Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][S:16]([C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[C:20]=2[O:27][CH2:28][CH:29]=[CH2:30])(=[O:18])=[O:17])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[CH2:28]([O:27][C:20]1[C:21]([Cl:26])=[CH:22][C:23]([Cl:25])=[CH:24][C:19]=1[S:16]([NH:15][C:6]1([C:4]([OH:5])=[O:3])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)(=[O:18])=[O:17])[CH:29]=[CH2:30]
Reactant: C=CCOc1c(Cl)cc(Cl)cc1S(=O)(=O)NC1(C(=O)OCC)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C=CCOc1c(Cl)cc(Cl)cc1S(=O)(=O)NC1(C(=O)O)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.6 %

Procedure:
The mixture of 2-(2-allyloxy-3,5-dichloro-benzenesulfonylamino)-indan-2-carboxylic acid ethyl ester (33) (143 mg, 0.30 mmol) and KOH (500 mg, 8.9 mmol) is dissolved in EtOH (5 mL) and water (0.5 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 8 h. After concentration in vacuo, the residue is dissolved in water (20 mL) and acidified with conc. HCl until pH˜3. After filtration, the solid is purified by HPLC to give a pure product (34) as white solid (91 mg, 69%).
Reaction SMILES: ClCCl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:23][C:24]1[CH:25]=[C:26]([C:41]2[CH:42]=[CH:43][C:44]([CH2:47]O)=[N:45][CH:46]=2)[CH:27]=[C:28]([NH:30][C:31]2[N:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[CH:33][N:32]=2)[CH:29]=1.C(Br)(Br)(Br)[Br:50]>S([O-])([O-])(=O)=S.[Na+].[Na+]>[Br:50][CH2:47][C:44]1[N:45]=[CH:46][C:41]([C:26]2[CH:27]=[C:28]([NH:30][C:31]3[N:36]=[C:35]([C:37]([F:38])([F:40])[F:39])[CH:34]=[CH:33][N:32]=3)[CH:29]=[C:24]([CH3:23])[CH:25]=2)=[CH:42][CH:43]=1
Reactant: BrC(Br)(Br)Br
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2ccc(CO)nc2)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2ccc(CBr)nc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dichloromethane (3.24 mL) and triphenylphosphine (0.459 g, 1.75 mmol) was added to [5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]methanol (0.35 g, 0.971 mmol). Carbon tetrabromide (0.451 g, 1.36 mmol) was added slowly to the reaction mixture and stirred for 8 hours at room temperature. The reaction mixture was diluted with 10% sodium thiosulfate (5.00 mL) and the organic layer was separated, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/hexanes) to yield N-{3-[6-(bromomethyl)pyridin-3-yl]-5-methylphenyl}-4-(trifluoromethyl)pyrimidin-2-amine. MS APCI calc'd for C18H15BrF3N4 [M+H]+ 423 and 425. found 423 and 425.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[N:6][CH:7]=1.F[C:10]1[C:15]([C:16]2[N:21]=[C:20]([CH3:22])[N:19]=[C:18]([N:23]([CH2:33][C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=3)[CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[N:17]=2)=[CH:14][CH:13]=[CH:12][N:11]=1>>[CH3:41][O:40][C:37]1[CH:36]=[CH:35][C:34]([CH2:33][N:23]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)[C:18]2[N:19]=[C:20]([CH3:22])[N:21]=[C:16]([C:15]3[C:10]([NH:8][C:4]4[CH:5]=[N:6][CH:7]=[C:2]([CH3:1])[CH:3]=4)=[N:11][CH:12]=[CH:13][CH:14]=3)[N:17]=2)=[CH:39][CH:38]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3F)n2)cc1
Reactant: Cc1cncc(N)c1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3Nc3cncc(C)c3)n2)cc1
Yield: 25.7 %

