Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[Br:13][C:14]1[CH:19]=[C:18]([C:20]2[C:32]3[C:31]([CH3:33])=[C:30]([CH3:34])[S:29][C:28]=3[C:27]([Br:35])=[C:26]3[C:21]=2[CH:22]=[CH:23][CH:24]=[CH:25]3)[CH:17]=[C:16]([Br:36])[C:15]=1[OH:37].O[C@@H:39]([CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:40]([O:42][CH3:43])=[O:41].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CCOCC.C1C=CC=CC=1>[CH3:43][O:42][C:40](=[O:41])[C@H:39]([O:37][C:15]1[C:16]([Br:36])=[CH:17][C:18]([C:20]2[C:32]3[C:31]([CH3:33])=[C:30]([CH3:34])[S:29][C:28]=3[C:27]([Br:35])=[C:26]3[C:21]=2[CH:22]=[CH:23][CH:24]=[CH:25]3)=[CH:19][C:14]=1[Br:13])[CH2:44][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1
Reactant: Cc1sc2c(Br)c3ccccc3c(-c3cc(Br)c(O)c(Br)c3)c2c1C
Reactant: COC(=O)[C@@H](O)Cc1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: c1ccccc1
Product: COC(=O)[C@@H](Cc1ccccc1)Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc(C)c(C)c23)cc1Br
Temperature: 80 °C
Yield: 97.4 %

Procedure:
Diethylazodicarboxylate (0.262 mL, 1.67 mmol) was added dropwise to a stirred, room temperature solution of 2,6dibromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenol (0.60 g, 1.11 mmol), and (S)-2-hydroxy-3-phenylpropionic acid, methyl ester (0.300 g, 1.67 mmol), triphenylphosphine (0.437 g, 1.67 mmol) and benzene (5 mL) and the solution was heated in an 80° C. oil bath for 6 h. Upon cooling to room temperature, the reaction mixture was diluted with ether and silica gel (30 mL) was added. The reaction mixture was concentrated and the silica adsorbate was flash chromatographed (95:5 petroleum ether:ethyl acetate) to provide the title compound as a white solid (0.76 g, 97%): mp 174-175° C.: NMR (DMSO-d6); δ8.21 (ddd, J=8,1,1 Hz, 1H), 7.74 (d, J=2 Hz, 1H), 7.73 (d, J=2 Hz, 1H),7.67 (ddd, J=8, 6, 1 Hz, 1H), 7.53 (ddd, J=8, 7, 1 Hz, 1H), 7,43 (d, J=8 Hz, 1H), 7.35-7.24 (m, 5H), 5.11 (dd, J=7, 6 Hz, 1H), 3.61 (s, 3H), 3.43 (dd, 13, 6 Hz, 1H), 3.40 (dd, 13, 7 Hz, 1H), 2.44 (d, J=1 Hz, 3H), 1.60 (d, J=1 Hz, 3H); MS (+FAB): 3 bromine isotope pattern 700(20%), 702 (70%), 704 (75%), 706 (25%); Anal. Calc. for C30H23Br3O3S: C, 51.23; H, 3.30; N, 0.00. Found: C, 51.52; H, 3.36; N, 0.12.
Reaction SMILES: [O:1]=[C:2]1[C@@H:8]2[CH2:9][C@@H:4]([CH2:5][CH2:6][C@@H:7]2[NH:10]C(=O)OCC2C=CC=CC=2)[O:3]1>C(OCC)(=O)C.[Pd]>[NH2:10][C@H:7]1[CH2:6][CH2:5][C@@H:4]2[CH2:9][C@H:8]1[C:2](=[O:1])[O:3]2
Reactant: O=C(N[C@H]1CC[C@@H]2C[C@H]1C(=O)O2)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: N[C@H]1CC[C@@H]2C[C@H]1C(=O)O2
Yield: 99.5 %

