Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]([Cl:5])(Cl)(=[O:3])=[O:2].Cl.[CH3:7][O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][NH:15][CH2:16]2)=[CH:11][CH:10]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:7][O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][N:15]([S:1]([Cl:5])(=[O:3])=[O:2])[CH2:16]2)=[CH:11][CH:10]=1
Reactant: COc1ccc2c(c1)CNCC2
Reactant: O=S(=O)(Cl)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)CN(S(=O)(=O)Cl)CC2
Reaction time: 1 h

Procedure:
To a stirred, precooled solution (−40° C.) of 0.41 mL of sulfuryl chloride in 10 mL of chloroform was added a mixture of 1.0 g of 7-methoxy-1,2,3,4-tetrahydro-isoquinoline-hydrochloride and 2.1 mL of triethylamine in 25 mL of chloroform at −40° C. Stirring was continued at −30° C. for one hour and additionally at 5° C. for one hour. The mixture was poured on ice, the organic layer extracted with cold water, dried (sodium sulfate) and concentrated. The residue was redissolved in diethyl ether and chromatographed on silica gel (isohexane/ethyl acetate=8/2 v/v) yielding 0.62 g of 7-methoxy-3,4-dihydro-1H-isoquinoline-2-sulfonyl chloride as an oil. EI-MS: 261 (M+).
Reaction SMILES: [NH2:1][C@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[O:13])[C@@H:4]([CH3:21])[CH2:3]1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.N1C=CC=CC=1.[C:38](OCC)(=[O:40])[CH3:39]>CN(C=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([N:1]([C@H:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([C:12](=[O:13])[C:14]3[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=3)[C@@H:4]([CH3:21])[CH2:3]2)[C:38](=[O:40])[CH3:39])=[CH:25][CH:24]=1
Reactant: C[C@H]1C[C@@H](N)c2ccccc2N1C(=O)c1ccc(F)cc1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CCOC(C)=O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(F)cc2)c2ccccc21
Temperature: 60 °C
Reaction time: 1 h
Yield: 18 %

Procedure:
To a solution of (2S, 4R)-(4-amino-2-methyl-3,4-dihydro-2H-quinolin-1-yl)-(4-fluoro-phenyl)-methanone (1.0 g, 3.5 mmol) in DMF (20 mL, dry) was added 4-chlorophenylboronic acid (1.1 g, 7.0 mmol), pyridine (850 uL, 10.5 mmol) and copper(II)acetate (1.27 g, 7.0 mmol). The heterogeneous green mixture was stirred open to air for 1 h and then warmed to 60° C. and stirred over night (14 h). The mixture was then cooled to rt, poured into rapidly stirred ethyl acetate (150 mL); solids were removed by filtration through Celite®. The extracts were washed several times with water and then once with brine. The extracts were then dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (95% methylene chloride/5% ethyl acetate) to afford the aniline product (250 mg, 18%) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:9][CH:8]=2)[C:3]=1[C:20]#[N:21].[CH2:22]([N:29]1[CH2:34][CH2:33][C:32](=[CH:35][C:36](OCC)=[O:37])[CH2:31][CH2:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:22]([N:29]1[CH2:30][CH2:31][C:32]2([N:6]3[N:5]=[C:4]([C:7]4[CH:8]=[CH:9][C:10]([O:13][C:14]5[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=5)=[CH:11][CH:12]=4)[C:3]([C:20]#[N:21])=[C:2]3[NH:1][C:36](=[O:37])[CH2:35]2)[CH2:33][CH2:34]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)n[nH]c1N
Reactant: CCOC(=O)C=C1CCN(Cc2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NC(=O)CC21CCN(Cc2ccccc2)CC1
Temperature: 80 °C
Yield: 53.9 %

