Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH3:14])[N:8]=1.Br[C:16]([CH3:22])([CH3:21])[C:17]([O:19][CH3:20])=[O:18].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[I:1][C:2]1[C:3]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH3:14])[N:8]=2)=[CH:4][N:5]([C:16]([CH3:22])([CH3:21])[C:17]([O:19][CH3:20])=[O:18])[N:6]=1
Reactant: CSc1nccc(-c2cn[nH]c2I)n1
Reactant: COC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)n1cc(-c2ccnc(SC)n2)c(I)n1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a mixture compound A (60 g, 0.19 mol) and methyl 2-bromo-2-methylpropanoate (102 g, 0.57 mol) in DMF (400 mL) was added freshly ground potassium carbonate (65 g, 0.47 mol) in one portion. The reaction mixture was stirred at 80° C. for 18 hours. LC-MS indicated the reaction was complete. The reaction mixture was filtered and the filtrate was partitioned between ethyl acetate (1200 mL) and brine (300 mL). The aqueous layer was extracted with EtOAc (2×500 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel chromatography using 5-30% EtOAc in petroleum ether as eluent to give compound B-49-1 (62 g, 78%) as syrup, which solidified on standing.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([NH:18][C:19]2[C:22](=[O:23])[C:21](=[O:24])[C:20]=2[N:25]2[CH2:30][CH2:29][CH2:28][CH:27]([CH:31]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[F:44])[O:32][CH2:33][CH2:34][CH2:35][O:36][CH3:37])[CH2:26]2)[CH2:9][NH:10]C(=O)OC(C)(C)C)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>>[NH2:10][CH2:9][C@@H:8]([NH:18][C:19]1[C:22](=[O:23])[C:21](=[O:24])[C:20]=1[N:25]1[CH2:30][CH2:29][CH2:28][CH:27]([CH:31]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[F:44])[O:32][CH2:33][CH2:34][CH2:35][O:36][CH3:37])[CH2:26]1)[CH2:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COCCCOC(c1ccccc1F)C1CCCN(c2c(N[C@H](CNC(=O)OC(C)(C)C)CC3CCCCC3)c(=O)c2=O)C1
Solvent: O=C(O)C(F)(F)F
Product: COCCCOC(c1ccccc1F)C1CCCN(c2c(N[C@H](CN)CC3CCCCC3)c(=O)c2=O)C1
Yield: 56.2 %

Procedure:
tert-butyl (2S)-3-cyclohexyl-2-(2-(3-((2-fluorophenyl)(3-methoxypropoxy)methyl)piperidin-1-yl)-3,4-dioxocyclobut-1-enylamino)propylcarbamate (17.4 mg, 0.03 mmol) was treated with neat TFA for 30 min. TFA was removed in vacuo, and the residue was purified by HPLC to give 3-((S)-1-amino-3-cyclohexylpropan-2-ylamino)-4-(3-((2-fluorophenyl)(3-methoxypropoxy)methyl)piperidin-1-yl)cyclobut-3-ene-1,2-dione (8.7 mg, 60%) as a TFA salt. 1H NMR (CD3OD) δ 0.8-2.1 (20H), 3.0 (1H), 3.1 (1H), 3.25 (s, 3H), 3.3 (m, 6H), 3.5 (2H), 4.45 (d, 1H), 4.63 (m, 1H), 7.15 (1H), 7.21 (1H), 7.35 (1H), 7.40 (1H). MS ESI+ve m/z 516 (M+1).
Reaction SMILES: [C:1]1([C:7]2[C:11]3[CH:12]=[CH:13][C:14]4[O:18][CH:17]([CH2:19][OH:20])[CH2:16][C:15]=4[C:10]=3[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.S(=O)(=O)(O)[OH:23]>CC(C)=O.[O-2].[Cr+6].[O-2].[O-2]>[C:1]1([C:7]2[C:11]3[CH:12]=[CH:13][C:14]4[O:18][CH:17]([C:19]([OH:23])=[O:20])[CH2:16][C:15]=4[C:10]=3[O:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(O)O
Reactant: OCC1Cc2c(ccc3c(-c4ccccc4)noc23)O1
Agent: [Cr+6]
Agent: [O-2]
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)C1Cc2c(ccc3c(-c4ccccc4)noc23)O1
Reaction time: 8 h
Yield: 43.2 %

