Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:7].[OH-].[K+].[CH3:22][C:23]1C=CC(S(OCCC=C)(=O)=O)=[CH:25][CH:24]=1>CS(C)=O.CCOC(C)=O>[CH2:25]([N:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:6](=[O:7])[C:5]1[CH:15]=[CH:16][C:17]([O:18][CH3:19])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH2:24][CH:23]=[CH2:22]
Reactant: C=CCCOS(=O)(=O)c1ccc(C)cc1
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1OC
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: C=CCCN(C(=O)c1ccc(OC)c(OC)c1)c1ccccc1
Temperature: 80 °C
Yield: 50 %

Procedure:
To a solution of 3,4-dimethoxybenzanilide 33 (771 mg, 3 mmol) and KOH (4 equiv) in DMSO (6 mL) was added but-3-enyl 4-methylbenzenesulfonate (2.85 g, 4 equiv) [prepared as reported in the Journal of the American Chemical Society 2009, 6003] at room temperature and the mixture was heated at 80° C. for 72 h. The mixture was cooled, taken up in EtOAc and washed twice with water. The organic layer was dried over magnesium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography on SiO2 (gradient of diethylether in petroleum ether) to afford the title compound 34 (Yield 467 mg, 50%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=2)=[N:2]1.C(OC([N:28]1[CH2:33][CH2:32][CH:31]([NH2:34])[CH2:30][CH2:29]1)=O)(C)(C)C.O.ON1C2C=CC=CC=2N=N1.[ClH:46].C(N=C=NCCCN(C)C)C.CN1CCOCC1.Cl.CO>CO>[ClH:46].[ClH:46].[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:13]=[CH:14][C:15]([C:16]([NH:34][CH:31]3[CH2:32][CH2:33][NH:28][CH2:29][CH2:30]3)=[O:18])=[CH:19][CH:20]=2)=[N:2]1
Reactant: O=C(O)c1ccc(/C=C/c2n[nH]c3ccccc23)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN1CCOCC1
Solvent: CO
Product: O=C(NC1CCNCC1)c1ccc(/C=C/c2n[nH]c3ccccc23)cc1
Temperature: 60 °C
Yield: 69.3 %

Procedure:
The product obtained using (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid (500 mg, 1.66 mmol) obtained in Step 6 of Example 1, 1-tert-butoxycarbonyl-4-aminopiperidine (500 mg, 2.49 mmol), 1-hydroxybenzotriazole monohydrate (291 mg, 2.16 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (450 mg, 2.32 mmol) and N-methylmorpholine (0.37 mL, 3.32 mmol) in a similar manner to Example 5, was dissolved in methanol (2.00 mL), and the solution was added with 4 moL/L hydrogen chloride-methanol solution (1.50 mL), followed by heating under reflux at 60° C. for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from acetone to obtain Compound 120 (337 mg, 48%).
Reaction SMILES: [Cl:1][CH:2]([Cl:36])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([C@H:24]([NH:26]C(=O)OC(C)(C)C)[CH3:25])=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)[O:7]C1(C)C)=[O:4].C(O)(C(F)(F)F)=O>C(Cl)Cl.C1(C)C=CC=CC=1>[NH2:26][C@@H:24]([C:21]1[CH:22]=[CH:23][C:18]([C:15]2[CH:16]=[CH:17][C:12]([C@@H:8]([OH:7])[C@H:9]([NH:5][C:3](=[O:4])[CH:2]([Cl:36])[Cl:1])[CH2:10][F:11])=[CH:13][CH:14]=2)=[CH:19][CH:20]=1)[CH3:25]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)c1ccc(-c2ccc([C@H]3OC(C)(C)N(C(=O)C(Cl)Cl)[C@@H]3CF)cc2)cc1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](N)c1ccc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.4 %