Procedure:
A mixture of 5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile (1.0 g, 3.6 mmol), ethyl 2-(1-benzylpiperidin-4-ylidene)acetate (1.1 g, 4.3 mmol) and K2CO3 (745 mg, 5.4 mmol) in DMF (20 mL) was heated to 80° C. for 16 hr under N2. The reaction was quenched with water (20 mL) and extracted with EA (20 mL×3). The combined organic layers were dried over Na2SO4, concentrated and purified by chromatography column on silica gel using 30% of EA in PE as eluant to give the product (950 mg, 54.9%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 11.92 (s, 1H), 7.84 (d, J=8.8 Hz, 2H), 7.48-7.40 (m, 2H), 7.36-7.29 (m, 4H), 7.27-7.23 (m, 1H), 7.20 (t, J=7.6 Hz, 1H), 7.15-7.07 (m, 4H), 3.55 (s, 2H), 3.01 (s, 2H), 2.81-2.73 (m, 2H), 2.39-2.27 (m, 2H), 2.26-2.16 (m, 2H), 1.83-1.74 (m, 2H). MS (ESI, m/e) [M+1]+ 489.9.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH2:4].[Br:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1.Br>CN(C)C=O.C1(C)C=CC=CC=1.O>[Br:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([NH:4][CH2:3][CH2:2][OH:1])=[O:18])=[CH:15][CH:14]=1
Reactant: NCCO
Reactant: O=C(Cl)c1ccc(OCCCCCCBr)cc1
Agent: Br
Solvent: Cc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCCO)c1ccc(OCCCCCCBr)cc1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 300 ml of 2-hydroxyethylamine in 1.2 liter of dimethylformamide at 0° C. was added dropwise 450 ml of 4-(6-bromohexyloxy)benzoyl chloride in 50 ml of toluene over a 30 minute period. After an additional 30 minutes of stirring, 48% hydrobromic acid (about 200 ml) was added until the pH reached 5-5.5, and the mixture was diluted with 1200 ml of water and extracted with isopropyl acetate (total of 2500 ml). The extracts were washed with water and saturated sodium chloride solution, filtered, and concentrated to a volume of about 1 liter. The mixture was cooled and the solid which separated was collected by filtration and dried at 40° C. to give 332.7 g of 4-(6-bromohexyloxy)-N-(2-hydroxyethyl)benzamide.
Reaction SMILES: [CH2:1]([O:4][NH:5][C:6](=[C:9]1[C:14](=[O:15])[CH2:13][C:12]([CH3:17])([CH3:16])[CH2:11][C:10]1=[O:18])[CH2:7][CH3:8])[CH:2]=[CH2:3].[OH-].[Na+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CC(C)=O.O>[CH2:1]([O:4][N:5]=[C:6]([C:9]1[C:10](=[O:18])[CH2:11][C:12]([CH3:17])([CH3:16])[CH2:13][C:14]=1[O:15][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:7][CH3:8])[CH:2]=[CH2:3]
Reactant: BrCc1ccccc1
Reactant: C=CCONC(CC)=C1C(=O)CC(C)(C)CC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: C=CCON=C(CC)C1=C(OCc2ccccc2)CC(C)(C)CC1=O
Temperature: 60 °C
Reaction time: 10 h

