Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[NH:14][N:15]=[C:16]([CH3:17])[C:3]=12.[CH2:18]1[CH2:24][CH:23]2[NH:25][CH:20]([CH2:21][CH2:22]2)[CH2:19]1>>[CH:23]12[NH:25][CH:20]([CH2:21][CH2:22]1)[CH2:19][CH:18]([N:14]1[C:4]3=[N:5][N:6]=[C:7]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:2]([Cl:1])=[C:3]3[C:16]([CH3:17])=[N:15]1)[CH2:24]2
Reactant: Cc1n[nH]c2nnc(-c3ccccc3)c(Cl)c12
Reactant: C1CC2CCC(C1)N2
Product: Cc1nn(C2CC3CCC(C2)N3)c2nnc(-c3ccccc3)c(Cl)c12

Procedure:
Compound XIIIa was synthesized from 4-chloro-3-methyl-5-phenyl-1H-pyrazolo[3,4-c]pyridazine and nortropane following the general procedure for the Mitsunobu reaction described in Example 20.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:26]=[CH:25][C:24](B4OC(C)(C)C(C)(C)O4)=[CH:23][CH:22]=3)[O:18][C:19]=2[CH3:20])=[CH:8][C:7]=1[CH3:36].Br[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:1][O:2][C:3](=[O:37])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:22]=[CH:23][C:24]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=4)=[CH:25][CH:26]=3)[O:18][C:19]=2[CH3:20])=[CH:8][C:7]=1[CH3:36]
Reactant: COC(=O)CCc1ccc(OCCc2nc(-c3ccc(B4OC(C)(C)C(C)(C)O4)cc3)oc2C)cc1C
Reactant: Brc1ccccn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COC(=O)CCc1ccc(OCCc2nc(-c3ccc(-c4ccccn4)cc3)oc2C)cc1C
Temperature: 100 °C

Procedure:
3-[2-Methyl-4-(2-{5-methyl-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-oxazol-4-yl}-ethoxy)-phenyl]-propionic acid methyl ester (167 mg; 0.328 mmol) is dissolved in anhydrous toluene (1 mL), degassed, and filled with nitrogen three times. [1,1′-Bis-(diphenylphosphino)ferrocene]dichloropalladium(II) (15 mg, 0.02 mmol), 2-bromopyridine (67 ul, 0.7 mmol), and sodium carbonate (150 uL, 10 M aqueous, 1.5 mmol) are added, and the degassing procedure is repeated. The reaction is heated to 100° C. and monitored by HPLC. Upon complete consumption of starting material, the reaction is allowed to cool to room temperature and diluted with ethyl acetate. Celite is added and the mixture is filtered and rinsed with more ethyl acetate and water. The solution is further diluted with water and the two phases are separated. The organic layer is washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:12].C(OC(=O)C)(=O)C.[N+:20]([O-])([OH:22])=[O:21]>C(O)(=O)C>[Br:1][C:2]1[CH:10]=[C:9]([N+:20]([O-:22])=[O:21])[C:8]([OH:11])=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:12]
Reactant: O=[N+]([O-])O
Reactant: O=C1CCc2c(Br)ccc(O)c21
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: O=C1CCc2c(Br)cc([N+](=O)[O-])c(O)c21
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.1 %

Procedure:
4-Bromo-7-hydroxyindan-1-one (3.06 g, 13.5 mmol) was suspended in acetic acid (20 mL), and acetic anhydride (1.66 mL, 17.6 mmol) and fuming nitric acid (838 μL, 20.2 mmol) dissolved in acetic acid (10 mL) were added. The mixture was stirred at room temperature for 3 hr. The solvent was evaporated under reduced pressure and the precipitated yellow crystals were collected by filtration to give the title compound (2.98 g, yield 79%).
Reaction SMILES: C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.C(OC([NH:26][CH:27]([C:31]([O:34][CH3:35])([CH3:33])[CH3:32])[C:28](O)=O)=O)(C)(C)C.[NH2:36][C:37]1[CH:38]=[C:39]([C:44]2[CH:49]=[CH:48][C:47]([C:50]#[N:51])=[CH:46][CH:45]=2)[CH:40]=[CH:41][C:42]=1[NH2:43]>C(N(CC)CC)C>[NH2:26][CH:27]([C:28]1[NH:43][C:42]2[CH:41]=[CH:40][C:39]([C:44]3[CH:45]=[CH:46][C:47]([C:50]#[N:51])=[CH:48][CH:49]=3)=[CH:38][C:37]=2[N:36]=1)[C:31]([O:34][CH3:35])([CH3:32])[CH3:33]
Reactant: COC(C)(C)C(NC(=O)OC(C)(C)C)C(=O)O
Reactant: N#Cc1ccc(-c2ccc(N)c(N)c2)cc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Product: COC(C)(C)C(N)c1nc2cc(-c3ccc(C#N)cc3)ccc2[nH]1

