Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2)([O-])=O.C1C2C(=C(NC(=O)C)C=CC=2)CC1.N(C1C2CCCCC=2C(C#N)=CC=1)=C=O.[OH:44][C@H:45]1[C@@H:52]2[N:48]([C:49](=[O:66])N(C3C4CCCCC=4C(C#N)=CC=3)[C:51]2=[O:53])[CH2:47][CH2:46]1>>[OH:44][C@H:45]1[C@@H:52]2[N:48]([C:49](=[O:66])[N:1]([C:4]3[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[C:10]4[C:5]=3[CH:6]=[CH:7][CH:8]=[N:9]4)[C:51]2=[O:53])[CH2:47][CH2:46]1
Reactant: N#Cc1ccc(N2C(=O)[C@@H]3[C@H](O)CCN3C2=O)c2c1CCCC2
Reactant: N#Cc1ccc([N+](=O)[O-])c2cccnc12
Agent: CC(=O)Nc1cccc2c1CCC2
Agent: N#Cc1ccc(N=C=O)c2c1CCCC2
Product: N#Cc1ccc(N2C(=O)[C@@H]3[C@H](O)CCN3C2=O)c2cccnc12

Procedure:
The title compound was synthesized from compound 12C by procedures analogous to those described in Experiment 3A and Experiment 2 (2E to 2F). 99.8% at 2.05 min (retention time) (Conditions: YMC S5 ODS (4.6×50 mm); Eluted with 0% to 100% B; 4 min gradient; (A=90% H2O-10% MeOH-0.1% H3PO4 and B=10% H2O-90% MeOH-0.1% H3PO4); Flow rate at 4 mL/min. UV detection at 220 nm). LC/MS nm/z 309 [M+H]+.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5](Br)[N:6]=1.C([Li])CCC.[Cl-].[C:14]([O:18][C:19]([N:21]1[CH:26]2[CH2:27][CH2:28][CH:22]1[CH2:23][C:24](=[O:29])[CH2:25]2)=[O:20])([CH3:17])([CH3:16])[CH3:15].[Cl-].[NH4+]>C(OCC)C>[C:14]([O:18][C:19]([N:21]1[CH:26]2[CH2:27][CH2:28][CH:22]1[CH2:23][C:24]([OH:29])([C:5]1[N:6]=[CH:2][S:3][CH:4]=1)[CH2:25]2)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(=O)C2
Reactant: Brc1csc(Br)n1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1C2CCC1CC(O)(c1cscn1)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 17.7 %

Procedure:
2,4-dibromothiazole (1.1 g, 4.52 mmol) in diethyl ether (5 mL) was added to a solution of n-butyl lithium (2.5 M, 2 mL, 5 mmol) in diethyl ether (10 mL) at −78° C. and stirred for 0.5 hours. Trimethylsiliyl chloride (0.57 mL, 4.52 mmol) was added and the reaction mixture stirred for a further 0.5 hours before more n-butyl lithium (2.5M, 2 mL, 5 mmol) was added and stirred for 0.5 hours. 3-Oxo-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (0.9 g, 4 mmol) in diethyl ether (5 mL) was added and stirred for 0.5 hours before the reaction mixture was warmed to room temperature. Saturated aqueous ammonium chloride was added and the mixture extracted into ethyl acetate, dried over magnesium sulphate, filtered and the solvent removed by evaporation under vacuum. The residue was purified by flash chromatography on silica eluting with 20-30% ethyl acetate/cyclohexane. The fractions containing the desired product were concentrated under vacuum to give the title compound (0.22 g). LCMS m/z 311.3 [M+H]+. R.T.=3.05 min. (Analytical Method 3).
Reaction SMILES: OC1O[N:5]=[N+:4]2[CH2:7][S:8][CH2:9][C:3]=12.[F:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[C:18]#[C:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]([Cl:26])[N:21]=1>C1(C)C=C(C)C=C(C)C=1>[Cl:26][C:22]1[N:21]=[C:20]([C:19]2[C:18]([C:12]3[CH:13]=[CH:14][C:15]([F:17])=[CH:16][C:11]=3[F:10])=[N:5][N:4]3[C:3]=2[CH2:9][S:8][CH2:7]3)[CH:25]=[CH:24][N:23]=1
Reactant: Fc1ccc(C#Cc2ccnc(Cl)n2)c(F)c1
Reactant: Oc1on[n+]2c1CSC2
Solvent: Cc1cc(C)cc(C)c1
Product: Fc1ccc(-c2nn3c(c2-c2ccnc(Cl)n2)CSC3)c(F)c1

