Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].Br[CH2:34][C:35]([NH2:37])=[O:36]>>[CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:21][CH2:22][N:23]([CH2:34][C:35](=[O:36])[NH2:37])[CH2:24][CH2:25]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: NC(=O)CBr
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n1C1CCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCN(CC(N)=O)CC4)cn3)nc2n1C1CCCC1
Yield: 44.2 %

Procedure:
Following General Procedure D, 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (100 mg, 0.230 mmol) and 2-bromo acetamide (95 mg, 0.690 mmol) gave 2-[5-(4-carbamoylmethyl piperazin-1-yl)-pyridin-2-ylamino]-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (50 mg, 45%).
Reaction SMILES: N#N.[I:3][CH:4]1[CH:9]2[O:10][C:11](=[O:12])[CH:7]3[CH:8]2[C:13]2([CH2:15][CH2:14]2)[CH:5]1[CH:6]3[C:16]([OH:18])=[O:17].[CH3:19][Si](C=[N+]=[N-])(C)C>CO>[I:3][CH:4]1[CH:9]2[O:10][C:11](=[O:12])[CH:7]3[CH:8]2[C:13]2([CH2:15][CH2:14]2)[CH:5]1[CH:6]3[C:16]([O:18][CH3:19])=[O:17]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)C1C2C(=O)OC3C(I)C1C1(CC1)C32
Agent: N#N
Solvent: CO
Product: COC(=O)C1C2C(=O)OC3C(I)C1C1(CC1)C32
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of 6-iodo-2-oxohexahydrospiro[3,5-methanocyclopenta[b]furan-4,1-cyclopropane]-7-carboxylic acid (5.00 g, 14.96 mmol) in dry MeOH (75 mL) was added TMSCH2N2 (2.0 M in hexanes, 37.0 mL, 74.83 mmol). The reaction mixture was stirred at rt overnight, concentrated under reduced pressure and purified by FC (hept/EA, 4:1) to give the title compound as a white solid. TLC: rf (hept/EA, 4:1)=0.18.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10][C:9]=1[N:15]([CH3:32])[C:16](=[O:31])[C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([S:27]([CH3:30])(=[O:29])=[O:28])[CH:18]=1.C([O-])([O-])=O.[K+].[K+].CC1C=CC(S(O[CH2:50][CH:51]2[CH2:54][O:53][CH2:52]2)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>CN(C=O)C.CCOC(C)=O>[CH3:30][S:27]([C:19]1[CH:18]=[C:17]([CH:22]=[C:21]([C:23]([F:25])([F:26])[F:24])[CH:20]=1)[C:16]([N:15]([CH3:32])[C:9]1[CH:10]=[N:11][C:12]([CH3:14])=[CH:13][C:8]=1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[O:1][CH2:50][CH:51]1[CH2:54][O:53][CH2:52]1)=[O:31])(=[O:29])=[O:28]
Reactant: Cc1cc(-c2ccccc2O)c(N(C)C(=O)c2cc(C(F)(F)F)cc(S(C)(=O)=O)c2)cn1
Reactant: Cc1ccc(S(=O)(=O)OCC2COC2)cc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(-c2ccccc2OCC2COC2)c(N(C)C(=O)c2cc(C(F)(F)F)cc(S(C)(=O)=O)c2)cn1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a solution N-(4-(2-hydroxyphenyl)-6-methylpyridin-3-yl)-N-methyl-3-(methylsulfonyl)-5-(trifluoromethyl)benzamide (100 mg, 215 μmol, example 318, intermediate a) in DMF (2 ml) was added K2CO3 (59.5 mg, 431 μmol) and oxetan-3-ylmethyl 4-methylbenzenesulfonate (57.4 mg, 237 μmol). The reaction mixture was stirred for 2 hours at room temperature and for 18 hours at 80° C. The reaction mixture was poured on 30 mL 10% aqueous NaHCO3 solution and 30 mL EtOAc and the layers were separated. The aqueous layer was extracted a second time with 30 mL EtOAc. The organic layers were washed with 30 mL brine, dried over MgSO4, filtered and concentrated under vacuum. The compound was purified by silica gel chromatography on a 10 g column using an MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Colorless solid (87 mg, 76%). MS (ESI): m/z=535.150 [M+H]+.