Procedure:
The title compound was prepared according to Method 4 using T3P and triethylamine in the first step with 2-{[(tert-butoxy)carbonyl]amino}-3-methoxy-3-methylbutanoic acid and 3′,4′-diaminobiphenyl-4-carbonitrile (Preparation 82). The reaction was concentrated to dryness, triturated with ether and purified using preparative HPLC. Rt=3.21 minutes MS m/z 321 [M+H]+
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][N:5]=[C:4]([CH3:9])[CH:3]=1.[C:10]([C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1)([OH:12])=[O:11]>>[CH3:9][C:4]1[CH:3]=[C:2]([C:16]2[CH:17]=[CH:18][C:13]([C:10]([OH:12])=[O:11])=[CH:14][CH:15]=2)[C:7]([CH3:8])=[CH:6][N:5]=1
Reactant: Cc1cc(Br)c(C)cn1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Product: Cc1cc(-c2ccc(C(=O)O)cc2)c(C)cn1

Procedure:
The title compound was prepared from 4-bromo-2,5-dimethylpyridine (WO 93/15062) and 4-carboxyphenylboronic acid using a similar procedure to Description 18 as a white solid (67%).
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([N:26]=[C:27]=[O:28])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].N1C=CC=CC=1>O1CCCC1>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18][C:27](=[O:28])[NH:26][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc2c(c1)CCCN2Cc1ccccc1
Reactant: CCCCCCCN=C=O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCCCCCCNC(=O)Oc1ccc2c(c1)CCCN2Cc1ccccc1
Temperature: 65 °C
Reaction time: 48 h

Procedure:
Mixture of 1-benzyl-1, 2, 3, 4-tetrahydro-quinolin-6-ol (0.239 g., 1 mmol), heptyl isocyanate (0.169 g., 1.2 mmol) and pyridine (1 ml) in dry tetrahydrofuran (10 ml), was heated with stirring at 65° C. for 48 hours. Reaction mixture was quenched with water (1 ml) and concentrated under vaccum. The separated solid was washed with water (2×5 ml) and crystallised with ether to give (2 g) as oil; yield: 0.200 g. (52.6%), C24H32N2O2; 1H NMR δ ppm (CDCl3): 0.86 (bs, 3H), 1.20-1.29 (m, 6H), 1.55-1.58 (m, 4H), 1.96-2.06 (m, 2H), 2.79 (t, 2H), 3.17-3.36 (m, 4H), 4.44 (st, 2H), 4.87 (bs, 1H), 6.39-6.44 (m, 1H4), 6.71-6.75 (m, 2M), 7.25-7.34 (m, 5H); IR vmax (Neat) (cm−1): 757, 902, 1.70, 1160, 1199, 1228, 1348, 1458, 1502, 1618, 1718, 2362, 2857, 2928, 3028, 3342, 3854; MS: m/z=380 (M+).
Reaction SMILES: C(C1N=C(N2CCC(F)(F)C2)C2C(=NN(CC)N=2)N=1)(C)(C)C.[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:40][CH2:39][C@H:38]([O:41]C(=O)C(F)(F)F)[CH2:37]2)[C:30]2[N:35]=[N:34][NH:33][C:31]=2[N:32]=1)([CH3:26])([CH3:25])[CH3:24].Br[CH2:49][C:50]1[C:54]([CH3:55])=[N:53][O:52][N:51]=1>CO>[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:40][CH2:39][C@H:38]([OH:41])[CH2:37]2)[C:30]2[C:31](=[N:33][N:34]([CH2:49][C:50]3[C:54]([CH3:55])=[N:53][O:52][N:51]=3)[N:35]=2)[N:32]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: Cc1nonc1CBr
Reactant: CC(C)(C)c1nc(N2CC[C@H](OC(=O)C(F)(F)F)C2)c2nn[nH]c2n1
Agent: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Solvent: CO
Product: Cc1nonc1Cn1nc2nc(C(C)(C)C)nc(N3CC[C@H](O)C3)c2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from Trifluoro-acetic acid (S)-1-(5-tert-butyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)-pyrrolidin-3-yl-ester and 3-(bromomethyl)-4-methyl-1,2,5-oxadiazole. After completion of the substitution reaction methanol was added and the mixture was stirred for 1 h at room temperature and subsequently subjected to purification with preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and NEt3. After evaporation of the product containing fractions the title compound was isolated as light-yellow gum. MS (m/e): 359.3 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:10][C:11]([N:13]([CH3:15])[CH3:14])=[O:12])=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.Br[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>CC#N>[CH3:15][N:13]([CH3:14])[C:11](=[O:12])[CH2:10][N:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: CCOC(=O)CBr
Reactant: COc1ccc(NCC(=O)N(C)C)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)CN(CC(=O)N(C)C)c1ccc(OC)cc1
Temperature: 60 °C
Reaction time: 16 h
Yield: 85.6 %

