Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.[CH3:14][C:15]([OH:24])([CH3:23])[CH2:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.Cl>CN(C=O)C>[CH3:23][C:15]([OH:24])([CH3:14])[CH2:16][CH:17]1[CH2:18][CH2:19][N:20]([C:11]([C:6]2[NH:7][C:8]3[C:4]([CH:5]=2)=[CH:3][C:2]([CH3:1])=[CH:10][CH:9]=3)=[O:13])[CH2:21][CH2:22]1
Reactant: Cc1ccc2[nH]c(C(=O)O)cc2c1
Reactant: CC(C)(O)CC1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1ccc2[nH]c(C(=O)N3CCC(CC(C)(C)O)CC3)cc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 71.4 %

Procedure:
To a solution of 1800 mg of 5-methylindole-2-carboxylic acid and 1500 mg of 2-methyl-1-(piperidin-4-yl)-2-propanol in 25 mL of DMF were added 2100 mg of 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride and 1500 mg of 1-hydroxybenzotriazole, followed by stirring at room temperature for 1 day. 0.5M aqueous hydrochloric acid was added to the reaction liquid, followed by extraction with ethyl acetate. The organic layer was washed with 0.5M aqueous sodium hydroxide solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography [chloroform:methanol=1:0-10:1], and then crystallized from a mixture of ethyl acetate/diisopropyl ether to obtain 2140 mg of 2-methyl-1-{1-[(5-methyl-1H-indol-2-yl)carbonyl]piperidin-4-yl}propan-2-ol as a white crystal.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl-:5].[CH2:6]([NH+:8]([CH2:15][CH3:16])[CH2:9][CH2:10][NH2+:11][CH2:12][CH2:13]O)[CH3:7].[Cl-]>ClCCl>[Cl-:3].[Cl:5][CH2:13][CH2:12][NH2+:11][CH2:10][CH2:9][NH+:8]([CH2:15][CH3:16])[CH2:6][CH3:7].[Cl-:3]
Reactant: O=S(Cl)Cl
Reactant: CC[NH+](CC)CC[NH2+]CCO
Agent: [Cl-]
Solvent: ClCCl
Product: CC[NH+](CC)CC[NH2+]CCCl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of thionyl chloride (SOCl2) (16.9 g, 0.14 mol) in dichloromethane (20 ml) was added dropwise to a vigorously stirred suspension of N1,N1-diethyl-N2-(2-hydroxyethyl)ethane-1,2-diaminium chloride (21 g, 0.11 mol) in dichloromethane (120 ml) which was cooled at 0° C. The ice bath was removed and the reaction mixture was allowed to stir at room temperature for 1 hour. The mixture was then allowed to reflux for 1 hour. After cooling, the suspension was filtered and the product was washed with dichloromethane (40 ml) to give a colorless solid. (20 g, 78%). 1H NMR (methanol-d4): δ 4.03 (t, 3JHH=6.1, 2H, CH2Cl), 3.68 (br s, 4 H, CH2NH), 3.61 (t, 3JHH=5.7, 2H, Et2NCH2), 3.38 (q, 3JHH=7.3, 4H, CH3CH2), 1.43 (t, 3JHH=7.3, 6H, CH3).