Procedure:
A solution of 3-hydroxy-4H,6H-thiazolo[3,4-c][1,2,3]oxadiazol-7-ium, inner salt (0.63 g, 4.3 mmol) (prepared from thiazolidine-4-carboxylic acid by nitrosation and treatment with trifluoroacetic anhydride as described in Sutcliffe et al. Tetrahedron 2000, 24, 10011-10021) and 4-[2-(2,4-difluorophenyl)ethynyl)-2-chloropyrimidine (1.0 g, 4.0 mmol) in mesitylene (15 mL) was heated at 155-160° C. under nitrogen for 48 h. The reaction mixture was concentrated under reduced pressure. The crude residue was purified by medium pressure liquid chromatography using 0 to 50% ethyl acetate in hexanes as eluant to give 0.09 g of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]([O:12]CC)=O)=[CH:4][CH:3]=1.[NH2:16][C:17]1[NH:21][N:20]=[CH:19][C:18]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23].C(OCC)(=O)C>CCCCCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([OH:12])[N:21]3[N:20]=[CH:19][C:18]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:17]3[N:16]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)c1ccc(Cl)cc1
Reactant: CCOC(=O)c1cn[nH]c1N
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)c1cnn2c(O)cc(-c3ccc(Cl)cc3)nc12
Temperature: 160 °C
Reaction time: 3 h
Yield: 52.3 %

Procedure:
A mixture of ethyl 3-(4-chloro-phenyl)-3-oxo-propionate (18.1 g, 0.080 mol) and ethyl 5-amino-1H-pyrazole-4-carboxylate (13.7 g, 0.088 mol) was stirred at for 3 h 160° C. Ethyl acetate (40 mL) and hexane (40 mL) were successively added to the cooled mixture and stirring was continued at 0° C. for 0.5 h. The crystals were isolated by filtration and triturated for 1.2 h with 0.2 N HCl (80 mL). The solid was filtered off, washed with water and dried to give ethyl 5-(4-chloro-phenyl)-7-hydroxy-pyrazolo[1,5-a]pyrimidine-3-carboxylate (13.3 g, 52%). White solid. MS (ISN) 316.3 [(M−H)−]; mp 190-192° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[CH:8][C:9]1[C:17]2[C:12](=[CH:13][C:14]([NH:18][C:19]3[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=3[C:21](O)=[O:22])=[CH:15][CH:16]=2)[NH:11][N:10]=1.Cl.[CH2:29]([O:32][NH2:33])[CH:30]=[CH2:31].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:29]([O:32][NH:33][C:21](=[O:22])[C:20]1[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=1[NH:18][C:14]1[CH:13]=[C:12]2[C:17]([C:9](/[CH:8]=[CH:7]/[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[N:10][NH:11]2)=[CH:16][CH:15]=1)[CH:30]=[CH2:31]
Reactant: O=C(O)c1ccccc1Nc1ccc2c(C=Cc3ccccn3)n[nH]c2c1
Reactant: C=CCON
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=CCONC(=O)c1ccccc1Nc1ccc2c(/C=C/c3ccccn3)n[nH]c2c1
Reaction time: 8 h
Yield: 73.8 %