Procedure:
A portion (5.5 g) of the 7,8-dihydro-3-phenylfuro[2,3-g]-1,2-benzisoxazole-7-methanol prepared in Example 1 was dissolved in 200 ml of acetone. To the stirred solution, a mixture of chromium (VI) oxide (10 g), water (20 ml) and concentrated sulfuric acid (16 g) was added dropwise over time, and the solution was left to stand overnight. The insolubles were filtered off by suction. After distilling off the acetone, water was added to the residue and the mixture was subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with water and dried, followed by distilling off the solvent. The residue was recrystallized with acetonitrile to yield 2.5 g of 7,8-dihydro-3-phenylfuro[2,3-g]-1,2-benzisoxazole-7-carboxlic acid. m.p. 219°-220° C. This compound exhibited a mass spectrum having a molecular ion peak at m/e 281.
Reaction SMILES: [NH:1]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C@H:2]([C:9](O)=[O:10])[CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:52]([O:56][C:57](=[O:86])[NH:58][CH:59]([CH:80]1[CH2:85][CH2:84][CH2:83][CH2:82][CH2:81]1)[C:60]([N:62]1[CH2:66][CH2:65][CH:64]2[NH:67][CH2:68][CH:69]([C:70]3[C:78]4[C:73](=[CH:74][C:75]([F:79])=[CH:76][CH:77]=4)[NH:72][CH:71]=3)[CH:63]12)=[O:61])([CH3:55])([CH3:54])[CH3:53]>CN1C(=O)CCC1.C(OCC)C>[C:52]([O:56][C:57](=[O:86])[NH:58][CH:59]([CH:80]1[CH2:81][CH2:82][CH2:83][CH2:84][CH2:85]1)[C:60]([N:62]1[CH2:66][CH2:65][CH:64]2[N:67]([C:9](=[O:10])[CH:2]([NH:1][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:3]3[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]3)[CH2:68][CH:69]([C:70]3[C:78]4[C:73](=[CH:74][C:75]([F:79])=[CH:76][CH:77]=4)[NH:72][CH:71]=3)[CH:63]12)=[O:61])([CH3:55])([CH3:53])[CH3:54]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C1CCCCC1
Reactant: CC(C)(C)OC(=O)NC(C(=O)N1CCC2NCC(c3c[nH]c4cc(F)ccc34)C21)C1CCCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)NC(C(=O)N1CC(c2c[nH]c3cc(F)ccc23)C2C1CCN2C(=O)C(NC(=O)OC(C)(C)C)C1CCCCC1)C1CCCCC1
Temperature: 0 °C
Reaction time: 16 h
Yield: 82.4 %

Procedure:
To a solution containing Boc-Chg-OH (167 mg, 0.64 mmol) in anhydrous NMP (6 mL) was cooled to 0° C. HATU (247 mg, 0.64 mmol) and DIPEA (94 mg, 0.73 mmol) were added followed by the addition of crude 49 (300 mg, 0.62 mmol). The reaction mixture was slowly warmed to ambient temperature. After 16 h, the reaction mixture was diluted with diethyl ether and washed successively with water, 1M HCl, water, aqueous NaHCO3, and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by flash silica gel chromatography (2:1-1:1 hexanes/EtOAc) to afford 370 mg (82%) of 121 as a white solid. 1H NMR (300 MHz, CDCl3), mixture of rotomers: δ8.32 (dd, J=5.4, 8.7 Hz, 0.4H, minor rotomer), 8.21 (dd, J=5.7, 9.0 Hz, 1.6H, major rotomer), 8.12 (br s, 0.4H), 8.06 (br s, 1.6H), 7.06 (m, 2H), 7.01 (m, 2H), 6.98 (m, 2H), 6.94 (m, 2H), 5.31 (app d, J=9.3 Hz, 2H), 5.22 (app d, J=9.6 Hz, 2H), 4.60 (d, J=5.1 Hz, 2H), 4.46-4.32 (m, 10H), 4.04 (d, J=5.7 Hz, 2H), 3.64 (dd, J=6.0, 10.8 Hz, 2H), 3.33 (m, 2H), 2.43 (dd, J=5.4, 13.4 Hz, 2H), 1.89-1.55 (m, 10H), 1.47 (s, 3.6H, minor rotomer), 1.44 (s, 14.4H, major rotomer), 1.28-1.02 (m, 10H) ppm. Mass spectrum, m/z [724.5] (M+H)+.
Reaction SMILES: [CH2:1]([C:7]1[CH:8]=[C:9]([C:13]2[N:17]([CH3:18])[C:16]([C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[C:15](I)[N:14]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[N:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>>[CH2:1]([C:7]1[CH:8]=[C:9]([C:13]2[N:17]([CH3:18])[C:16]([C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[C:15]([C:36]3[CH:37]=[CH:38][N:33]=[CH:34][CH:35]=3)[N:14]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: OB(O)c1ccncc1
Reactant: CCCCCCc1cccc(-c2nc(I)c(C(=O)N3CCC(N4CCCC4)CC3)n2C)c1
Product: CCCCCCc1cccc(-c2nc(-c3ccncc3)c(C(=O)N3CCC(N4CCCC4)CC3)n2C)c1