Procedure:
To a solution of the product of step 1 (130 mg. 0.241 mmol) in DCM (3 mL) is added TFA (0.7 mL) and stirred at room temperature for 1 hour. Reaction is diluted with toluene (10 mL) and concentrated. The crude product is dissolved in DMF (2 mL) and DIPEA (200 μL), and purified using HPLC eluting from 5% acetonitrile/water to 100 acetonitrile/water to give the title compound (60 mg). 1H NMR (400 MHz, CD3OD) δ 1.69 (d, 3H, J=4.0 Hz), 4.31-4.41 (m, 1.5H), 4.44-4.55 (m, 1.5H) 4.56-4.63 (m, 0.5H), 4.68-4.74 (m, 0.5H), 5.02 (d, 1H, J=4.0 Hz) 6.31 (s, 1H), 7.48-7.57 (m, 4H), 7.63 (d, 2H, J=8.0 Hz), 7.72 (d, 2H, J=8.0 Hz). m/z (Cl) 382 [M-OH].
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Li][N:19]([Si](C)(C)C)[Si](C)(C)C.Cl>C1COCC1>[N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:17]=[CH:16][C:13]([C:14]([NH2:19])=[NH:15])=[CH:12][CH:11]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: [Li]N([Si](C)(C)C)[Si](C)(C)C
Reactant: N#Cc1ccc(OCCN2CCOCC2)cc1
Agent: Cl
Solvent: C1CCOC1
Product: N=C(N)c1ccc(OCCN2CCOCC2)cc1
Reaction time: 0.5 h
Yield: 93 %

Procedure:
4-(2-Morpholin-4-yl-ethoxy)-benzonitrile (Maybridge CC 42116)(2.7 g; 11.64 mmol) in THF (10 ml) is combined with LiN(TMS)2 (30 mmol; 30 ml of a 1M solution in THF) and stirred for 30 minutes at 55° C., kept at room temperature for 30 minutes and cooled to 5° C., while 3N HCl (28 ml) is added slowly. After 10 minutes the reaction mixture is washed with TBME and the aqueous phase is adjusted to pH ˜11 with solid NaOH, saturated with solid K2CO3 and extracted with TBME/MeOH (˜10:1) several times. The combined organic phases are dried over Na2SO4, filtered and evaporated to yield the title compound as yellow crystals (2.7 g; 93%). 1H-NMR (400 MHz; DMSO-d6): 7.72 (d, 2H); 6.96 (d, 2H); 6.31 (bs, 3H); 4.13 (t, 2H); 3.59 (m, 4H); 2.71 t, 2H); 2.49 (m, 4H). MS (m/z) ES+: 250 (MH+).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:10]1[N:14]([CH3:15])[CH:13]=[N:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[CH2:17][C:18]1[N:23]=[C:22]([NH2:24])[CH:21]=[CH:20][N:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>C(#N)C>[CH3:15][N:14]1[C:10]([C:3](=[N:2][O:1][CH2:17][C:18]2[N:23]=[C:22]([NH2:24])[CH:21]=[CH:20][N:19]=2)[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[CH:11][N:12]=[CH:13]1
Reactant: Cn1cncc1C(=NO)c1ccccc1
Reactant: Nc1ccnc(CCl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CC#N
Product: Cn1cncc1C(=NOCc1nccc(N)n1)c1ccccc1
Temperature: 25 °C
Reaction time: 29 h
Yield: 60.4 %

