Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[C:4]([Cl:9])[CH:3]=1.C([Mg]Cl)(C)C.N1C=CC=CC=1S[C:22](=[O:33])[C:23]1[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[CH:26]=[CH:25][C:24]=1[CH3:32].[NH4+].[Cl-]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:22]([C:23]2[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[CH:26]=[CH:25][C:24]=2[CH3:32])=[O:33])=[C:4]([Cl:9])[CH:3]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)Sc1ccccn1
Reactant: Clc1cc(Br)ccc1I
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1ccc([N+](=O)[O-])cc1C(=O)c1ccc(Br)cc1Cl
Temperature: -60 °C
Reaction time: 0.5 h

Procedure:
The reaction was run under an argon atmosphere using dry glassware. 4-Bromo-2-chloroiodobenzene (25.5 g, 80.9 mmol) was dissolved in dry THF (400 mL) and cooled to −60° C. Isopropylmagnesium chloride (2 M in THF, 40.4 mL, 80.9 mmol) was added under stirring during 30 minutes. The reaction mixture was allowed to warm up to −40° C. and the mixture was stirred at −40° C. for 4 h. Compound 491 (22.2 g, 80.9 mmol) was added and the mixture was stirred at −40° C. for 3 h after which it was allowed to warm to room temperature and stirred for 17 h. A saturated aqueous solution of NH4Cl (200 mL) was added and the mixture was stirred for 1 h. The phases were separated and the aqueous phase was extracted with Et2O (4×100 mL). The combined organic phases were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography using CH2Cl2/petroleum ether (40-60) 2:3 as the eluent to afford the title compound as yellow crystalline compound.
Reaction SMILES: [Cl:1][C:2]1[C:24]([N:25]2[CH2:30][CH2:29][CH:28]([C:31]([F:34])([F:33])[F:32])[CH2:27][CH2:26]2)=[CH:23][C:5]2[N:6]([CH3:22])[C:7]([NH:9][C:10]3[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=3[C:18]([F:21])([F:20])[F:19])[C:13]#[N:14])=[N:8][C:4]=2[CH:3]=1>[Ni].C1COCC1>[F:20][C:18]([F:19])([F:21])[C:17]1[CH:16]=[CH:15][C:12]([CH2:13][NH2:14])=[CH:11][C:10]=1[NH:9][C:7]1[N:6]([CH3:22])[C:5]2[CH:23]=[C:24]([N:25]3[CH2:30][CH2:29][CH:28]([C:31]([F:33])([F:34])[F:32])[CH2:27][CH2:26]3)[C:2]([Cl:1])=[CH:3][C:4]=2[N:8]=1
Reactant: Cn1c(Nc2cc(C#N)ccc2C(F)(F)F)nc2cc(Cl)c(N3CCC(C(F)(F)F)CC3)cc21
Agent: [Ni]
Solvent: C1CCOC1
Product: Cn1c(Nc2cc(CN)ccc2C(F)(F)F)nc2cc(Cl)c(N3CCC(C(F)(F)F)CC3)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-(5-chloro-1-methyl-6-(4-trifluoromethyl-piperidin-1-yl)-1H-benzo[d]imidazol-2-ylamino)-4-trifluoromethyl-benzonitrile (1.20 g; 2.39 mmol), Ra—Ni (14 mg; 0.24 mmol) and THF (50 mL) was shaken under H2-atmosphere (5 atm) overnight at rt. The mixture was filtered through celite and the celite pad was washed with THF and EtOAc. Concentration and crystallization from Et2O/PE gave the sub-title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]2[CH2:6][CH2:7][N:8]([C:11]([CH:13]3[CH2:18][O:17][CH2:16][CH2:15][O:14]3)=[O:12])[CH2:9][CH2:10][C:4]=2[CH:3]=1.O1CCOCC1C=O.Cl[C:30]1[N:35]=[C:34]([NH:36][C:37]2[C:48]([F:49])=[CH:47][CH:46]=[CH:45][C:38]=2[C:39]([NH:41][CH2:42][C:43]#[CH:44])=[O:40])[C:33]([Cl:50])=[CH:32][N:31]=1>>[Cl:50][C:33]1[C:34]([NH:36][C:37]2[C:48]([F:49])=[CH:47][CH:46]=[CH:45][C:38]=2[C:39]([NH:41][CH2:42][C:43]#[CH:44])=[O:40])=[N:35][C:30]([NH:1][C:2]2[CH:20]=[CH:19][C:5]3[CH2:6][CH2:7][N:8]([C:11]([CH:13]4[CH2:18][O:17][CH2:16][CH2:15][O:14]4)=[O:12])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:31][CH:32]=1
Reactant: C#CCNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: Nc1ccc2c(c1)CCN(C(=O)C1COCCO1)CC2
Agent: O=CC1COCCO1
Product: C#CCNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)CCN(C(=O)C2COCCO2)CC3)ncc1Cl