Procedure:
To a stirred solution of 2-(4-methoxyphenylamino)-N,N-dimethylacetamide (19) (10.7 g, 51.2 mmol) in MeCN (80 mL) and DIPEA (13.4 ml, 77 mmol) was added ethyl bromoacetate (6.84 ml, 61.4 mmol) the reaction was stirred at 60° C. for 16 h. The volatiles were removed in vacuo, and the crude mixture was dissolved in EtOAc (150 mL), washed with 1M HCl (aq.) (150 mL), brine (150 mL), dried (MgSO4), filtered and solvents removed in vacuo to afford a purple oil. The residue was purified by silica gel chromatography (120 g, 60-100% EtOAc in isohexane) to afford ethyl 2-((2-(dimethylamino)-2-oxoethyl)(4-methoxyphenyl)amino)acetate (X) (12.9 g, 85%) as a purple oil: m/z 295.4 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 6.81-6.71 (m, 2H), 6.60-6.47 (m, 2H), 4.24-3.96 (m, 6H), 3.66 (s, 3H), 2.99 (br s, 3H), 2.83 (br s, 3H), 1.19 (t, J=7.1 Hz, 3H).
Reaction SMILES: CO[C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:31])[CH2:12][S:13][CH:14]2[C:18]([CH3:19])=[C:17]([CH3:20])[C:16](=[O:21])[N:15]2[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[N:6][CH:5]=1.CC1C=CC(N)=NC=1>>[CH3:30][O:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][N:15]2[C:16](=[O:21])[C:17]([CH3:20])=[C:18]([CH3:19])[CH:14]2[S:13][CH2:12][C:11]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([CH3:3])=[CH:5][N:6]=2)=[O:31])=[CH:28][CH:27]=1
Reactant: COC(=O)c1ccc(NC(=O)CSC2C(C)=C(C)C(=O)N2Cc2ccc(OC)cc2)nc1
Agent: Cc1ccc(N)nc1
Product: COc1ccc(CN2C(=O)C(C)=C(C)C2SCC(=O)Nc2ccc(C)cn2)cc1