Reaction SMILES: C(OC(=O)C=C([NH:8][CH:9]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([CH2:20]N=[N+]=[N-])[CH:14]=1)[C:10]([OH:12])=O)C)C.[CH2:25]([O:27]C(Cl)=O)C.[NH2:31][CH:32]1[C:38](=[O:39])[N:37]2[CH:33]1[S:34][C:35]([CH3:44])([CH3:43])[CH:36]2[C:40]([OH:42])=[O:41].O1CCCC1.O>C(N(CC)CC)C.O1CCCC1>[NH2:8][CH:9]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([CH2:20][O:27][CH3:25])[CH:14]=1)[C:10]([NH:31][CH:32]1[C:38](=[O:39])[N:37]2[CH:33]1[S:34][C:35]([CH3:44])([CH3:43])[CH:36]2[C:40]([OH:42])=[O:41])=[O:12]
Reactant: CCOC(=O)Cl
Reactant: CC1(C)SC2C(N)C(=O)N2C1C(=O)O
Reactant: CCOC(=O)C=C(C)NC(C(=O)O)c1ccc(O)c(CN=[N+]=[N-])c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: COCc1cc(C(N)C(=O)NC2C(=O)N3C2SC(C)(C)C3C(=O)O)ccc1O
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
α-(3-Ethoxy-1-methyl-3-oxo-1-propen-1-yl)amino-3-(azidomethyl)-4-hydroxybenzeneacetic acid (0.05 mole) is added to tetrahydrofuran (THF) at -10° C. Ethylchloroformate (0.05 mole) is slowly added with stirring while maintaining the temperature at -10° C. After 30 minutes, 6-amino-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]-heptane-2-carboxylic acid in 1 to 1 mixture of THF/water containing 0.05 mole of triethylamine is added to the thus formed solution. The mixture is stirred at -10° C. for about 30 minutes and then at about 20° C. for 30 minutes. The pH is adjusted to 2 and the reaction mixture is extracted with ethyl ether. The pH is then adjusted to 4.5 to 5.5 and the reaction mixture is extracted with ethyl acetate. The ethyl acetate is dried over sodium sulfate, filtered to remove the drying agent and evaporated to give the title compound.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][C:5]#[C:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]([CH3:27])[S:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:9][CH2:8]1.[CH3:28][NH:29][CH2:30][CH2:31][CH3:32]>CO>[CH3:27][N:13]([C@H:10]1[CH2:11][CH2:12][C@H:7]([C:6]#[C:5][CH2:4][CH2:3][CH2:2][N:29]([CH3:28])[CH2:30][CH2:31][CH3:32])[CH2:8][CH2:9]1)[S:14]([C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=1)(=[O:16])=[O:15]
Reactant: CCCNC
Reactant: CN([C@H]1CC[C@H](C#CCCCI)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Solvent: CO
Product: CCCN(C)CCCC#C[C@H]1CC[C@H](N(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
320 mg (corresponds to 0.59 mmol) of crude trans-N-[4-(5-Iodo-pent-1-ynyl)-cyclohexyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide in 6 ml MeOH was treated with 0.6 ml (5.93 mmol) of N-methylpropylamine. The reaction was stirred overnight at 65° C. and partitioned between aqueous 1N NaOH /Et2O (3×), the organic phases were dried over Na2SO4 and evaporated. Purification by flash column chromatography on silica gel (CH2Cl2, then CH2Cl2/MeOH 95:5 to 9:1) gave 128 mg (47% over two steps) of trans-N-Methyl-N-{4-[5-(methyl-propyl-amino)-pent-1-ynyl]-cyclohexyl}-4-trifluoromethyl-benzenesulfonamide, MS: 459 (MH+). The following compounds can be obtained in analogy:
Reaction SMILES: [NH2:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12][CH:13]([CH:20]([CH3:22])[CH3:21])[C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])=[O:11])[C:5]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:4][CH:3]=1.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>O1CCCC1.C(N(CC)CC)C.C(OCC)(=O)C>[CH3:29][S:30]([NH:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12][CH:13]([CH:20]([CH3:22])[CH3:21])[C:14](=[O:19])[C:15]([F:16])([F:18])[F:17])=[O:11])[C:5]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[N:4][CH:3]=1)(=[O:32])=[O:31]
Reactant: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ncc(N)c1=O)C(=O)C(F)(F)F
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ncc(NS(C)(=O)=O)c1=O)C(=O)C(F)(F)F
Reaction time: 8 h

Procedure:
To a solution of 2-(5-amino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl)-N-(3,3,3-trifluoro-1-isopropyl-2-oxopropyl)acetamide (0.345 g) in tetrahydrofuran (7 mL) and triethylamine (0.36 mL) at 0° C. was added methanesulfonoyl chloride (0.19 mL) and the resulting solution was allowed to stir overnight. The mixture was diluted with ethyl acetate and the solution washed (1N hydrochloric acid, water, 5% sodium bicarbonate). The organic layer was dried and evaporated. The residue was dissolved in tetrahydrofuran (1 mL), and to it was added 3N aqueous potassium hydroxide (0.07 mL). The solution was allowed to stir for 12 h. The reaction was quenched by addition of 1N hydrochloric acid and the product was extracted into ethyl acetate. The organic layer was washed (water, brine), and the solution was dried and evaporated. The resulting material was purified by chromatography, with tetrahydrofuran:dichloromethane (10:90) as the eluent, to provide 2-(5-methylsulfonylamino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl)-N-(3,3,3-trifluoro-1-isopropyl-2-oxopropyl)acetamide as a white solid (0.146 g); NMR (DMSO/D2O): 9.35 (s,1), 8.84 (d,1), 8.01 (s,1), 7.50 (m,5), 4.68 (m,2), 4.55 (d,1), 3.10 (s,3), 2.16 (m,1), 0.89 (d,3), 0.83 (d,3).
Reaction SMILES: C(O)C.[C:4]([C:7]1[C:15]2[S:14][C:13](=[O:16])[NH:12][C:11]=2[C:10]([OH:17])=[CH:9][CH:8]=1)(=[O:6])[CH3:5].I([Cl:21])(=O)=O.I(Cl)(=O)=O.C([N+](C)(C)C)C1C=CC=CC=1>O>[Cl:21][CH2:5][C:4]([C:7]1[C:15]2[S:14][C:13](=[O:16])[NH:12][C:11]=2[C:10]([OH:17])=[CH:9][CH:8]=1)=[O:6]
Reactant: O=I(=O)Cl
Reactant: CC(=O)c1ccc(O)c2[nH]c(=O)sc12
Agent: C[N+](C)(C)Cc1ccccc1
Solvent: CCO
Solvent: O
Product: O=C(CCl)c1ccc(O)c2[nH]c(=O)sc12
Temperature: 78 °C

Procedure:
Ethanol (1500 mL) was added to a mixture of 7-acetyl-4-hydroxy-3H-benzothiazol-2-one (150 g) (WO2004/016578) and benzyltrimethylammonium dichloroiodate (374 g) in a flask fitted with an overhead stirrer. The mixture was heated to 78° C. for 1 h and left to cool to room temperature overnight. The mixture was poured into water (2 L), and the precipitate collected by filtration, washed with water, filtered to near dryness, and suspended in ethyl acetate. The mixture was heated to reflux and allowed to cool to room temperature with stirring. The solid was collected by filtration, washed with cold ethyl acetate (200 mL) then re-suspended in diethyl ether (1 L). The solid was collected, filtered again and washed with ether (200 mL) and dried in vacuo to give the subtitled compound.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Br:7][C:8]1[C:16]([CH3:17])=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][CH:9]=1.O>C1COCC1>[Br:7][C:8]1[C:16]([CH3:17])=[CH:15][C:11]([CH2:12][OH:13])=[CH:10][CH:9]=1