Procedure:
To a solution of N-hydroxy-1-(1-methyl-1H-imidazol-5-yl)-1-phenylmethanimine (3.90 g, 19.4 mmol) and 2-(chloromethyl)pyrimidin-4-amine (3.06 g, 21.3 mmol) in acetonitrile (50 mL) were added cesium carbonate (13.3 g, 40.7 mmol) and potassium iodide (322 mg, 1.93 mmol). After stirring at room temperature for 29 h, N-N-dimethylformamide (5 mL) was added and the mixture was further at room temperature for 72 h. The reaction mixture was filtered, the insolubles washed with acetone, and the filtrate concentrated in vacuo. Purification on silica gel afforded 2-[({[(1-methyl-1H-imidazol-5-yl)(phenyl)methylene]amino}oxy)methyl]pyrimidin-4-amine [3.61 g, yield 16%; HPLC/MS: m/z=309 (M+H); log P(HCOOH)<0.23].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]3([CH2:22][O:23][P:24]([C:30]([CH3:33])([CH3:32])[CH3:31])([C:26]([CH3:29])([CH3:28])[CH3:27])=[O:25])[CH2:20][O:19][C:18]([CH3:21])=[N:17]3)=[C:10]([Cl:34])[CH:9]=2)=[C:4]([F:35])[CH:3]=1.[CH3:36][C:37]1[CH:42]=[CH:41][C:40]([SH:43])=[CH:39][CH:38]=1.C(N(C(C)C)CC)(C)C.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd].O>[Cl:34][C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([S:43][C:40]3[CH:41]=[CH:42][C:37]([CH3:36])=[CH:38][CH:39]=3)=[CH:3][C:4]=2[F:35])[CH:13]=[CH:12][C:11]=1[CH2:14][CH2:15][C:16]1([CH2:22][O:23][P:24]([C:30]([CH3:33])([CH3:32])[CH3:31])([C:26]([CH3:29])([CH3:28])[CH3:27])=[O:25])[CH2:20][O:19][C:18]([CH3:21])=[N:17]1
Reactant: Cc1ccc(S)cc1
Reactant: CC1=NC(CCc2ccc(-c3ccc(Br)cc3F)cc2Cl)(COP(=O)(C(C)(C)C)C(C)(C)C)CO1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC1=NC(CCc2ccc(-c3ccc(Sc4ccc(C)cc4)cc3F)cc2Cl)(COP(=O)(C(C)(C)C)C(C)(C)C)CO1
Yield: 31.8 %

Procedure:
A solution of 4-[2-(4′-bromo-3-chloro-2′-fluorobiphenyl-4-yl)ethyl]-4-di(tert-butyl)phosphoryloxymethyl-2-methyl-2-oxazoline (0.41 g), 4-methylbenzenethiol (87 mg), diisopropylethylamine (180 mg), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (18.1 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (20.9 mg) in 1,4-dioxane (3 mL) was heated under reflux for 8 hr under a nitrogen atmosphere. Tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (18.1 mg) and Xantphos (20.9 mg) were added to the reaction mixture, and the mixture was further heated under reflux for 5 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (0.14 g) as a colorless oil.
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[N:9]([CH3:15])[CH:8]=[CH:7]2>C(O)(=O)C>[Br:1][C:7]1[C:6]2[C:11](=[CH:12][CH:13]=[C:4]([F:3])[CH:5]=2)[C:10](=[O:14])[N:9]([CH3:15])[CH:8]=1
Reactant: Cn1ccc2cc(F)ccc2c1=O
Reactant: BrBr
Solvent: CC(=O)O
Product: Cn1cc(Br)c2cc(F)ccc2c1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 84.3 %

Procedure:
Bromine (232 mg, 1.45 mmol, 0.097 mL) in acetic acid (1.0 mL) was added dropwise, quickly to 6-fluoro-2-methylisoquinolin-1-one (283 mg, 1.61 mmol) in acetic acid (7.0 mL) under N2 and cooled in an ice bath. The ice bath was removed and the thick suspension was stirred for 10 min at room temperature. Ice and water and ethyl acetate were added. Extractive work up with ethyl acetate, washing with aqueous 0.5 N NaOH, H2O, saturated aqueous KHSO4 and brine, gave the title compound as a cream solid (313 mg) which was carried on without purification.
Reaction SMILES: [CH2:1]([O:7][C:8]1[C:9](=[O:20])[O:10][C:11]2[C:18]([OH:19])=[CH:17][CH:16]=[CH:15][C:12]=2[C:13]=1[OH:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:21]([O:24][CH2:25][CH2:26][CH2:27]Br)(=[O:23])[CH3:22]>>[CH2:1]([O:7][C:8]1[C:9](=[O:20])[O:10][C:11]2[C:18]([O:19][CH2:27][CH2:26][CH2:25][O:24][C:21](=[O:23])[CH3:22])=[CH:17][CH:16]=[CH:15][C:12]=2[C:13]=1[OH:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCOc1c(O)c2cccc(O)c2oc1=O
Reactant: CC(=O)OCCCBr
Product: CCCCCCOc1c(O)c2cccc(OCCCOC(C)=O)c2oc1=O