Procedure:
The product from Example 1, Part C and 5-methylpyridin-2-ylamine were reacted as described in Example 5. After evaporation of the reaction solvent the residue was partitioned between water and EtOAc, and the organic phase was washed with EtOAc. The combined organics were washed with brine, dried (Na2SO4), filtered, and evaporated. The title compound was obtained by silica gel chromatography. 1H NMR (400 MHz, CDCl3) δ 8.43 (br s, 1H), 8.09 (m, 1H), 8.02 (d, J=9 Hz, 1H), 7.51 (m, 1H), 7.21 (d, J=9 Hz, 2H), 6.83 (d, J=9 Hz, 2H), 5.07 (d, J=15 Hz, 1H), 4.61 (s, 1H), 4.14 (d, J=15 Hz, 1H), 3.77 (s, 3H), 2.89 (m, 2H), 2.30 (s, 3H), 1.95 (s, 3H), 1.83 (s, 3H). MS: m/z (MH+) 412.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[CH:10]=[CH:9][N:8]=[CH:7][C:6]=2[N:5]=[C:4]1[C:12]1[C:13]([NH2:18])=[N:14][CH:15]=[CH:16][N:17]=1)[CH3:2].[Br:19]N1C(=O)CCC1=O.S([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[Br:19][C:16]1[N:17]=[C:12]([C:4]2[N:3]([CH2:1][CH3:2])[C:11]3[CH:10]=[CH:9][N:8]=[CH:7][C:6]=3[N:5]=2)[C:13]([NH2:18])=[N:14][CH:15]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCn1c(-c2nccnc2N)nc2cnccc21
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCn1c(-c2nc(Br)cnc2N)nc2cnccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.8 %

Procedure:
To a solution of 3-(1-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)pyrazin-2-amine (0.45 g, 1.8 mmol) (see Example 1) in THF is added N-bromosuccinimide (0.37 g, 2.1 mmol). The reaction is stirred for 4 hours at ambient temperature. Sodium sulfite (excess) was added and stirred vigorously for 30 minutes. The mixture was then concentrated to dryness and treated with water. After sonication, the solids were collected on filter. Rinsing (×2) with diethyl ether afforded 5-bromo-3-(1-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)pyrazin-2-amine (0.47 g, 79%) as tan solids.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH2:12]([O:14][C:15]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=[O:16])[CH3:13]>C(O)(C)C>[N+:9]([C:3]1[CH:4]=[CH:5][C:6]([N:20]2[CH2:19][CH2:18][N:17]([C:15]([O:14][CH2:12][CH3:13])=[O:16])[CH2:22][CH2:21]2)=[N:7][C:2]=1[NH2:1])([O-:11])=[O:10]
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: CCOC(=O)N1CCNCC1
Solvent: CC(C)O
Product: CCOC(=O)N1CCN(c2ccc([N+](=O)[O-])c(N)n2)CC1

Procedure:
6-Amino-2-chloro-5-nitropyridine (Acros, 3.66 g 21 mmol) and 1-ethoxycarbonylpiperazine (6.36 g 42 mmol) in isopropanol (85 ml) are refluxed for 3 h. The reaction mixture with a yellow precipitate is poured on water/Na2CO3 and extracted twice with methylene chloride. The combined organic phases are dried over Na2SO4, filtered and evaporated to dryness to yield the title compound as yellow crystals, which are purified by recrystallisation from tert.-butyl methyl ether (5.5 g 89%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].[N-]=C=O.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=[O:22])=[CH:16][CH:15]=1>C(Cl)(Cl)Cl>[CH:16]1[C:17]([NH:20][C:21]([NH:5][C:4]2[CH:6]=[CH:7][C:8]([Cl:9])=[C:2]([Cl:1])[CH:3]=2)=[O:22])=[CH:18][CH:19]=[C:14]([Cl:13])[CH:15]=1
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: [N-]=C=O
Solvent: ClC(Cl)Cl
Product: O=C(Nc1ccc(Cl)cc1)Nc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A cold solution of 3,4-dichloroaniline (13.2 parts) in chloroform 75 parts was added to the isocyanate solution from A (120 parts containing 7.5 parts of 4-chlorophenyl isocyanate). The mixture was stirred at room temperature for 16 hours, then the solid filtered off, washed with chloroform and dried.
Reaction SMILES: CC([CH:4]1[CH2:5][C:6]([C:8]2([CH:11]3O[CH:12]3[CH2:14][C:15]([CH:17]=[CH:18]1)=[CH2:16])[O:10]C2)=[O:7])C.CC1CCC=CC(=O)CCCC=1>CCOCC>[OH:10][CH:8]1[C:6](=[O:7])[CH:5]=[CH:4][CH2:18][CH2:17][C:15]([CH3:16])=[CH:14][CH2:12][CH2:11]1
Reactant: C=C1C=CC(C(C)C)CC(=O)C2(CO2)C2OC2C1
Agent: C/C1=C\CCC(O)C(=O)/C=C\CC1
Agent: C=C1/C=C/C(C(C)C)CC(=O)C2(CO2)C2OC2C1
Agent: CC1=CCCCC(=O)C=CCC1
Solvent: CCOCC
Product: CC1=CCCC(O)C(=O)C=CCC1