Reactant: Cc1cc(C(=O)O)ccc1Br
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(CO)ccc1Br
Reaction time: 0.25 h
Yield: 100 %

Procedure:
LiAlH4 (1.75 g, 46 mmol) was added in portions to a stirred solution of 4-bromo-5-methylbenzoic acid (10 g, 46 mmol) in THF (100 mL) at 0° C. After 15 min, H2O (50 mL) was added drop wise to the reaction which was then extracted with EtAOc (100 mL×3). The combined organic layers were washed with brine (200 mL×2), dried (Na2SO4), and concentrated under reduced pressure to yield compound 2 as a light yellow syrup (9.25 g, 46 mmol, 100% yield). 1H NMR, (400 MHz, CDCl3): δ 7.52 (d, J=8.2 Hz, 1H), 7.25 (d, J=2.4 Hz, 1H), 6.88-7.10 (m, 1H), 4.63 (s, 2H), 2.43 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH2:10][CH2:11][N:12]=2)=[CH:4][C:3]=1C.Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]1[O:26][N:25]=[C:24]([CH3:27])[CH:23]=1.C[C:29]1[O:33]N=C(CCC(OC)=O)C=1>>[OH:33][CH2:29][CH:10]1[O:9][C:8]([C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]3[O:26][N:25]=[C:24]([CH3:27])[CH:23]=3)=[CH:7][CH:6]=2)=[N:12][CH2:11]1
Reactant: Cc1cc(C2=NCCO2)ccc1O
Reactant: COC(=O)CCc1cc(C)on1
Reactant: Cc1cc(CCCCCCCBr)on1
Product: Cc1cc(CCCCCCCOc2ccc(C3=NCC(CO)O3)cc2)on1
Yield: 45 %

Procedure:
5-{7-[4-(4,5-Dihydro-2-oxazolyl)-2-methylphenoxy]heptyl}-3-methylisoxazole [IX; R=CH3, R2, R3, R4, R5 and R6 =H, R1 =2-CH3, Y=(CH2)7, oxazole at 4-position] was prepared from 4,5-dihydro-2-(4-hydroxy-3-methylphenyl)oxazole and 5-(7-bromoheptyl)-3-methylisoxazole according to the procedure of Example 9, part (d), and was obtained in 45% yield as a light-tan solid, m.p. 90°-92° C., when recrystallized first from methanol and then from tertiary-butyl methyl ether.
Reaction SMILES: S(Cl)(Cl)=O.[CH2:5]([C:7]1[N:8]=[C:9]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[NH:10][C:11](=[O:20])[C:12]=1[CH:13]([CH2:17][CH2:18][CH3:19])[C:14]([OH:16])=[O:15])[CH3:6].[CH3:27]O>>[CH2:5]([C:7]1[N:8]=[C:9]([N:21]2[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]2)[NH:10][C:11](=[O:20])[C:12]=1[CH:13]([CH2:17][CH2:18][CH3:19])[C:14]([O:16][CH3:27])=[O:15])[CH3:6]
Reactant: CO
Reactant: CCCC(C(=O)O)c1c(CC)nc(N2CCCCC2)[nH]c1=O
Solvent: O=S(Cl)Cl
Product: CCCC(C(=O)OC)c1c(CC)nc(N2CCCCC2)[nH]c1=O

Procedure:
To a solution cold solution of methanol (40 mL) was added thionyl chloride (5.8 mL; 80 mmol) dropwise. The acidic solution was added to a flask containing 2-(4-ethyl-6-oxo-2-(piperidin-1-yl)-1,6-dihydropyrimidin-5-yl)pentanoic acid (2.416 g; 7.86 mmol) and the mixture was heated to reflux for 18 h. The reaction mixture was concentrated under reduced pressure and the product was used as such in the next reaction.
