Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([NH2:7])(=[O:6])=[O:5].[CH2:8]([C:10]1[N:14]([C:15]2[CH:16]=[C:17]([CH:21]3[C:30]([CH3:32])([CH3:31])[CH2:29][C:28]4[C:23](=[CH:24][CH:25]=[C:26]([C:33](O)=[O:34])[CH:27]=4)[NH:22]3)[CH:18]=[CH:19][CH:20]=2)[N:13]=[N:12][N:11]=1)[CH3:9].C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O>[CH2:8]([C:10]1[N:14]([C:15]2[CH:16]=[C:17]([CH:21]3[C:30]([CH3:31])([CH3:32])[CH2:29][C:28]4[C:23](=[CH:24][CH:25]=[C:26]([C:33]([NH:7][S:4]([CH3:3])(=[O:6])=[O:5])=[O:34])[CH:27]=4)[NH:22]3)[CH:18]=[CH:19][CH:20]=2)[N:13]=[N:12][N:11]=1)[CH3:9]
Reactant: CCc1nnnn1-c1cccc(C2Nc3ccc(C(=O)O)cc3CC2(C)C)c1
Reactant: CS(N)(=O)=O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1nnnn1-c1cccc(C2Nc3ccc(C(=O)NS(C)(=O)=O)cc3CC2(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.6 %

Procedure:
To a suspension of 60% sodium hydride (160 mg, 3.9 mmol) in N,N-dimethylformamide (1.5 mL) was added methanesulfonamide (380 mg, 4.0 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h. A solution of 2-[3-(5-ethyl-tetrazol-1-yl)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (150 mg, 0.4 mmol) and 1,1′-carbonyldiimidazole (136 mg, 0.84 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 70° C. After stirring at 70° C. for 1 h, the above suspension of methanesulfonamide and sodium hydride in N,N-dimethylformamide was added and the mixture was allowed to stir at 25° C. for 1 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded N-{2-[3-(5-ethyl-tetrazol-1-yl)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl}-methanesulfonamide (72 mg, 40%) as a white solid: LC/MS m/e calcd for C22H26N6O3S (M+H)+: 455.55, observed: 455.2.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][C@:10]([CH:15]3[CH2:17][CH2:16]3)([C:13]#[N:14])[C:9]2=[O:18])[CH:5]=[CH:4][N:3]=1.[NH2:19][C:20]1[CH:21]=[N:22][N:23]([C:25]2([CH2:29][OH:30])[CH2:28][CH2:27][CH2:26]2)[CH:24]=1.C(O)(=O)C>CC(O)C>[CH:15]1([C@:10]2([C:13]#[N:14])[CH2:11][CH2:12][N:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:19][C:20]4[CH:21]=[N:22][N:23]([C:25]5([CH2:29][OH:30])[CH2:28][CH2:27][CH2:26]5)[CH:24]=4)[N:7]=3)[C:9]2=[O:18])[CH2:17][CH2:16]1
Reactant: N#C[C@@]1(C2CC2)CCN(c2ccnc(Cl)n2)C1=O
Reactant: Nc1cnn(C2(CO)CCC2)c1
Solvent: CC(C)O
Solvent: CC(=O)O
Product: N#C[C@@]1(C2CC2)CCN(c2ccnc(Nc3cnn(C4(CO)CCC4)c3)n2)C1=O
Yield: 62.6 %

Procedure:
A solution of (3S)-1-(2-chloropyrimidin-4-yl)-3-cyclopropyl-2-oxopyrrolidine-3-carbonitrile (150 mg) obtained in Step E of Example 103, (1-(4-amino-1H-pyrazol-1-yl)cyclobutyl)methanol (95 mg) obtained in Step C of Example 127 and acetic acid (34 mg) in propan-2-ol (4.0 mL) was stirred in a microwave reactor at 160° C. for 1 hr. The reaction mixture was concentrated under reduced pressure, the residue was poured into saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate), and recrystallized (diisopropyl ether/ethyl acetate) to give the title compound (140 mg).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([O:11][CH3:12])=[O:10])[CH2:5][CH2:4]1.C(N(CC)CC)C.Cl[C:21]([O:23][CH2:24][CH2:25][Cl:26])=[O:22].Cl>C(Cl)(Cl)Cl>[Cl:26][CH2:25][CH2:24][O:23][C:21]([NH:2][C@H:3]1[CH2:4][CH2:5][C@H:6]([C:9]([O:11][CH3:12])=[O:10])[CH2:7][CH2:8]1)=[O:22]
Reactant: COC(=O)[C@H]1CC[C@H](N)CC1
Reactant: O=C(Cl)OCCCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H]1CC[C@H](NC(=O)OCCCl)CC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Methyl trans-4-aminocyclohexanecarboxylate hydrochloride (5.00 g) obtained in Reference Example 2(1) is dissolved in chloroform (60 ml), and thereto is added triethylamine (11 ml) under ice-cooling, followed by dropwise addition of a solution of 2-chloroethyl chloroformate (3.3 ml) in chloroform (10 ml). After stirring at room temperature for 2.5 hours, to the reaction solution is added 5% hydrochloric acid and the mixture is extracted with chloroform. The organic layer is washed with saturated brine, dried over sodium sulfate, and then evaporated to remove the solvent under reduced pressure. The resulting residue is suspended in chloroform/diisopropyl ether. The precipitates are collected by filtration and dried to give methyl trans-4-{[(2-chloroethoxy)carbonyl]amino}cyclohexanecarboxylate (5.11 g). APCI-MS M/Z:264/266[M+H]+
Reaction SMILES: Br[C:2]1[CH2:6][CH2:5][CH2:4][C:3]=1[N:7]1[C:15]2[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[C:9]2[CH2:17][N:18]([CH3:21])[CH2:19][CH2:20][C:8]1=2.[NH:22]1[CH:26]=[C:25](B(O)O)[CH:24]=[N:23]1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[NH:22]1[CH:26]=[C:25]([C:2]2[CH2:6][CH2:5][CH2:4][C:3]=2[N:7]2[C:15]3[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=3[C:9]3[CH2:17][N:18]([CH3:21])[CH2:19][CH2:20][C:8]2=3)[CH:24]=[N:23]1
Reactant: OB(O)c1cn[nH]c1
Reactant: Cc1ccc2c(c1)c1c(n2C2=C(Br)CCC2)CCN(C)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2C2=C(c3cn[nH]c3)CCC2)CCN(C)C1
Temperature: 90 °C

