Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)C(C)C)(C)C.Cl.[NH2:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[C:21]([I:23])[CH:20]=[CH:19][C:18]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:13]([OH:15])=[O:14].[CH2:32]([O:39][C:40](N1C(=O)CCC1=O)=[O:41])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C=O)C>[CH2:32]([O:39][C:40]([NH:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[C:21]([I:23])[CH:20]=[CH:19][C:18]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:13]([OH:15])=[O:14])=[O:41])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: N[C@@H](Cc1cc(I)ccc1OCc1ccccc1)C(=O)O
Reactant: O=C1CCC(=O)N1C(=O)OCc1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@@H](Cc1cc(I)ccc1OCc1ccccc1)C(=O)O)OCc1ccccc1
Reaction time: 8 h

Procedure:
9.25 ml (53.09 mol) of N,N-diisopropylethylamine are added to a solution of 10.46 g (24.13 mmol) of 2(S)-amino-3-(2-benzyloxy-5-iodophenyl)propionic acid hydrochloride (Example 9A) in DMF. 6.615 g (26.54 mmol) of N-(benzyloxycarbonyl)succinimide (Z-OSuc) are added thereto. The resulting solution is stirred overnight and then concentrated on a rotary evaporator in vacuo. The residue is taken up in dichloromethane and extracted twice each with a 0.1N hydrochloric acid solution and a saturated aqueous sodium chloride solution. The organic phase is dried, filtered and concentrated. The mixture is purified by column chromatography on silica gel (mobile phase: cyclohexane/diethyl ether 9:1 to 8:2).
Reaction SMILES: [C:1]([NH:5][C:6](=[O:29])[C:7]([NH:25][C:26](=[O:28])[CH3:27])([CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][N:19]=2)[CH2:14][CH2:13]1)[CH2:8][CH2:9][CH:10]=[CH2:11])([CH3:4])([CH3:3])[CH3:2].[CH3:30][C:31]1([CH3:38])[C:35]([CH3:37])([CH3:36])[O:34][BH:33][O:32]1.O>ClCCl.[Ir+].ClC1CCC=CCCC=1.C1(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([NH:5][C:6](=[O:29])[C:7]([NH:25][C:26](=[O:28])[CH3:27])([CH:12]1[CH2:13][CH2:14][N:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][N:19]=2)[CH2:16][CH2:17]1)[CH2:8][CH2:9][CH2:10][CH2:11][B:33]1[O:34][C:35]([CH3:37])([CH3:36])[C:31]([CH3:38])([CH3:30])[O:32]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC1(C)OBOC1(C)C
Reactant: C=CCCC(NC(C)=O)(C(=O)NC(C)(C)C)C1CCN(c2ccc(Cl)cn2)CC1
Agent: [Ir+]
Agent: ClC1=CCCC=CCC1
Agent: c1ccc(P(CCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: CC(=O)NC(CCCCB1OC(C)(C)C(C)(C)O1)(C(=O)NC(C)(C)C)C1CCN(c2ccc(Cl)cn2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.9 %