Reaction SMILES: C[Mg]Br.[CH3:4]COCC.[CH2:9]([O:16][C:17]([N:19]1[CH2:22][C:21](=[O:23])[CH2:20]1)=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1COCC1>[CH2:9]([O:16][C:17]([N:19]1[CH2:22][C:21]([OH:23])([CH3:4])[CH2:20]1)=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C1CN(C(=O)OCc2ccccc2)C1
Reactant: CCOCC
Agent: C[Mg]Br
Solvent: C1CCOC1
Product: CC1(O)CN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
To a 3.0 M solution of methylmagnesium bromide in Et2O (0.98 mL, 2.92 mmol), at 0° C., was added a solution of 3-oxoazetidine-1-carboxylic acid benzyl ester (0.5 g, 2.44 mmol) in anhydrous THF (5 mL) dropwise over 5 min under argon. The reaction mixture was stirred for 18 h at room temperature, and then quenched by addition of a saturated aqueous solution of NH4Cl (2.5 mL) and water (5 mL). The aqueous phase was extracted with EtOAc (10 mL). The organic layer was separated, dried over sodium sulphate and concentrated in vacuo to give 3-Hydroxy-3-methylazetidine-1-carboxylic acid benzyl ester as a colourless oil (0.54 g, 99%). LCMS (Method A): RT=3.60 min, [M+H]+ 221.9
Reaction SMILES: N1C=CC=CC=1.[CH3:7][C:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([N:19]3[CH2:24][CH2:23][C:22]4([CH2:33][C:32](=[O:34])[C:31]5[C:26](=[CH:27][CH:28]=[C:29]([C:35]6[CH:36]=[N:37][N:38]([CH3:40])[CH:39]=6)[CH:30]=5)[O:25]4)[CH2:21][CH2:20]3)=[O:18])=[CH:14][CH:15]=2)[NH:10][N:9]=1.[CH3:41][O:42][C:43]([C:45]1[CH:50]=[CH:49][C:48](B(O)O)=[CH:47][CH:46]=1)=[O:44]>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH3:7][C:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([N:19]3[CH2:20][CH2:21][C:22]4([CH2:33][C:32](=[O:34])[C:31]5[C:26](=[CH:27][CH:28]=[C:29]([C:35]6[CH:36]=[N:37][N:38]([CH3:40])[CH:39]=6)[CH:30]=5)[O:25]4)[CH2:23][CH2:24]3)=[O:18])=[CH:14][CH:15]=2)[N:10]([C:48]2[CH:49]=[CH:50][C:45]([C:43]([O:42][CH3:41])=[O:44])=[CH:46][CH:47]=2)[N:9]=1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: Cc1n[nH]c2cc(C(=O)N3CCC4(CC3)CC(=O)c3cc(-c5cnn(C)c5)ccc3O4)ccc12
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc(-n2nc(C)c3ccc(C(=O)N4CCC5(CC4)CC(=O)c4cc(-c6cnn(C)c6)ccc4O5)cc32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Pyridine (0.080 ml, 0.988 mmol) was added to a stirred mixture of 1′-[(3-methyl-1H-indazol-6-yl)carbonyl]-6-(1-methyl-1H-pyrazol-4-yl)spiro[chroman-2,4′-piperidin]-4-one (150 mg, 0.329 mmol), [4-(methoxycarbonyl)phenyl]boronic acid (119 mg, 0.659 mmol), Cu(OAc)2 (90 mg, 0.494 mmol) in CH2Cl2 (1.5 ml) and the mixture was stirred at room temperature overnight. The mixture was filtered and the solvent was evaporated under reduced pressure. The residue was purified by silicagel column chromatography (hexane/EtOAc) to give intended compound as colorless oil.