Procedure:
A solution of benzyl (1R,2S,5R)-7-oxo-6-oxa-bicyclo[3.2.1]octan-2-ylcarbamate (20 g, 72.6 mmol) in ethyl acetate (125 mL) was treated with 1.3 g of 10% Pd/C and hydrogenated overnight at 55 psi of H2 in a Parr shaker overnight. The catalyst was filtered and the filtrate concentrated in vacuo to give 10.2 g (100%) of (1R,2S,5R)-2-amino-6-oxa-bicyclo[3.2.1]octan-7-one as an oil. This was used without further purification. MS found: (M+H)+=142.06.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]([C:13]2[NH:17][C:16]([CH2:18][CH:19]3[CH2:23][CH2:22][O:21][CH2:20]3)=[N:15][N:14]=2)=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+]>CO.O>[CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]([C:13]2[NH:17][C:16]([CH2:18][CH:19]3[CH2:23][CH2:22][O:21][CH2:20]3)=[N:15][N:14]=2)=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1cc(-c2nnc(CC3CCOC3)[nH]2)c(C)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(C)c(-c2nnc(CC3CCOC3)[nH]2)cc1C(=O)O
Temperature: 70 °C
Reaction time: 3 h
Yield: 87.3 %

Procedure:
To a round-bottom flask was added a solution of methyl 2,4-dimethyl-5-(5-((tetrahydrofuran-3-yl)methyl)-4H-1,2,4-triazol-3-yl)benzoate (compound 130.5, 600 mg, 1.90 mmol, 1.00 equiv) in methanol (10 mL). A solution of sodium hydroxide (381 mg, 9.53 mmol, 5.00 equiv) in water (5 mL) was added and the resulting mixture was stirred for 3 h at 70° C. in an oil bath. After cooling to room temperature, the organic solvent was then removed under reduced pressure and the pH of the remaining aqueous phase was adjusted to 3-4 with hydrogen chloride (aq., 1 M). The resulting solids were collected via filtration and dried in an oven under reduced pressure to yield 0.500 g (87%) of the title compound as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][CH3:11])[C:3]=1[C:4]#[N:5].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C1COCC1>[C:4]([C:3]1[C:2]([F:1])=[CH:9][CH:8]=[CH:7][C:6]=1[N:10]([CH3:11])[S:23]([CH3:22])(=[O:25])=[O:24])#[N:5]
Reactant: CNc1cccc(F)c1C#N
Reactant: CS(=O)(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(c1cccc(F)c1C#N)S(C)(=O)=O
Reaction time: 0.5 h
Yield: 69.8 %

Procedure:
To a stirred solution of 2-fluoro-6-methylamino-benzonitrile (1.5 g, 10 mmol) in THF (50 mL) at −78° C. was added LiHMDS (1M in THF, 16 mL, 16 mmol) dropwise over 5 min. The resulting pale yellow solution was stirred for an additional 30 min, then methanesulfonyl chloride (1.16 mL, 15 mmol) was added. After 30 min, the reaction mixture was quenched with saturated NH4Cl (1 mL), diluted with ethyl acetate (100 mL), dried (MgSO4), filtered and concentrated to give viscous yellow oil. The crude product was purified on silica gel column (2:3 EtOAc/hexanes) to give the title compound as a white solid (1.5936 g, 70% yield). 1HNMR (500 MHz, CDCl3) δ: 7.65–7.61 (1H, m), 7.86 (1H, d, J=8.24 Hz), 7.22 (1H, t, J=8.24 Hz), 3.38 (3H, s), 3.13 (3H, s). HRMS (ESI) calcd for C17H22FN2O7S (M+H): 417.1132; found: 417.1116.
Reaction SMILES: C=O.[O:3]([CH2:10][C@@H:11]1[NH:16][CH2:15][CH2:14][N:13]([C:17]2[C:26]3[CH:25]=[C:24]([CH3:27])[S:23][C:22]=3[NH:21][C:20]3[CH:28]=[CH:29][CH:30]=[CH:31][C:19]=3[N:18]=2)[CH2:12]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[CH:33](Cl)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH3:33][N:16]1[CH2:15][CH2:14][N:13]([C:17]2[C:26]3[CH:25]=[C:24]([CH3:27])[S:23][C:22]=3[NH:21][C:20]3[CH:28]=[CH:29][CH:30]=[CH:31][C:19]=3[N:18]=2)[CH2:12][C@@H:11]1[CH2:10][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN[C@@H](COc2ccccc2)C1
Reactant: CC(Cl)Cl
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN(C)[C@@H](COc2ccccc2)C1
Reaction time: 0.03 h
Yield: 63.3 %