Procedure:
To a solution of 2-(1-allyloxyaminopropylidene)-5,5-dimethylcyclohexane-1,3-dione (2.5 g) in acetone (30 ml), sodium hydroxide (0.4 g) in water (2 ml) was added at room temperature and then benzyl bromide (2.0 g) was added. After stirring for 10 hours at 60° C the reaction mixture was poured into ice-water and extracted with chloroform. The extract was washed with one normal sodium hydroxide and dried over magnesium sulfate. The solvent was removed in vacuo and an oily substance which solidified on standing at 0° C was obtained. Recrystallization from the mixture of methanol and water gave the desired product as crystal.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][N:7]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.Cl.[CH3:43][O:44][NH:45][CH3:46]>CN(C=O)C>[CH3:43][O:44][N:45]([CH3:46])[C:8]([C:3]1[C:2]([NH2:1])=[N:7][CH:6]=[CH:5][N:4]=1)=[O:10]
Reactant: Nc1nccnc1C(=O)O
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1nccnc1N
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 3-aminopyrazine-2-carboxylic acid (1 g, 7.2 mmol) in DMF (15 ml) is added EDC hydrochloride (1.7 g, 8.6 mmol), HOBt (1.16 g, 8.6 mmol), diisopropylethylamine (3.08 ml, 18 mmol) and N-methoxy-N-methylamine hydrochloride (0.84 g, 8.6 mmol), and the resulting solution is stirred at room temperature for 15 hours. The reaction is concentrated in vacuo, and sat. aq. NaHCO3 (50 ml) is added to the residue. The product is extracted into EtOAc (3×60 ml), washed with sat. aq. NaCl (2×50 ml), dried (MgSO4) and concentrated in vacuo to afford a yellow residue. Purification by flash chromatography (SiO2, 0-5% MeOH in DCM) yields 3-amino-pyrazine-2-carboxylic acid methoxy-methylamide as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=1.[CH2:9]([C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)[CH2:10][C:11]#[CH:12]>>[F:8][C:4]1[N:3]=[C:2]([C:12]#[C:11][CH2:10][CH2:9][C:13]2[S:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: Fc1cccc(Br)n1
Reactant: C#CCCc1nc2ccccc2s1
Product: Fc1cccc(C#CCCc2nc3ccccc3s2)n1
Yield: 29.7 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-6-fluoro-pyridine (66 mg, 0.37 mmol) and 2-but-3-ynyl-benzo[d]thiazole (70 mg, 0.37 mmol, Example 35(A)). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 7:3) to yield 31 mg (0.11 mmol, 29%) of 2-(4-(6-fluoropyridin-2-yl)but-3-ynyl)benzo[d]thiazole as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH2:12][N:13]1[C:19](=[O:20])[C@@H:18]([NH:21][C:22](=[O:34])[C@@H:23]([N:25]([CH3:33])[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH3:24])[CH2:17][O:16][C:15]3[CH:35]=[CH:36][CH:37]=[CH:38][C:14]1=3)=[C:7]([O:39][CH3:40])[CH:6]=[CH:5]2.C1(P(C2C=CC=CC=2)C2[C:61]3[O:60][C:59]4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C[OH:84]>CC([O-])=O.CC([O-])=O.[Pd+2]>[C:28]([O:27][C:26]([N:25]([CH3:33])[C@@H:23]([CH3:24])[C:22]([NH:21][C@H:18]1[CH2:17][O:16][C:15]2[CH:35]=[CH:36][CH:37]=[CH:38][C:14]=2[N:13]([CH2:12][C:8]2[C:7]([O:39][CH3:40])=[CH:6][CH:5]=[C:4]3[C:9]=2[CH:10]=[CH:11][C:2]([C:59]([O:60][CH3:61])=[O:84])=[CH:3]3)[C:19]1=[O:20])=[O:34])=[O:32])([CH3:30])([CH3:31])[CH3:29]
Reactant: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Reactant: CO
Reactant: COc1ccc2cc(Br)ccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)COc2ccccc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: COC(=O)c1ccc2c(CN3C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)COc4ccccc43)c(OC)ccc2c1
Temperature: 70 °C
Yield: 714.3 %