Procedure:
A solution of 2-acetylamino-2-(5′-chloro-3,4,5,6-tetrahydro-2H-[1,2]bipyridinyl-4-yl)-hex-5-enoic acid, tert-butylamide (1.0 g, 2.38 mmol) in dichloromethane (10 mL) was treated with chloro-1,5-cyclooctadiene iridium(I) dimer (48 mg, 3 mol %) and 1,2-bis(diphenylphosphino)ethane (57 mg, 6 mol %) under an atmosphere of nitrogen. The solution was stirred at room temperature for 30 minutes and then 4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (609 mg, 0.69 mL, 4.76 mmol) was added dropwise, and the reaction was then stirred overnight at room temperature. The reaction was poured into water and extracted with ethyl acetate (3×). The combined organic phase was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. Purification by flash column chromatography (silica gel, 10-40% ethyl acetate in heptane) gave the title compound as a white solid (1.07 g, 82%); 1H NMR (CDCl3, 300 MHz) δ 8.05 (d, J=2 Hz, 1H), 7.35 (dd, J1=9.0 Hz, J2=2.5 Hz, 1H), 6.96 (br s, NH, 1H), 6.53 (d, J=9.0 Hz, 1H), 5.78 (m, 1H), 5.46 (br s, NH, 1H), 4.36 (d, J=13 Hz, 1H), 4.12 (d, J=13 Hz, 1H), 2.83 (td, J1=13.5 Hz, J2=5 Hz, 1H), 2.72 (td, J1=12.5 Hz, J2=2 Hz, 2H), 2.42 (tt, J1=12 Hz, J2=3 Hz, 1H), 1.97 (s, 3H), 1.77 (m, 2H), 1.32-1.48 (m, 4H), 1.28 (s, 9H), 1.20 (s, 12H), 1.03-1.25 (m, 2H) and 0.72 (t, J=7.5 Hz, 2H); MS (+CI): m/z for C28H46BClN4O4: expected 548.3. found 549.3 (M+H)+, 571.3 (M+Na)+.
Reaction SMILES: [ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@@H:5]3[NH2:12])[CH2:3]1)[CH2:9]2.[NH:13]1[C:21]2[C:16](=[CH:17][C:18]([C:22](O)=[O:23])=[CH:19][CH:20]=2)[CH:15]=[CH:14]1.N>>[ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@@H:5]3[NH:12][C:22]([C:18]3[CH:17]=[C:16]4[C:21](=[CH:20][CH:19]=3)[NH:13][CH:14]=[CH:15]4)=[O:23])[CH2:3]1)[CH2:9]2
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Reactant: NC1C2CC3CC1CN(C3)C2
Agent: Cl
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1ccc2[nH]ccc2c1

Procedure:
Prepared from (4s)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine hydrochloride and indole-5-carboxylic acid (Aldrich) according to methods A and C; yield 27 mg, 0.08 mmol (37%): 1H NMR (300 MHz, methanol-d4) δ 1.97 (d, J=13 Hz, 2H), 2.21 (s, 1H), 2.37 (d, J=14 Hz, 2H), 2.49 (s, 2H), 3.58 (s, 2H), 3.69 (s, 4H), 4.42 (s, 1H), 6.57 (dd, J=3, 1 Hz, 1H), 7.34 (d, J=3 Hz, 1H), 7.45 (d, J=8 Hz, 1H), 7.64 (dd, J=9, 2 Hz, 1H), 8.10-8.17 (m, 2H); MS (DCI/NH3) m/z 296 (M+H)+; Anal. C18H21N3O.HCl.0.5H2O: C, H, N.
Reaction SMILES: C([N:6]1[CH2:11][CH:10]=[C:9]([C:12]2[C:17]3[S:18][CH:19]=[CH:20][C:16]=3[CH:15]=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)(OCC)=O.[OH-].[K+]>C(O)CO.O>[S:18]1[CH:19]=[CH:20][C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([C:9]3[CH2:10][CH2:11][NH:6][CH2:7][CH:8]=3)[C:17]1=2
Reactant: CCOC(=O)N1CC=C(c2cccc3ccsc23)CC1
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: C1=C(c2cccc3ccsc23)CCNC1
Temperature: 25 °C
Yield: 64.9 %

Procedure:
Dissolve N-carbethoxy-4-(benzo[b]thiophene-7-yl)-1,2,3,6-tetrahydropyridine (105 mg, 0.3652mmol) in 1 mL ethylene glycol and add potassium hydroxide (102 mg, 1.826 mmol) dissolved in 1 mL of water. The reaction mixture is heated at reflux for 8 hours and then cooled to room temperature. It is then diluted with 5 mL water and extracted with ethyl acetate (3×5 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. The reside is purified over silica gel to provide the title compound as a yellow oil (51 mg), MS(ion spray)=216.3 (M+1).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][C:10](=[O:14])[CH2:11][CH2:12][CH3:13].[OH-].[Na+]>>[CH:9]([C:10]([CH2:11][CH2:12][CH3:13])=[O:14])=[CH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC(C)=O
Reactant: O=Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: CCCC(=O)C=Cc1ccccc1
Temperature: 60 °C
Reaction time: 10 h
Yield: 79.7 %