Procedure:
The title compound was prepared in an analogous manner to that described in Example 164 using 5-methylpyridin-3-amine (0.075 g, 0.690 mmol) (Aldrich) and 4-(2-fluoropyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine. Purification using an ISCO Combiflash Companion (12 g column, 30-70% EtOAc in hexanes over 30 min; the product eluted with 45% EtOAc) gave the title compound as a yellow amorphous solid (25.7%). 1H NMR (400 MHz, d6-DMSO) δ 11.93 (s, 1H); 8.81 (dd, J=7.8, 1.8 Hz, 1H); 8.61 (d, J=2.3 Hz, 1H); 8.39 (dd, J=4.7, 2.0 Hz, 1H); 8.02 (s, 1H); 7.93 (s, 1H); 7.25 (dd, J=10.2, 8.8 Hz, 4H); 6.85-7.00 (m, 5H); 4.82 (d, J=14.7 Hz, 4H); 3.74 (s, 3H); 3.71 (s, 3H); 2.59 (s, 3H); 2.26 (s, 3H). m/z (ESI, +ve ion) 534.0 (M+H)+.
Reaction SMILES: OC1C=CC([CH:8]2[CH:13]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]4[O:24][CH2:23][C:22](=[O:25])[N:21]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:20]=4[CH:31]=3)[CH2:12][CH2:11][CH2:10][N:9]2[C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])=CC=1.C1(C)C=CC(S([O:51][CH2:52][CH2:53][O:54][C:55]2[CH:60]=[CH:59][CH:58]=[C:57]([O:61][CH3:62])[CH:56]=2)(=O)=O)=CC=1>>[CH3:62][O:61][C:57]1[CH:56]=[C:55]([CH:60]=[CH:59][CH:58]=1)[O:54][CH2:53][CH2:52][O:51][C:16]1[CH:17]=[CH:18][C:19]([CH:12]2[CH2:11][CH2:10][N:9]([C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:33])[CH2:8][CH:13]2[O:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]3[O:24][CH2:23][C:22](=[O:25])[N:21]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:20]=3[CH:31]=2)=[CH:20][CH:31]=1
Reactant: COCCCN1C(=O)COc2ccc(COC3CCCN(C(=O)OCc4ccccc4)C3c3ccc(O)cc3)cc21
Reactant: COc1cccc(OCCOS(=O)(=O)c2ccc(C)cc2)c1
Product: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OCCOc4cccc(OC)c4)cc3)cc21

Procedure:
Analogously to Method I, 0.500 g of benzyl 4-hydroxyphenyl-3-[4-(3-methoxypropyl)-3-oxo-3,4-dihydro-2H-benz[1,4]oxazin-6-ylmethoxy]piperidinecarboxylate and 0.414 g of 2-(3-methoxyphenoxy)ethyl toluene-4-sulphonate are reacted. The title compound is obtained as a colourless oil. Rf=0.31 (2:1 EtOAc-heptane); Rt=5.51.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([S:13]([N:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]3[S:25][C:26]4[CH2:27][NH:28][CH:29]([CH3:33])[CH2:30][C:31]=4[N:32]=3)=[O:23])[CH2:18][CH2:17]1)(=[O:15])=[O:14])[CH:7]=[CH:6]2.[OH-:34].[Na+].OO>CC(C)=O>[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([S:13]([N:16]1[CH2:17][CH2:18][N:19]([C:22]([C:24]3[S:25][C:26]4[CH2:27][NH:28][CH:29]([CH3:33])[CH2:30][C:31]=4[N+:32]=3[O-:34])=[O:23])[CH2:20][CH2:21]1)(=[O:14])=[O:15])[CH:7]=[CH:6]2
Reactant: [OH-]
Reactant: CC1Cc2nc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3)sc2CN1
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: CC(C)=O
Product: CC1Cc2c(sc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3)[n+]2[O-])CN1
Temperature: 25 °C
Reaction time: 192 h