Procedure:
A solution of 5-(2-bromocyclopent-1-enyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.29 mmol), 1H-pyrazole-4-boronic acid (75 mg, 0.580 mmol) and potassium carbonate (120 mg, 0.87 mmol) in 1,2-DME (4 mL)-water (2 mL) was purged with nitrogen. Pd(PPh3)4 (16 mg, 0.0147 mmol) was added and the reaction mixture was heated at 90° C. for 45 min. The reaction mixture concentrated under vacuum, residue diluted with water (20 mL) and extracted with EtOAc (50 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under vacuum to obtain crude which was purified by reverse phase HPLC to yield 5-(2-(1H-pyrazol-4-yl)cyclopent-1-enyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (CD3OD, TFA salt) δ (ppm): 7.38 (s, 1H), 7.0 (m, 2H), 6.4 (m, 2H), 4.7 (m, 1H), 4.4 (m, 1H), 3.78 (m, 1H), 3.42 (m, 1H), 3.11 (m, 4H), 2.6-3.0 (m, 5H), 2.4 (s, 3H), 2.2 (m, 2H).
Reaction SMILES: [CH3:1][N:2]([CH3:38])[CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[S:18][C:17]3[C:16]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[N:15][C:14]([Sn](CCCC)(CCCC)CCCC)=[N:13][C:12]=3[CH:11]=2)[CH2:5][CH2:4]1.Br[C:40]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[C:43](=[O:50])[NH:42][CH:41]=1>>[CH3:38][N:2]([CH3:1])[CH:3]1[CH2:4][CH2:5][N:6]([CH2:9][C:10]2[S:18][C:17]3[C:16]([N:19]4[CH2:20][CH2:21][O:22][CH2:23][CH2:24]4)=[N:15][C:14]([C:40]4[C:49]5[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=5)[C:43](=[O:50])[NH:42][CH:41]=4)=[N:13][C:12]=3[CH:11]=2)[CH2:7][CH2:8]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2sc(CN3CCC(N(C)C)CC3)cc2n1
Reactant: O=c1[nH]cc(Br)c2ccccc12
Product: CN(C)C1CCN(Cc2cc3nc(-c4c[nH]c(=O)c5ccccc45)nc(N4CCOCC4)c3s2)CC1

Procedure:
Following General Procedure G for Stille coupling, N,N-dimethyl-1-((4-morpholino-2-(tributylstannyl)thieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-amine and 4-bromoisoquinolin-1(2H)-one were reacted to give 217. LCMS m/z: 505.7 (MH+)
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].ClC1C=CC=C(C(OO)=[O:23])C=1>C(Cl)Cl>[CH2:3]([CH:2]1[CH2:1][O:23]1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCCCCCCCCCCCC
Solvent: ClCCl
Product: CCCCCCCCCCCCC1CO1

Procedure:
In a flask equipped with a mechanical stirrer and an addition funnel was placed 19.8 g (0.1 mole) of 1-tetradecene and 150 ml of CH2Cl2. The solution was stirred and a suspension of 23 g(0.106 mole) of m-chloroperbenzoic acid in 250 ml of CH2Cl2 was added dropwise. After stirring overnight, the CH2Cl2 solution was washed with 10% aqueous NaHSO3, saturated NaHCO3 solution and then dried over Na2SO4. The residue, after removal of solvent, was distilled through a vigreux column to obtain the title compound, bp 78°-81°/0.01 mmHg as a colorless liquid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][C@@H:11]([CH3:18])[CH2:12][CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])=[CH:4][CH:3]=1.[B:19](OC)([O:22]C)[O:20]C.Cl>O1CCCC1>[CH3:18][C@@H:11]([CH2:12][CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])[CH2:10][CH2:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([B:19]([OH:22])[OH:20])=[CH:3][CH:4]=1
Reactant: COB(OC)OC
Reactant: CC(C)=CCC[C@H](C)CCOc1ccc(Br)cc1
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)=CCC[C@H](C)CCOc1ccc(B(O)O)cc1
Temperature: -78 °C
Yield: 67 %