Procedure:
(7-Amino-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-1,4-dioxinan-2-yl-methanone, prepared in a similar manner as 7-Amino-8-methoxy-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-1,4-dioxinan-2-yl-methanone of Example 633b, was reacted with 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-N-prop-2-ynyl-benzamide, in a similar manner as Example 601b, to yield desired product 2-{5-Chloro-2-[3-([1,4]dioxane-2-carbonyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-3-fluoro-N-prop-2-ynyl-benzamide as a lyophylate (18%); 1H NMR (400 MHz, DMSO-d6) δ 9.30 (s, 1H), 9.19 (d, J=8.44 Hz, 1H), 8.97 (m, 1H), 8.17 (s, 1H), 7.52-7.45 (m, 3H), 7.25 (s, 1H), 7.15 (m, 1H), 6.87 (m, 1H), 4.38 (m, 1H), 4.01 (m, 2H), 3.84-3.3 (bm, H2O+11H), 3.11 (s, 1H), 2.81 (m, 1H), 2.67 (m, 2H); MS (m/e) 579.16 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:10][C:11]2[CH:17]=[C:16]([CH2:18][C:19]([O:21]C)=[O:20])[CH:15]=[CH:14][C:12]=2[N:13]=1.[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:10][C:11]2[CH:17]=[C:16]([CH2:18][C:19]([OH:21])=[O:20])[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: COC(=O)Cc1ccc2nc(Nc3ccccc3Cl)oc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)Cc1ccc2nc(Nc3ccccc3Cl)oc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
In THF (200 ml) was dissolved methyl 2-(2-chlorophenylamino)-6-benzoxazolylacetate (3.35 g, 10.6 mmol). After addition of 0.25N NaOH (200 ml), the mixture was stirred at room temperature for 16 hours. The reaction mixture was distilled under reduced pressure to remove the solvent. The residue was acidified with 1N HCl, followed by extraction with a chloroform/methanol (10/1) mixture. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent, whereby the title compound (2.94 g, 92%) was obtained as a pale brown solid.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[Cl:29][C:30]1[CH:35]=[N:34][C:33](Cl)=[CH:32][N:31]=1.CN(C)C=O.C(N(CC)C(C)C)(C)C>>[Cl:29][C:30]1[N:31]=[CH:32][C:33]([N:20]2[CH2:21][CH2:22][C:16]3[C:15]([N:23]4[CH2:24][CH2:25][O:26][CH2:27][CH2:28]4)=[N:14][C:13]([C:10]4[CH:9]=[CH:8][C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:12][CH:11]=4)=[N:18][C:17]=3[CH2:19]2)=[N:34][CH:35]=1
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCNC3)cc1
Reactant: Clc1cnc(Cl)cn1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCN(c2cnc(Cl)cn2)C3)cc1

Procedure:
1-Ethyl-3-(4-(4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (0.0507 g, 0.132 mmol) and 2,5-dichloropyrazine (0.0320 g, 0.215 mmol) were combined then added dry N,N-Dimethylformamide (0.910 mL, 11.8 mmol) followed by N,N-Diisopropylethylamine (0.0456 mL, 0.262 mmol). The reaction was microwaved on 200 watts, 120° C. for 30 minutes on a CEM microwave. The reaction mixture was purified by HPLC. 1H NMR (500 MHz, DMSO) δ 8.67 (s, 1H), 8.30 (d, J=2.5, 1H), 8.21 (d, J=8.7, 2H), 8.02 (d, J=2.5, 1H), 7.49 (d, J=8.8, 2H), 6.17 (t, J=5.6, 1H), 4.57 (s, 2H), 3.79-3.65 (m, 6H), 3.50 (d, J=4.3, 4H), 3.12 (dt, J=14.1, 7.1, 2H), 2.86 (s, 2H), 1.06 (t, J=7.2, 3H). LC/MS-m/z+495.2 (M+H)+
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:11]([O:18][C:19]1[CH:24]=[C:23]([O:25][CH2:26][CH2:27][CH2:28][C:29]#[N:30])[C:22]([CH2:31][CH3:32])=[CH:21][C:20]=1[C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CCOCC>[CH2:11]([O:18][C:19]1[CH:24]=[C:23]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][NH2:30])[C:22]([CH2:31][CH3:32])=[CH:21][C:20]=1[C:33]1[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCc1cc(-c2ccc(F)cc2)c(OCc2ccccc2)cc1OCCCC#N
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOCC
Product: CCc1cc(-c2ccc(F)cc2)c(OCc2ccccc2)cc1OCCCCN
Yield: 47.1 %