Procedure:
A solution of 2-[3-(2-Pyridin-2-yl-vinyl)-1H-indazol-6-ylamino]-benzoic acid (50.0 mg, 0.084 mmol), O-allyl-hydroxylamine hydrochloride (18.3 mg, 0.17 mmol), triethylamine(58 μl, 0.42 mmol), dissolved in DMF (0.8 mL), was treated with HATU (48 mg, 0.13 mmol). The mixture was stirred overnight, then purified by reverse phase HPLC yielding 25.5 mg (74%) of the title compound as a yellow solid. 1H NMR (DMSO-d6): δ 9.28 (1H, s), 8.67 (2H, d, J=3.4), 8.05 (4H, m), 7.48 (5H, m), 7.23 (1H, s), 7.04 (1H, d, J=7.6 Hz), 6.91 (1H, m), 3.69 (3H, s). ESIMS (M+H+): 386.1.
Reaction SMILES: [H-].[Na+].[CH2:3](Br)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CN([CH:14]=[O:15])C>>[CH2:3]([O:15][CH2:14][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: BrCc1ccccc1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: c1ccc(COCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of the above alcohol (430 mg, 3.0 mmol) in DMF (10 mL) was added NaH (144 mg of a 60% dispersion in mineral oil, 3.60 mmol) and the mixture was then cooled in an ice bath. Benzyl bromide (437 uL, 3.60 mmol) was then added and the mixture was stirred at room temperature for 3 h. After normal aqueous work-up and short column chromatographic purification, 600 mg of desired benzyl ether was obtained.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[NH2:25][CH2:26][C:27]1([C:30]([OH:32])=[O:31])[CH2:29][CH2:28]1.C[O-].[Na+].Cl>CO.O>[C:23]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:9]=2)[C:14]([OH:15])=[C:5]([C:3]([NH:25][CH2:26][C:27]2([C:30]([OH:32])=[O:31])[CH2:29][CH2:28]2)=[O:4])[N:6]=1)#[N:24]
Reactant: NCC1(C(=O)O)CC1
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: N#Cc1nc(C(=O)NCC2(C(=O)O)CC2)c(O)c2ccc(Oc3ccccc3)cc12
Yield: 25.7 %

Procedure:
After a mixture of 1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (101 mg, 0.318 mmol), 1-aminomethyl-cyclopropanecarboxylic acid (110 mg, 0.955 mmol, prepared according to literature: Ohno, Mitsuru et al Synlett 1991, 919-920), and NaOMe in MeOH (1.6 mL, 0.5 M solution) was microwaved at 120° C. for 1 h, the reaction mixture was cooled, diluted with water and acidified with 2 M HCl aqueous solution, the resulted solids were collected via filtration, water-washed and air-dried to give solids, which were further column purified to give the desired product (33 mg). LC MS ESI+: 404 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:22][C@@H:23]2[C@@H:28]3[CH2:29][C@@H:25]([CH:26]=[CH:27]3)[C@@H:24]2[C:30]([NH2:32])=[O:31])=[C:4]2[N:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH:16]4[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]4)[CH:15]=3)[NH:8][C:5]2=[N:6][CH:7]=1.[C:33](OC(=O)C)(=[O:35])[CH3:34]>N1C=CC=CC=1>[C:33]([N:19]1[CH2:20][CH2:21][CH:16]([N:14]2[CH:15]=[C:11]([C:9]3[NH:8][C:5]4=[N:6][CH:7]=[C:2]([Cl:1])[C:3]([NH:22][C@@H:23]5[C@@H:28]6[CH2:29][C@@H:25]([CH:26]=[CH:27]6)[C@@H:24]5[C:30]([NH2:32])=[O:31])=[C:4]4[N:10]=3)[CH:12]=[N:13]2)[CH2:17][CH2:18]1)(=[O:35])[CH3:34]
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc3[nH]c(-c4cnn(C5CCNCC5)c4)nc23)[C@H]2C=C[C@@H]1C2
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)N1CCC(n2cc(-c3nc4c(N[C@H]5[C@@H](C(N)=O)[C@@H]6C=C[C@H]5C6)c(Cl)cnc4[nH]3)cn2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
(1S,2S,3R,4R)-3-[6-Chloro-2-(1-piperidin-4-yl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine-7-ylamino]-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (100 mg, 0.20 mmol) and acetic anhydride (45.1 mg, 0.442 mmol) were combined in pyridine (1 mL) and stirred at ambient temperature overnight. The mixture was concentrated and the crude product was purified employing reverse phase chromatography (Gilson) to afford following lyophilization of desired fractions a white lyophilate—the title compound (100%). 1H NMR (d-chloroform): 8.38 (d, J=8 Hz, 1H), 8.12 (s, 2H), 7.80 (s, 1H), 6.48 (m, 1H), 6.43 (m, 1H), 5.81 (br s, 1H), 5.40 (br s, 1H), 5.35 (m, 1H), 4.81 (m, 1H), 4.47 (m, 1H), 4.04 (m, 1H), 3.31 (t, J=8 Hz, 1H), 3.17 (s, 1H), 3.03 (s, 1H), 2.82 (m, 1H), 2.65 (m, 1H), 2.36-1.98 (m, 8H), 1.67 (d, J=8 Hz, 1H), 1.26 (d, J=8 Hz, 1H). MS: 494.9 (M+H). HPLC retention time: 1.88 minutes (G Method).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:26]=[CH:25][CH:24]=[CH:23][C:11]=3[C:12]=2[C:13](=[O:22])[C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[CH:15]=2)=[CH:4][CH:3]=1.[CH3:27][N:28]([CH3:33])[CH2:29][CH2:30][CH2:31]Cl>>[CH3:27][N:28]([CH3:33])[CH2:29][CH2:30][CH2:31][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:26]=[CH:25][CH:24]=[CH:23][C:11]=3[C:12]=2[C:13](=[O:22])[C:14]2[CH:15]=[C:16]([CH3:21])[CH:17]=[C:18]([CH3:20])[CH:19]=2)=[CH:6][CH:7]=1
Reactant: CN(C)CCCCl
Reactant: Cc1cc(C)cc(C(=O)c2c(-c3ccc(O)cc3)oc3ccccc23)c1
Product: Cc1cc(C)cc(C(=O)c2c(-c3ccc(OCCCN(C)C)cc3)oc3ccccc23)c1