Procedure:
To a mixture of benzaldehyde (30.00 g, 0.283 mole) and 2-pentanone (67.33 g, 0.782 mole) was added 10% aqueous sodium hydroxide (40.00 g, 0.10 mole) and the mixture was heated and stirred at 55-65° C. for 10 hr. The reaction mixture was cooled to room temperature and the aqueous layer was once separated. 5% Brine (20 g) was added and after stirring, the aqueous layer was separated. This step was repeated twice. The low boiling point content such as 2-pentanone, benzaldehyde and the like in the obtained organic layer were distilled away under reduced pressure to give the title compound as a pale-yellow green oil (138-150° C./1.33 kPa). (39.25 g, yield 79.7%)
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][O:9][C:10]2[N:15]=[N:14][C:13]([C:16]3[CH:57]=[CH:56][C:19]([CH2:20][C:21]4[N:22]([C:34]5[CH:35]=[C:36]([N:40]6[S:44](=[O:46])(=[O:45])[N:43](COCC[Si](C)(C)C)[C:42](=[O:55])[CH2:41]6)[CH:37]=[CH:38][CH:39]=5)[CH:23]=[C:24]([C:26]5[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=5[Cl:33])[N:25]=4)=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[CH:1]1([CH2:7][CH2:8][O:9][C:10]2[N:15]=[N:14][C:13]([C:16]3[CH:57]=[CH:56][C:19]([CH2:20][C:21]4[N:22]([C:34]5[CH:35]=[C:36]([N:40]6[S:44](=[O:45])(=[O:46])[NH:43][C:42](=[O:55])[CH2:41]6)[CH:37]=[CH:38][CH:39]=5)[CH:23]=[C:24]([C:26]5[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=5[Cl:33])[N:25]=4)=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C[Si](C)(C)CCOCN1C(=O)CN(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(OCCC5CCCCC5)nn4)cc3)c2)S1(=O)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: O=C1CN(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(OCCC5CCCCC5)nn4)cc3)c2)S(=O)(=O)N1

Procedure:
5-{3-[2-{-4-[6-(2-Cyclohexyl-ethoxy)-pyridazin-3-yl]-benzyl}-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,1-dioxo-2-(2-trimethylsilanyl-ethoxymethyl)-[1,2,5]thiadiazolidin-3-one (17 mg, 0.02 mmol) was treated as described in general procedure W using tetrabutylammonium fluoride (26 mg, 0.1 mmol) to give 5-{3-[2-{-4-[6-(2-cyclohexyl-ethoxy)-pyridazin-3-yl]-benzyl}-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[CH:20]([OH:27])[CH2:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20](=[O:27])[CH2:21][CH:22]2[CH2:23][CH2:24][CH2:25][CH2:26]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(c1ccccc1)n1c(C(O)CC2CCCC2)cc2cc(F)cnc21
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=C(CC1CCCC1)c1cc2cc(F)cnc2n1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.6 %