Procedure:
Dry ether (10 mL) was added to anhydrous aluminum chloride (693 mg) at 0° C. under nitrogen and stirred until dissolution was complete. Lithium aluminum hydride (197 mg) was added in one portion and the solution heated to reflux. 1-Benzyloxy-2-(4-fluorophenyl)-4-ethyl-5-[(3-cyanopropyl)oxy]-benzene (1.05 g) dissolved in dry ether (5 mL) was added dropwise at reflux. The heat was removed and the mixture stirred at ambient temperature for 4.5 hours. The reaction was quenched by addition of water, followed by 6N sulfuric acid until a clear solution was obtained. This was extracted with ether. The aqueous solution was cooled and treated with 50% sodium hydroxide. The basic mixture was extracted with ether. The organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford 500 mg of 1-Benzyloxy-2-(4-fluorophenyl)-4-ethyl-5-[(4-aminobutyl)oxy]-benzene as an oil, which was not further purified but carried forward. Mass Spec (EI), m/e=394.3 (M+H).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]([OH:12])=[O:11])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[CH2:13](O)[CH:14]=[CH2:15].Cl.C(N=C=NCCCNC)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:7]([O:6][P:4]([CH2:9][C:10]([O:12][CH2:15][CH:14]=[CH2:13])=[O:11])([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: CCOP(=O)(CC(=O)O)OCC
Reactant: C=CCO
Agent: CCN=C=NCCCNC
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: C=CCOC(=O)CP(=O)(OCC)OCC
Yield: 82.2 %

Procedure:
29.2 g of the diethylphosphonoacetic acid thus obtained was dissolved in 350 ml of methylene chloride, and 17.8 g of allyl alcohol, 1.92 g of 4-dimethylaminopyridine and 29.0 g of 1-ethyl-3-(3-methylaminopropyl)carbodiimide hydrochloride were added thereto with stirring under cooling with ice. The mixture was stirred at room temperature overnight. The reaction solution was evaporated under reduced pressure. The residue was dissolved in ethyl acetate, then sequentially washed with 1N hydrochloric acid, water, a saturated sodium hydrogencarbonate aqueous solution and a saturated sodium chloride aqueous solution, and dried over anhydrous magnesium sulfate. The drying agent was separated by filtration, and then the solvent was distilled off under reduced pressure to obtain 28.9 g of allyl diethylphosphonoacetate.
Reaction SMILES: Cl[C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=2[F:16])=[O:7])=[CH:4][N:3]=1.C(N(C(C)C)CC)(C)C.[NH:28]1[CH2:38][CH2:37][CH:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:30][CH2:29]1>O1CCOCC1.CN(C1C=CN=CC=1)C>[CH2:35]([O:34][C:32]([CH:31]1[CH2:37][CH2:38][N:28]([C:2]2[CH:18]=[CH:17][C:5]([C:6](=[O:7])[NH:8][C:9]3[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=3[F:16])=[CH:4][N:3]=2)[CH2:29][CH2:30]1)=[O:33])[CH3:36]
Reactant: CCOC(=O)C1CCNCC1
Reactant: O=C(Nc1ccc(I)cc1F)c1ccc(Cl)nc1
Agent: CN(C)c1ccncc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CCN(c2ccc(C(=O)Nc3ccc(I)cc3F)cn2)CC1
Temperature: 95 °C
Yield: 55 %