Procedure:
Reaction of 2-p-hydroxyphenyl-3-(3',5'-dimethylbenzoyl)benzofuran with 3-dimethylaminopropyl chloride according to the procedure described in Example 7 gave the title compound.
Reaction SMILES: Cl.[F:2][C:3]([F:13])([F:12])[C:4]1[N:5]=[C:6]([C:9]([NH2:11])=[NH:10])[S:7][CH:8]=1.C([O:16][C:17]([C:19]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:20][O-])=O)C.[Na+].CC[O-].[Na+]>CCO>[O:22]([C:19]1[C:17]([OH:16])=[N:10][C:9]([C:6]2[S:7][CH:8]=[C:4]([C:3]([F:2])([F:12])[F:13])[N:5]=2)=[N:11][CH:20]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)C(=C[O-])Oc1ccccc1
Reactant: N=C(N)c1nc(C(F)(F)F)cs1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Oc1nc(-c2nc(C(F)(F)F)cs2)ncc1Oc1ccccc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
To a solution of compound 282 (280 mg, 1 eq.) in dry EtOH (6 mL) was added compound 291 (1.38 g, 5 eq.) under nitrogen, followed by NaOEt (165 mg, 1 eq.). The reaction mixture was stirred at 90° C. for 2 hrs. EtOH was evaporated and a DCM/water mixture was added. Aqueous layer was acidified to pH 5 with aqueous 1N HCl and was extracted with DCM. The combined organic layers were dried over Na2SO4, filtered, concentrated in vacuo, and purified by chromatography on silica gel (DCM/MeOH) to yield compound AI1 as a beige oil in 81% yield. MS (ESI, EI+): m/z=340 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1([CH2:21][CH2:22][CH3:23])[C:11]2[NH:12][C:13]3[C:18]([C:10]=2[CH2:9][CH2:8][O:7]1)=[C:17](Br)[CH:16]=[CH:15][C:14]=3[CH3:20])[CH3:2].[C:25]([Cu])#[N:26]>CN1CCCC1=O.O>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1([CH2:21][CH2:22][CH3:23])[C:11]2[NH:12][C:13]3[C:18]([C:10]=2[CH2:9][CH2:8][O:7]1)=[C:17]([C:25]#[N:26])[CH:16]=[CH:15][C:14]=3[CH3:20])[CH3:2]
Reactant: CCCC1(CC(=O)OCC)OCCc2c1[nH]c1c(C)ccc(Br)c21
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCCC1(CC(=O)OCC)OCCc2c1[nH]c1c(C)ccc(C#N)c21
Temperature: 220 °C
Yield: 87.5 %