Reaction SMILES: CC(C)([O-])C.[K+].O1CCCC1.[C:12]([CH2:14]P(=O)(OCC)OCC)#[N:13].[O:23]1[CH2:28][CH2:27][CH:26]([CH:29]=O)[CH2:25][CH2:24]1>>[O:23]1[CH2:28][CH2:27][CH:26](/[CH:29]=[CH:14]/[C:12]#[N:13])[CH2:25][CH2:24]1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: O=CC1CCOCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#C/C=C/C1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1.0 M of potassium tert-butoxide in tetrahydrofuran (9.20 mL, 0.00920 mol) at 0° C. was added dropwise a solution of diethyl cyanomethylphosphonate (1.56 mL, 0.00965 mol) in tetrahydrofuran (11.73 mL, 0.1447 mol). The reaction was warmed to room temperature and then cooled at 0° C. again. To the reaction mixture was added a solution of tetrahydro-2H-pyran-4-carbaldehyde (1.0 g, 0.0088 mol) in tetrahydrofuran (2.35 mL, 0.0289 mol). The reaction was allowed to warm up to room temperature and stirred overnight. After being quenched with water, the mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried and evaporated to dryness. The crude mixture was used directly in next step. LCMS (M+H) 138.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][C@H:10]2[CH2:23][NH:24][CH2:25][C:26](OCC)=[O:27])[CH:5]=[CH:6][C:7]=1[Cl:8].[N:31]([Si](C)(C)C)=[C:32]=[O:33].C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[CH2:11][C@H:10]2[CH2:23][N:24]2[CH2:25][C:26](=[O:27])[NH:31][C:32]2=[O:33])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C[Si](C)(C)N=C=O
Reactant: CCOC(=O)CNC[C@@H]1CN(C(=O)OC(C)(C)C)CCO[C@H]1c1ccc(Cl)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](CN2CC(=O)NC2=O)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution (1.9 mL) of tert-butyl (6R,7R)-7-(3,4-dichlorophenyl)-6-{[(2-ethoxy-2-oxoethyl)amino]methyl}-1,4-oxazepane-4-carboxylate (180 mg) in THF were added isocyanatotrimethylsilane (0.078 mL) and triethylamine (0.082 mL), and the mixture was stirred at room temperature for 2 hr. Then, isocyanatotrimethylsilane (0.156 ml) and triethylamine (0.164 mL) were added, and the mixture was stirred at 50° C. for 2 hr, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate). The obtained residue was diluted with methanol (1.4 mL), triethylamine (0.080 ml) was added, and the mixture was stirred at 50° C. for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (115 mg).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([O:15][CH3:16])=[C:12]([SH:14])[CH:13]=1.[CH2:17]([S:19]([C:22]1[CH:27]=[CH:26][C:25](Br)=[CH:24][CH:23]=1)(=[O:21])=[O:20])[CH3:18]>CN1C(=O)CCC1>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([O:15][CH3:16])=[C:12]([S:14][C:25]2[CH:24]=[CH:23][C:22]([S:19]([CH2:17][CH3:18])(=[O:21])=[O:20])=[CH:27][CH:26]=2)[CH:13]=1
Reactant: CCS(=O)(=O)c1ccc(Br)cc1
Reactant: COc1ccc(Cl)cc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CCS(=O)(=O)c1ccc(Sc2cc(Cl)ccc2OC)cc1
Temperature: 90 °C

Procedure:
Potassium carbonate (0.315 g) was added to a stirred solution of the product from step (i) (0.4 g) and ethyl-(4-bromo-phenyl)-sulfone (0.285 g) in NMP (10 ml) and the mixture heated at 90° C. for 1 h. The mixture was partitioned between water/ethylacetate, the organics separated, dried, and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 25% ethylacetate/isohexane. Yield 0.4 g
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([O:12]CC)=[O:11])=[CH:7][C:6]=2[CH:15]=1.[Br-].[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Zn+]>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.O>[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([OH:12])=[O:11])=[CH:7][C:6]=2[CH:15]=1
Reactant: [Zn+]c1ccccn1
