Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:13])([CH3:12])[C:7](=[O:14])[C:6]([C:15]([NH:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:16])=[C:5]2[OH:26].[N:27]1[CH:32]=[CH:31][CH:30]=[C:29](B(O)O)[CH:28]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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:26][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:29]3[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=3)[CH:3]=2)[C:8]([CH3:13])([CH3:12])[C:7](=[O:14])[C:6]=1[C:15]([NH:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:16]
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2cc(Br)ccc2C(C)(C)C1=O
Reactant: OB(O)c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2cc(-c3cccnc3)ccc2C(C)(C)C1=O
Temperature: 150 °C
Yield: 40 %

Procedure:
A suspension of 1,1-dimethylethyl N-((6-bromo-4-hydroxy-1,1-dimethyl-2-oxo-naphthalen-3-yl)carbonyl)glycinate (284 mg, 669 μmol, see Example 39), pyridin-3-ylboronic acid (165 mg, 1339 μmol), and Na2CO3 (2.0M aqueous solution (669 μL, 1339 μmol)) in 1,4-dioxane (5 mL) was treated with Pd(PPh3)4 (77 mg, 67 μmol) in a microwave vial. The vessel was capped, degassed, backfilled with argon (2×), and heated at 150° C. in a microwave for 1200 sec. The reaction was diluted with EtOAc (50 mL), washed with water (50 mL) and brine (50 mL), dried over MgSO4, concentrated in vacuo, and purified by silica gel chromatography (eluant: 20-28-40% EtOAc/hexane) affording 113 mg of the title compound. MS m/e=423.2 (M+H)+.
Reaction SMILES: [F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([OH:39])=[CH:8][C:9]=1[CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]([CH2:28][CH:29]=[C:30]([F:38])[C:31]([F:37])([F:36])[C:32]([F:35])([F:34])[F:33])[CH3:27].[BH4-].[Na+]>CO>[F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C@@H:16]2[OH:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([OH:39])=[CH:8][C:9]=1[CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]([CH2:28][CH:29]=[C:30]([F:38])[C:31]([F:36])([F:37])[C:32]([F:33])([F:34])[F:35])[CH3:27]
Reactant: CN(CC=C(F)C(F)(F)C(F)(F)F)CCCCC[C@@H]1Cc2cc(O)ccc2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@@H]2F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN(CC=C(F)C(F)(F)C(F)(F)F)CCCCC[C@@H]1Cc2cc(O)ccc2[C@@H]2[C@@H]1[C@@H]1CC[C@H](O)[C@@]1(C)C[C@@H]2F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 12.9 %

Procedure:
1.86 g of 11β-fluoro-7α-{5-[(3,4,4,5,5,5-hexafluoro-pent-2-enyl)-methyl-amino]-pentyl}-3-hydroxy-estra-1,3,5(10)-trien-17-one is dissolved in 15 ml of methanol and carefully mixed with 222 mg of sodium borohydride. After 15 minutes of stirring at room temperature, the batch is added to saturated common salt solution, extracted with methylene chloride, dried on magnesium sulfate and concentrated by evaporation in a vacuum. After the crude product is chromatographed on silica gel with a hexane-ethyl acetate gradient and an ethyl acetate-acetone gradient, 241 mg of 11β-fluoro-7α-{5-[(3,4,4,5,5,5-hexafluoro-pent-2-enyl)-methyl-amino]-pentyl}-estra-1,3,5(10)-triene-3,17β-diol with a melting point of 122° C. is obtained, [α]D=+47° (c=0.5 in CHCl3).
Reaction SMILES: [CH2:1]([C:3]1([CH2:7][OH:8])[CH2:6][O:5][CH2:4]1)[CH3:2].[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:1]([C:3]1([CH2:7][O:8][S:16]([C:13]2[CH:14]=[CH:15][C:10]([CH3:9])=[CH:11][CH:12]=2)(=[O:18])=[O:17])[CH2:6][O:5][CH2:4]1)[CH3:2]
Reactant: CCC1(CO)COC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCC1(COS(=O)(=O)c2ccc(C)cc2)COC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.3 %