Procedure:
5-Bromo-8-methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid ethyl ester (1.27 g, 3.22 mmol) and CuCN (0.433 g, 4.83 mmol) was dissolved in N-methyl-2-pyrrolidinone (15 mL) and the solution was divided into the 4 microwave reaction vessels (3.75 mL each). The reaction vessels were heated in microwave at 220 ° C. for 15 minutes. The reaction mixtures in 4 vessels were combined and then diluted with water (30 mL). The crude mixture was extracted with EtOAc (3×50 mL). The combined organic phase was washed with brine (100 mL), dried over Na2SO4 and concentrated. The residue was purified by flash chromatography (silica, 20% EtOAc in hexanes) to give 0.959 g (88%) of title compound as a white solid. 1H NMR (CDCl3): 300 MHz δ 9.75 (bs, 1H), 7.33 (d, J=7.52 Hz, 1H), 6.93 (d, J=7.52 Hz, 1H), 4.21 (m, 2H), 4.11 (m, 1H), 4.03 (m, 1H), 3.08 (t, J=5.52, 2H), 2.99 (d, J=4.17 Hz, 2H), 2.57 (s, 3H), 2.06 (m, 2H), 1.42 (m, 1H), 1.26 (t, J=7.16 Hz, 3H), 1.18 (m, 1H), 0.88 (t, J=7.32 Hz, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:13]3[CH2:18][CH2:17][C:16](=O)[CH2:15][CH:14]=3)=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].CC(O)=O.Cl.[CH3:25][NH2:26].[OH-].[Na+]>ClCCCl>[CH3:25][NH:26][CH:16]1[CH2:17][CH2:18][C:13]([C:8]2[C:7]3[C:11](=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[NH:10][CH:9]=2)=[CH:14][CH2:15]1
Reactant: CN
Reactant: O=C1CC=C(c2c[nH]c3cc([N+](=O)[O-])ccc23)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CNC1CC=C(c2c[nH]c3cc([N+](=O)[O-])ccc23)CC1
Reaction time: 16 h
Yield: 88.8 %

Procedure:
A solution of compound 119 (0.5 g, 1.951 mmol) in 1,2-dichloroethane (10 mL) was treated with AcOH (0.11 mL, 1.951 mmol), methylamine hydrochloride (0.13 g, 1.951 mmol), NaBH(OAC)3 (0.62 g, 2.926 mmol) at room temperature and stirred for over night (16 h). The reaction was basified with 2 N NaOH (25 mL) and product was extracted into ethyl acetate (2×25 mL). The combined ethyl acetate layer washed with brine (15 mL) and dried (Na2SO4). Solvent was evaporated and crude was purified by column chromatography (2M NH3 in MeOH:CH2Cl2, 1:9) to obtain compound 120 (0.47 g, 89%) as a solid. mp 170-172° C.; 1H NMR (DMSO-d6) δ 1.37-1.50 (m, 1H), 1.90-1.99 (m, 2H), 2.33 (s, 3H), 2.43-2.64 (m, 4H), 6.14 (brs, 1H), 7.80 (s, 1H), 7.86-7.96 (m, 2H), 8.30 (d, 1H, J=2.1 Hz); ESI-MS (m/z, %): 272 (MH+, 100), 241 (43).
Reaction SMILES: [NH2:1][C@@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].[CH:8]1([C:14]([O:16][CH:17]([O:21][C:22](ON2C(=O)CCC2=O)=[O:23])[CH:18]([CH3:20])[CH3:19])=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>C(#N)C.O>[CH:8]1([C:14]([O:16][CH:17]([O:21][C:22]([NH:1][CH:2]([CH2:3][OH:4])[C:5]([OH:7])=[O:6])=[O:23])[CH:18]([CH3:19])[CH3:20])=[O:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: N[C@H](CO)C(=O)O
Reactant: CC(C)C(OC(=O)ON1C(=O)CCC1=O)OC(=O)C1CCCCC1
Solvent: CC#N
Solvent: O
Product: CC(C)C(OC(=O)NC(CO)C(=O)O)OC(=O)C1CCCCC1
Yield: 9.4 %

Procedure:
Following the general procedure for the synthesis of acyloxyalkyl carbamates, D-serine (0.40 g, 3.80 mmol) and 1-(2,5-dioxoazolidinyloxycarbonyloxy)-2-methylpropyl cyclohexanecarboxylate (1.0 g, 2.93 mmol) were reacted in the acetonitrile/water mixture to provide 0.091 g (10% yield) of the title compound (34) as a white wax after work-up and mass-guided preparative HPLC purification. 1H NMR (CDCl3, 400 MHz): δ=6.58 (dd, 1H), 6.11 (dd, 1H), 4.42-4.31 (m, 1H), 4.11-3.92 (br dd, 2H), 2.38 (m, 1H), 2.11 (m, 1H), 1.97 (br d, 2H), 1.77 (br d, 2H), 1.6 (br d, 1H), 1.4 (q, 2H), 1.2 (br m, 3H), 0.99 (dd, 6H). MS (ESI) m/z 354.22 (M+Na)+; 330.21 (M−H)−.
Reaction SMILES: CO[NH:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[N:7]=1)=[NH:5].[Cl-].[NH4+]>CCO.O>[CH3:12][C:8]1[N:7]=[C:6]([C:4]([NH2:5])=[NH:3])[CH:11]=[CH:10][CH:9]=1
Reactant: CONC(=N)c1cccc(C)n1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Cc1cccc(C(=N)N)n1
Temperature: 80 °C