Procedure:
A mixture of tert-butyl (S)-1-((S)-5-((6-bromo-2-methoxynaphthalen-1-yl)methyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (1.8 g, 2.94 mmol, Eq: 1.00), Pd(OAc)2 (33.0 mg, 147 μmol, Eq: 0.05) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (170 mg, 294 μmol, Eq: 0.10) in a microwave tube was evacuated and purged with N2. MeOH (1.43 g, 1.8 mL, 44.5 mmol, Eq: 15.1) and TEA were added, the vessel was purged with CO and heated at 70° C. under CO overnight. The mixture was concentrated and the residue was purified by silica gel chromatography to afford methyl 5-(((S)-3-((S)-2-(tert-butoxycarbonyl (methyl)amino)propanamido)-4-oxo-3,4-dihydrobenzo[b][1,4]oxazepin-5(2H)-yl)methyl)-6-methoxy-2-naphthoate (1.24 g, 2.1 mmol, 71.3%).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[NH:12][C:13](=[O:24])[C:14]2[N:19]([CH3:20])[N:18]=[C:17]([CH2:21][CH2:22][CH3:23])[C:15]=2[N:16]=1)C=C.C1(O)C=CC=CC=1.N1CCCCC1>C(O)C.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>[OH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[NH:12][C:13](=[O:24])[C:14]2[N:19]([CH3:20])[N:18]=[C:17]([CH2:21][CH2:22][CH3:23])[C:15]=2[N:16]=1
Reactant: C=CCOc1ccccc1-c1nc2c(CCC)nn(C)c2c(=O)[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Solvent: CCO
Solvent: Oc1ccccc1
Product: CCCc1nn(C)c2c(=O)[nH]c(-c3ccccc3O)nc12
Yield: 9.2 %

Procedure:
A mixture of 5-(2-allyloxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (0.25 g, 0.0008 mol), phenol (0.145 g, 0.0015 mol), piperidine (0.131 g, 0.0015 mol) and tetrakis(triphenylphosphine)palladium(0) (0.046 g, 0.00004 mol) in absolute ethanol (5ml) was refluxed overnight under nitrogen. The mixture was allowed to cool, the solvent evaporated under vacuum and the residue dissolved in ethyl acetate (40 ml). This solution was washed with water (3×10 ml), 1M HCl (3×10 ml) and brine (1×10 ml). After drying (Na2SO4) and filtration, the filtrate was evaporated under vacuum to give the crude product. The title phenol (0.021 g, 10%) was obtained after trituration with diethyl ether and crystallisation from ethyl acetate/pentane, m.p. 233°-238° C. Found: C,63.17; H,5.65; N,19.52. C15H16N4O2 requires C,63.36; H,5.67; N,19.71%.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])[CH2:2][CH2:3]C.[CH3:12][NH:13][C:14](=O)[O:15]CC.P(Cl)(Cl)(Cl)(Cl)Cl.[C:25]1(C)C=CC=CC=1>>[CH3:12][NH:13][C:14](=[O:15])[O:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[CH:1]([CH2:2][CH3:3])[CH3:25]
Reactant: CCOC(=O)NC
Reactant: CCCCc1ccccc1O
Reactant: Cc1ccccc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: CCC(C)c1ccccc1OC(=O)NC

Procedure:
To a solution of 2-sec butylphenol (1.5 g, 0.01 mole) and ethyl N-methylcarbamate (1.03 g, 0.01 mole), along with phosphorus pentachloride (1.05 g, 0.05 mole) in toluene (10 ml) was stirred at 28° C. and afterwards it was refluxed for 7 hours and worked up as usual to get the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([Cl:16])[N:3]=1.N1([N:23]2[CH2:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]2=O)CCCCC1.[C:33](=[O:36])([O-])[O-].[Na+].[Na+]>CN(C)C=O>[ClH:16].[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([N:23]2[CH2:31][CH2:30][CH:31]([N:23]3[CH2:24][C:25]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:33]3=[O:36])[CH2:25][CH2:24]2)[N:3]=1
Reactant: O=C1c2ccccc2CN1N1CCCCC1
Reactant: O=C([O-])[O-]
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2nc(N3CCC(N4Cc5ccccc5C4=O)CC3)nc(N)c2cc1OC
Product: Cl

