]([N:44]([CH2:48][CH3:49])[CH2:45][CH2:46][NH2:47])[CH3:43]>>[C:36]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:37]=[CH:38][C:39]([C:6]([N:8]2[CH2:12][C:11](=[N:13][O:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)[CH2:10][C@H:9]2[C:24]([NH:47][CH2:46][CH2:45][N:44]([CH2:48][CH3:49])[CH2:42][CH3:43])=[O:26])=[O:7])=[CH:40][CH:41]=1
Reactant: CCN(CC)CCN
Reactant: COc1ccc(CON=C2C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C2)cc1
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1
Product: CCN(CC)CCNC(=O)[C@@H]1CC(=NOCc2ccc(OC)cc2)CN1C(=O)c1ccc(-c2ccccc2)cc1

Procedure:
Following the general method as outlined in Example 2, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-pyrrolidinecarboxylic acid, [1,1′-biphenyl]-4carboxylic acid, and N1,N1-diethyl-1,2-ethanediamine the title compound was obtained after column chromatography as an off-white solid as a mixture of E/Z-isomers.
Reaction SMILES: CI.CN([CH:6]=[O:7])C.[Br:8][C:9]1[C:18]([O:19][S:20]([C:23]([F:26])([F:25])[F:24])(=[O:22])=[O:21])=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=1O.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[Br:8][C:9]1[C:18]([O:19][S:20]([C:23]([F:26])([F:24])[F:25])(=[O:21])=[O:22])=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=1[O:7][CH3:6]
Reactant: CN(C)C=O
Reactant: COC(=O)c1cc(O)c(Br)c(OS(=O)(=O)C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Product: COC(=O)c1cc(OC)c(Br)c(OS(=O)(=O)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In a 1-liter egg plant-type flask, methyl iodide (6.67 mL, 105 mmol) was added to a DMF (200 mL) solution of methyl 4-bromo-3-hydroxy-5-{[(trifluoromethyl)sulfonyl]oxy}benzoate (19.9 g) and potassium carbonate (14.5 g, 105 mmol), and stirred at room temperature for 4 hours. The reaction solution was diluted with ethyl acetate, washed with water and saturated saline water, dried with sodium sulfate, filtered, and concentrated to obtain a crude product. This was purified through silica gel column chromatography (Biotage [SiO2, 40+M]) with a hexane/ethyl acetate developer system to obtain the title compound as a colorless solid.