Procedure:
To a solution of N-Methoxy-6-methyl-pyridine-2-carboxamidine (1 eq, 32.9 mmol, 4.94 g) in EtOH (40 ml) and water (10 ml) at room temperature is added ammonium chloride (1 eq, 32.9 mmol, 1.76 g). The resulting mixture is heated to 80° C. for 4 hours and then allowed to cool to room temperature overnight. The solvent is removed in vacuo to afford the title compound which is used in subsequent steps without further purification. [2M+H]+=271
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[CH:8]=[C:7]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:6]2=[O:25])#[CH:2].Br[C:27]1[CH:32]=[CH:31][N:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=1.C(N(CC)CC)C>[Cu]I.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.CN(C=O)C>[F:19][C:16]1[CH:17]=[CH:18][C:13]([N:9]2[C:10]3[C:5](=[CH:4][C:3]([C:1]#[C:2][C:27]4[CH:32]=[CH:31][N:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=4)=[CH:12][CH:11]=3)[C:6](=[O:25])[C:7]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:8]2)=[CH:14][CH:15]=1
Reactant: C#Cc1ccc2c(c1)c(=O)c(C(=O)OCC)cn2-c1ccc(F)cc1
Reactant: FC(F)(F)c1cc(Br)ccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(-c2ccc(F)cc2)c2ccc(C#Cc3ccnc(C(F)(F)F)c3)cc2c1=O
Yield: 45.1 %

Procedure:
Compound R (20 mg, 0.06 mmol), 4-bromo-2-(trifluoromethyl)pyridine (16.2 mg, 0.07 mmol), CuI (1.1 mg, 0.006 mmol), triethylamine (25 μL, 0.18 mmol), PdCl2(PPh3)2 (2.7 mg, 0.003 mmol), and DMF (600 μL) were added to a small microwave vial. The vial was capped and placed in microwave reactor at 150° C. for fifteen minutes. The reaction was filtered over Celite®, washed very well with a 5% MeOH in DCM solution and concentrated to dryness. Purification by reverse phase HPLC afforded 13 mg (45%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 8.84 (d, J=4.96 Hz, 1H), 8.52-8.5 (m, 2H), 8.17 (s, 1H), 7.93 (d, J=5.04 Hz, 1H), 7.87 (dd, J=8.8 Hz, 1H), 7.81-7.77 (m, 2H), 7.55 (t, J=8.64, 8.68 Hz, 2H), 7.07 (d, J=8.8 Hz, 1H), 4.24 (q, J=7.04, 7.08 Hz, 2H), 1.28 (t, J=7.12, 7.08 Hz, 3H); ES-MS [M+1]+: 481.2.
Reaction SMILES: [CH2:1]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[CH:5]2[CH2:15][CH2:16][N:2]1[CH2:3][CH2:4]2.Br[C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[N:24]=[CH:23][N:22]=[C:21]2[O:28][CH3:29]>>[CH3:29][O:28][C:21]1[C:20]2[C:25](=[CH:26][CH:27]=[C:18]([N:7]3[C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=4[C:14]4[CH2:1][N:2]5[CH2:3][CH2:4][CH:5]([C:6]3=4)[CH2:15][CH2:16]5)[CH:19]=2)[N:24]=[CH:23][N:22]=1
Reactant: COc1ncnc2ccc(Br)cc12
Reactant: c1ccc2c3c([nH]c2c1)C1CCN(CC1)C3
Product: COc1ncnc2ccc(-n3c4c(c5ccccc53)CN3CCC4CC3)cc12