Procedure:
To a mixture of (3-ethyl-oxetan-3-yl)-methanol (11.6 g, 0.1 mol) and DMAP (18.3 g, 0.15 mol) in DCM (100 mL) was added 4-methyl-benzenesulfonyl chloride (19 g, 0.1 mol). The mixture was stirred at room temperature for 1 h, then filtered. The filtrate was washed with HCl aq. (1 M) and water, dried over anhydrous Na2SO4 and concentrated to give the title compound (19 g).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[NH2:14][C:15]1[CH:22]=[CH:21][C:20](Br)=[CH:19][C:16]=1[C:17]#[N:18].C(=O)([O-])[O-].[K+].[K+]>O.COCCOC>[NH2:14][C:15]1[CH:22]=[CH:21][C:20]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=2)=[CH:19][C:16]=1[C:17]#[N:18]
Reactant: N#Cc1cc(Br)ccc1N
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: N#Cc1cc(-c2ccc(C(F)(F)F)cc2)ccc1N
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
In 250 ml of water and 500 ml of 1,2-dimethoxyethane, was mixed 26.5 g of 4-(trifluoromethyl)benzeneboronic acid, 25 g of 2-amino-5-bromo-benzonitrile and 57.9 g of potassium carbonate. The mixture was bobbled through with nitrogen for 10 minutes, then 1 g of bis(triphenylphosphine)palladium(II) choride was added and the reaction mixture was heated at reflux overnight. The reaction mixture was cooled to room temperature, added 700 ml of water and extracted with 800 ml of ethyl acetate. The organic phase was washed first with 300 ml of saturated sodium chloride, then 300 ml of 2 M calcium chloride and at last with 300 ml of water. The organic phase was dried with magnesium sulfate, evaporated to an oil and trituated with ether. Yield 30.5 g (92%).
Reaction SMILES: ClC(OCC(C)C)=O.[C:9]([NH:28][C:29]1[S:30][CH:31]=[C:32]([C:34](=[N:38][O:39][CH2:40][CH3:41])[C:35]([OH:37])=O)[N:33]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CN1CCOCC1.[CH3:49][C:50]([O:52][CH2:53][C:54]1[CH2:63][S:62][C@@H:57]2[C@H:58]([NH2:61])[C:59](=[O:60])[N:56]2[C:55]=1[C:64]([OH:66])=[O:65])=[O:51]>C(Cl)Cl.C(N(CC)CC)C.O1CCCC1>[C:50]([O:52][CH2:53][C:54]1[CH2:63][S:62][C@@H:57]2[CH:58]([NH:61][C:35](=[O:37])[C:34]([C:32]3[N:33]=[C:29]([NH:28][C:9]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[S:30][CH:31]=3)=[N:38][O:39][CH2:40][CH3:41])[C:59](=[O:60])[N:56]2[C:55]=1[C:64]([OH:66])=[O:65])(=[O:51])[CH3:49]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: CCON=C(C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: -20 °C
Reaction time: 0.05 h

Procedure:
1.17 ml of isobutyl chloroformate was added dropwise under an inert atmosphere to a mixture of 4.1 g of the product of Step C, 36 ml of tetrahydrofuran, 27 ml of methylene chloride and 0.99 ml of N-methyl-morpholine cooled to -20° C. and after standing at -20° C. for 3 minutes, the mixture was cooled to -35° C. and a solution of 2.45 g of 7-aminocephalosporanic acid in 45 ml of methylene chloride and 252 ml of triethylamine were added thereto. The mixture stood for 21/2 hours with spontaneous heating and was then evaporated to dryness. The residue was taken up in a mixture of methylene chloride, water and N hydrochloric acid with a pH of 1-2 and the mixture was extracted with methylene chloride. The organic extracts were washed with water, dried and vacuum filtered. The filtrate was evaporated to dryness and the residue was taken up in ethyl acetate. The solution was diluted with isopropyl ether and was stirred and vacuum filtered The recovered product was rinsed with isopropyl ether and dri to obtain 4.87 g of the anti isomer of 3-acetoxymethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-ethoxyiminoacetamido]-ceph-3-em-4-carboxylic acid. The said product was dissolved in 10 ml of hot ethyl acetate and the solution was slowly diluted with isopropyl ether. The mixture was stirred and was vacuum filtered and the recevered product was rinsed with isopropyl ether and dried to obtain 4.53 g of purified product.
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][Si](C(C)C)(C(C)C)C(C)C)=[CH:9][CH:8]=[C:7]([F:22])[C:3]=1[C:4]([OH:6])=[O:5].O=S(Cl)Cl.[CH3:27]O>>[F:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[C:7]([F:22])[C:3]=1[C:4]([O:6][CH3:27])=[O:5]
Reactant: CO
Reactant: CC(C)[Si](Oc1ccc(F)c(C(=O)O)c1F)(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Product: COC(=O)c1c(F)ccc(O)c1F
Yield: 75 %