Procedure:
Periplanone-B analogue of (4E, 8R, 9R, 10R)-8,9-epoxy-5-methyl-10,10-methylene-oxy-4-cyclodecen-1-one, suitable as cockroach attractant can be prepared by reacting 6-methyl-2,6-cyclodecadien-1-one with a silylating reagent under the presence of a basic catalyst to form a silyldienol ether, reacting the resultant ether with an organic peracid to obtain (2Z, 6E)-10-hydroxy-6-methyl-2,6-cyclodecadien-1-one, reacting the resultant product with a peroxide under the presence of a basic catalyst after protecting hydroxy groups thereof with protection groups to obtain an epoxide, reacting the epoxide with chloromethyl lithium or dimethyl sulfonium methylide thereby introducing a spiroepoxy group and then removing the protection groups, to obtain (1S, 4E, 8R, 9R, 10S)-8,9-epoxy-5-methyl-10,10-methyleneoxy-4-cyclodecen-1-ol and, further, oxidizing the resultant product with a chromic acid type or dimethyl sulfoxide type oxidizing agents.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[CH3:11][NH2:12].[BH4-].[Na+]>C(O)C>[CH3:11][NH:12][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: CN
Reactant: COc1ccc(C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CNCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of p-methoxybenzaldehyde (25 ml; 200 mmol) and 8M methylamine in ethanol (100 ml; 800 mmol) in 100 ml of ethanol was stirred at rt for 18 hours. After removing the volatiles in vacuo, the residue was dissolved in 300 ml of fresh ethanol and sodium borohydride (8.5 g; 225 mmol) was added portionwise over 1.5 hr. Following the addition, the reaction mixture was concentrated to ˜⅓ volume and water (50 ml) was added. After cooling in an ice bath, the stirred mixture was carefully acidified to pH ˜2 with 5% aqueous H2SO4. After stirring 15 minutes, the mixture was basified to pH 14 with 6N NaOH and extracted with ethyl ether (400 ml). The ether layer was washed with water (200 ml), brine (100 ml) and dried over MgSO4. Concentration afforded 28.04 g (93%) of B51.1 as a colorless liquid. (M+H)+=152.13 (HPLC>94%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:15]CC3CCOCC3)=[C:7]([N+:12]([O-])=O)[CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH:23]([OH:26])([CH3:25])C>C(#N)C.[Pt]>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH2:15])=[C:7]([NH:12][CH2:11][CH:2]3[CH2:25][CH2:23][O:26][CH2:4][CH2:3]3)[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cnc2cc(Br)ccc2c1NCC1CCOCC1
Reactant: CC(C)O
Agent: [Pt]
Solvent: CC#N
Product: Nc1c(NCC2CCOCC2)cnc2cc(Br)ccc12
Reaction time: 2 h

Procedure:
7-Bromo-3-nitro-N-(tetrahydro-2H-pyran-4-ylmethyl)quinolin-4-amine (20 g, 55 mmol) was dissolved in a mixture of acetonitrile (500 mL) and isopropyl alcohol (50 mL) and the solution was placed in a pressure bottle. Platinum on carbon (5%, 2 g) was then added and the reaction mixture was shaken under H2 at 48 PSI (3.3×105 Pa). After 2 hours, the reaction mixture was filtered through a pad of CELITE filter agent. The pad was rinsed with acetonitrile and the combined filtrates were concentrated under reduced pressure to give 7-bromo-N-(tetrahydro-2H-pyran-4-ylmethyl)quinoline-3,4-diamine which was carried forward without further purification assuming quantitative yield.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH:4]=[O:5].C([O-])([O-])=O.[K+].[K+].[CH2:17]([O:19][CH:20]([O:23][CH2:24][CH3:25])[CH2:21]Br)[CH3:18]>CN(C=O)C>[CH2:17]([O:19][CH:20]([O:23][CH2:24][CH3:25])[CH2:21][O:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH:4]=[O:5])[CH3:18]
Reactant: CCOC(CBr)OCC
Reactant: O=Cc1cc(F)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(COc1ccc(F)cc1C=O)OCC
Yield: 32.8 %