Procedure:
In the same manner as in Reference Example 1, except that an equimolar amount of 3-hexyloxy-4,8-dihydroxy-2H-1-benzopyran-2-one was used in place of 3-ethoxy-4,5-dihydroxy-2H-1-benzopyran-2-one, and 3-bromopropyl acetate was used in place of 2-bromoethyl acetate in Reference Example 1, 3-hexyloxy-4-hydroxy-8-(3-acetoxypropyloxy)-2H-1-benzopyran-2-one was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7](F)=[C:6]([C:9]#[N:10])[CH:5]=[CH:4][N:3]=1.[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1>>[Cl:1][C:2]1[C:7]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:6]([CH:5]=[CH:4][N:3]=1)[C:9]#[N:10]
Reactant: C1CCNC1
Reactant: N#Cc1ccnc(Cl)c1F
Product: N#Cc1ccnc(Cl)c1N1CCCC1
Yield: 94 %

Procedure:
Prepared in 94% yield from 2-chloro-4-cyano-3-fluoropyridine and pyrrolidine according to the procedure described for Example 178A. MS (ESI+) m/z 207.9 (M+H)+; 1H NMR (DMSO-d6) δ 1.91-1.95 (m, 4H), 3.62-3.67 (m, 4H), 7.63 (d, J=4.7 Hz, 1H), 7.98 (d, J=4.7 HZ, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[C:5]2[CH2:14][CH2:15][CH2:16][C:4]=2[N:3]=1.[CH3:17][O:18][C:19]([C:21]1([C:25]2[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=2)[CH2:24][CH2:23][CH2:22]1)=[O:20]>C(O)(C)C>[CH3:17][O:18][C:19]([C:21]1([C:25]2[CH:26]=[CH:27][C:28]([NH:31][C:2]3[N:7]=[C:6]([N:8]4[CH2:13][CH2:12][O:11][CH2:10][CH2:9]4)[C:5]4[CH2:14][CH2:15][CH2:16][C:4]=4[N:3]=3)=[CH:29][CH:30]=2)[CH2:22][CH2:23][CH2:24]1)=[O:20]
Reactant: Clc1nc2c(c(N3CCOCC3)n1)CCC2
Reactant: COC(=O)C1(c2ccc(N)cc2)CCC1
Solvent: CC(C)O
Product: COC(=O)C1(c2ccc(Nc3nc4c(c(N5CCOCC5)n3)CCC4)cc2)CCC1
Yield: 21 %

Procedure:
A solution of 2-chloro-4-morpholin-4-yl-6,7-dihydro-5H-cyclopentapyrimidine (0.53 g, 2.8 mmol) and 1-(4-amino-phenyl)-cyclobutanecarboxylic acid methyl ester (0.57 g, 2.8 mmol) in anhydrous isopropanol (10 mL) was stirred under reflux for 18 hours. After cooling to a temperature in the range of 25° C. to 40° C., the mixture was concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel) to afford the title compound as a white solid (0.24 g, 27% yield).
Reaction SMILES: [CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[N:17]=[C:16]([NH:18][C:19]4[CH:24]=[CH:23][C:22]5[O:25][CH2:26][CH2:27][O:28][C:21]=5[CH:20]=4)[C:15]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:14][N:13]=3)=[CH:4][C:3]=2[O:2]1.C1COC2C=CC(NC3N=C(NC4C=CC5OCCOC=5C=4)C(Br)=CN=3)=CC=2[O:36]1.OC1C=CC(B(O)O)=CC=1>>[CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[N:17]=[C:16]([NH:18][C:19]4[CH:24]=[CH:23][C:22]5[O:25][CH2:26][CH2:27][O:28][C:21]=5[CH:20]=4)[C:15]([C:29]4[CH:34]=[CH:33][C:32]([OH:36])=[CH:31][CH:30]=4)=[CH:14][N:13]=3)=[CH:4][C:3]=2[O:2]1
Reactant: Brc1cnc(Nc2ccc3c(c2)OCCO3)nc1Nc1ccc2c(c1)OCCO2
Reactant: c1ccc(-c2cnc(Nc3ccc4c(c3)OCCO4)nc2Nc2ccc3c(c2)OCCO3)cc1
Agent: OB(O)c1ccc(O)cc1
Product: Oc1ccc(-c2cnc(Nc3ccc4c(c3)OCCO4)nc2Nc2ccc3c(c2)OCCO3)cc1