Procedure:
In analogy to the procedure described for example 7, [2-(3-hexyl-phenyl)-5-iodo-3-methyl-3H-imidazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 2) was reacted with pyridin-4-yl-boronic acid to give the title compound as light yellow oil. MS: 500.3 (MH+).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:11][C:12]1[CH:17]=[CH:16][N:15]=[CH:14][C:13]=1[NH2:18].F[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N+:26]([O-:28])=[O:27]>C1COCC1.CCCCCC.C(OCC)(=O)C>[CH3:11][C:12]1[CH:17]=[CH:16][N:15]=[CH:14][C:13]=1[NH:18][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N+:26]([O-:28])=[O:27]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: Cc1ccncc1N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccncc1Nc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.3 %

Procedure:
1M LiHMDS solution (9.25 mL, 9.25 mmol) in THF was added drop wise to a cooled solution of 4-Methyl-pyridin-3-ylamine (1 g, 9.25 mmol) in THF (10 mL) at 0° C. under nitrogen atmosphere. The resulting mixture was added drop wise to a solution of 1-fluoro-2-nitro-benzene (0.98 mL, 9.25 mmol) in THF at 0° C. The resulting reaction mass was stirred at room temperature overnight. The reaction was monitored by TLC (50% ethyl acetate in hexane). The reaction mixture was diluted with ethyl acetate and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel (50% ethyl acetate in hexane) to afford 600 mg of the product (28.32% yield).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2([CH2:17][CH2:16][N:15]([C:18](=[O:27])[C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=3[F:26])[CH2:14][CH2:13]2)[NH:11][C@@H:10]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:9]1=[O:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.CCOCC.C[Si]([Cl:46])(C)C>CC(CC)=O>[ClH:46].[CH2:1]([N:8]1[C:12]2([CH2:17][CH2:16][N:15]([C:18](=[O:27])[C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=3[F:26])[CH2:14][CH2:13]2)[NH:11][C@@H:10]([CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:9]1=[O:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)Cl
Agent: O=C(c1cccc(F)c1F)N1CCC2(CC1)N[C@@H](Cc1ccccc1)C(=O)N2Cc1ccccc1
Solvent: CCOCC
Solvent: O
Solvent: CCC(C)=O
Product: Cl
Reaction time: 8 h

Procedure:
1,3-(S)-dibenzyl-8-(2,3-difluorobenzoyl)-1,4,8-triazaspiro[4,5]decan-2-one (370 mg, 0.8 mmol) was dissolved in ethyl methyl ketone (2.9 mL), water (8 μL), ether (30 mL) and TMSCl (108 μL) were added and the mixture was stirred overnight. The solid matter was isolated by filtration, washed with ether, and dried in vacuo. The product 1,3-(S)-dibenzyl-8-(2,3-difluorobenzoyl)-1,4,8-triazaspiro[4,5]decan-2-one hydrochloride was obtained in a yield of 317 mg (80%).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.[CH3:8][Si:9]([CH3:16])([CH3:15])[CH2:10][CH2:11][O:12][CH2:13]Cl.O>C1COCC1>[NH:3]1[CH:7]=[CH:6][N:5]=[C:4]1[CH2:13][O:12][CH2:11][CH2:10][Si:9]([CH3:16])([CH3:15])[CH3:8]
Reactant: C[Si](C)(C)CCOCCl
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCc1ncc[nH]1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 63.9 %