Procedure:
To a stirred suspension containing 2-hydroxy-5-fluorobenzaldehyde (500 mg, 3.57 mmol) and K2CO3 (524 mg, 13.79 mmol) in DMF (10 mL), bromoacetaldehyde diethyl acetal (0.6 mL, 3.93 mmol) was added dropwise. The mixture was refluxed for 4 h. After cooling, the precipitate was filtered off and the solvent was evaporated in vacuo. The crude residue was adsorbed on silica gel and purified by flash chromatography, eluting with hexane/EtOAc (4:1) to give 12 (300 mg, 33%) as an oil. 1H NMR (500 MHz, CDCl3): δ: 10.30 (1H, s, CHO), 7.31 (1H, d, J=7.85 Hz), 7.10 (1H, t, J=7.80 Hz), 6.87 (1H, d, J=8.86 Hz), 4.75 (1H, s, CH), 3.97 (2H, d, J=2.35 Hz, CH2), 3.67-3.64 (2H, m, CH2CH3), 3.53-3.50 (2H, m, CH2CH3), 1.11 (6H, t, J=6.00 Hz, 2×CH3).
Reaction SMILES: [I:1][C:2]1[CH:7]=[C:6]([C:8]([NH:10][CH2:11][C:12]([F:15])([F:14])[F:13])=[O:9])[CH:5]=[CH:4][C:3]=1[N:16]1[CH:20]=[C:19]([C:21]([OH:23])=O)[N:18]=[N:17]1.[CH:24]1([NH2:27])[CH2:26][CH2:25]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.C(N(CC)CC)C>[CH:24]1([NH:27][C:21]([C:19]2[N:18]=[N:17][N:16]([C:3]3[CH:4]=[CH:5][C:6]([C:8]([NH:10][CH2:11][C:12]([F:14])([F:13])[F:15])=[O:9])=[CH:7][C:2]=3[I:1])[CH:20]=2)=[O:23])[CH2:26][CH2:25]1
Reactant: O=C(NCC(F)(F)F)c1ccc(-n2cc(C(=O)O)nn2)c(I)c1
Reactant: NC1CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NCC(F)(F)F)c1ccc(-n2cc(C(=O)NC3CC3)nn2)c(I)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.2 %

Procedure:
To a solution of 1-(2-iodo-4-{[(2,2,2-trifluoroethyl)amino]carbonyl}phenyl)-1H-1,2,3-triazole-4-carboxylic acid (2.08 g, 4.73 mmol) obtained in Example 379d) in DMF (20 ml) were sequentially added cyclopropylamine (500 mg), triethylamine (1.0 ml), HOBt (360 mg) and WSC (1.4 g), and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column (ethyl acetate/hexane=1/20 to 1/1) to give the title compound as a colorless powder (1.66 g, 73%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:12]=[C:11]([CH2:13][S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[NH2:17])[C:6]2[O:7][CH2:8][O:9][CH2:10][C:5]=2[CH:4]=1.[CH3:22][C:23]([CH3:28])([CH3:27])[C:24](Cl)=[O:25].C(O)C(N)(CO)CO>ClCCl.C(N(C(C)C)CC)(C)C.CN(C1C=CN=CC=1)C>[Cl:2][C:3]1[CH:12]=[C:11]([CH2:13][S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[NH:17][C:24](=[O:25])[C:23]([CH3:28])([CH3:27])[CH3:22])[C:6]2[O:7][CH2:8][O:9][CH2:10][C:5]=2[CH:4]=1
Reactant: Nc1ccccc1SCc1cc(Cl)cc2c1OCOC2
Reactant: CC(C)(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: NC(CO)(CO)CO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1ccccc1SCc1cc(Cl)cc2c1OCOC2
Reaction time: 24 h
Yield: 63.8 %