Procedure:
In a manner similar to the preparation of N2,N4-bis(3,4-ethylenedioxyphenyl)-5-phenyl-2,4-pyrimidinediamine, N2,N4-bis(3,4-ethylenedioxyphenyl)-5-bromo-2,4-pyrimidinediamine and 4-hydroxyphenylboronic acid were reacted to yield N2,N4-bis(3,4-ethylenedioxyphenyl)-5-(4-hydroxyphenyl)-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 9.53 (s, 1H), 8.92 (s, 1H), 7.78 (s, 1H), 7.74 (bs, 1H), 7.24 (bs, 1H), 7.22 (d, 2H, J=8.7 Hz), 7.12-7.09 (m, 2H), 6.97 (dt, 1H, J=2.4 and 8.7 Hz), 6.83 (d, 2H, J=8.4 Hz), 6.72 (d, 1H, J=8.1 Hz), 6.62 (d, 1H, J=9.0 Hz), 4.19 (s, 4H), 4.17 (s, 4H); LCMS: ret. time: 23.51 min.; purity: 95%; MS (m/e): 471 (MH+).
Reaction SMILES: CS(O[CH2:6][C@@H:7]1[N:12]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([OH:28])([C:24]([F:27])([F:26])[F:25])[C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=2)[CH2:11][CH2:10][N:9]([C:29]([O-:31])=[O:30])[CH2:8]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].[C:38]1([SH:44])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C(#N)C>[C:38]1([S:44][CH2:6][C@@H:7]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([OH:28])([C:24]([F:25])([F:26])[F:27])[C:20]([F:23])([F:21])[F:22])=[CH:15][CH:14]=3)[CH2:11][CH2:10][N:9]([C:29]([O:31][C:16]([CH3:19])([CH3:17])[CH3:15])=[O:30])[CH2:8]2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CS(=O)(=O)OC[C@H]1CN(C(=O)[O-])CCN1c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Reactant: Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)[C@@H](CSc2ccccc2)C1
Temperature: 120 °C
Yield: 122.8 %