Procedure:
6-Chloro-N-(2-fluoro-4-iodo-phenyl)-nicotinamide (80 mg, 0.22 mmol) was dissolved in dioxane (6 mL) and the mixture was treated with diisopropyl ethyl amine (0.11 mL, 0.66 mmol), ethyl isonipecotate (100 mg, 0.66 mmol) and a catalytic amount of DMAP. This solution was then heated in a sealed tube at 95° C. for 21 h. The mixture was then cooled and the solvent was evaporated. The residue was chromatographed with a silica gel column and 20-40% EtOAc in hexanes gradient to afford the product. (60 mg, Yield: 55%)
Reaction SMILES: [C:1]1([C:7]([CH2:14][CH2:15][CH3:16])([CH2:11][CH2:12][CH3:13])[C:8](O)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C)C=O.C(Cl)(=O)C([Cl:25])=O>>[C:1]1([C:7]([CH2:14][CH2:15][CH3:16])([CH2:11][CH2:12][CH3:13])[C:8]([Cl:25])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCC(CCC)(C(=O)O)c1ccccc1
Solvent: CN(C)C=O
Product: CCCC(CCC)(C(=O)Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of the product of Example 1C (4.13 g, 18.77 mmol) and N,N-dimethylformamide (1.45 mL, 18.77 mmol) in hexanes (700 mL) was treated with oxalyl chloride (4.91 mL, 56.31 mmol) and stirred at 25° C. for 2 hours. The mixture was treated with celite®, and then filtered through a pad of celite®. The filtrate was concentrated in vacuo to afford the title compound which was used directly in the next procedure.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:17]=[C:16]([F:18])[C:15]([N:19]2[C:24](=[O:25])[CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[N:21]([CH3:30])[C:20]2=[O:31])=[CH:14][C:5]=1[O:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][C:12]=1[OH:13].Br[CH2:33][C:34]([O:36][CH3:37])=[O:35].[Cl-].[NH4+]>CN(C)C=O>[Cl:3][C:4]1[CH:17]=[C:16]([F:18])[C:15]([N:19]2[C:24](=[O:25])[CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[N:21]([CH3:30])[C:20]2=[O:31])=[CH:14][C:5]=1[O:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][C:12]=1[O:13][CH2:33][C:34]([O:36][CH3:37])=[O:35]
Reactant: COC(=O)CBr
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3cnccc3O)c(Cl)cc2F)c1=O
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccncc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 7.5 %

Procedure:
To a mixture of 30 mg of sodium hydride and N,N-dimethylformamide, 0.31 g of 3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-4-hydroxypyridine was added and stirred at room temperature for 1 hour. Then 0.114 g of methyl bromoacetate was added to the mixture, and stirred for 8 hours at room temperature. The mixture was poured into saturated ammonium chloride solution, and extracted with ethyl acetate. The organic layer was washed with saturated ammonium chloride solution and saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 27 mg of 3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-4-(methoxycarbonyl)methoxypyridine [present compound 7-42].
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH2:27]O)[S:6][C:7]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:15]([F:26])[CH:14]=2)[O:10][N:9]=1)[CH3:2].C(Br)(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl.[NH:54]1[CH2:57][CH:56]([C:58]([O:60][CH3:61])=[O:59])[CH2:55]1.C(N(CC)C(C)C)(C)C>>[CH2:1]([C:3]1[CH:4]=[C:5]([CH2:27][N:54]2[CH2:57][CH:56]([C:58]([O:60][CH3:61])=[O:59])[CH2:55]2)[S:6][C:7]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[C:15]([F:26])[CH:14]=2)[O:10][N:9]=1)[CH3:2]
Reactant: COC(=O)C1CNC1
Reactant: CCc1cc(CO)sc1-c1noc(-c2ccc(Oc3ccccc3)c(F)c2)n1
Agent: BrC(Br)(Br)Br
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(CN2CC(C(=O)OC)C2)sc1-c1noc(-c2ccc(Oc3ccccc3)c(F)c2)n1