Procedure:
To a solution of 2,6-difluoro-3-triisopropylsilyloxy-benzoic acid (see example 2) (7 g, 21.1 mmol, 1.0 eq) in MeOH (100 mL) was added SOCl2 (10 mL) dropwise. The reaction mixture was heated at reflux for 3 h, then cooled and the solvent removed in vacuo. Water was added and the aqueous layer was extracted with EtOAc. The organic extract was washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo to give the title compound as a solid (3 g, 75%) which was used in the next step without further purification.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[CH2:5][C@:6]([CH3:11])([C:8]([OH:10])=[O:9])[NH2:7].S(Cl)(Cl)=O.[CH3:19]O>>[I:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[CH2:5][C@:6]([CH3:11])([C:8]([O:10][CH3:19])=[O:9])[NH2:7]
Reactant: CO
Reactant: C[C@@](N)(Cc1cccc(I)c1)C(=O)O
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@](C)(N)Cc1cccc(I)c1

Procedure:
A solution of 3-iodo-α-methyl-D-phenylalanine (0.9 g) in MeOH (50 ml) was treated with thionyl chloride (3.5 ml) and the mixture was heated to reflux for 3 days. The solvent was removed under reduced pressure and the residue was dissolved in EtOAc and washed with aqueous sodium bicarbonate, brine, dried (MgSO4) and evaporated to dryness to give the title compound (0.73 g) LCMS RT=2.12 min.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:11]2[C:20]3[C:15](=[CH:16][C:17]([OH:22])=[C:18]([OH:21])[CH:19]=3)[N:14]=[CH:13][N:12]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].O.O.O.O.O.[OH-].C[N+](C)(C)C.[CH2:40]([CH:42]1[O:44][CH2:43]1)Br>CN(C=O)C.O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:11]2[C:20]3[C:15](=[CH:16][C:17]4[O:22][CH2:40][CH:42]([CH2:43][OH:44])[O:21][C:18]=4[CH:19]=3)[N:14]=[CH:13][N:12]=2)=[CH:4][CH:3]=1
Reactant: Oc1cc2ncnc(N3CCc4ccc(Cl)cc43)c2cc1O
Reactant: BrCC1CO1
Agent: C[N+](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: OCC1COc2cc3ncnc(N4CCc5ccc(Cl)cc54)c3cc2O1
Temperature: 50 °C
Reaction time: 16 h
Yield: 11 %

Procedure:
To 4-(6-chloro-2,3-dihydro-indol-1-yl)-quinazoline-6,7-diol (99 mg, 0.316 mmol; from Example 69) dissolved in DMF (2 mL) was added H2O (100 μL), K2CO3 (s) (65 mg, 0.473 mmol), and tetramethylammonium hydroxide pentahydrate (11 mg, 0.06 mmol) followed by epibromohydrin (28 μL, 0.331 mmol). The mixture was stirred at 50° C. under N2(g) for 16 hours. Following extractive work-up, and chromatography on silica (20% acetone/CH2Cl2) analogous to that described for Example 78 the product was obtained in 11% yield. (M.P. 219°-222° C. (dec); LC-MS: 370 (MH+); anal. RP18-HPLC RT: 3.98 min.).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)=[CH:11][CH:10]=2)O1.[NH2:28][C:29](=[O:43])[C@@H:30]([NH:32][C:33]1[N:38]=[C:37](Cl)[N:36]=[C:35]([C:40]([NH2:42])=[O:41])[CH:34]=1)[CH3:31].C([O-])([O-])=O.[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[NH2:28][C:29](=[O:43])[C@@H:30]([NH:32][C:33]1[N:38]=[C:37]([C:9]2[CH:10]=[CH:11][C:12]([O:15][C:16]3[CH:17]=[CH:18][C:19]([O:22][C:23]([F:24])([F:25])[F:26])=[CH:20][CH:21]=3)=[CH:13][CH:14]=2)[N:36]=[C:35]([C:40]([NH2:42])=[O:41])[CH:34]=1)[CH3:31]
Reactant: C[C@H](Nc1cc(C(N)=O)nc(Cl)n1)C(N)=O
Reactant: CC1(C)OB(c2ccc(Oc3ccc(OC(F)(F)F)cc3)cc2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: C[C@H](Nc1cc(C(N)=O)nc(-c2ccc(Oc3ccc(OC(F)(F)F)cc3)cc2)n1)C(N)=O
Temperature: 10 °C
Yield: 31.3 %