Procedure:
A 5 mL vial was charged with (3R)-3-(((methylsulfonyl)oxy)methyl)-4-(4-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)phenyl)-1-piperazinecarboxylate (0.300 g, 0.559 mmol), potassium carbonate (0.190 g, 1.38 mmol), benzenethiol (0.070 mL, 0.69 mmol, Sigma-Aldrich, St. Louis, Mo.) and acetonitrile (2 mL). The reaction mixture was heated in an Initiator microwave reactor (Biotage AB, Inc., Uppsala, Sweden) at 120° C. for 30 min. The reaction mixture was partitioned between water (20 mL) and EtOAc (20 mL). The aqueous phase was extracted with EtOAc (20 mL). The combined organic phases were washed with saturated aqueous NaCl (40 mL). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (25 g of silica, 0-30% EtOAc in hexanes) to afford tert-butyl (3R)-3-((phenylsulfanyl)methyl)-4-(4-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)phenyl)-1-piperazinecarboxylate (0.189 g) as a white solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[CH:9][CH:10]=2)[N:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:4]=1[C:22]([O:24][CH3:25])=[O:23].[Cl:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](Cl)=[O:31].C(N(CC)CC)C>C(Cl)Cl>[CH3:25][O:24][C:22]([C:4]1[N:5]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:6]2[C:11]([C:12](=[O:13])[C:3]=1[CH2:2][NH:1][C:30](=[O:31])[C:29]1[CH:33]=[CH:34][CH:35]=[C:27]([Cl:26])[CH:28]=1)=[CH:10][CH:9]=[C:8]([O:14][CH3:15])[CH:7]=2)=[O:23]
Reactant: COC(=O)c1c(CN)c(=O)c2ccc(OC)cc2n1-c1ccccc1
Reactant: O=C(Cl)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1c(CNC(=O)c2cccc(Cl)c2)c(=O)c2ccc(OC)cc2n1-c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of methyl 3-(aminomethyl)-7-methoxy-4-oxo-1-phenyl-1,4-dihydroquinoline-2-carboxylate (intermediate K) (30 mg, 0.089 mmol), 3-chlorobenzoyl chloride (35 mg, 0.200 mmol), and triethylamine (40 mg, 0.305 mmol) in methylene chloride (4 mL) was stirred at 0° C. for 1 hr. After this time, the reaction mixture was concentrated, and the crude material was triturated with diethyl ether. The product 3-[(3-chloro-benzoylamino)-methyl]-7-methoxy-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid methyl ester was obtained without further purification. MS calcd. for C26H21ClN2O5 [(M+H)+] 477.1, obsd. 476.9.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[N:11]=[C:12]=[O:13].[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1>C(Cl)Cl>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([NH:11][C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[O:13])[CH:4]=1
Reactant: C1CCNC1
Reactant: O=C=Nc1cc([N+](=O)[O-])ccc1F
Solvent: ClCCl
Product: Nc1ccc(F)c(NC(=O)N2CCCC2)c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A mixture of 1-fluoro-2-isocyanato-4-nitrobenzene (1.125 g, 6.18 mmoles) and pyrrolidine (485 mg, 6.8 mmoles) in DCM (20 mL) was stirred at r.t. for 14 hrs. After concentrated, the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous citric acid solution and dried over MgSO4, followed by hydrogenation with Pd/C (wet, 10%, 0.15 g) under a hydrogen balloon overnight. After filtration and concentration, the reasonable pure N-(5-amino-2-fluorophenyl)pyrrolidine-1-carboxamide (3, 1.44 g) was used for the next reactions. MS+: 224.2, UV: λ=271.6 nm. 1H NMR: (DMSO) δ7.44 (s, 1H), δ6.78 (m, 1H), δ6.20 (m, 1H), δ3.32 (m, 4H), δ1.83 (m, 4H).
Reaction SMILES: [N:1]1([C:5](=[O:22])[CH2:6][C:7]2[CH:12]=[CH:11][C:10]([O:13]CC3C=CC=CC=3)=[CH:9][C:8]=2[Cl:21])[CH2:4][CH2:3][CH2:2]1>C(O)C.[OH-].[OH-].[Pd+2]>[N:1]1([C:5](=[O:22])[CH2:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=2[Cl:21])[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cc1ccc(OCc2ccccc2)cc1Cl)N1CCC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: O=C(Cc1ccc(O)cc1Cl)N1CCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(azetidin-1-yl)-2-[4-(benzyloxy)-2-chlorophenyl]ethanone (520 mg, 1.65 mmol) was dissolved in ethanol (2 ml). and palladium hydroxide on carbon (20%) (116 mg, 0.165 mmol) added. The mixture was stirred under an atmosphere of hydrogen gas at RT overnight. The mixture was filtered and the filtrate concentrated under reduced pressure. The reside was purified by column chromatography using a Biotage RP C18 cartridge (30 g) using a gradient eluant of 10-100% water:acetonitrile+0.05% formic acid. to afford the title compound. LC/MS (m/z): 226 (M+H)+.
Reaction SMILES: [H-].[Na+].CS(C)=O.[I-].[CH3:8][S+](C)C.[CH:12]1[N:13]=[CH:14][N:15]2[CH2:20][CH2:19][CH2:18][C:17](=[O:21])[C:16]=12>CCCCC.O1CCCC1.CN(C)C=O.[Cl-].[Na+].O>[O:21]1[CH2:8][C:17]21[CH2:18][CH2:19][CH2:20][N:15]1[CH:14]=[N:13][CH:12]=[C:16]21
Reactant: C[S+](C)C
Reactant: O=C1CCCn2cncc21
Agent: [Cl-]
Agent: [H-]
Agent: [I-]
Solvent: CCCCC
Solvent: O
Solvent: C1CCOC1
Product: c1ncn2c1C1(CCC2)CO1
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
Sodium hydride (22 mmol) washed with pentane is admixed under argon with 20 ml of dimethyl sulphoxide. The mixture is heated at 60° C. for an hour and then diluted with 5 ml of tetrahydrofuran. The mixture is cooled to 0° C. and a solution of 21 mmol of trimethyl-sulphonium iodide in 5 ml of N,N-dimethylformamide is added at 0° C., after which the mixture is stirred for 10 minutes. A solution of 20 mmol of 6,7-dihydro-5H-imidazo[1,5-a]pyridin-8-one [426219-51-4] in 5 ml of N,N-dimethylformamide is added and the reaction mixture is stirred at 60° C. for 18 hours. The reaction mixture is poured into cold brine and extracted with tert-butyl methyl ether. The combined organic phases are washed with brine, dried with sodium sulphate and evaporated. From the residue the title compound is identified by means of flash chromatography (SiO2 60 F) on the basis of the Rf value.
Reaction SMILES: C[N:2]1[CH2:7][CH2:6][C:5]([C:19]#[CH:20])([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[N+:16]([O-:18])=[O:17])[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].Cl[C:28]([O:30][CH2:31][CH3:32])=[O:29]>C1C=CC=CC=1>[CH2:31]([O:30][C:28]([N:2]1[CH2:7][CH2:6][C:5]([C:19]#[CH:20])([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[N+:16]([O-:18])=[O:17])[CH2:4][CH2:3]1)=[O:29])[CH3:32]
Reactant: C#CC1(Oc2ccc(F)cc2[N+](=O)[O-])CCN(C)CC1
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Product: C#CC1(Oc2ccc(F)cc2[N+](=O)[O-])CCN(C(=O)OCC)CC1
Yield: 83.9 %