Procedure:
Add aqueous 37% formaldehyde (1.1 eqiv) to a solution of (R)-10-(3-phenoxymethyl-piperazin-1-yl)-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene (520 mg) in dichloroethane (60 mL per 1 mmol non-alkylated starting material). Stir the mixture 2 minutes and add sodium triacetoxyborohydride (1.5 mmol per 1 mmol non-alkylated starting material). Stir the suspension for 30 minutes and quench with a saturated aqueous solution of sodium bicarbonate. Extract the aqueous phase 3 times with dichloromethane and combine the organic phases, dry over magnesium sulfate, filter and concentrate. Purify the residue via chromatography on silica gel (methylene chloride/methanol (90:10) to provide the title compound as a yellow solid (265 mg, 49%): mp 74-88° C.; 1H NMR (CDCl3) δ 2.28 (s, 3H), 2.47 (s, 3H), 2.50-2.39 (m, 1H), 2.66-2.58 (m, 1H), 2.91 (dt, 1H), 3.11 (dd, 1H), 3.26 (dt, 1H), 3.93 (bd, 1H), 4.14-4.03 (m, 3H), 4.91 (bs, 1H), 6.31-6.29 (m, 1H), 6.59 (dt, 1H), 7.00-6.86 (m, 5H), 7.03 (dd, 1H), 7.32-7.27 (m, 2H); MS (APCI) m/z (rel intensity) 419.3 (100).
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][C:10]([F:13])([F:12])[C:9](=[O:14])[N:8]([CH3:15])[C:7]3[CH:16]=[N:17][C:18]([NH:20][C:21]4[CH:29]=[CH:28][C:24]([C:25]([OH:27])=O)=[CH:23][C:22]=4[O:30][CH3:31])=[N:19][C:6]2=3)[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.[NH2:63][CH:64]1[CH2:69][CH2:68][N:67]([CH3:70])[CH2:66][CH2:65]1>C(OCC)(=O)C.CN(C)C=O>[CH:1]1([N:5]2[CH2:11][C:10]([F:13])([F:12])[C:9](=[O:14])[N:8]([CH3:15])[C:7]3[CH:16]=[N:17][C:18]([NH:20][C:21]4[CH:29]=[CH:28][C:24]([C:25]([NH:63][CH:64]5[CH2:69][CH2:68][N:67]([CH3:70])[CH2:66][CH2:65]5)=[O:27])=[CH:23][C:22]=4[O:30][CH3:31])=[N:19][C:6]2=3)[CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCC1)CC(F)(F)C(=O)N2C
Reactant: CN1CCC(N)CC1
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCC1)CC(F)(F)C(=O)N2C
Reaction time: 0.25 h
Yield: 46 %

Procedure:
A mixture of 0.100 g (0.23 mmole) of 4-(9-cyclobutyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-1), 0.093 g (0.92 mmole) of triethylamine, 0.148 g (0.39 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate and 5 mL of dimethylformamide was stirred for 15 minutes and then 0.040 g (0.35 mmole) of 4-amino-1-methyl-piperidine was added. The mixture was stirred for 3 hours, then taken up in 100 mL of ethyl acetate and washed twice with 100 mL of water and then 100 mL of brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethane-methanol-ammonium hydroxide (gradient 100:0:0-92:8:0.3) to give 0.056 g of 4-(9-cyclobutyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide (I-4).
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH2:9]Cl)=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17]C)[CH:12]=2)[N:5]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[N:3]=1.[CH3:25][S:26]([C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1)(=[O:28])=[O:27].COC1C=C(C2C3CCN(C4C=CC=C(S(C)(=O)=O)C=4)C=3N=C(N3CCOCC3)N=2)C=CC=1>>[CH3:25][S:26]([C:29]1[CH:35]=[CH:34][C:32]([N:33]2[C:2]3[N:3]=[C:4]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[N:5]=[C:6]([C:11]4[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=4)[C:7]=3[CH2:8][CH2:9]2)=[CH:31][CH:30]=1)(=[O:27])=[O:28]
Reactant: COc1cccc(-c2nc(N3CCOCC3)nc(Cl)c2CCCl)c1
Reactant: CS(=O)(=O)c1ccc(N)cc1
Agent: COc1cccc(-c2nc(N3CCOCC3)nc3c2CCN3c2cccc(S(C)(=O)=O)c2)c1
Product: CS(=O)(=O)c1ccc(N2CCc3c(-c4cccc(O)c4)nc(N4CCOCC4)nc32)cc1