Procedure:
To a 250 mL round bottomed flask charged with 1-(1-benzenesulfonyl-5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-ethanol (12.5 g, 32.2 mmol) in dichloromethane (300 mL) was added Dess-Martin periodinane (17.8 g, 41.9 mmol) at 25° C. The reaction mixture was stirred at 25° C. for 1 h and then quenched with a saturated aqueous sodium bicarbonate solution (200 mL). The mixture was extracted with ethyl acetate (500 mL), washed with a saturated aqueous sodium bicarbonate solution (3×150 mL), brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give 1-(1-benzenesulfonyl-5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-ethanone (9.9 g, 80%) as a light yellow solid which was used in the next step without further purification: LC/MS m/e calcd for C20H19FN2O3S [M+H]+ 387.45, observed 387.1.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][O:5][CH:6]([C:9]1[CH:10]=[N:11][C:12]([CH3:15])=[N:13][CH:14]=1)[C:7]#[N:8].C(Br)(Br)(Br)[Br:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOCC>C(Cl)Cl>[Br:17][CH2:2][CH2:3][CH2:4][O:5][CH:6]([C:9]1[CH:10]=[N:11][C:12]([CH3:15])=[N:13][CH:14]=1)[C:7]#[N:8]
Reactant: BrC(Br)(Br)Br
Reactant: Cc1ncc(C(C#N)OCCCO)cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1ncc(C(C#N)OCCCBr)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2-(3-hydroxypropoxy)-2-(2-methylpyrimidin-5-yl)acetonitrile (54 mg, 0.26 mmol) and CBr4 (259 mg, 0.782 mmol) in DCM (3 ml) was cooled at 0° C. Triphenylphosphine (205 mg, 0.782 mmol) in DCM (1 ml) was added dropwise over a period of 5 minutes. The reaction was stirred for 2 hours and then allowed to warm to room temperature. To the mixture was added Et2O (5 mL) and the cloudy solution was filtred through a plug of celite. The resulting solution was concentrated in vacuo and purified by flash chromatography to yield 2-(3-Bromopropoxy)-2-(2-methylpyrimidin-5-yl)acetonitrile.
Reaction SMILES: [CH:1]1([CH2:6][C@@H:7]([C:19]([NH:21][NH:22][C:23]2[C:28]([F:29])=[C:27]([N:30]3[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]3)[N:26]=[C:25]([S:37][CH3:38])[N:24]=2)=[O:20])[CH2:8][N:9]([O:12]C2CCCCO2)[CH:10]=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)(=O)C.O>[CH:1]1([CH2:6][C@@H:7]([C:19]([NH:21][NH:22][C:23]2[C:28]([F:29])=[C:27]([N:30]3[CH2:31][CH2:32][N:33]([CH3:36])[CH2:34][CH2:35]3)[N:26]=[C:25]([S:37][CH3:38])[N:24]=2)=[O:20])[CH2:8][N:9]([OH:12])[CH:10]=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CSc1nc(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OC2CCCCO2)c(F)c(N2CCN(C)CC2)n1
Solvent: O
Solvent: CC(=O)O
Product: CSc1nc(NNC(=O)[C@H](CC2CCCC2)CN(O)C=O)c(F)c(N2CCN(C)CC2)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 65.1 %

Procedure:
((2R)-2-(Cyclopentylmethyl)-3-{2-[5-fluoro-6-(4-methyl-1-piperazinyl)-2-(methylthio)-4-pyrimidinyl]hydrazino}-3-oxopropyl)(tetrahydro-2H-pyran-2-yloxy)formamide (2.5 g, 22.58 mmol) was dissolved in acetic acid/water (4:1, 1 L) and stirred at RT for 3 days. The reaction mixture was concentrated to dryness and co-evaporated with toluene (20 mL) followed by methanol (50 mL)/triethylamine (20 mL). The residue was dissolved in methanol (120 mL) and triethylamine (20 mL) and purified by Gilson HPLC (10-95% acetonitrile/water, 8 min gradient time) to provide ((2R)-2-(cyclopentylmethyl)-3-{2-[5-fluoro-6-(4-methyl-1-piperazinyl)-2-(methylthio)-4-pyrimidinyl]hydrazino}-3-oxopropyl)hydroxyformamide as a reddish foamy solid (6.90 g, 65.1%). LCMS: (M+H)+: 470.2.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][CH:30]([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)=[CH:15][CH:14]=1>>[OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH:21]3[CH2:22][CH2:23][N:24]([C:27]([O:29][CH:30]([CH3:32])[CH3:31])=[O:28])[CH2:25][CH2:26]3)=[CH:17][CH:18]=2)=[CH:5][CH:4]=1
Reactant: CC(C)OC(=O)N1CCC(COc2ccc(Br)cc2)CC1
Reactant: OCc1ccc(B(O)O)cc1
Product: CC(C)OC(=O)N1CCC(COc2ccc(-c3ccc(CO)cc3)cc2)CC1
Yield: 4.2 %