Reaction SMILES: [N:1]1([C:6]2[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.N1N=CN(C2C=[C:20]3C(=CC=2)NC=[C:21]3[CH2:27][CH2:28][OH:29])C=1>CS(C)=O>[N:1]1([C:6]2[CH:12]=[C:11]3[C:9](=[CH:8][CH:7]=2)[NH:10][CH:20]=[C:21]3[CH2:27][CH2:28][OH:29])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: OCCc1c[nH]c2ccc(-n3cnnc3)cc12
Reactant: Nc1ccc(-n2ccnc2)cc1
Solvent: CS(C)=O
Product: OCCc1c[nH]c2ccc(-n3ccnc3)cc12

Procedure:
Prepared from 4-(imidazol-1-yl)aniline (EP497512) as described for Intermediate 3, δ (360 MHz, D6 -DMSO) 2.87 (2H, t, J=7.2 Hz, CH2), 3.64-3.70 (1H, m, CH2 --OH), 4.61 (1H, t, J=5.3 Hz, OH), 7.08 (1H, s, Ar--H), 7.25-7.27 (2H, m, Ar--H), 7.44 (1H, d, J=8.8 Hz, Ar--H), 7.64 (1H, d, J=2.5 Hz, Ar--H), 7.70 (1H, d, J=2.1 Hz, Ar--H), 8.11 (1H, s, Ar--H), 11.00 (1H, s, NH), m/e 228 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH3:11])=[O:9])=[C:4]([NH:14]S(C2C=CC=CC=2)(=O)=O)[CH:3]=1.[N+:24]([C:27]1[CH:36]=[CH:35][C:30]([C:31](=[O:34])[CH2:32]Br)=[CH:29][CH:28]=1)([O-:26])=[O:25]>>[CH3:11][O:10][C:8](=[O:9])[CH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:13][CH:12]=2)[NH:14][C:32]=1[C:31](=[O:34])[C:30]1[CH:29]=[CH:28][C:27]([N+:24]([O-:26])=[O:25])=[CH:36][CH:35]=1
Reactant: O=C(CBr)c1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)/C=C/c1ccc(Cl)cc1NS(=O)(=O)c1ccccc1
Product: COC(=O)Cc1c(C(=O)c2ccc([N+](=O)[O-])cc2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans 4-chloro-2-(phenylsulfonylamino)cinnamate (step 1 of Example 8, Method A) and 4-nitrophenacyl bromide.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:8][C@@H:9]2[CH:16]3[CH2:17][N:12]4[CH2:13][CH:14]([CH2:18][CH:10]2[CH2:11]4)[CH2:15]3)[CH:5]=[N:6][CH:7]=1.[NH:19]1[C:27]2[C:22](=[CH:23][C:24](B(O)O)=[CH:25][CH:26]=2)[CH:21]=[CH:20]1.N>>[NH:19]1[C:27]2[C:22](=[CH:23][C:24]([C:2]3[CH:3]=[C:4]([NH:8][C@@H:9]4[CH:16]5[CH2:17][N:12]6[CH2:13][CH:14]([CH2:18][CH:10]4[CH2:11]6)[CH2:15]5)[CH:5]=[N:6][CH:7]=3)=[CH:25][CH:26]=2)[CH:21]=[CH:20]1
Reactant: Brc1cncc(NC2C3CC4CC2CN(C4)C3)c1
Reactant: OB(O)c1ccc2[nH]ccc2c1
Agent: N
Product: c1cc2cc(-c3cncc(NC4C5CC6CC4CN(C6)C5)c3)ccc2[nH]1

Procedure:
Prepared from the product of Example 69A (150 mg, 0.50 mmol) and 5-indolylboronic acid (160 mg, 1.0 mmol; Aldrich) according to Method E: 1H NMR (300 MHz, methanol-D4) δ ppm 1.59-1.77 (m, 1H), 1.79-1.93 (m, 2H), 1.93-2.07 (m, 2H), 2.28-2.32 (m, 2H), 3.10-3.32 (m, 6H), 3.88 (s, 1H), 6.51 (dd, J=3.0, 0.7 Hz, 1H), 7.27 (d, J=3.4 Hz, 1H), 7.30-7.34 (m, 1H), 7.36 (d, J=1.7 Hz, 1H), 7.47 (d, J=8.3 Hz, 1H), 7.78 (d, J=1.0 Hz, 1H), 7.93 (d, J=2.4 Hz, 1H), 8.03 (d, J=1.7 Hz, 1H). MS (DCI/NH3) m/z=345 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([C@@H:4]1[C:23]([OH:24])=[C:22]([C:25]([NH2:27])=[O:26])[C:20](=[O:21])[C@:19]2([OH:28])[C@H:5]1[CH2:6][C@H:7]1[C:17](=[C:18]2[OH:29])[C:15](=[O:16])[C:14]2[C:13]([OH:30])=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:8]1)[CH3:3].[I:31]N1C(=O)CCC1=O>S(=O)(=O)(O)O>[CH3:3][N:2]([C@@H:4]1[C:23](=[O:24])[C:22]([C:25]([NH2:27])=[O:26])=[C:20]([OH:21])[C@:19]2([OH:28])[C@H:5]1[CH2:6][C@H:7]1[C:17]([C:18]2=[O:29])=[C:15]([OH:16])[C:14]2[C:9](=[C:10]([I:31])[CH:11]=[CH:12][C:13]=2[OH:30])[CH2:8]1)[CH3:1]