Procedure:
In acetone (10 ml), 1-[(6-chloronaphthalen-2-yl)sulfonyl]-4-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine hydrochloride (400 mg) was suspended, followed by the addition of a 1N aqueous solution (0.38 ml) of sodium hydroxide and a 30% aqueous solution (3.50 ml) of hydrogen peroxide. The resulting mixture was stirred at room temperature for 8 days. After the reaction mixture was concentrated under reduced pressure, the residue was purified by chromatography through a synthetic adsorbent (“Diaion® HP-20”, trade name; water˜water : acetonitrile=2:5), whereby the title compound (84 mg, 39%) was obtained.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:8]2[C:20]3[NH:19][C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12]=3[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[OH-].C([N+]([CH2:29][CH3:30])(CC)CC)C>CC(C)=O.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>[C:30]1([C:9]2[CH:10]=[CH:11][C:12]3[C:13]4[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=4)[NH:19][C:20]=3[C:8]=2[C:4]2[CH:3]=[CH:2][CH:7]=[CH:6][CH:5]=2)[CH:29]=[CH:6][CH:7]=[CH:2][CH:3]=1
Reactant: Ic1cccc(-c2cccc3c2[nH]c2ccccc23)c1
Reactant: CC[N+](CC)(CC)CC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [OH-]
Solvent: CC(C)=O
Product: c1ccc(-c2ccc3c([nH]c4ccccc43)c2-c2ccccc2)cc1
Temperature: 70 °C

Procedure:
91 g (242 mmol) of 3-iodophenylcarbazole 18 and 91 g (246 mmol) of phenylcarbazoleboronic ester 19 are suspended in acetone, and a 350 ml of 20% tetraethylammonium hydroxide solution (493 mmol) are added, the mixture is carefully degassed using argon. 4.6 g (4 mmol) of tetrakistriphenylphosphinepalladium are subsequently added. The reaction is heated to 70° C. The progress of the reaction is followed by means of thin-layer chromatography. When the reaction is complete, the batch is cooled to room temperature, and the precipitated product is filtered off with suction. The crude product is recrystallised from acetonitrile, giving a beige solid.
Reaction SMILES: C(=O)(OC)[O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([F:12])=[CH:5][C:4]=1[Br:13].[OH-].[K+].Cl>CO>[Br:13][C:4]1[CH:5]=[C:6]([F:12])[C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:3]=1[OH:2]
Reactant: COC(=O)Oc1cc([N+](=O)[O-])c(F)cc1Br
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=[N+]([O-])c1cc(O)c(Br)cc1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.7 %

Procedure:
To a solution of 2-bromo-4-fluoro-5-nitrophenyl methyl carbonate (8.90 g, 30.27 mmol) in methanol (100 mL) was added KOH (4.25 g, 75.68 mmol) portionwise at 0° C. After the addition was complete the reaction mixture was allowed to warm to room temperature and stirred for 1.5 h. The reaction mixture was acidified by 1N HCl. The solvent was evaporated and water was added. The aqueous layer was extracted with DCM (3×10 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated to give 2-bromo-4-fluoro-5-nitro-phenol (7.05 g, 99%). 1H NMR (400 MHz, CDCl3) δ 7.75 (d, J=6.6 Hz, 1H), 7.51 (d, J=9.6 Hz, 1H), 5.62 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([N:10]2[CH2:21][CH2:20][N:19]3[C:12](=[CH:13][C:14]4[CH2:15][C:16]([CH3:23])([CH3:22])[CH2:17][C:18]=43)[C:11]2=[O:24])[C:7]=1[CH:8]=[O:9].[CH3:25][N:26]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[C:28]([NH:41][C:42]2[CH:51]=[C:45]3[CH2:46][N:47]([CH3:50])[CH2:48][CH2:49][N:44]3[N:43]=2)[C:27]1=[O:52].C([O-])(=O)C.[K+].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C>[CH3:22][C:16]1([CH3:23])[CH2:15][C:14]2[CH:13]=[C:12]3[N:19]([CH2:20][CH2:21][N:10]([C:6]4[CH:5]=[N:4][CH:3]=[C:2]([C:30]5[CH:29]=[C:28]([NH:41][C:42]6[CH:51]=[C:45]7[CH2:46][N:47]([CH3:50])[CH2:48][CH2:49][N:44]7[N:43]=6)[C:27](=[O:52])[N:26]([CH3:25])[CH:31]=5)[C:7]=4[CH:8]=[O:9])[C:11]3=[O:24])[C:18]=2[CH2:17]1
Reactant: CN1CCn2nc(Nc3cc(B4OC(C)(C)C(C)(C)O4)cn(C)c3=O)cc2C1
Reactant: CC1(C)Cc2cc3n(c2C1)CCN(c1cncc(Br)c1C=O)C3=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: CN1CCn2nc(Nc3cc(-c4cncc(N5CCn6c(cc7c6CC(C)(C)C7)C5=O)c4C=O)cn(C)c3=O)cc2C1
Temperature: 110 °C
Yield: 49.4 %