Procedure:
The crude product of the title compound was synthesized by conducting the reaction similar to that mentioned in Example 1 (1f) using {4-ethyl-5-[5-(3-fluoro-4-phenoxyphenyl)-1,2,4-oxadiazol-3-yl]-2-thienyl}methanol (0.16 g, 0.40 mmol) that was obtained in Example 14 (14a), carbon tetrabromide (0.17 g, 0.52 mmol), triphenylphosphine (0.14 g, 0.52 mmol), methyl 3-azetidinecarboxylate hydrochloride (91 mg, 0.60 mmol), and N,N-diisopropylethylamine (0.21 mL, 1.2 mmol). Subsequently, the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:3 to 1:2) as the eluent to afford the title compound (0.15 g) in a yield of 77% as a pale yellow oily product.
Reaction SMILES: C(OC([CH2:11][NH:12][CH:13]([CH:38]([CH3:40])[CH3:39])[C:14]([NH:16][CH:17]([C:30]1[NH:35][C:34](=[O:36])[CH:33]=[C:32]([CH3:37])[N:31]=1)[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:20]=1)=[O:15])=O)C1C=CC=CC=1.[H][H]>[OH-].[OH-].[Pd+2].CO>[C:26]([C:21]1[CH:20]=[C:19]([CH2:18][CH:17]([C:30]2[NH:35][C:34](=[O:36])[CH:33]=[C:32]([CH3:37])[N:31]=2)[NH:16][C:14](=[O:15])[CH:13]([NH:12][CH3:11])[CH:38]([CH3:40])[CH3:39])[CH:24]=[CH:23][C:22]=1[OH:25])([CH3:27])([CH3:28])[CH3:29]
Reactant: [H][H]
Reactant: Cc1cc(=O)[nH]c(C(Cc2ccc(O)c(C(C)(C)C)c2)NC(=O)C(NCC(=O)OCc2ccccc2)C(C)C)n1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CNC(C(=O)NC(Cc1ccc(O)c(C(C)(C)C)c1)c1nc(C)cc(=O)[nH]1)C(C)C

Procedure:
A mixture of 2-(1-(2-(benzyloxycarbonylmethylamino)-3-methyl-butyrylamino)-2-(3-tert-butyl-4-hydroxyphenyl)ethyl)-6-methyl-4-pyrimidinone (0.71 g, 1.294 mmol), 20% palladium hydroxide/carbon (0.15 g) and methanol (20 ml) was stirred in a hydrogen atmosphere for 4 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: methylene chloride:methanol=15:1), giving two diastereoisomers A and B of the titled compound, A (296 mg, 38%) being eluted first and then B (77 mg, 9.4%). (A)
Reaction SMILES: Cl.Cl.[CH3:3][Si:4]([CH3:31])([CH3:30])[CH2:5][CH2:6][O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:18]3[CH:19]=[N:20][N:21]([C:23]4([CH2:27][C:28]#[N:29])[CH2:26][NH:25][CH2:24]4)[CH:22]=3)[C:12]=2[CH:11]=[CH:10]1.O=[C:33]1[CH2:39][CH:38]2[N:40]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH:35]([CH2:36][CH2:37]2)[CH2:34]1.C(N(CC)C(C)C)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[C:28]([CH2:27][C:23]1([N:21]2[CH:22]=[C:18]([C:17]3[C:12]4[CH:11]=[CH:10][N:9]([CH2:8][O:7][CH2:6][CH2:5][Si:4]([CH3:30])([CH3:3])[CH3:31])[C:13]=4[N:14]=[CH:15][N:16]=3)[CH:19]=[N:20]2)[CH2:24][N:25]([CH:33]2[CH2:34][CH:35]3[N:40]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH:38]([CH2:37][CH2:36]3)[CH2:39]2)[CH2:26]1)#[N:29]
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(=O)C2
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CNC4)c3)ncnc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C2CCC1CC(N1CC(CC#N)(n3cc(-c4ncnc5c4ccn5COCC[Si](C)(C)C)cn3)C1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of {3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile dihydrochloride (2.6 g, 6.3 mmol) in THF (30 mL) were added tert-butyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (1.3 g, 6.3 mmol), N,N-diisopropylethylamine (4.4 mL, 25 mmol) and sodium triacetoxyborohydride (2.2 g, 10 mmol). The mixture was stirred at room temperature overnight and quenched by addition of 20 mL of brine. The solution was extracted with EtOAc. The extract was dried over anhydrous Na2SO4. After removing solvent, the residue was purified by combiflash column eluting with 30-80% EtOAc in hexanes to give the desired product tert-butyl 3-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-8-azabicyclo[3.2.1]octane-8-carboxylate. LC-MS: 619.3 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][CH2:5]2.[N:11]([O-])=[O:12].[Na+]>Cl.O>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([N:11]=[O:12])[CH2:6][CH2:5]2
Reactant: Cc1ccc2c(c1)CCN2
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Cc1ccc2c(c1)CCN2N=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 98.7 %