Procedure:
A 50-mL vial with a screw-top septum was charged with 200 mg of 4,4,5,5-tetramethyl-2-(4-(4-(trifluoromethoxy)phenoxy)phenyl)-1,3,2-dioxaborolane, 1 equivalent (S)-6-((1-amino-1-oxopropan-2-yl)amino)-2-chloropyrimidine-4-carboxamide (129 mg, 0.53 mmol), 1.5 mL 2M aqueous Na2CO3, 0.07 equivalents PdCl2(PPh3)2 (28 mg, 0.04 mmol), and 8 mL dioxane. The vial was purged with nitrogen and heated to 10° C. for 6 h, at which time the reaction was complete. The mixture was diluted with 100 mL EtOAc and washed two times with 100 mL water. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was chromatographed by combiflash using a 40-gram silica column with a gradient EtOAc (100% max) in hexane to provide 76 mg (31% yield) of (S)-6-((1-amino-1-oxopropan-2-yl)amino)-2-(4-(4-(trifluoromethoxy)phenoxy)phenyl)pyrimidine-4-carboxamide as a white solid. m/z 461, 1H NMR (CD3OD): 8.56-8.49 (m, 2H), 7.35-7.27 (m, 2H), 7.17-7.11 (m, 3H), 7.09-7.02 (m, 2H), 4.64-4.49 (m, 1H), 4.56-1.49 (m, 3H).
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].Br[C:21]1[S:25][C:24]([C:26]2[N:30]([CH3:31])[N:29]=[CH:28][N:27]=2)=[CH:23][C:22]=1[Cl:32].CC([O-])=O.[K+].C(OP(OCC(Br)CBr)(OCC(Br)CBr)=O)C(Br)CBr>CCCC[N+](CCCC)(CCCC)CCCC.[Br-].CN1C(=O)CCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:32][C:22]1[CH:23]=[C:24]([C:26]2[N:30]([CH3:31])[N:29]=[CH:28][N:27]=2)[S:25][C:21]=1[C:13]1[N:8]2[N:9]=[C:10]([CH3:12])[CH:11]=[C:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[C:7]2=[N:15][C:14]=1[C:16]([F:18])([F:19])[F:17]
Reactant: CCC(CC)c1cc(C)nn2cc(C(F)(F)F)nc12
Reactant: Cn1ncnc1-c1cc(Cl)c(Br)s1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN1CCCC1=O
Product: CCC(CC)c1cc(C)nn2c(-c3sc(-c4ncnn4C)cc3Cl)c(C(F)(F)F)nc12
Temperature: 125 °C
Yield: 39.8 %

Procedure:
In a dry 25 mL round bottom flask, 8-(1-ethyl-propyl)-6-methyl-2-trifluoromethyl-imidazo[1,2-b]pyridazine (182 mg, 0.671 mmol), 5-(5-bromo-4-chloro-thiophen-2-yl)-1-methyl-1H-[1,2,4]triazole (225 mg, 0.805 mmol), KOAc (330.2 mg, 3.36 mmol), and TBAB (217 mg, 0.671 mmol) are dissolved in NMP (3 mL). The mixture is degassed with bubbling nitrogen for 20 minutes. Then, Pd(OAc)2 (8 mg, 0.034 mmol) and TDBPP (20.4 g, 0.34 moles) are added. The reaction mixture is heated to 125° C. for 3 hours to give the title compound (125 mg, 0.267 mmol, 40%). 1H-NMR (CDCl3), δ 0.88 (t, J=7.2 Hz, 6H), 1.87 (m, 4H), 2.537 (s, 3H), 3.32 (m, 1H), 4.16 (s, 3H), 6.86 (s, 1H), 7.51 (s, 1H), 7.91 (s, 1H) ppm. ES-MS (m/z): calcd for C20H20ClF3N6S (M+H)+: 468.93; found: 469.2.
Reaction SMILES: I[C:2]1[CH:19]=[N:18][C:5]2[NH:6][CH2:7][CH2:8][N:9]([C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:11])[C:4]=2[CH:3]=1.[CH3:20][N:21]([CH3:42])[CH2:22][CH2:23][NH:24][C:25](=[O:41])[C:26]1[CH:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][CH:27]=1>>[C:10]([N:9]1[CH2:8][CH2:7][NH:6][C:5]2[N:18]=[CH:19][C:2]([C:29]3[CH:30]=[CH:31][C:26]([C:25]([NH:24][CH2:23][CH2:22][N:21]([CH3:20])[CH3:42])=[O:41])=[CH:27][CH:28]=3)=[CH:3][C:4]1=2)(=[O:11])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(c1ccccc1)N1CCNc2ncc(I)cc21
Reactant: CN(C)CCNC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: CN(C)CCNC(=O)c1ccc(-c2cnc3c(c2)N(C(=O)c2ccccc2)CCN3)cc1
Yield: 24 %