Procedure:
A 25-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 3-bromo-5-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}pyridine-4-carbaldehyde 107f (233 mg, 0.60 mmol), 1-methyl-3-({5-methyl-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}amino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydropyridin-2-one 135a (231 mg, 0.60 mmol), Pd(dppf)Cl2 (49 mg, 0.060 mmol), potassium acetate (118 mg, 1.2 mmol), K3PO4.trihydrate (320 mg, 1.2 mmol), acetonitrile (12 mL), and water (5 drops). After three cycles of vacuum/argon flush, the mixture was heated at 110° C. for 2 h. It was then filtered and the filtrate was evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 30:1 dichloromethane/methanol to afford 150a (168 mg, 49%) as a solid. MS-ESI: [M+H]+ 567
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:40]([O:42]C(C)(C)C)=[O:41])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]4[CH:25]=[CH:24][S:23][C:22]=4[C:26]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[O:27])=[CH:18][C:17]4[CH:34]=[C:35]([O:38][CH3:39])[CH:36]=[CH:37][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O.C1C=CC=CC=1>ClCCCl>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:40]([OH:42])=[O:41])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]4[CH:25]=[CH:24][S:23][C:22]=4[C:26]([N:28]4[CH2:29][CH2:30][O:31][CH2:32][CH2:33]4)=[O:27])=[CH:18][C:17]4[CH:34]=[C:35]([O:38][CH3:39])[CH:36]=[CH:37][C:16]=4[C:15]=23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1ccc2c(c1)C=C(c1ccsc1C(=O)N1CCOCC1)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)OC(C)(C)C)cc21
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Solvent: c1ccccc1
Product: COc1ccc2c(c1)C=C(c1ccsc1C(=O)N1CCOCC1)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)O)cc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 119.3 %

Procedure:
In a 2 dram vial, dissolve tert-Butyl 13-cyclohexyl-3-methoxy-6-(2-(4-morpholinylcarbonyl)-3-thienyl)-7H-indolo[2,1-a][2]benzazepine-10-carboxylate (37.7 mg, 0.059 mmol) in 1,2-Dichloroethane (1 mL) add TFA (1 mL, 12.98 mmol). The reaction was capped under a nitrogen atmosphere and stirred at room temperature for 1.5 hrs. Transfer reaction contents to a 25 mL pear flask using benzene to rinse. Remove volatiles in vacuo. Dissolve product in benzene and rotovap to aid in trace TFA removal. Obtained 41 mg of title compound as a yellow brown film. A LC-MS was obtained to confirm product and the product used in the next step without further purification. LC-MS: Shimadzu Analytical HPLC using Discovery VP software: % A=5% acetonitrile, 95% water, 10 mmol Ammonium Acetate % B=95% acetonitrile, 5% water, 10 mmol Ammonium Acetate; Initial % B=0; Final % B=100; Gradient=3 min; Runtime=5 min; Flow rate=5 ml/min; Wavelength=220 nm; Column=Waters Xterra, 3 mm×50 mm, S7. Retention Time=1.73 min, MS m/z 583 (MH+), m/z 581 (M−H)−.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][OH:8])[CH:2]=1.[Cl:9][C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[S:17]([NH:20][C:21]1[C:26](Cl)=[N:25][C:24]([Cl:28])=[CH:23][N:22]=1)(=[O:19])=[O:18]>>[Cl:28][C:24]1[N:25]=[C:26]([O:8][CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[C:21]([NH:20][S:17]([C:11]2[CH:12]=[CH:13][CH:14]=[C:15]([Cl:16])[C:10]=2[Cl:9])(=[O:19])=[O:18])=[N:22][CH:23]=1
Reactant: O=S(=O)(Nc1ncc(Cl)nc1Cl)c1cccc(Cl)c1Cl
Reactant: OCc1cccnc1
Product: O=S(=O)(Nc1ncc(Cl)nc1OCc1cccnc1)c1cccc(Cl)c1Cl