Procedure:
In the same manner as Example 1-A-01, from 4-[4-chloro-5-(2-chloroethyl)-6-(3-methoxyphenyl)-pyrimidin-2-yl]-morpholine and 4-methanesulfonylaniline, 4-(3-methoxy-phenyl)-7-(3-methanesulfonylphenyl)-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine was obtained, and subsequently, further in the same manner as Example 1-A-09, the desired compound was obtained.
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([N:10]2[CH2:14][CH2:13][C@@H:12]([N:15]([CH3:24])[C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][N:17]=3)[CH2:11]2)=[N:3][CH:2]=1.[Cl-].N.[N-:27]=[N+:28]=[N-:29].[Na+]>CN(C)C=O>[N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([N:10]2[CH2:14][CH2:13][C@@H:12]([N:15]([CH3:24])[C:16]3[CH:23]=[CH:22][C:19]([C:20]4[N:27]=[N:28][NH:29][N:21]=4)=[CH:18][N:17]=3)[CH2:11]2)=[N:3][CH:2]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CN(c1ccc(C#N)cn1)[C@@H]1CCN(c2ncnc3[nH]ccc23)C1
Agent: N
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(c1ccc(-c2nn[nH]n2)cn1)[C@@H]1CCN(c2ncnc3[nH]ccc23)C1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
A mixture of (R)-6-((1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)(methyl)amino)nicotinonitrile (100 mg, 0.3 mmol), ammonia chloride (84 mg, 1.57 mmol) and sodium azide (108 mg, 1.66 mmol) in N,N-dimethylformamide (5.0 mL) was stirred at 120° C. for 16 h. The volatile was removed under vacuum and the residue was purified by chromatography on silica gel to give the title compound. MS (m/z): 363.0 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[N:6]=[C:5](Cl)[S:4][N:3]=1.CC(O)C.C(N(CC)CC)C.[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=1>CCOC(C)=O.CCCCCCC>[Br:1][C:2]1[N:6]=[C:5]([NH:26][CH2:25][C:24]2[CH:27]=[CH:28][C:21]([O:20][CH3:19])=[CH:22][CH:23]=2)[S:4][N:3]=1
Reactant: COc1ccc(CN)cc1
Reactant: Clc1nc(Br)ns1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: CC(C)O
Product: COc1ccc(CNc2nc(Br)ns2)cc1
Reaction time: 2 h
Yield: 67.5 %