Procedure:
A stirred suspension of 1.2 grams of 60% sodium hydride (0.03 mole-in mineral oil) in 25 mL of THF was cooled to 0° C. to 5° C., and a solution of 2.0 grams (0.03 mole) of imidazole in 30 mL of THF was added dropwise. Upon completion of addition, the reaction mixture was stirred at 0° C. for an additional 15 minutes, then a solution of 4.7 grams (0.03 mole) of 2-(trimethylsilyl)ethoxymethyl chloride in 10 mL of THF was added dropwise. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature as it stirred during an 18 hour period. After this time, the reaction mixture was stirred with 50 mL of water, and the mixture was extracted with ethyl acetate. The extract was washed with an aqueous solution saturated with sodium chloride and was then dried with magnesium sulfate. The mixture was filtered and the filtrate was concentrated under reduced pressure to a residual oil. The residue was distilled under reduced pressure, yielding 3.8 grams of the subject compound; bp 71° C./0.1 torr. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: C(CCSC(C1C=CC=CC=1OCCCCCCC1C=CC=CC=1)CC(O)=O)(O)=O.C(C1C=CC=CC=1/C=C/CCC(OCC)=O)CCCCCCCCCCC.[F:58][C:59]([F:74])([F:73])[CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][Mg]Br.CO[C:77]1[CH:82]=[CH:81][CH:80]=[CH:79][C:78]=1[C:83]1[O:84][CH2:85][C:86]([CH3:89])([CH3:88])[N:87]=1>O1CCCC1>[F:58][C:59]([F:74])([F:73])[CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][C:77]1[CH:82]=[CH:81][CH:80]=[CH:79][C:78]=1[C:83]1[O:84][CH2:85][C:86]([CH3:89])([CH3:88])[N:87]=1
Reactant: FC(F)(F)CCCCCCCCCCC[Mg]Br
Reactant: COc1ccccc1C1=NC(C)(C)CO1
Agent: CCCCCCCCCCCCc1ccccc1/C=C/CCC(=O)OCC
Agent: O=C(O)CCSC(CC(=O)O)c1ccccc1OCCCCCCc1ccccc1
Solvent: C1CCOC1
Product: CC1(C)COC(c2ccccc2CCCCCCCCCCCC(F)(F)F)=N1

Procedure:
Following the procedures of Example 1(a), (b) and (c), 12,12,12-trifluorododecylmagnesium bromide (from 29.19 mmoles of 12,12,12-trifluorododecyl bromide and 25.71 mmoles of magnesium) was reacted with 2-(2-methoxyphenyl)-4,4-dimethyloxazoline (20.17 mmoles) in tetrahydrofuran to give 2-[2-(12,12,12-trifluorododecyl)-phenyl]-4,4-dimethyloxazoline. The oxazoline (14.39 mmoles) was converted to the methiodide salt and then reduced with sodium borohydride (13.43 mmoles) to yield the desired product as an oil.
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].[CH3:6][C:7]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:8]=1[C:9](Cl)=O>N1C=CC=CC=1>[CH3:6][C:7]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:8]=1[C:9]1[NH:5][C:3](=[S:4])[NH:2][N:1]=1
Reactant: NNC(N)=S
Reactant: Cc1ccc(C(=O)Cl)c(C)c1
Solvent: c1ccncc1
Product: Cc1ccc(-c2n[nH]c(=S)[nH]2)c(C)c1
Temperature: 150 °C
Yield: 43 %