Procedure:
5-Methylindoline (1.0 g, 7.5 mmol) was stirred in 3N HCl (20 mL) at 0° C. Sodium nitrite (0.621 g, 9.0 mmol) in water (2 mL) was added dropwise and the mixture was stirred at 0° C. for 5 min. followed by RT for 20 min. The reaction mixture was extracted with DCM (500 mL), and the organic layer was dried over sodium sulfate and concentrated under vacuum to obtain 1.2 g of 5-methyl-1-nitrosoindoline.
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:9]=[C:10]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH:11]=[CH:12][CH:13]=2)[CH:7]2[CH:3]1[CH2:4][NH:5][CH2:6]2.C(=O)([O-])O.[Na+].Br[CH2:25][CH2:26][C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH:29][CH:28]=1>CN(C)C=O>[NH:29]1[C:30]2[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:27]([CH2:26][CH2:25][N:5]2[CH2:6][CH:7]3[CH:3]([C:2]3([C:8]3[CH:9]=[C:10]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH:11]=[CH:12][CH:13]=3)[CH3:1])[CH2:4]2)=[CH:28]1
Reactant: CC1(c2cccc(NS(C)(=O)=O)c2)C2CNCC21
Reactant: BrCCc1c[nH]c2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(c2cccc(NS(C)(=O)=O)c2)C2CN(CCc3c[nH]c4ccccc34)CC21
Temperature: 55 °C

Procedure:
To a solution of the hydrochloride salt of N-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide (Preparation 53, 50 mg, 0.165 mmol) in N,N-dimethylformamide (2 ml) was added sodium hydrogen carbonate (35 mg, 0.413 mmol) and 3-(2-bromoethyl)indole (37 mg, 0.165 mmol). The reaction mixture was heated at 55° C. for 48 h, cooled to room temperature and concentrated in vacuo. Water (10 ml) was added and the product was extracted with ethyl acetate (3×10 ml). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo to give a brown oil. The crude product was purified by chromatography using a Biotage Flash 12™ cartridge packed with silica gel (8 g), eluting with hexane:ethyl acetate (100:0 and then 0:100). The title compound was obtained as a glass (22 mg, 33%).
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]([F:15])([F:14])[S:10]([OH:13])(=[O:12])=[O:11].COC1C=CC(C[S:23][C@@H:24]2[CH2:28][N:27]([C:29]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=3)=[O:30])[C@H:26]([C:42]([N:44]3[CH2:49][CH2:48][N:47]([CH:50]=[N:51][C:52]([O:54][CH2:55][C:56]4[CH:61]=[CH:60][C:59]([N+:62]([O-:64])=[O:63])=[CH:58][CH:57]=4)=[O:53])[CH2:46][CH2:45]3)=[O:43])[CH2:25]2)=CC=1>C1(OC)C=CC=CC=1>[F:8][C:9]([F:15])([F:14])[S:10]([OH:13])(=[O:12])=[O:11].[SH:23][C@@H:24]1[CH2:28][N:27]([C:29]([O:31][CH2:32][C:33]2[CH:34]=[CH:35][C:36]([N+:39]([O-:41])=[O:40])=[CH:37][CH:38]=2)=[O:30])[C@H:26]([C:42]([N:44]2[CH2:45][CH2:46][N:47]([CH:50]=[N:51][C:52]([O:54][CH2:55][C:56]3[CH:57]=[CH:58][C:59]([N+:62]([O-:64])=[O:63])=[CH:60][CH:61]=3)=[O:53])[CH2:48][CH2:49]2)=[O:43])[CH2:25]1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCN(C=NC(=O)OCc4ccc([N+](=O)[O-])cc4)CC3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: O=C(N=CN1CCN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h

Procedure:
15 ml of trifluoroacetic acid and 460 μl of trifluoromethanesulfonic acid were added to a solution of 2.50 g of (2S,4S)-4-(4-methoxybenzylthio)-2-[4-(N-4-nitrobenzyloxycarbonylformimidoyl)piperazin-1-ylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidine [prepared as described in step (i) above] in 3 ml of anisole, and the resulting mixture was stirred for 1 hour, whilst ice-cooling. The solvent was removed by distillation under reduced pressure, and the resulting residue was washed with diethyl ether, to give 2.55 g of (2S,4S)-4-mercapto-2-[4-(N-4-nitrobenzyloxycarbonylformimidoyl)piperazin-1-ylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidine trifluoromethanesulfonate as a powder. The whole of this product was dissolved in a mixture of ethyl acetate and water, and the solution was made alkaline by adding an aqueous solution of sodium hydrogencarbonate. The ethyl acetate layer was separated and washed with water and with an aqueous solution of sodium chloride, in that order. The solution was dried over anhydrous sodium sulfate, and then the solvent was removed by distillation under reduced pressure, to give 2.0 g of the title compound, as a powder.