Reactant: CCOC(=O)c1cc2cc(Br)ccc2o1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: O
Product: O=C(O)c1cc2cc(-c3ccccn3)ccc2o1
Temperature: 60 °C
Yield: 84.7 %

Procedure:
A mixture of ethyl 5-bromo-benzofuran-2-carboxylate (1.0 g, 3.8 mmol), (prepared as described herein in Preparation1), 2-pyridinyl zinc bromide (15 mL, 7.5 mmol), tetrakis(triphenylphosphine)palladium (0) (100 mg), was stirred under an argon atmosphere and heated to 60° C. overnight. The mixture was cooled, poured into water, extracted with ethyl acetate, washed with brine, dried (MgSO4), and evaporated. Purification by chromatography gave 770 mg of 5-pyridin-2yl-benzofuran-2-carboxylic acid.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C@@H:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:10]([NH:12][CH2:13][CH2:14][NH:15][C:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[S:18][N:17]=1)=[O:11].C(N(CC)CC)C.[C:38]1([S:44](Cl)(=[O:46])=[O:45])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>ClCCl>[S:18]1[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:16]([NH:15][CH2:14][CH2:13][NH:12][C:10](=[O:11])[C@H:9]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[NH:8][S:44]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)(=[O:46])=[O:45])=[N:17]1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: N[C@H](C(=O)NCCNc1nsc2ccccc12)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCNc1nsc2ccccc12)[C@@H](NS(=O)(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18 %

Procedure:
(S)-2-amino-N-(2-(benzo[d]isothiazol-3-ylamino)ethyl)-2-phenyl-acetamide trifluoroacetate salt (100 mg, 0.31 mmol) was dissolved in anhydrous dichloromethane (5 mL) with triethylamine (52 μL, 0.37 mmol). The solution was cooled on an ice-water bath and then a solution of benzenesulfonyl chloride (47 μL, 0.37 mmol) in dichloromethane (0.5 mL) was added dropwise. The reaction mixture was allowed to stir overnight while warming to room temperature. The solution was diluted with dichloromethane, washed with saturated sodium bicarbonate solution, then dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under reduced pressure. Purification by column chromatography, on silica gel, eluting with a mixture of 30% ethyl acetate in hexanes, and selected fractions were combined and concentrated under reduced pressure to yield (S)-N-(2-(benzo[d]isothiazol-3-ylamino)ethyl)-2-phenyl-2-(phenylsulfonamido)acetamide (26 mg) as a white solid. 1H NMR (300 MHz, CDCl3): 7.78 (d, 1H), 7.70 (t, 3H), 7.48 (m, 2H), 7.38 (q, 3H), 7.10 (m, 5H), 6.00 (d, 1H), 5.90 (broad s, 1H), 4.78 (d, 1H), 3.63 (broad s, 2H), 3.52 ppm (m, 2H). MW=467 confirmed by LC-MS, tr=3.94 min (Method B) MH+=468.
Reaction SMILES: [O:1]([CH3:3])[Na].Cl[C:5]1[CH:10]=[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[N:8]=[C:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:6]=1>CO>[CH3:3][O:1][C:5]1[CH:10]=[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[N:8]=[C:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:6]=1
Reactant: CO[Na]
Reactant: COc1ccc(COc2cc(Cl)nc(-c3ccccc3)n2)cc1
Solvent: CO
Product: COc1ccc(COc2cc(OC)nc(-c3ccccc3)n2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 63.4 %

Procedure:
NaOCH3 (2.64 g, 0.049 mol) was dissolved in MeOH (180 ml). 4-Chloro-6-(4-methoxybenzyloxy)-2-phenylpyrimidine (3.19 g, 9.78 mmol) was added and the reaction mixture was stirred at 0° C. for 1 h. The mixture was then heated to reflux temperature for 7 h. The solvent was evaporated and the compound was purified by column chromatography (Heptane→Heptane/EtOAc 9/1) to give the title compound, (2 g, 64%), MS (M+H)+323.