Procedure:
The title compound (1.6 mg, 4%) was prepared from [4-(hydroxymethyl)phenyl]boronic acid (15.2 mg, 0.1 mmol) and 1-methylethyl 4-{[(4-bromophenyl)oxy]methyl}-1-piperidinecarboxylate (Example 9, Step 2, 36 mg, 0.10 mmol) in a manner similar to Example 9, Step 3. LRMS (ESI), m/z 406 (M+Na).
Reaction SMILES: Cl.[CH3:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]1[C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][C:10]=1[C:19]([F:22])([F:21])[F:20]>Cl>[CH3:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]1[C:9]1[CH:18]=[CH:17][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=1[C:19]([F:21])([F:20])[F:22]
Reactant: COC(=O)c1ccc(N2CCCCC2C)c(C(F)(F)F)c1
Agent: Cl
Product: CC1CCCCN1c1ccc(C(=O)O)cc1C(F)(F)F
Temperature: 25 °C
Yield: 84.7 %

Procedure:
A solution of methyl 4-(2-methylpiperidin-1-yl)-3-(trifluoromethyl)benzoate. Hydrochloride salt (25 g, 74 mmol) in HCl 4M (200 mL) was stirred at 100° C. for 16 hours. After cooling to room temperature, the precipitate was filtered off and dried under vacuum to afford the title compound (18 g, 85%) of as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])=[N:6][CH:7]=1.BrC1C=NC(C2C=CC=CC=2)=NC=1.C([N:36]1[CH:40]=[CH:39][N:38]=[C:37]1[C:41]1[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=1)C1C=CC=CC=1>>[C:10]1([C:8]([C:5]2[N:4]=[CH:3][C:2]([C:40]3[NH:36][C:37]([C:41]4[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=4)=[N:38][CH:39]=3)=[CH:7][N:6]=2)=[O:9])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(c1ccccc1)c1ncc(Br)cn1
Reactant: c1ccc(Cn2ccnc2-c2cccnc2)cc1
Agent: Brc1cnc(-c2ccccc2)nc1
Product: O=C(c1ccccc1)c1ncc(-c2cnc(-c3cccnc3)[nH]2)cn1

Procedure:
The title compound is prepared by the method described in Example 1, except that (5-bromopyrimidin-2-yl)(phenyl)methanone (prepared according to the procedure described in WO 2008/121670 p. 94) is used instead of 5-bromo-2-phenylpyrimidine and 3-(1-benzyl-1H-imidazol-2-yl)pyridine is used instead of 1-benzyl-2-phenyl-1H-imidazole in Step C.
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](O)=[O:26])=[CH:23][CH:22]=4)=[N:19][C:6]2=3)[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.CN(C(=[N+](C)C)ON1C2=NC=CC=C2N=N1)C.F[P-](F)(F)(F)(F)F.Cl.[CH:62]1[C:74]2[CH:73]([CH2:75][O:76][C:77](=[O:85])[NH:78][CH:79]3[CH2:84][CH2:83][NH:82][CH2:81][CH2:80]3)[C:72]3[C:67](=[CH:68][CH:69]=[CH:70][CH:71]=3)[C:66]=2[CH:65]=[CH:64][CH:63]=1>C(OCC)(=O)C.CN(C)C=O>[CH:62]1[C:74]2[CH:73]([CH2:75][O:76][C:77](=[O:85])[NH:78][CH:79]3[CH2:80][CH2:81][N:82]([C:25](=[O:26])[C:24]4[CH:28]=[CH:29][C:21]([NH:20][C:18]5[N:17]=[CH:16][C:7]6[N:8]([CH3:15])[C:9](=[O:14])[C:10]([F:12])([F:13])[CH2:11][N:5]([CH:1]7[CH2:4][CH2:3][CH2:2]7)[C:6]=6[N:19]=5)=[CH:22][CH:23]=4)[CH2:83][CH2:84]3)[C:72]3[C:67](=[CH:68][CH:69]=[CH:70][CH:71]=3)[C:66]=2[CH:65]=[CH:64][CH:63]=1
Reactant: O=C(NC1CCNCC1)OCC1c2ccccc2-c2ccccc21
Reactant: CN1C(=O)C(F)(F)CN(C2CCC2)c2nc(Nc3ccc(C(=O)O)cc3)ncc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CN1C(=O)C(F)(F)CN(C2CCC2)c2nc(Nc3ccc(C(=O)N4CCC(NC(=O)OCC5c6ccccc6-c6ccccc65)CC4)cc3)ncc21
Reaction time: 0.25 h
Yield: 50.1 %