Procedure:
Prepared by the method of Example 31 using pyridine-3-methanol (0.13 g) and 2,3-dichloro-N-(3,5-dichloro-2-pyrazinyl)benzenesulphonamide (Example 74) (0.3 g). Yield 0.19 g.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[C:3]=1[CH3:19].[Br:20][C:21]1[CH:22]=[CH:23][C:24]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[C:25]([NH2:27])[CH:26]=1.Cl.O1CCOCC1>CN1C(=O)CCC1>[Br:20][C:21]1[CH:22]=[CH:23][C:24]([N:28]2[CH2:29][CH2:30][O:31][CH2:32][CH2:33]2)=[C:25]([NH:27][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[F:18])[C:3]=2[CH3:19])[CH:26]=1
Reactant: Cc1c(-c2ccccc2F)nc2ccccc2c1Cl
Reactant: Nc1cc(Br)ccc1N1CCOCC1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: C1COCCO1
Product: Cc1c(-c2ccccc2F)nc2ccccc2c1Nc1cc(Br)ccc1N1CCOCC1

Procedure:
Prepared according to Procedure K, Method 2 using 4-chloro-2-(2-fluorophenyl)-3-methylquinoline (230 mg, 848 μmol), 5-bromo-2-morpholinobenzenamine (109 mg, 424 μmol) and 4N hydrochloric acid solution in dioxane (0.011 mL, 42 μmol) in NMP (0.50 mL) to afford a colorless solid upon purification by chromatography on silica gel, eluting with EtOAc gradient in hexane. Mass Spectrum (ESI) m/e=492.1 & 494.1 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[O:8][C:9]3[C:14]([C@@:15]4([CH2:19][O:18][C:17]([NH2:20])=[N:16]4)[C:4]=2[CH:3]=1)=[CH:13][C:12]([C:21]1[C:22]([F:27])=[N:23][CH:24]=[CH:25][CH:26]=1)=[CH:11][CH:10]=3.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[O:36]1[CH2:41][CH:40]=[C:39](B2OC(C)(C)C(C)(C)O2)[CH2:38][CH2:37]1>O1CCOCC1.O.CCOC(C)=O.C([O-])([O-])=O.[Na+].[Na+].CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[O:36]1[CH2:37][CH:38]=[C:39]([C:2]2[N:7]=[CH:6][C:5]3[O:8][C:9]4[C:14]([C@@:15]5([CH2:19][O:18][C:17]([NH2:20])=[N:16]5)[C:4]=3[CH:3]=2)=[CH:13][C:12]([C:21]2[C:22]([F:27])=[N:23][CH:24]=[CH:25][CH:26]=2)=[CH:11][CH:10]=4)[CH2:40][CH2:41]1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: NC1=N[C@@]2(CO1)c1cc(-c3cccnc3F)ccc1Oc1cnc(Cl)cc12
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: NC1=N[C@@]2(CO1)c1cc(-c3cccnc3F)ccc1Oc1cnc(C3=CCOCC3)cc12
Temperature: 120 °C