Procedure:
(7-Iodo-3,4-dihydro-2H-pyrido[2,3-b]pyrazin-1-yl)phenyl-methanone (50 mg) was reacted with N-(2-dimethylaminoethyl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzamide as in General Procedure 4A to give the title compound as a light yellow solid (24% yield). M.p. 145-147° C., LCMS: m/z=430.26 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.28 (s, 6H), 2.48-2.53 (m, 2H), 3.48-3.54 (m, 2H), 3.66-3.71 (m, 2H0, 4.01 (t, J=4.8 Hz, 2H), 5.55 (bs, 1H), 6.84-6.87 (m, 1H), 7.09-7.15 (m, 2H), 7.38-7.52 (m, 6H), 7.71 (d, J=8.1 Hz, 2H), 8.05 (d, J=2.0 Hz, 1H).
Reaction SMILES: [C:1]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:35])[O:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]([C:20](=[O:34])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26]C(OC(C)(C)C)=O)[CH3:19])[CH2:12][CH2:11]1.[ClH:42].O1CCOCC1>O1CCOCC1>[ClH:42].[ClH:42].[C:1]1([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:35])[O:9][CH:10]1[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][N:18]([C:20](=[O:34])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH2:26])[CH3:19])[CH2:14][CH2:15]1
Reactant: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCCNC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCCN
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 105.9 %

Procedure:
The compound (1.59 g, 2.80 mmol) obtained in Example 11b was dissolved in 1,4-dioxane (7 mL), 4 N hydrochloric acid-dioxane (7.00 mL, 28.0 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 20 minutes. Since insoluble material was precipitated, methanol (4 mL) was added, and the mixture was stirred at room temperature for 40 minutes. The solvent was evaporated under reduced pressure to give the title compound (1.60 g; yield, 100%) as a white solid.
Reaction SMILES: [Cl-].[CH2:2]([N+:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[BH4-].[Na+]>C(O)C.O>[CH2:2]([N:9]1[CH2:10][CH:11]=[C:12]([CH3:15])[CH2:13][CH2:14]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Cc1cc[n+](Cc2ccccc2)cc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC1=CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.9 %

Procedure:
To a stirred solution of the product from Method A (38 grams/0.171 mol) dissolved in 140 mL of 10:1 ethanol/water at 0° C. was added 16 grams (0.427 mol) of sodium borohydride portion-wise over 25 minutes. The resulting mixture stirred for 18 hours at room temperature, at which time, the reaction was quenched upon addition of 100 mL of water. The reaction mixture was filtered, the filter cake washed with water and ethylacetate, and the combined filtrates concentrated under reduced pressure to remove the organics. The residue was diluted with water (100 mL) and extracted 3 times with 150 mL with ethylacetate. The combined ethylacetate extracts were dried over Na2SO4 and concentrated to dryness in vacuo affording 32 grams (100%) of the title compound as a yellow oil. LRMS: 188 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([NH2:14])[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7].[O:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[CH:21]=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([NH:14][CH2:21][C:17]2[O:16][CH:20]=[CH:19][CH:18]=2)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: O=Cc1ccco1
Reactant: COC(=O)c1cccc(N)c1C(=O)OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)c1cccc(NCc2ccco2)c1C(=O)OC
Reaction time: 0.08 h
Yield: 109.2 %