Procedure:
The reaction of 3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (127 mg, 0.6 mmol; Example 187A) and 6-bromo-4-methoxyquinazoline (215 mg, 0.9 mmol; ChemBridge) was performed as described in Example 68 to afford the title compound as the minor product: 1H NMR (300 MHz, methanol-d4) δ ppm 1.95-2.21 (m, 4H) 2.90-2.97 (m, 1H) 3.09-3.30 (m, 4H) 4.23 (s, 3H) 4.35 (s, 2H) 7.08-7.13 (m, 3H) 7.41-7.47 (m, 1H) 7.89 (dd, J=9, 2 Hz, 1H) 8.10 (d, J=9 Hz, 1H) 8.14 (d, J=2 Hz, 1H) 8.85 (s, 1H); MS (DCI/NH3) m/z 371 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[CH2:20])=[CH:17][CH:16]=1.C(N(CC)C(C)C)(C)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH:20]=[CH:19][C:18]2[CH:21]=[CH:22][C:15]([O:14][CH3:13])=[CH:16][CH:17]=2)=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=1
Reactant: COc1ccc(Br)c([N+](=O)[O-])c1
Reactant: C=Cc1ccc(OC)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C=Cc2ccc(OC)cc2[N+](=O)[O-])cc1
Temperature: 80 °C
Reaction time: 15 h
Yield: 49.5 %

Procedure:
To a solution of 1-bromo-4-methoxy-2-nitrobenzene (2.3 g) in acetonitrile (20 ml) was sequentially added 4-methoxystyrene (1.5 g), N,N-diisopropylethylamine (3.9 g), 2-(di-tert-butylphosphino)biphenyl (145 mg) and palladium(II) acetate (112 mg), and the solution was stirred for 15 hours at 80° C. The solution was extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (1.4 g).
Reaction SMILES: [S:1]1(=[O:11])(=[O:10])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.[CH2:12]([NH2:16])[CH2:13][CH2:14][CH3:15]>C(O)C>[CH2:12]([NH:16][CH:3]1[CH2:2][S:1](=[O:10])(=[O:11])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]1=2)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCN
Reactant: O=S1(=O)C=Cc2ccccc21
Solvent: CCO
Product: CCCCNC1CS(=O)(=O)c2ccccc21
Yield: 112.2 %

Procedure:
9.0 g (54 mmol) of benzothiophene 1,1-dioxide and 7.9 g (108 mmol) of n-butylamine were suspended in 130 ml of ethanol, and the mixture was heated at reflux temperature for 3 h. The reaction mixture was concentrated under reduced pressure, giving 14.5 g of butyl-(1,1-dioxo-2,3-dihydro-1H-benzo[b]thiophen-3-yl)-amine as an oil.
Reaction SMILES: [C:1]([C:8]([CH2:23][CH2:24][NH2:25])=[C:9]([CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1)[C:10]([OH:12])=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Cl:26][C:27]1[CH:32]=[C:31]([Cl:33])[C:30]([Cl:34])=[CH:29][C:28]=1O.CCN=C=NCCCN(C)C>C(Cl)Cl>[Cl:26][C:27]1[CH:32]=[C:31]([Cl:33])[C:30]([Cl:34])=[CH:29][C:28]=1[O:11][C:10](=[O:12])[C:9]([CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1)=[C:8]([C:1]([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2])[CH2:23][CH2:24][NH2:25]
Reactant: Oc1cc(Cl)c(Cl)cc1Cl
Reactant: CC(C)(C)OC(=O)C(CCN)=C(Cc1c[nH]c2ccccc12)C(=O)O
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C(CCN)=C(Cc1c[nH]c2ccccc12)C(=O)Oc1cc(Cl)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 52.9 %

Procedure:
A solution of acid in Example 20a (195 mg, 0.57 mmol) in 8 mL anhydrous methylene chloride was treated with 2,4,5-trichlorophenol (112 mg, 0.57 mmol) and EDCI (160 mg, 0.85 mmol). The reaction mixture was stirred for 24 hours at ambient temperature under nitrogen atmosphere. The mixture was washed with 10% citric acid and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated to yield a residue that was purified by flash chromatography on silica gel. Elution with EtOAc/hexane (1/5~1/1, v/v, with 1% HOAc) afforded the title compound (158 mg, 54% yield) as an oil: 1H NMR (CDCl3, 60 MHz) δ1.45 (s, 9H), 2.58 (q, 2H), 3.28 (q, 2H), 3.85 (q, 2H), 4.80 (br, 1H), 7.2 (s, 1H), 7.5 (s, 1H), 6.8-7.8 (m, 6H), 10.1 (br, 1H).