Reaction SMILES: C([Li])CCC.CCCCCC.C(NC(C)C)(C)C.[Cl:19][C:20]1[N:28]=[C:27]([Cl:29])[C:26]([F:30])=[CH:25][C:21]=1[C:22]([OH:24])=[O:23].CN([CH:34]=[O:35])C.Cl>C1COCC1>[Cl:19][C:20]1[C:21]2[C:22](=[O:24])[O:23][CH:34]([OH:35])[C:25]=2[C:26]([F:30])=[C:27]([Cl:29])[N:28]=1
Reactant: O=C(O)c1cc(F)c(Cl)nc1Cl
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C1OC(O)c2c(F)c(Cl)nc(Cl)c21
Reaction time: 0.25 h
Yield: 67.7 %

Procedure:
To a butyllithium-hexane solution (100 mL, 160 mmol) in THF (200 mL) was slowly added diisopropylamine (27.4 mL, 192 mmol) in THF (15 mL) at −78° C. The mixture was stirred at the same temperature for 15 min. A solution of 2,6-dichloro-5-fluoronicotinic acid (14.98 g, 71.4 mmol) in THF (15 mL) was added and the mixture was stirred for 2 h. Next, DMF (29.3 mL, 378 mmol) was added and the mixture was stirred for 1 h. Hydrochloric acid (1N, 400 mL) was added and the mixture was subsequently extracted with EtOAc (2×300 mL). The organic phase was basified with saturated aq NaHCO3 solution and the aqueous phase was separated. The aqueous phase was re-acidified with 1N HCl (300 mL) and extracted with EtOAc (2×300 mL). The organic phase was washed with H2O (200 mL) and brine (200 mL), dried over MgSO4, and evaporated. The residue was washed with Hexane/EtOAc (1/8) to give the title compound as a white solid (11.5 g, 67.7%). 1H NMR (500 MHz, DMSO-d6) δ ppm 6.85 (br s, 1 H), 8.82 (br s, 1 H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][CH:27]=1)[CH2:6][N:7]1[CH:12]=[CH:11][N:10]2[CH:13]=[C:14]([NH:19][CH2:20][CH:21]([CH3:23])[CH3:22])[C:15](=[O:18])[C:16]([OH:17])=[C:9]2[C:8]1=[O:24].C(Cl)(Cl)Cl.[C:32](Cl)(=[O:34])[CH3:33].S([O-])(O)(=O)=O.[K+]>N1C=CC=CC=1>[Cl:2][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][CH:27]=1)[CH2:6][N:7]1[CH:12]=[CH:11][N:10]2[CH:13]=[C:14]([N:19]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:32](=[O:34])[CH3:33])[C:15](=[O:18])[C:16]([OH:17])=[C:9]2[C:8]1=[O:24]
Reactant: CC(C)CNc1cn2ccn(Cc3cccc(Cl)c3)c(=O)c2c(O)c1=O
Reactant: CC(=O)Cl
Agent: Cl
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(=O)N(CC(C)C)c1cn2ccn(Cc3cccc(Cl)c3)c(=O)c2c(O)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-(3-Chlorobenzyl)-9-hydroxy-7-isobutylamino-2H-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride (23 mg) was added to chloroform (2 ml), and pyridine (0.062 ml) and acetyl chloride (0.024 ml) were successively added at 0° C. The mixture was stirred at room temperature for 2 hr. 5% Aqueous potassium hydrogen sulfate solution was added to the obtained reaction mixture, and the mixture was extracted with ethyl acetate. The solvent was evaporated and the obtained residue was dissolved in tetrahydrofuran (0.5 ml)-methanol (0.1 ml), and 1N aqueous sodium hydroxide solution (0.084 ml) was added. The mixture was stirred at room temperature for 30 min. 2N Aqueous hydrochloric acid (0.056 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried and concentrated. Crystallization from ethyl acetate-diisopropyl ether gave N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazin-7-yl]-N-isobutylacetamide (18.2 mg).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])[CH:5]=[CH:6][CH:7]=1.N1C=CN=C1.[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>CN(C=O)C>[Si:22]([O:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])[CH:5]=[CH:6][CH:7]=1)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]