Procedure:
To a stirred solution of 3-amino-phthalic acid dimethyl ester (8.23 g, 39.32 mmol) in methylene chloride (200 ml) under a nitrogen atmosphere, 2-furaldehyde (8.14 ml, 98.30 mmol) and acetic acid (13.57 ml, 235.92 mmol) were added. The mixture was stirred for 5 minutes, followed by addition of sodium triacetoxyborohydride (25 g, 117.96 mmol). The reaction was stirred overnight, washed with water (2×200 ml), saturated aqueous sodium bicarbonate (2×200 ml), and brine (200 ml), and dried over MgSO4. The solvent was evaporated in vacuo to give a brown oil (12.42 g), which was used directly without purification.
Reaction SMILES: Cl.[CH:2]([N:5]1[C:9]([C:10]2[N:19]=[C:18]3[N:12]([CH2:13][CH2:14][O:15][C:16]4[CH:23]=[C:22]([CH:24]5[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]5)[CH:21]=[CH:20][C:17]=43)[CH:11]=2)=[N:8][C:7]([CH3:30])=[N:6]1)([CH3:4])[CH3:3].C(N(CC)CC)C.Cl[CH2:39][C:40]([NH:42][CH:43]([CH3:45])[CH3:44])=[O:41]>C(Cl)Cl.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH:43]([NH:42][C:40](=[O:41])[CH2:39][N:27]1[CH2:28][CH2:29][CH:24]([C:22]2[CH:21]=[CH:20][C:17]3[C:18]4[N:12]([CH:11]=[C:10]([C:9]5[N:5]([CH:2]([CH3:4])[CH3:3])[N:6]=[C:7]([CH3:30])[N:8]=5)[N:19]=4)[CH2:13][CH2:14][O:15][C:16]=3[CH:23]=2)[CH2:25][CH2:26]1)([CH3:45])[CH3:44]
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(C4CCNCC4)cc2OCC3)n(C(C)C)n1
Reactant: CC(C)NC(=O)CCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc(-c2cn3c(n2)-c2ccc(C4CCN(CC(=O)NC(C)C)CC4)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 96 h
Yield: 51.4 %

Procedure:
To a suspension of 2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene hydrochloride (150 mg, 0.35 mmol) in DCM (2 mL) was added triethylamine (107 μL, 0.77 mmol). The resultant mixture was stirred for 10 minutes before the addition of 2-chloro-N-isopropyl-acetamide (52 mg, 0.38 mmol) and tetrabutylammonium iodide (13 mg, 0.04 mmol). The reaction was stirred at RT for 4 days before the reaction was washed with sodium hydrogen carbonate solution (sat. aq.). The aqueous phase was extracted with 10% MeOH in DCM (×3) and the combined organic layers dried (Na2SO4) then concentrated in vacuo. The resultant residue was purified by flash column chromatography (SiO2, gradient 0-10% MeOH in DCM) affording 277 (88 mg, 0.18 mmol, 51%). LCMS: RT=2.85 min, [M+H]+=492. 1H NMR δ (ppm) (CDCl3): 8.43 (1H, d, J=8.29 Hz), 7.59 (1H, s), 7.01 (1H, dd, J=8.34, 1.82 Hz), 6.97 (1H, s), 6.89 (1H, d, J=1.76 Hz), 5.92-5.82 (1H, m), 4.48-4.44 (2H, m), 4.42-4.38 (2H, m), 4.13-4.02 (1H, m), 3.10-2.85 (4H, m), 2.58-2.46 (1H, m), 2.38 (3H, s), 2.35-2.20 (2H, m), 1.94-1.84 (2H, s), 1.81-1.68 (2H, m), 1.54 (6H, d, J=6.64 Hz), 1.16 (6H, d, J=6.55 Hz)
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][C:9]=2[CH3:16])=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:25])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1>[CH3:16][C:9]1[C:8]([C:5]2[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=2)=[N+:13]([O-:25])[C:12]([C:14]#[N:15])=[CH:11][CH:10]=1
Reactant: Cc1ccc(C#N)nc1-c1ccc(F)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(C#N)[n+]([O-])c1-c1ccccc1
Temperature: 50 °C
Yield: 9.2 %

Procedure:
A solution of 6-(4-fluorophenyl)-5-methylpyridine-2-carbonitrile (750 mg, 3.86 mmol) and m-chloroperbenzoic acid (purity 69%, 2.4 g, 96.5 mmol) in tetrahydrofuran (8 mL) was stirred with heating at 50° C. for 3 days. Saturated aqueous sodium thiosulfate solution was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The combined organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/3→1/2) to give the title compound (74.8 mg, 9%) as white crystals.