Procedure:
A glass microwave reaction vessel was charged with (S)-3-chloro-7-(2-fluoropyridin-3-yl)-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-oxazol]-2′-amine (0.075 g, 0.196 mmol), potassium phosphate (0.125 g, 0.588 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.082 g, 0.392 mmol) and Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II) (0.014 g, 0.020 mmol) in dioxane (1.2 mL) and water (0.40 mL). The reaction mixture was stirred and heated in microwave at 120° C. for 30 min. The mixture was diluted with EtOAc and saturated Na2CO3. The organic layer was washed twice with saturated Na2CO3, dried over Na2SO4 and concentrated in vacuo. The crude was purified by silica gel chromatography (12 g, 2-10% MeOH-DCM, then 10% MeOH-DCM) provided (S)-3-(3,6-dihydro-2H-pyran-4-yl)-7-(2-fluoropyridin-3-yl)-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-oxazol]-2′-amine as a grey solid. Found MS: MH+=431.
Reaction SMILES: [O:1]=[C:2]1[NH:7][N:6]=[C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.S(Cl)([Cl:19])=O>ClCCl>[O:1]=[C:2]1[NH:7][N:6]=[C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([Cl:19])=[O:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: O=S(Cl)Cl
Reactant: O=C1CCC(c2ccc(C(=O)O)cc2)=NN1
Solvent: ClCCl
Product: O=C1CCC(c2ccc(C(=O)Cl)cc2)=NN1
Reaction time: 24 h

Procedure:
10 mmol (2.2 g) of 4-(1,4,5,6-tetrahydro-6-oxo-3-pyridazinyl)benzoic acid are suspended in 50 ml of dichloromethane, after which 1.5 ml (20 mmol) of thionyl chloride are added and the mixture is stirred for 24 hours while being boiled gently.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][S:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Cl)=[CH:16][CH:15]=1.C([O-])(=O)C.[Na+].Cl>II>[CH3:12][S:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH:1][C:2]2[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=2[N+:9]([O-:11])=[O:10])=[CH:16][CH:15]=1
Reactant: Nc1ccc(F)cc1[N+](=O)[O-]
Reactant: CSc1ccc(CCl)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: II
Product: CSc1ccc(CNc2ccc(F)cc2[N+](=O)[O-])cc1
Temperature: 120 °C
Yield: 51.3 %

Procedure:
24.8 g of 2-amino-5-fluoronitrobenzene and 27.6 g of 4-methylthiobenzyl chloride are mixed and 14.4 g of anhydrous sodium acetate and 0.3 g of iodine are added. The mixture is heated at 120° C. for 12 hours, with stirring, and is then cooled, taken up with a dilute solution of hydrochloric acid and extracted with ethyl acetate. The organic phase is washed with dilute hydrochloric acid and then with water, dried over magnesium sulfate and evaporated to dryness. The oil obtained crystallizes from isopropyl ether to give 23.8 g of 2-(4-methylthiobenzyl)amino-5-fluoronitrobenzene in the form of crystals melting at 117° C.
Reaction SMILES: C([O:5][C:6](=[O:33])[CH2:7][C:8]1([C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:13]2[CH:14]=[CH:15][CH:16]=[C:12]2[C:11](=[O:17])[N:10]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][C:20]=2[F:26])[C:9]1=[O:27])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Br:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][N:10]2[C:9](=[O:27])[C:8]([C:28]([O:30][CH2:31][CH3:32])=[O:29])([CH2:7][C:6]([OH:33])=[O:5])[N:13]3[CH:14]=[CH:15][CH:16]=[C:12]3[C:11]2=[O:17])=[C:20]([F:26])[CH:21]=1
Reactant: CCOC(=O)C1(CC(=O)OC(C)(C)C)C(=O)N(Cc2ccc(Br)cc2F)C(=O)c2cccn21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C1(CC(=O)O)C(=O)N(Cc2ccc(Br)cc2F)C(=O)c2cccn21
Yield: 83.5 %