Reactant: CN(C)[C@@H]1C(O)=C(C(N)=O)C(=O)[C@@]2(O)C(O)=C3C(=O)c4c(O)cccc4C[C@H]3C[C@@H]12
Reactant: O=C1CCC(=O)N1I
Agent: O=S(=O)(O)O
Product: CN(C)[C@@H]1C(=O)C(C(N)=O)=C(O)[C@@]2(O)C(=O)C3=C(O)c4c(O)ccc(I)c4C[C@H]3C[C@@H]12
Temperature: 0 °C

Procedure:
Five grams of sancycline was dissolved in 85 mL of concentrated sulfuric acid that was cooled to 0° C. (on ice). N-iodosuccinimide (NIS) was added to the reaction in 300 mg portions every 15 minutes and reacted for 5 hours. The reaction is removed from the ice bath. The mixture, analyzed by HPLC or TLC, show the product of D-ring iodotetracyclines. After the reaction was complete, the sulfuric acid was dripped slowly 1 L of ice water and extracted 7 times with 300 mL of n-butanol. The solvent was removed in vacuo to produce a mixture of three products. The 7-iodo regioisomer, 9-regioisomer and 7,9-diiodosancycline derivative of sancycline were purified by preparative HPLC chromatography or by methods known in the art.
Reaction SMILES: S(O[CH2:12][CH2:13][CH2:14][CH:15]=[CH:16][C:17]#[C:18][CH2:19][CH3:20])(C1C=CC(C)=CC=1)(=O)=O.[Br-:21].[Na+]>CN(C)C=O>[Br:21][CH2:12][CH2:13][CH2:14][CH:15]=[CH:16][C:17]#[C:18][CH2:19][CH3:20]
Reactant: CCC#CC=CCCCOS(=O)(=O)c1ccc(C)cc1
Reactant: [Br-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC#CC=CCCCBr
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
To a solution of 42.7 g. of 1-tosyloxynon-4-en-6-yne (0.14 moles) in 150 ml. of anhydrous dimethylformamide is added 18.7 g. of sodium bromide (0.16 moles) and the mixture is heated at 75° for 2 hour and then allowed to stir overnight at room temperature. The reaction mixture is then diluted with 200 ml. of ice water and extracted with pentane. The pentane extract is washed with water and dried over sodium sulfate. Evaporation of solvent in vacuo and distillation of the residual oil gave 34.3 g. of 1-bromonon-4-en-6-yne (84% yield) b.p. 52°-55° at 0.15 mm.
Reaction SMILES: [Br-].[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH:12]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:13].[Li][CH2:34]CCC.[CH:38](=O)[CH2:39][CH2:40]/[CH:41]=[CH:42]/[CH2:43][CH2:44][CH2:45][CH2:46]C>>[CH3:34][C:12]([C:3]1[CH:4]=[CH:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:2]=1)=[CH:13][CH2:38][CH2:39]/[CH:40]=[CH:41]/[CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]
Reactant: CC(c1ccc2ccccc2c1)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: [Li]CCCC
Reactant: CCCCC/C=C/CCC=O
Agent: [Br-]
Product: CCCCC/C=C/CCC=C(C)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 43.8 %

Procedure:
Starting from (1-(2-naphthyl)ethyltriphenylphosphonium bromide (4.50 g, 9.05 mmol, 1.0 equiv.), n-BuLi (1.6 M in hexanes, 5.7 mL, 9.05 mmol, 1.0 equiv.) and (E)-dec-4-enal (2.09 g, 13.6 mmol, 1.5 equiv.), and after stirring the mixture at 25° C. for 3 h, 1.16 g (44%) of the title compound as a light yellow oil was obtained after purification by flash chromatography on SiO2 (cyclohexane).