Procedure:
The product from step 1 (75 mg, 0.22 mmol) was dissolved in a mixture of dichloromethane and diisopropyl ethyl amine (4 mL , ˜40:1), PS DMAP resin (0.10 g, Argonaut 1.41 mmol/g) was added in followed by 2,2-dimethylpropanoyl chloride (0.15 mL, 1.25 mmol). The reaction was agitated for 24 hours and then treated with PS trisamine (Argonaut 4.27 mmol/g) for 6 h filtered and the solvent removed under a stream of nitrogen. The residue was chromatographed on silica to give the title product 55 mg (65%). 1H NMR (CDCl3) δ 9.87 (s, 1 H), 8.45 (dd, 1 H), 7.39 (dd, 1 H), 7.33 (dt, 1 H), 7.00 (dt, 1 H), 6.80 (dd, 2 H), 4.98 (s, 2 H), 4.77 (s, 2 H), 3.84 (s, 2 H), 1.28 (s, 9 H); MS (ESI+) for C20H22ClNO3S m/z 392 (M+H)+.
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:13]3[CH2:15][CH2:16][CH2:17][NH:18][C:12]=3[CH:11]=[CH:10][C:9]=2[NH:8][C:7](=[O:19])[C:6]1=[O:20])[CH2:2][CH2:3][CH3:4].CN(C)C=O.ClCCl.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(N(CC)CC)C>[CH2:1]([N:5]1[C:14]2[C:13]3[CH2:15][CH2:16][CH2:17][N:18]([S:30]([CH3:29])(=[O:32])=[O:31])[C:12]=3[CH:11]=[CH:10][C:9]=2[NH:8][C:7](=[O:19])[C:6]1=[O:20])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)c(=O)[nH]c2ccc3c(c21)CCCN3
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCn1c(=O)c(=O)[nH]c2ccc3c(c21)CCCN3S(C)(=O)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 19 %

Procedure:
The product from Example 89 (0.12 g, 0.45 mmol) was solubilized in a minimal amount of dimethylformamide and then treated with 2 mL dichloromethane, methanesulfonyl chloride (0.17 g) and triethylamine (0.15 g). After stirring at room temperature for 4 h, the mixture was washed with water, dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography (4:1 heptane:ethyl acetate as eluant) to give the title compound (30 mg, 17% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([N:20]2[S:24](=[O:26])(=[O:25])[NH:23][C:22](=[O:27])[CH2:21]2)=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[C:14](Br)[CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28]([O:35][C:36]1[CH:46]=[CH:45][CH:44]=[C:43]([O:47][CH2:48][CH2:49][CH:50]=[CH2:51])[C:37]=1[C:38]([N:40]([CH3:42])[CH3:41])=[O:39])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.C(N(CC)CC)C>C(#N)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:28]([O:35][C:36]1[CH:46]=[CH:45][CH:44]=[C:43]([O:47][CH2:48][CH2:49]/[CH:50]=[CH:51]/[C:14]2[CH:15]=[CH:16][C:17]3[C:12](=[CH:11][C:10]([N:20]4[CH2:21][C:22](=[O:27])[NH:23][S:24]4(=[O:26])=[O:25])=[C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:18]=3)[CH:13]=2)[C:37]=1[C:38]([N:40]([CH3:42])[CH3:41])=[O:39])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C1CN(c2cc3cc(Br)ccc3cc2OCc2ccccc2)S(=O)(=O)N1
Reactant: C=CCCOc1cccc(OCc2ccccc2)c1C(=O)N(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CN(C)C(=O)c1c(OCC/C=C/c2ccc3cc(OCc4ccccc4)c(N4CC(=O)NS4(=O)=O)cc3c2)cccc1OCc1ccccc1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a microwave vial is added 5-(3-benzyloxy-7-bromonaphthalen-2-yl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (36 mg, 0.082 mmol), 2-benzyloxy-6-but-3-enyloxy-N,N-dimethylbenzamide (53 mg, 0.163 mmol), Pd(OAc)2 (5 mg, 0.021 mmol) and 2-(di-t-butylphosphino)biphenyl (6 mg, 0.021 mmol). The mixture is diluted with acetonitrile (2 mL) and triethylamine (0.023 mL, 0.163 mmol). This is stirred in a microwave for 30 min at 100° C. The reaction mixture is filtered, acidified with 1 N HCl solution and extracted with EtOAc. The organic layer is concentrated and used directly in the next step.