Procedure:
A round-bottom flask was charged with 3-bromo-5-chloro-1,2,4-thiadiazole (2.73 g, 13.69 mmol), i-PrOH (25 mL), and triethylamine (3.82 ml, 27.4 mmol) to give a clear solution. 4-Methoxybenzylamine (2.132 ml, 16.42 mmol) was added dropwise at room temperature, and the resulting mixture was stirred for 2 h before being diluted with EtOAc. The organic solution was washed with saturated aq. sodium bicarbonate solution, washed with water, washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by chromatography on silica gel (0 to 40% EtoAc/Heptane) to give a white solid. The solid was suspended in heptane, and the slurry was filtered. The collected solid was washed with heptane (3×), then dried under a stream of N2 overnight to give 3-bromo-N-(4-methoxybenzyl)-1,2,4-thiadiazol-5-amine (2.774 g, 9.24 mmol, 67.5% yield) as a white, fluffy solid. 1H NMR (400 MHz, DMSO-d6) δ=9.20 (br. s., 1 H), 7.33-7.20 (m, 2 H), 7.01-6.84 (m, 2 H), 4.43 (br. s., 2 H), 3.74 (s, 3 H). m/z (ESI) 300.0 (M+H)+.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[C:16]([CH3:28])=[C:17]([CH3:27])[C:18]4[O:22][C:21]([CH3:24])([CH3:23])[CH2:20][C:19]=4[C:25]=3[CH3:26])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.ClC1C=CC=C(C(OO)=[O:37])C=1.C(=O)([O-])O.[Na+]>C1COCC1.C(OCC)(=O)C>[CH3:1][S:2]([C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[C:16]([CH3:28])=[C:17]([CH3:27])[C:18]4[O:22][C:21]([CH3:23])([CH3:24])[CH2:20][C:19]=4[C:25]=3[CH3:26])[CH2:11][CH2:10]2)=[CH:7][CH:8]=1)=[O:37]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)CC(C)(C)O4)CC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1c(C)c(N2CCN(c3ccc(S(C)=O)cc3)CC2)c(C)c2c1OC(C)(C)C2
Reaction time: 2 h
Yield: 45.6 %

Procedure:
To the THF/ethyl acetate (1:1, 6.0 mL) solution of 1-[4-(methylsulfanyl)phenyl]-4-(2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)piperazine (200 mg, 0.50 mmol) synthesized in Example 89, m-chloroperbenzoic acid (70%, 124 mg, 0.50 mmol) was added under ice cooling, followed by stirring for 2 hours. The reaction solution was added with an aqueous solution of sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over sodium sulfate. The solvent was removed by distillation under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate) and the resulting solids were recrystallized from hexane-THF to obtain the title compound 94 mg (yield 46%). Melting point was 223 to 227° C. (hexane-THF).
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]2[CH2:11][C:10](=O)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:19]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[CH3:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O.C(O)(=O)C>[C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]2[CH2:11][CH:10]([N:24]3[CH2:25][CH2:26][N:21]([CH2:19][CH3:20])[CH2:22][CH2:23]3)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CCN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: CCN1CCN(C2CN(C(c3ccccc3)c3ccccc3)C2)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 88.9 %

Procedure:
To a mixed solution of a commercially available product of 1-(diphenylmethyl)azetidin-3-one (10.1 g, 42.6 mmol), TH-IF (100 mL) and acetic acid (5.00 mL) was added ethylpiperazine (6.48 mL, 51.1 mmol) at room temperature. The resultant mixture was stirred at room temperature for 45 minutes. Sodium triacetoxyborohydride (18.1 g, 85.1 mmol) was added to the reaction mixture at room temperature and then stirred at room temperature for 15 hours. Sodium hydrogen carbonate and water were added to the reaction mixture, and the resultant solution was then extracted with ethyl acetate. An organic layer was washed with saturated brine, then dried over anhydrous magnesium sulfate, and then filtrated. The solvent was evaporated under a reduced pressure, and the resultant residue was purified by silica gel column chromatography (ethyl acetate-methanol) and was then further purified by NH silica gel column chromatography (heptane:ethyl acetate=2:1 and the 1:1) to give the title compound (12.7 g, yield: 89%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].[CH:17](Br)([CH3:19])[CH3:18].Cl>>[CH:17]([N:14]1[CH2:15][CH2:16][CH:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=2)[CH2:12][CH2:13]1)([CH3:19])[CH3:18]
Reactant: CC(C)Br
Reactant: CS(=O)(=O)c1cccc(C2CCNCC2)c1
Agent: Cl
Product: CC(C)N1CCC(c2cccc(S(C)(=O)=O)c2)CC1