Reaction SMILES: [OH:1][CH:2]([C:5]1[N:6]=[C:7]([Cl:10])[S:8][CH:9]=1)[CH2:3][NH2:4].[C:11]([CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24](=O)[CH3:25])=[CH:19][CH:18]=1)([O:13][CH3:14])=[O:12]>>[ClH:10].[C:11]([CH2:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:23][CH:24]([NH:4][CH2:3][CH:2]([OH:1])[C:5]2[N:6]=[C:7]([Cl:10])[S:8][CH:9]=2)[CH3:25])=[CH:21][CH:22]=1)([O:13][CH3:14])=[O:12]
Reactant: COC(=O)COc1ccc(CC(C)=O)cc1
Reactant: NCC(O)c1csc(Cl)n1
Product: COC(=O)COc1ccc(CC(C)NCC(O)c2csc(Cl)n2)cc1
Product: Cl

Procedure:
Prepared analogously to Example 13 by reaction of 2-hydroxy-2-(2-chloro-thiazol-4-yl)ethanamine with 1-(4-carbomethoxymethoxyphenyl)-propan-2-one followed by precipitation of the hydrochloride with ethereal hydrochloric acid.
Reaction SMILES: C1N=CN([C:6](N2C=NC=C2)=[O:7])C=1.[C:13]([C:17]1[CH:21]=[C:20]([NH2:22])[N:19]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)[N:18]=1)([CH3:16])([CH3:15])[CH3:14].[NH2:30][C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34]([O:41][C:42]2[CH:47]=[CH:46][N:45]=[C:44]([NH2:48])[N:43]=2)=[CH:33][CH:32]=1>C(Cl)Cl>[NH2:48][C:44]1[N:43]=[C:42]([O:41][C:34]2[C:35]3[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:31]([NH:30][C:6]([NH:22][C:20]3[N:19]([C:23]4[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=4)[N:18]=[C:17]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:21]=3)=[O:7])=[CH:32][CH:33]=2)[CH:47]=[CH:46][N:45]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2N)cc1
Reactant: Nc1nccc(Oc2ccc(N)c3ccccc23)n1
Solvent: ClCCl
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Oc3ccnc(N)n3)c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of CDI (17.24 g, 106 mmol) in DCM (150 mL) was added 3-tert-butyl-1-p-tolyl-1H-pyrazol-5-amine (24.38 g, 106 mmol) in 1 g portions over 40 min and the reaction stirred at RT for 2 hr. An aliquot of this solution (5.0 mL,) was added dropwise to a suspension of 4-(4-aminonaphthalen-1-yloxy)pyrimidin-2-amine (720 mg, 2.85 mmol) in DCM (15 mL) and the mixture maintained at RT for 2 hr. The reaction mixture was diluted with DCM (20 mL) and was washed with water (30 mL) and brine (30 mL) and then dried (MgSO4) and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, EtOAc in isohexane, 20-60%, gradient elution) to afford the title compound, Intermediate P1, as a beige solid (1.21 g, 83%); Rt 2.12 min (Method 2); m/z 508 (M+H)+, (ES+)+.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[C:4]([N:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5].CCN(C(C)C)C(C)C.[Cl:27][C:28]1[CH:29]=[C:30]2[CH:36]=[C:35]([C:37](O)=[O:38])[NH:34][C:31]2=[CH:32][N:33]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[O:5]=[C:4]([N:6]1[CH2:7][CH2:8][CH2:9][CH2:10]1)[C@@H:3]([NH:2][C:37]([C:35]1[NH:34][C:31]2=[CH:32][N:33]=[C:28]([Cl:27])[CH:29]=[C:30]2[CH:36]=1)=[O:38])[CH2:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(O)c1cc2cc(Cl)ncc2[nH]1