Reactant: O=[N+]([O-])c1ccccc1-c1cccc(O)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1cccc(-c2ccccc2[N+](=O)[O-])c1
Reaction time: 0.75 h

Procedure:
2-(3-Hydroxyphenyl)nitrobenzene, as described above in Step B, (8.07 g, 37.52 mmol), imidazole (7.66 g, 112.56 mmol) and tert-butyldimethylsilyl chloride (6.22 g, 41.27 mmol) were dissolved in DMF (30 mL) and stirred for 0.75 hour. The DMF was removed in vacuo and the resulting residue was taken up in water and dimethyl ether and extracted with dimethyl ether (3×). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel, eluting with a gradient of 0%→4% EtOAc in hexanes, to yield the above-titled compound.
Reaction SMILES: [N:1]1([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH2:4][CH:3]([C:7]([O:9]CC)=O)[CH2:2]1.[F-].[Cs+].N#N.[Si]([C:27]([F:30])([F:29])[F:28])(C)(C)C.Cl>C1COCC1>[F:28][C:27]([F:30])([F:29])[C:7]([CH:3]1[CH2:4][CH2:5][CH2:6][N:1]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:2]1)=[O:9]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CCOC(=O)C1CCCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Agent: N#N
Agent: [Cs+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC(C(=O)C(F)(F)F)C1
Reaction time: 3 h
Yield: 37 %

Procedure:
1-tert-butyl 3-ethyl piperidine-1,3-dicarboxylate (424 mg, 1.65 mmol) and CsF (ca 10 mg) were combined in a vial under N2. Dry THF (3 mL) was added, followed by Me3SiCF3 (256 μL, 1.05 equiv). After stirring for 3 h, 4N aq HCl (4 mL) was added to the vial and the mixture was stirred for 1 h. The mixture was extracted with diethyl ether (2×15 mL). The combined organic layers were washed with brine (8 mL), dried over Na2SO4, and concentrated to afford tert-butyl 3-(2,2,2-trifluoroacetyl)piperidine-1-carboxylate (173 mg. 37%)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH2:8].[CH:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[OH-].[K+].C1(CBr)CCCCC1.Cl>C1(C)C=CC=CC=1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([NH2:8])[CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: O=Cc1ccccc1
Reactant: NCc1ccccn1
Agent: BrCC1CCCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Solvent: Cc1ccccc1
Product: NC(CC1CCCCC1)c1ccccn1
Reaction time: 12.5 h
Yield: 45 %

Procedure:
A mixture of 2.16 g of 2-picolylamine (20 mmoles) and 2.12 g of benzaldehyde (20 mmoles) was stirred for 5-20 hours. The reaction mixture was diluted with 20 ml of toluene with stirring, then 1.12 g (20 mmoles) of potassium hydroxide added followed by the addition of 3.7 g of tetrabutylammonium iodide (10 mmoles) and 3.55 g of cyclohexylmethyl bromide (20 mmoles). The mixture was refluxed for 6-24 hours, then cooled and stirred with 10 ml of a 2N HCl for 2-6 hours. The organic phase was discarded, the aqueous acidic phase was washed with methylene chloride. The aqueous phase was basified with ammonium hydroxide and the racemic amine extracted with methylene chloride to yield 45%-55% racemic 1-(2-pyridyl)-2-cyclohexylethylamine as a light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[C:8]([Cl:10])[CH:9]=1)[CH:6]=[O:7].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:19][CH2:20][O:21][C:22](=[O:24])[CH3:23]>CN(C=O)C.CCOC(C)=O>[C:22]([O:21][CH2:20][CH2:19][O:11][C:4]1[CH:3]=[C:2]([Cl:1])[CH:9]=[C:8]([Cl:10])[C:5]=1[CH:6]=[O:7])(=[O:24])[CH3:23]
Reactant: CC(=O)OCCBr
Reactant: O=Cc1c(O)cc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)OCCOc1cc(Cl)cc(Cl)c1C=O
Temperature: 100 °C
Reaction time: 72 h

Procedure:
To a soln. of 4,6-dichlorosalicylaldehyde (3.72 mmol) in 5 mL DMF was added Cs2CO3 (3.72 mmol) followed by KI (3.72 mmol) and 2-bromoethylacetate (8.68 mmol). The reaction mixture was heated to 100° C. for 4 h and then stirred at RT for 3 days. The mixture was diluted with EtOAc and washed 3 times with water and then with brine. The comb. org. layers were dried over MgSO4 and conc. in vacuo. Purification with CC (20-100% EtOAc/Hept) gives the desired compound as beige solid.
Reaction SMILES: [CH3:1]/[C:2](/[NH2:6])=[CH:3]\[C:4]#[N:5].[C:7]([CH2:10][C:11](=O)[CH3:12])(=O)[CH3:8]>>[C:4]([C:3]1[C:2]([CH3:1])=[N:6][C:7]([CH3:8])=[CH:10][C:11]=1[CH3:12])#[N:5]
Reactant: C/C(N)=C\C#N
Reactant: CC(=O)CC(C)=O
Product: Cc1cc(C)c(C#N)c(C)n1

Procedure:
3-Cyano-2,4,6-trimethylpyridine was prepared from 3-aminocrotonitrile and acetylacetone following the procedure of Kato and Noda (Chem. Pharm. Bull. 24, 303, 1976).
Reaction SMILES: B(Br)(Br)Br.[Cl:5][C:6]1[CH:11]=[C:10]([CH2:12][C:13]([OH:15])=[O:14])[CH:9]=[CH:8][C:7]=1[C:16]1[C:21]([F:22])=[CH:20][C:19]([O:23]C)=[CH:18][C:17]=1[F:25].[CH3:26]O>ClCCl>[Cl:5][C:6]1[CH:11]=[C:10]([CH2:12][C:13]([O:15][CH3:26])=[O:14])[CH:9]=[CH:8][C:7]=1[C:16]1[C:21]([F:22])=[CH:20][C:19]([OH:23])=[CH:18][C:17]=1[F:25]
Reactant: CO
Reactant: COc1cc(F)c(-c2ccc(CC(=O)O)cc2Cl)c(F)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COC(=O)Cc1ccc(-c2c(F)cc(O)cc2F)c(Cl)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
Boron tribromide (1.494 mL, 15.80 mmol) was added dropwise to 2-(2-chloro-2′,6′-difluoro-4′-methoxybiphenyl-4-yl)acetic acid (Intermediate 2-5; 822 mg, 2.63 mmol) in dichloromethane (30 mL) at ambient temperature under nitrogen. The resulting solution was stirred at ambient temperature for 90 minutes. The reaction mixture was cautiously added to ice water cooled methanol (50 mL) and the mixture was stirred for a further 20 minutes. The reaction mixture was evaporated to dryness and redissolved in EtOAc (150 mL), and washed sequentially with 2M HCl (50 mL) and saturated brine (50 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford methyl 2-(2-chloro-2′,6′-difluoro-4′-hydroxybiphenyl-4-yl)acetate (822 mg, 100%) as a yellow gum.