Procedure:
A suspension of thiosemicarbazide (800 mg, 8.78 mmol) in 9 mL of pyridine was added 2,4-dimethylbenzoyl chloride (1.68 g, 10 mmol). The reaction was heated at 150° C. for 10 min using a microwave synthesizer. The yellow solution was evaporated to dryness and then diluted with water. The white solid was then collected and washed with water. The solid was suspended in 20 mL of 1 M aq. NaHCO3. The suspension was heated at 180° C. for 1 h using a microwave synthesizer. Then the mixture was filtered hot and the aqueous solution was cooled in ice and acidified to pH 3 with conc. HCl. The solid was filtered and washed with water and dried to give white powder (43%).
Reaction SMILES: CO[C:3]([CH:5]1[C:11](=[O:12])[C:10]2[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:9]=2[N:8]([CH3:18])[C:7](=[O:19])[CH2:6]1)=[O:4]>C1(C)C(C)=CC=CC=1>[F:17][C:14]1[CH:15]=[CH:16][C:9]2[N:8]([CH3:18])[C:7](=[O:19])[CH2:6][CH:5]([C:3](=[O:4])[NH:8][C:9]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:10]=3)[C:11](=[O:12])[C:10]=2[CH:13]=1
Reactant: COC(=O)C1CC(=O)N(C)c2ccc(F)cc2C1=O
Solvent: Cc1ccccc1C
Product: CN1C(=O)CC(C(=O)Nc2ccc(F)cc2)C(=O)c2cc(F)ccc21

Procedure:
The mixture of 5.0 g of 7-fluoro-1-methyl-2,3,4,5-tetrahydro-1-benzazepine-2,5-dione-4-carboxylic acid methyl ester, 2.3 g of 4-fluoroaaniline and 120 ml of xylene is refluxed under nitrogen for 40 hours, cooled with ice and diluted with 65 ml of petroleum ether. The precipitate formed is filtered off and recrystallized from acetonitrile, to yield the 7-fluoro-1-methyl-4-(4-fluorophenylcarbamoyl)-2,3,4,5-tetrahydro-1-benzazepine-2,5-dione melting at 180°-182°.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:34]=[CH:33][C:9]([CH2:10][NH:11][C:12]([C:14]2[CH:15]=[C:16]3[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@@H:20]([CH:30]([CH3:32])[CH3:31])[C:17]3=[N:18][CH:19]=2)=[O:13])=[CH:8][CH:7]=1)(=[O:5])=[O:4])[CH3:2].[C:35](OC(N1C(C)C2C(=NC=C(C(O)=O)C=2)[C@@H]1C(C)C)=O)(C)(C)C>>[CH2:1]([S:3]([C:6]1[CH:7]=[CH:8][C:9]([CH2:10][NH:11][C:12]([C:14]2[CH:15]=[C:16]3[CH:22]([CH3:35])[N:21]([C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[C@@H:20]([CH:30]([CH3:31])[CH3:32])[C:17]3=[N:18][CH:19]=2)=[O:13])=[CH:33][CH:34]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: CC(C)[C@H]1c2ncc(C(=O)O)cc2C(C)N1C(=O)OC(C)(C)C
Reactant: CCS(=O)(=O)c1ccc(CNC(=O)c2cnc3c(c2)CN(C(=O)OC(C)(C)C)[C@H]3C(C)C)cc1
Product: CCS(=O)(=O)c1ccc(CNC(=O)c2cnc3c(c2)C(C)N(C(=O)OC(C)(C)C)[C@H]3C(C)C)cc1
Reaction time: 0.02 h

Procedure:
Procedure same as that for tert-butyl(S)-3-((4-(ethylsulfonyl)benzyl)carbamoyl)-7-isopropyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate, using (7S)-6-(tert-butoxycarbonyl)-7-isopropyl-5-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxylic acid as a starting material. LC-MS tR=0.95 min in 1 min chromatography, MS (ESI) m/z 502.6 [M+H]+. 1H NMR (CD3OD, 400 MHz, mixture of diastereomers): δ 8.93 (s, 1H), 7.79 (d, J=8.4 Hz, 2H), 7.50 (d, J=8.4 Hz, 2H), 7.24 (s, 1H), 5.06-4.88 (m, 2H), 4.82-4.70 (m, 2H), 3.06 (q, J=7.2 Hz, 2H), 2.48-2.26 (m, 1H), 1.59 (d, J=7.2 Hz, 0.9H), 1.56 (d, J=7.2 Hz, 2.1H), 1.53 (s, 9H), 1.25 (t, J=7.2 Hz, 3H), 1.09 (d, J=7.2 Hz, 0.9H), 0.97 (broad s, 2.1H), 0.83 (broad s, 2.1H), 0.48 (d, J=7.2 Hz, 0.9H).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:67])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47](OS(C3C=CC=CC=3[N+]([O-])=O)(=O)=O)[CH:46]([O:63][CH2:64][CH2:65][CH3:66])[CH2:45]2)[CH:7]([CH3:68])[CH2:6][CH2:5][C:4]1=[O:69])[CH3:2].[N-:70]=[N+:71]=[N-:72].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:67])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([N:70]=[N+:71]=[N-:72])[CH:46]([O:63][CH2:64][CH2:65][CH3:66])[CH2:45]2)[CH:7]([CH3:68])[CH2:6][CH2:5][C:4]1=[O:69])[CH3:2]
Reactant: CCCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CCC2C)C(OC)CC3C)CCC1OS(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CCC2C)C(OC)CC3C)CCC1N=[N+]=[N-]
Temperature: 70 °C
Yield: 55.9 %