Reactant: N[C@@H](Cc1cccnc1)C(=O)N1CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(N[C@@H](Cc1cccnc1)C(=O)N1CCCC1)c1cc2cc(Cl)ncc2[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (S)-2-amino-3-pyridin-3-yl-1-pyrrolidin-1-ylpropan-1-one hydrochloride (Preparation 54, 239 mg, 0.94 mmol) in DMF (5 mL) was added DIPEA (0.60 mL, 3.28 mmol), 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation 18, 184 mg, 0.94 mmol) and TBTU (330 mg, 1.03 mmol). The reaction mixture was stirred at rt for 16 h. The solvent was removed in vacuo and the residue partitioned between ethyl acetate (100 mL) and sodium hydroxide solution (2×100 mL, 1N). The organic phase was dried (MgSO4) and evaporated to dryness give the title compound as a brown solid. δH (CD3OD): 1.74–1.94 (4H, m), 3.12–3.39 (4H, m), 3.41–3.48 (1H, m), 3.69–3.75 (1H, m), 5.07–5.12 (1H, m), 7.16 (1H, s), 7.34–7.39 (1H, m), 7.67 (1H, s), 7.79–7.83 (1H, m), 8.37–8.42 (1H, m), 8.45–8.51 (1H, m), 8.56 (1H, s); m/z (ES+)=398 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH2:9])[C:3]=1I.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([C:24]#[CH:25])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(NC(C)C)(C)C>C1COCC1.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.[Cu]I>[NH2:9][C:4]1[C:3]([C:25]#[C:24][CH:21]2[CH2:20][CH2:19][N:18]([C:16]([O:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:17])[CH2:23][CH2:22]2)=[C:2]([Cl:1])[N:7]=[C:6]([CH3:8])[N:5]=1
Reactant: Cc1nc(N)c(I)c(Cl)n1
Reactant: C#CC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Cc1nc(N)c(C#CC2CCN(C(=O)OC(C)(C)C)CC2)c(Cl)n1
Temperature: 52.5 °C
Yield: 86.8 %

Procedure:
Dissolve 6-chloro-5-iodo-2-methyl-pyrimidin-4-amine (20 g, 74.22 mmol), 4-ethynyl-piperidine-1-carboxylic acid tert-butyl ester (18.64 g, 89.06 mmol), and diisopropylamine (10.44 mL, 74.22 mmol) in THF (200 mL) in a 3-neck flask. Alternately evacuate and charge the flask with nitrogen 3 times. Add bis(triphenylphosphine)palladium(II) chloride (2.63 g, 3.71 mmol) and copper(I) iodide (0.713 g, 3.71 mmol) to the solution. Heat the mixture to between 50 to 55° C. for 16 h. Cool the mixture to RT and add more bis(triphenylphosphine)palladium(II) chloride (1.31 g, 1.86 mmol), copper(I) iodide (0.356 g, 1.86 mmol) and 4-ethynyl-piperidine-1-carboxylic acid tert-butyl ester (1.55 g, 7.42 mmol). Heat the mixture to 60° C. for 3.5 h. Cool the mixture to RT and concentrate under reduced pressure. Dilute the material with DCM (300 mL) and wash with saturated aqueous ammonium chloride solution (100 mL), water (100 mL), and saturated aqueous sodium chloride (100 mL). Dry the solution over MgSO4, filter, and concentrate under reduced pressure. Purify the residue using silica gel chromatography (800 g silica gel column) eluting with 20% to 100% EtOAc in hexanes. Concentrate the purified fractions to give the title compound as a pale orange powder (22.6 g, 86%). LC-ES/MS m/z (35Cl/37Cl) 351.2/353.1 (M+1).