Procedure:
A suspension of 223 g of N-methyl-4-ethynyl-4-(4-fluoro-2-nitrophenoxy)piperidine, 2 l of dry benzene, 165 g of anhydrous potassium carbonate and 130.3 g of ethyl chloroformate was stirred at reflux for 18 hr under nitrogen. The mixture was filtered and the solvent evaporated. The residue was dissolved in ether, washed with hydrochloric acid, saturated sodium bicarbonate solution, water and saturated sodium chloride solution. The ether solution was dried over anhydrous sodium sulfate and filtered. Evaporation of solvent provided an oil, which was dried at 50°-55° (1 mm). The oil crystallized to provide 226 g (83.8%) of product, mp 56°-68°.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[C:12]([C:15]1[N:19]2[N:20]=[C:21]([C:24](=O)[CH3:25])[CH:22]=[CH:23][C:18]2=[N:17][CH:16]=1)([OH:14])[CH3:13].Cl.[NH2:28][NH:29][C:30]([NH2:32])=[O:31].C(N(CC)CC)C>CO>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[C:12]([C:15]1[N:19]2[N:20]=[C:21](/[C:24](=[N:28]/[NH:29][C:30]([NH2:32])=[O:31])/[CH3:25])[CH:22]=[CH:23][C:18]2=[N:17][CH:16]=1)([OH:14])[CH3:13]
Reactant: CC(=O)c1ccc2ncc(C(C)(O)c3cc4cccnc4cc3F)n2n1
Reactant: NNC(N)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: C/C(=N\NC(N)=O)c1ccc2ncc(C(C)(O)c3cc4cccnc4cc3F)n2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.7 %

Procedure:
To a solution of 1-(3-(1-(7-fluoroquinolin-6-yl)-1-hydroxyethyl)imidazo[1,2-b]pyridazin-6-yl)ethanone (35 mg, 0.09 mmol) in methanol (20 mL) was added semicarbazide hydrochloride (20 mg, 0.18 mmol). Triethyl amine was added dropwise to adjust the pH to 5-6. The reaction mixture was stirred at room temperature overnight. The solution was concentrated in reduced pressure and the residue was purified by column chromatography (3%-50% MeOH in CH2Cl2) to afford 23 mg (yield: 62%) title compound. 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.47 (s, 1H), 8.87 (d, 1H), 8.52 (m, 2H), 8.06 (d, 1H), 7.92 (d, 1H), 7.85 (s, 1H), 7.54 (m, 2H), 6.62 (b, 2H), 6.24 (s, 1H), 2.13 (s, 3H), 1.53 (s, 3H). LCMS (method A): [MH]+=408, tR=4.03 min.