Procedure:
By heating in an analogous fashion 2.4 g of 4-amino-2chloro-6,7-dimethoxyquinazoline, 2.2 g of 2(-piperidinyl)-isoindolin-1-one, 2.0 g of anhydrous sodium carbonate and 20 ml of dimethylformamide, the 2-[1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-piperidinyl]-isoindolin-1-one monohydrochloride is obtained, melting at 288°-289° (dec.).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]([CH3:9])([CH3:8])[CH2:5][CH:6]=[CH2:7].[N:10]([C@@H:13]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[CH2:25])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:11]=[O:12]>C1COCC1>[CH3:8][C:4]([CH3:9])([CH2:5][CH:6]=[CH2:7])[CH2:3][N:2]([CH3:1])[C:11]([NH:10][C@@H:13]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[CH2:25])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:12]
Reactant: C=CCC(C)(C)CNC
Reactant: C=CCCCCC[C@H](N=C=O)C(=O)OCC
Solvent: C1CCOC1
Product: C=CCCCCC[C@H](NC(=O)N(C)CC(C)(C)CC=C)C(=O)OCC
Reaction time: 1 h

Procedure:
N,2,2-trimethylpent-4-en-1-amine (0.847 g, 6.66 mmol) was added to a solution of ethyl (2S)-2-isocyanatonon-8-enoate (1.50 g, 6.66 mmol) and THF (10 ml), and the solution aws stirred for 1 hour. The reaction mixture was concentrated and purified by silica gel chromatography (gradient elution, 20-30% EtOAc in hexane) to give the title compound. LRMS (M+1)=353.4.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]([C:17]([OH:19])=O)[C:6]3[C:11]([N:12]=2)=[CH:10][CH:9]=[C:8]([F:16])[CH:7]=3)[CH:3]=1.[C:20]1(S)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.N1C=CC=CC=1.O=[S:34](Cl)Cl>C(Cl)Cl>[F:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]([C:17](=[S:34])[O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:6]3[C:11]([N:12]=2)=[CH:10][CH:9]=[C:8]([F:16])[CH:7]=3)[CH:3]=1
Reactant: Sc1ccccc1
Reactant: O=C(O)c1c2cc(F)ccc2nc2ccc(F)cc12
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Fc1ccc2nc3ccc(F)cc3c(C(=S)Oc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,7-Difluoroacridine-9-carboxylic acid (1.0 g) was suspended in SOCl2 (5 mL) and the reaction mixture was refluxed for 3 h. The solvent was removed under reduced pressure leaving a brown solid which was dissolved in 20 mL of CH2Cl2 under argon. Thiophenol (468 mg) was added followed by pyridine (2 mL). The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with CH2Cl2 and washed with water (3×50 mL). The organic layer was dried over MgSO4 and concentrated to obtain a crude material which was chromatographed on silica gel (40% ethyl acetate/hexane) to yield 1.2 g of the pure product. 1H NMR (CDCl3) δ7.52-7.75 (m, 9H), 8.26-8.30 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15](O)=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([F:26])[CH:19]=2)[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:60][O:61][C:62]1[CH:67]=[CH:66][C:65]([CH2:68][NH2:69])=[CH:64][CH:63]=1>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:69][CH2:68][C:65]3[CH:66]=[CH:67][C:62]([O:61][CH3:60])=[CH:63][CH:64]=3)=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([F:26])[CH:19]=2)[N:3]=1
Reactant: C[C@@H]1CC[C@H](C(=O)O)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Reactant: COc1ccc(CN)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(CNC(=O)[C@H]2CC[C@@H](C)N(c3cc(-c4ccc(C#N)c(F)c4)nc(N)n3)C2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 89.5 %

Procedure:
To a solution of (3S,6R)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-6-methyl-3-piperidinecarboxylic acid (170 mg, 0.478 mmol) and HATU (218 mg, 0.574 mmol) in DMF (3 mL) was added Hunig's base (0.167 mL, 0.957 mmol), and the mixture was stirred at room temperature for 5 minutes. Then 1-[4-(methyloxy)phenyl]methanamine (65.6 mg, 0.478 mmol) was added, and the reaction mixture was stirred at room temperature for 0.5 hours. LCMS showed reaction was completed. The reaction was poured onto water, and the formed solid was filtered, washed by water and dried to give the title compound (203 mg) as a yellow solid. LC-MS (ES) m/z=475 [M+H]+.
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:19])C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:19]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)CONC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)CONC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2O
Yield: 89.4 %