Procedure:
Beginning with 4-(3-methanesulfonyl-phenyl)-piperidine and i-propylbromide: m.p. 220° C. (HCl); MS m/z (rel. intensity, 70 eV) 281 (M+, 4), 266 (bp), 187 (5), 129 (5), 115 (5)
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11]C)=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].B(Br)(Br)Br.O>C(Cl)Cl>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([OH:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)c1[nH]c2cc(OC)ccc2c1C
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1[nH]c2cc(O)ccc2c1C
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Ethyl 3-methyl-6-methoxy-1H-indole-2-carboxylate (1.00 g; synthesized according to the disclosures in the literature (Gan et al., J. Org. Chem., vol. 62, pp. 9298-9304, 1997)) was dissolved in methylene chloride (dehydrated, 13 mL), and boron tribromide (1 M/methylene chloride, 17.2 mL) was added dropwise under ice-cooling. The resulting mixture was allowed to warm to room temperature and stirred for 40 minutes. The reaction solution was then cooled with ice, followed by addition of water. The resulting mixture was extracted with chloroform, washed with saturated brine and dried over sodium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel chromatography (3:1-2:1 hexane/ethyl acetate) to yield the title compound (480 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2O[C:12](=O)[C:11]([C:15]#[N:16])=[C:10]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[CH:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH2:24]1[CH2:28]O[CH2:26][CH2:25]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:4]3[C:3]4[C:25](=[CH:24][CH:28]=[CH:7][CH:2]=4)[CH2:26][C:12]=3[C:11]([C:15]#[N:16])=[C:10]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[CH:9]=2)=[CH:4][CH:3]=1
Reactant: N#Cc1c(N2CCCC2)cc(-c2ccc(Cl)cc2)oc1=O
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: N#Cc1c(N2CCCC2)cc(-c2ccc(Cl)cc2)c2c1Cc1ccccc1-2

Procedure:
A mixture of 6-(4-chlorophenyl)-2-oxo-4-(pyrrolidin-1-yl)-2H-pyran-3-carbonitrile (300 mg), indanone-2 (132 mg) and NaH (33 mg) in THF was stirred for <5 min. After completion, the reaction solvent was evaporated under vacuum to dryness and crude solid was quenched with ice water and subsequently neutralized with dil. HCl, finally purified by column chromatography using ethylacetate-hexane as eluent. White solid; mp 197-199° C.; FAB MS 370 (M+); IR (KBr) 2217 cm−1 (CN).
Reaction SMILES: [Si]([O:8][CH:9]([C:22]1[O:23][C:24]([C:27]2[CH:32]=[C:31]([O:33][CH3:34])[N:30]=[C:29]([O:35][CH3:36])[N:28]=2)=[CH:25][N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(C(C)(C)C)(C)C.[Si](OC(C1OC([Sn](CCCC)(CCCC)CCCC)=CN=1)CCCCCCC1C=CC=CC=1)(C(C)(C)C)(C)C.ClC1N=C(OC)N=C(OC)C=1>>[CH3:36][O:35][C:29]1[N:28]=[C:27]([C:24]2[O:23][C:22]([C:9](=[O:8])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[N:26][CH:25]=2)[CH:32]=[C:31]([O:33][CH3:34])[N:30]=1
Reactant: COc1cc(-c2cnc(C(CCCCCCc3ccccc3)O[Si](C)(C)C(C)(C)C)o2)nc(OC)n1
Agent: CCCC[Sn](CCCC)(CCCC)c1cnc(C(CCCCCCc2ccccc2)O[Si](C)(C)C(C)(C)C)o1
Agent: COc1cc(Cl)nc(OC)n1
Product: COc1cc(-c2cnc(C(=O)CCCCCCc3ccccc3)o2)nc(OC)n1
Yield: 90 %