Procedure:
To a solution of 17-ethyl-1-hydroxy-12-[2'-(4"-(o-nitrophenylsulfonyloxy)-3"-propyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (111 mg) in N,N-dimethyl formamide (1.1 ml) was added an excess of sodium azide (32 mg) and the mixture heated to 70° C. After 5.5 hours the reaction was cooled to room temperature, diluted with ethyl acetate, extracted from half-saturated ammonium chloride, and washed with brine. The combined organics were dried over sodium sulfate and purified by flash chromatography on silica gel (ethyl acetate: hexane (1:2)+1% methanol) to give the title compound (52 mg).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[N+:6]([CH:9]=[C:10]1[NH:15][CH2:14][CH2:13][CH2:12][S:11]1)([O-:8])=[O:7].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([N:15]1[CH2:14][CH2:13][CH2:12][S:11][C:10]1=[CH:9][N+:6]([O-:8])=[O:7])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: O=[N+]([O-])C=C1NCCCS1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CCCSC1=C[N+](=O)[O-]
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
A solution of 20 g of methanesulfonyl chloride in 150 ml of methylene chloride was added drop-by-drop over a 55 minute period to a stirred mixture of 20 g of 2-(nitromethylene)-tetrahydro-2H-1,3-thiazine and 40 ml of triethylamine in 150 ml of methylene chloride, at -30° C., in a nitrogen atmosphere. The resulting mixture was stirred for 30 minutes at -30° C., and then washed with 2% hydrochloric acid. The aqueous phase was washed twice with methylene chloride. The resulting organic phases were combined, dried (Na2SO4), concentrated to about 50 ml, cooled to 0° C., and filtered. The crystalline solid was triturated with cold methylene chloride, to give N-(methylsulfonyl)-2-(nitromethylene)-tetrahydro-2H-1,3-thiazine (1A), as a crystalline solid, m.p.: 144-145° C. (with decomposition).
Reaction SMILES: N1CCCCC1.[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][C:8]1=[O:16].[I:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([CH:27]=O)[CH:25]=2)[NH:20][N:19]=1>CCO>[I:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([CH:27]=[C:9]3[C:10]4[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=4)[NH:7][C:8]3=[O:16])[CH:25]=2)[NH:20][N:19]=1
Reactant: O=C1Cc2ccccc2N1
Reactant: O=Cc1ccc2[nH]nc(I)c2c1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1Nc2ccccc2C1=Cc1ccc2[nH]nc(I)c2c1
Temperature: 75 °C
Reaction time: 14 h
Yield: 63.1 %