Procedure:
A mixture of 2-(4-bromo-2-fluorobenzyl)-4-ethoxycarbonyl-1,3-dioxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-4-acetic acid tert-butyl ester (28.7 g) and trifluoroacetic acid (125.1 g, 84.5 ml) in dichloromethane (100 ml) was refluxed for 3 hours and concentrated under reduced pressure. The residue was chromatographed on silica gel using chloroform as the eluent. Fractions containing the title compound were pooled and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate/n-hexane to give the title compound (21.4 g, 3.6%) as colorless crystals, mp 142°-144° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[N:8][N:7]2[CH:10]=[C:11]([C:13]3[O:14][C:15]([S:18][CH3:19])=[N:16][N:17]=3)[CH:12]=[C:6]2[C:5]=1[NH:20][C@@H:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][C:22]1([CH3:35])[CH3:34])(=[O:3])[NH2:2].C1C=C(Cl)C=C(C(OO)=[O:44])C=1>C(Cl)(Cl)Cl>[C:1]([C:4]1[CH:9]=[N:8][N:7]2[CH:10]=[C:11]([C:13]3[O:14][C:15]([S:18]([CH3:19])=[O:44])=[N:16][N:17]=3)[CH:12]=[C:6]2[C:5]=1[NH:20][C@@H:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][C:22]1([CH3:35])[CH3:34])(=[O:3])[NH2:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nnc(-c2cc3c(N[C@@H]4CCN(C(=O)OC(C)(C)C)CC4(C)C)c(C(N)=O)cnn3c2)o1
Solvent: ClC(Cl)Cl
Product: CS(=O)c1nnc(-c2cc3c(N[C@@H]4CCN(C(=O)OC(C)(C)C)CC4(C)C)c(C(N)=O)cnn3c2)o1

Procedure:
A solution of (R)-tert-butyl 4-((3-carbamoyl-6-(5-(methylthio)-1,3,4-oxadiazol-2-yl)pyrrolo[1,2-b]pyridazin-4-yl)amino)-3,3-dimethylpiperidine-1-carboxylate (306 mg, 0.610 mmol) and mCPBA (265 mg, 1.182 mmol) in chloroform (6 mL) was stirred at room temperature for 2 h. Additional mCPBA (78 mg) was added. After one more hour at room temperature, the staring material was consumed. The crude solution was taken to the next reaction without purification. MS (ES+) m/z: 518.3 (M+H).
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[CH:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19]CC)=[O:18])[N:7]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:6]1=[O:30])[CH2:2][CH2:3][CH3:4].[OH-].[Na+].CCOCC>C(O)C>[CH2:1]([N:5]1[C:9](=[O:10])[CH:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[N:7]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:6]1=[O:30])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCCCN1C(=O)N(CCCC)C(=O)C1CCCCCCC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Product: CCCCCCCCN1C(=O)N(CCCC)C(=O)C1CCCCCCC(=O)O

Procedure:
This ester (3.2 g) was dissolved in ethanol (15 ml) and 2 N-sodium hydroxide (15 ml) and left at room temperature for 1 hour. The acidic product was isolated by extraction with ether and purified by chromatography on silica gel to give 3-butyl-5-(6-carboxyhexyl)-1-octyl hydantoin as a colourless oil.
Reaction SMILES: [C:1]([NH:4][NH2:5])([NH2:3])=[NH:2].Cl.[OH-].[Na+].[CH2:9]([CH:11]([C:15](=O)[CH3:16])[C:12](=O)[CH3:13])[CH3:10]>O>[CH2:9]([C:11]1[C:15]([CH3:16])=[N:2][C:1]([N:4]2[C:12]([CH3:13])=[C:11]([CH2:15][CH3:16])[C:9]([CH3:10])=[N:5]2)=[N:3][C:12]=1[CH3:13])[CH3:10]
Reactant: N=C(N)NN
Reactant: CCC(C(C)=O)C(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCc1c(C)nc(-n2nc(C)c(CC)c2C)nc1C
Temperature: 80 °C
Reaction time: 8 h
Yield: 32.9 %

Procedure:
To aminoguanidine hydrochloride (1.76 g, 15.9 mmol), water (5 ml), sodium hydroxide (636 mg, 15.9 mmol), and 3-ethyl-2,4-pentanedione (manufactured by Tokyo Chemical Industry, purity: 90.0% or higher) (4.50 g, 35.0 mmol) were added, and then stirred at 80° C. for 8 hours. To the reaction mixture, water (30 ml) was added, and then stirred at 0° C. for 1 hour. The precipitated crystals were collected by filtration, washed with water, and dried under reduced pressure to obtain 5-ethyl-2-(4-ethyl-3,5-dimethylpyrazol-1-yl)-4,6-dimethylpyrimidine (1.35 g, 33%).