Procedure:
A mixture of 0.250 g (0.62 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)-benzoic acid (I-11), 0.250 g (2.48 mmole) of triethylamine, 0.319 g (0.74 mmole) of N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-methanaminium, hexafluorophosphate(1-) (1:1) and 5 mL of dimethylformamide was stirred for 15 minutes and then 0.267 g (0.74 mmole) of 4-piperidinyl-carbamic acid 9H-fluoren-9-ylmethyl ester monohydrochloride 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 hexane-ethyl acetate (gradient 50:50-0:100) to give 0.220 g of {1-[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)-benzoyl]-piperidin-4-yl}-carbamic acid 9H-fluoren-9-ylmethyl ester.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH:17]=[C:18]([NH:23]C(OCC3C=CC=CC=3)=O)[C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:15]=2)[CH:10]=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].CO>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH2:17][CH:18]([NH2:23])[C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:15]=2)[CH:10]=[N:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: [H][H]
Reactant: COC(=O)C(=Cc1ccc2c(cnn2C(=O)OC(C)(C)C)c1)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)C(N)Cc1ccc2c(cnn2C(=O)OC(C)(C)C)c1
Yield: 94.7 %

Procedure:
A mixture of 5-(2-benzyloxycarbonylamino-2-methoxycarbonyl-vinyl)-indazole-1-carboxylic acid tert-butyl ester (524 mg, 1.16 mmol) and 10% palladium on carbon (60 mg) in methanol (20 mL) was shaken for 4.5 h under 50 psi hydrogen gas using a Parr hydrogenator. The reaction mixture was evacuated and purged with nitrogen. Then, the reaction mixture was filtered through a pad of celite and the pad was rinsed with several portions of methanol. The methanol filtrate was evaporated to give the title compound (351 mg, 95%). 1H-NMR (CDCl3, 500 MHz) δ 8.12–8.10 (m, 2H), 7.55 (br s, 1H), 7.37 (dd, J=8.9, 1.5 Hz, 1H), 3.77–3.75 (m, 1H), 3.70 (s, 3H), 3.19 (dd, J=13.7, 5.5 Hz, 1H), 2.99 (dd, J=13.7, 8.0 Hz, 1H), 1.72 (s, 9H). Mass spec.: 320 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH2:6][N:7](CC(C=C)=CC)[CH2:8][CH2:9][C:10]=1[NH:11][CH:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:13])=[O:4]>CO.[OH-].[OH-].[Pd+2]>[CH3:1][O:2][C:3]([C:5]1[CH2:6][NH:7][CH2:8][CH2:9][C:10]=1[NH:11][CH:12]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH3:13])=[O:4]
Reactant: C=CC(=CC)CN1CCC(NC(C)c2ccccc2)=C(C(=O)OC)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COC(=O)C1=C(NC(C)c2ccccc2)CCNC1
Reaction time: 19 h
Yield: 101.6 %