Procedure:
Piperidine (0.01 mL, 0.1 mmol) was added to a suspension of oxindole (72 mg, 0.54 mmol) and 3-iodo-1H-indazole-5-carbaldehyde (146 mg, 0.54 mmol) in EtOH (10 mL). On heating to 75° C., the suspended solid dissolved, and a new precipitate formed. Heating was continued at 75° C. for 14 hrs. After the mixture was cooled to room temperature, suction filtration and rinsing with EtOH (4×2 mL) gave 3-((3-iodo-1H-indazol-5-yl)methylene)indolin-2-one (yellow solid, 131.9 mg, 63%). 1H NMR (400 MHz, d6-DMSO) δ 13.75 (br. s, 1H), 10.61 (br. s, 1H), 7.84 (s, 1H), 7.77 (m, 2H), 7.69 (d, J=8.8 Hz, 1H), 7.60 (d, J=8.0 Hz, 1H), 7.23 (m, 1H), 6.88 (d, J=8.0 Hz, 1H), 6.84 (m, 1H); MS ESI 388.0 [M+H]+, calcd for [C16H10IN3O+H]+ 388.0.
Reaction SMILES: Cl.[Cl:2][CH2:3][C:4]1[C:9]([CH2:10][NH:11][CH3:12])=[CH:8][C:7]([O:13][CH3:14])=[C:6]([O:15][CH3:16])[CH:5]=1.[OH-].[Na+]>[Cl-].C([N+](CCCCCCCC)(CCCCCCCC)C)CCCCCCC.C1C=CC=CC=1>[ClH:2].[CH3:16][O:15][C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][C:7]=1[O:13][CH3:14])[CH2:10][N:11]([CH3:12])[CH2:3]2
Reactant: CNCc1cc(OC)c(OC)cc1CCl
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: Cl
Agent: [Cl-]
Solvent: c1ccccc1
Product: COc1cc2c(cc1OC)CN(C)C2
Reaction time: 3 h
Yield: 7.8 %

Procedure:
23 g (0.1 mol) of N-(6-chloromethyl-3,4-dimethoxybenzyl)-methylamine hydrochloride was added at a temperature of from 15° to 18° C. to a suspension comprising 50 ml of a 50% sodium hydroxide aqueous solution, 230 ml of benzene and 1 ml of a 90% trioctylmethylammonium chloride aqueous solution over a period of 2 minutes. The mixture was stirred for 3 hours, and then the organic layer of the reaction solution was separated, washed with water and a saturated sodium chloride aqueous solution, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and 50 ml of 6N hydrochloric acid was added to the residue. The mixture was again evaporated under reduced pressure to dryness. The crystalline residue was washed with ethanol to obtain 12.65 g (yield: 51.2%) of the above identified compound. From the filtrate, 1.8 g (yield: 7.8%) of secondary crystals were obtained. The total amount was 14.4 g (total yield: 63.1%). Melting point: 227° C. (decomposed)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([Cl:20])=[CH:4][N:3]=1.[NH2:21][C:22]1[CH:23]=[CH:24][C:25]2[CH2:31][CH2:30][CH2:29][NH:28][C:27](=[O:32])[C:26]=2[CH:33]=1.CC1(C)[C@]2(CS(O)(=O)=O)C(C[C@H]1CC2)=O>C(O)(C)C>[Cl:20][C:5]1[C:6]([NH:8][C:9]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])=[N:7][C:2]([NH:21][C:22]2[CH:23]=[CH:24][C:25]3[CH2:31][CH2:30][CH2:29][NH:28][C:27](=[O:32])[C:26]=3[CH:33]=2)=[N:3][CH:4]=1
Reactant: Nc1ccc2c(c1)C(=O)NCCC2
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Agent: CC1(C)[C@@H]2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Product: CNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)C(=O)NCCC3)ncc1Cl
Yield: 15.3 %

Procedure:
Combined 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide (104 mg, 0.33 mmol), 8-Amino-2,3,4,5-tetrahydro-benzo[c]azepin-1-one (70 mg, 0.397 mmol), DL-10-Camphorsulfonic acid (82 mg, 0.353 mmol) and isopropanol (4 mL) in a microwave tube. Microwaved reaction at 120° C. for 30 minutes. Evaporated off solvent and purified with normal phase chromatography to yield a white solid, 2-[5-Chloro-2-(1-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-ylamino)-pyrimidin-4-ylamino]-3-fluoro-N-methyl-benzamide (23 mg, 15%). mp 200° C.; LCMS: m/z=455.37 (M+H+), 1H NMR (400 MHz, CD3OD) δ 8.06 (s, 1H), 7.66 (m, 1H), 7.43 (m, 2H), 7.03 (d, 1H, J=9.1 Hz), 3.03 (m, 2H), 2.84 (s, 3H), 2.75 (m, 2H), 1.98 (m, 2H).