Procedure:
To a solution of tert-butyl [({[(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]acetate 89 (0.23 g, 0.57 mml) in methanol (20 mL) was added 5% Pd/C (0.30 g). The mixture was hydrogenated under 35 psi hydrogen atmosphere at room temperature for 1 h. The catalyst was filtered out through Celite, and the filtrate was evaporated to give tert-butyl [({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]acetate 90 (0.16 g, 89%) as a clear thick oil.
Reaction SMILES: [Tl].Cl[C:3]1[C:4]([I:14])=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH:12]=[O:13].[H-].[Na+].IC.CN([CH:22]=[O:23])C>>[I:14][C:4]1[C:3]([O:23][CH3:22])=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6]([CH:12]=[O:13])=[CH:7][NH:8]2
Reactant: CN(C)C=O
Reactant: O=Cc1c[nH]c2ccc(Cl)c(I)c12
Agent: [H-]
Agent: [Na+]
Agent: [Tl]
Solvent: CI
Product: COc1ccc2[nH]cc(C=O)c2c1I

Procedure:
By employing thallium chemistry, the 4-iodo-5-methoxy-indole-3-carboxaldehyde was prepared according to the procedure of Moody, C. J.; Swann, E. J. Chem. Soc. Perkin I 1993, 21, 2561 and the 5-chloro-4-iodo-indole-3-carboxaldehyde according to the procedure of Ohta, T.; Yamato, Y.; Tahira, H.; Somei M., Heterocycles 1987, 11, 2817 (and references therein). These derivatives were subsequently reacted with NaH and iodomethane in DMF to provide the corresponding N-methyl derivatives, which were then used for the preparation of compounds 190, 280 and 212 following a procedure analogous to that described in example 1. Following the general procedure of Ohta, T.; Yamato, Y.; Tahira, H.; Somei M., Heterocycles 1987, 11, 2817 (and references therein), as used above for the preparation of the 5-chloro-4-iodo-indole-3-carboxaldehyde, the 4-halogenated derivatives for a number of commercially available 5 or 6 substituted indole-3-carboxyladehydes were prepared via thallium-mediated chemistry, using (i) reaction with thallium tris-trifluoro acetate, followed by (ii) reaction an electrophile, such as KI or CuBr2. The resulting 4,5− or 4,6− disubstituted indole-3-carboxaldehydes were subsequently methylated at the indole N-position, as described in examples 13 and 16. The products were used for condensation with appropriate pyrazolones as described in example 1, to provide the desired compounds. Compounds 203, 266, 267, 281, 214, 221, 220, 222, 223, 289, 218, 219, 225, 226, 227, 228, 229, and 230 were derived following the sequence of steps described above.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[CH:9]1([CH2:12][NH2:13])[CH2:11][CH2:10]1>CCN(C(C)C)C(C)C>[Br:8][C:4]1[N:3]=[C:2]([NH:13][CH2:12][CH:9]2[CH2:11][CH2:10]2)[CH:7]=[CH:6][CH:5]=1
Reactant: NCC1CC1
Reactant: Brc1cccc(Br)n1
Solvent: CCN(C(C)C)C(C)C
Product: Brc1cccc(NCC2CC2)n1
Yield: 82.4 %

Procedure:
A solution of 2,6-dibromopyridine (33.0 g, 139 mmol) and cyclopropanemethylamine (10.8 g, 153 mmol) in DIPEA (27 mL) was heated at reflux for 24 h in a sealed pressure tube. The reaction mixture was cooled, concentrated in vacuo, and the residue was partitioned between EtOAc (250 mL) and saturated aqueous NaHCO3 (200 mL). The organic layer was washed with water (200 mL) followed by brine (200 mL) and dried (Na2SO4). The organic layer was filtered, concentrated in vacuo, and purified by flash chromatography (silica, 10% EtOAc/hexanes) affording 26 g of amine 2-1 as a white solid in 82% yield.