Procedure:
A mixture of 4-(1-phenyl-ethyl amino)-1-(2-vinyl-but-2-enyl)-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester (6.0 g, 17.02 mmol) and 20% palladium hydroxide on carbon (2 g) in methanol (20 mL) was stirred under a hydrogen balloon for 19 h. The mixture was then filtered through a thin pad of celite and concentrated to provide 4-(1-phenyl-ethylamino)-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester as a colorless oil (4.5 g, 90%). MS: 261 (M+H)+.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]1=[O:11].[N+:12]([O-])([O-:14])=[O:13].[K+]>S(=O)(=O)(O)O>[N+:12]([C:8]1[CH:9]=[C:10]2[C:5]([CH2:4][CH2:3][C:2](=[O:11])[CH2:1]2)=[CH:6][CH:7]=1)([O-:14])=[O:13]
Reactant: O=C1CCc2ccccc2C1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=C1CCc2ccc([N+](=O)[O-])cc2C1

Procedure:
At 0° C., 100 g of 2-tetralone are dissolved in 460 ml of pure sulphuric acid and 84.6 g of potassium nitrate in powder form are added in small portions. The mixture is then poured onto ice and extracted using dichloromethane. Following evaporation of the solvent, the residue is purified by chromatography on silica gel using as eluant a 90/10 cyclohexane/tetrahydrofuran mixture.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH:3]1[C:9]#[N:10].[BH4-].[Na+].[Cl-].[NH4+]>CO>[OH:8][C@@H:5]1[CH2:4][C@H:3]([C:9]#[N:10])[C:2]([CH3:11])([CH3:1])[CH2:7][CH2:6]1
Reactant: CC1(C)CCC(=O)CC1C#N
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: CC1(C)CC[C@H](O)C[C@@H]1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.2 %

Procedure:
Under a nitrogen atmosphere, a solution of 2,2-dimethyl-5-oxocyclohexanecarbonitrile (4.0 g, 0.0265 mol) in methanol (30 ml) was added dropwise to a solution of sodium borohydride (1.00 g, 0.0265 mol) in methanol (40 ml) at 0° C. After 1 hour, sodium borohydride (0.0133 mol) was further added thereto and the resulting mixture was warmed up to room temperature. After 45 minutes, a saturated aqueous ammonium chloride solution was added to the reaction solution and then the methanol was concentrated under reduced pressure. The resulting aqueous solution was diluted with water and extracted with chloroform, and the organic layer was dried over anhydrous magnesium sulfate. The organic layer dried was concentrated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain cis-5-hydroxy-2,2-dimethylcyclohexanecarbonitrile (3.0550 g, 75%).
Reaction SMILES: [OH-].[K+].C([O:5][C:6](=[O:26])[C:7](=[O:25])[C:8]1[S:9][C:10]([O:13][CH2:14][CH2:15][O:16][CH:17]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:11][CH:12]=1)C>CO>[CH:17]1([O:16][CH2:15][CH2:14][O:13][C:10]2[S:9][C:8]([C:7](=[O:25])[C:6]([OH:26])=[O:5])=[CH:12][CH:11]=2)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: CCOC(=O)C(=O)c1ccc(OCCOC2CCCCCCC2)s1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(=O)c1ccc(OCCOC2CCCCCCC2)s1
Reaction time: 0.25 h
Yield: 95.6 %

Procedure:
1N Potassium hydroxide solution (10 mL) was added dropwise with stirring to a chilled solution of 5-[[2-(cyclooctyloxy)ethyl]oxy]-alpha-oxo-2-thiopheneacetic acid ethyl ester (4.43 g) in methanol (50 mL). After the reaction was stirred at 0°-5° C. for 15 minutes, the product was isolated as described in Example 6 to furnish 3.9 g of 5-[[2-(cyclooctyloxy)ethyl]oxy]-alpha-oxo-2-thiopheneacetic acid as a yellow-orange oil. Crystallization of the product from wet benzene-hexane furnished 3.1 g of the hydrated acid as a pale yellow crystalline solid, mp 60°-62 ° C.