Procedure:
2-(1-(tert-Butyldimethylsilyloxy)-7-phenylheptyl)-5-(2,6-dimethoxypyrimidin-4-yl)oxazole. The title compound was prepared from 2-(1-(tert-butyldimethylsilyloxy)-7-phenylheptyl)-5-(tributylstannyl)oxazole (200 mg, 0.302 mmol) and 6-chloro-2,4-dimethoxypyrimidine following General Procedure A. Flash chromatography (10% EtOAc/hexanes) yielded the title compound as a thick oil (138 mg, 90%): 1H NMR (CDCl3, 400 MHz) 6 7.73 (s, 1H), 7.28-7.24 (m, 2H), 7.18-7.15 (m, 3H), 6.67 (s, 1H), 4.85 (dd, 1H, J=7.3, 5.9 Hz), 4.03 (s, 3H), 4.00 (s, 3H), 2.59 (t, 2H, J=7.6 Hz), 1.96 (m, 2H), 1.62 (m, 2H), 1.36 (m, 4H), 0.90 (s, 9H), 0.10 (s, 3H), 0.00 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 172.3, 166.6, 165.4, 155.2, 149.0, 142.6, 128.3, 128.1, 128.0, 125.5, 95.8, 68.6, 54.8, 53.9, 36.2, 35.8, 31.3, 29.0, 25.6, 25.6, 24.9, 18.1, −5.1, −5.2.
Reaction SMILES: C(OC1N=NC(C#CC2C=CC(C(F)(F)F)=CN=2)=CC=1OCC1C=CC=CC=1)C1C=CC=CC=1.[CH2:35]([O:42][C:43]1[N:44]=[N:45][C:46]([C:57]#[CH:58])=[CH:47][C:48]=1[O:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[F:59][CH:60]([F:69])[O:61][C:62]1[CH:67]=[CH:66][C:65](I)=[CH:64][CH:63]=1>>[CH2:35]([O:42][C:43]1[N:44]=[N:45][C:46]([C:57]#[C:58][C:65]2[CH:66]=[CH:67][C:62]([O:61][CH:60]([F:69])[F:59])=[CH:63][CH:64]=2)=[CH:47][C:48]=1[O:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: C#Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Reactant: FC(F)Oc1ccc(I)cc1
Agent: FC(F)(F)c1ccc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)nc1
Product: FC(F)Oc1ccc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)cc1
Yield: 58 %

Procedure:
Prepared as described for 3,4-bis(benzyloxy)-6-{[5-(trifluoromethyl)pyridin-2-yl]ethynyl}pyridazine (Intermediate 6) from 3,4-bis(benzyloxy)-6-ethynylpyridazine (Intermediate 5) and 1-(difluoromethoxy)-4-iodobenzene in 58% yield.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].[C:6]([N:9]([C:14]1[C:15](=[O:28])[C:16]2[CH:20]=[C:19]([C:21]([O:23][CH3:24])=[O:22])[S:18][C:17]=2[C:25](=[O:27])[CH:26]=1)[CH2:10][CH2:11][O:12][CH3:13])(=[O:8])[CH3:7]>O1CCCC1>[C:6]([N:9]([C:14]1[C:15](=[O:28])[C:16]2[CH:20]=[C:19]([C:21]([O:23][CH3:24])=[O:22])[S:18][C:17]=2[C:25](=[O:27])[C:26]=1[NH:5][CH2:4][CH2:3][O:2][CH3:1])[CH2:10][CH2:11][O:12][CH3:13])(=[O:8])[CH3:7]
Reactant: COCCN
Reactant: COCCN(C(C)=O)C1=CC(=O)c2sc(C(=O)OC)cc2C1=O
Solvent: C1CCOC1
Product: COCCNC1=C(N(CCOC)C(C)=O)C(=O)c2cc(C(=O)OC)sc2C1=O
Temperature: 25 °C
Reaction time: 6.5 h

Procedure:
2-Methoxyethylamine (0.15 ml) was added to a solution of methyl 5-[N-acetyl-N-(2-methoxyethyl)amino]-4,7-dihydro-4,7-dioxobenzo[b]thiophene-2-carboxylate (0.39 g) in tetrahydrofuran (30 ml) and the mixture was stirred at room temperature for 6.5 hours. The solvent was evaporated and the residue was purified by silica gel column chromatography (elution with hexane-ethyl acetate 50:1 solution) to give methyl 5-[N-acetyl-N-(2-methoxyethyl)amino]-4,7-dihydro-6-(2-methoxyethyl)amino-4,7-dioxobenzo[b]thiophene-2-carboxylate (0.39 g) as a reddish purple oil.