Procedure:
2.5M n-Butylithium in hexanes (49.3 cm3, 0.12 mol) was added dropwise to a cooled (−78° C.) solution of 1-bromo-4-[(S)-3,7-dimethyloct-6-enyloxy]benzene (35 g, 0.11 mol) in tetrahydrofuran (350 cm3). The resultant solution was stirred at this temperature for 1 h and then trimethyl borate (23.8 g, 0.23 mol) was added dropwise to the mixture while maintaining the temperature at −78° C. 20% hydrochloric acid (250 cm3) was added and the resultant mixture was stirred for 1 h and then extracted into diethyl ether (2×200 cm3). The combined organic layers were washed with water (2×100 cm3) and dried (MgSO4). After filtration the solvent was removed under reduce pressure to yield 20.35 g (65%) of the desired product.
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:12])[N:7]=[N:8][C:9]=1[CH2:10][OH:11])([CH3:4])([CH3:3])[CH3:2].[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.C(N(CC)CC)C>ClCCl>[C:1]([C:5]1[C:6]([O:12][S:19]([C:16]2[CH:17]=[CH:18][C:13]([CH3:23])=[CH:14][CH:15]=2)(=[O:21])=[O:20])=[N:7][NH:8][C:9]=1[CH2:10][OH:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C1=C(CO)N=NC1=O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)Oc2n[nH]c(CO)c2C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 62.5 %

Procedure:
To a suspension of 4-tert-butyl-5-hydroxymethylpyrazol-3-one (6.25 g, 0.037 mol) in dry dichloromethane (200 ml) was added p-toluene sulfonyl chloride (9.8 g, 0.051 mol) followed by triethylamine (6.14 ml, 0.044 mol) dropwise. The solution was stirred at room temperature for 3 days. Dichloromethane (250 ml) was then added to dilute and the solution was washed with brine (250 ml), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography with 0%→30% ethyl acetate/dichloromethane as eluent to give the title compound (7.5 g). Data for the title compound: 1H NMR (400 MHz, DMSO) δ 1.28 (9H, s), 2.43 (3H, s), 4.49 (2H, m), 5.32 (1H, m), 7.47 (2H, m), 7.86 (2H, m), 12.28 (1H, s); MS (ES+) m/e 325 [MH]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][C:5]1[N:6]=[CH:7][N:8]2[CH:12]=[C:11]([C:13]3[C@H:14]([CH3:27])[C@@H:15]4[C@@H:22]([C@H:23]([OH:25])[CH3:24])[C:21](=[O:26])[N:16]4[C:17]=3[C:18]([O-:20])=[O:19])[S:10][C:9]=12.[Na+:28].Cl.C(O[C:33](=[NH:35])[CH3:34])C>>[C:33]([NH:1][CH2:2][CH2:3][S:4][C:5]1[N:6]=[CH:7][N:8]2[CH:12]=[C:11]([C:13]3[C@H:14]([CH3:27])[C@@H:15]4[C@@H:22]([C@H:23]([OH:25])[CH3:24])[C:21](=[O:26])[N:16]4[C:17]=3[C:18]([O-:20])=[O:19])[S:10][C:9]=12)(=[NH:35])[CH3:34].[Na+:28]
Reactant: CCOC(C)=N
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(c3cn4cnc(SCCN)c4s3)[C@H](C)[C@H]12
Agent: Cl
Agent: [Na+]
Product: CC(=N)NCCSc1ncn2cc(C3=C(C(=O)[O-])N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)sc12
Yield: 19.3 %

Procedure:
The procedure of Example 12 was repeated, except that 44.0 mg of sodium (1S,5R,6S)-2-[7-(2-aminoethyl)thioimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate and 63 mg of ethylacetimidate hydrochloride were used as the starting compounds. Thus, 9.3 mg of the title compound was prepared.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:5]2[C:10]([C:11]=1[CH:12](O)[C:13]([NH2:15])=[O:14])=[C:9]([O:17][CH3:18])[CH:8]=[CH:7][CH:6]=2)[CH3:2].C([SiH](CC)CC)C.C(OCC)(=O)C>FC(F)(F)C(O)=O>[CH2:1]([C:3]1[N:4]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:5]2[C:10]([C:11]=1[CH2:12][C:13]([NH2:15])=[O:14])=[C:9]([O:17][CH3:18])[CH:8]=[CH:7][CH:6]=2)[CH3:2]
Reactant: CCc1c(C(O)C(N)=O)c2c(OC)cccc2n1Cc1ccccc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CCc1c(CC(N)=O)c2c(OC)cccc2n1Cc1ccccc1
Yield: 62.2 %

Procedure:
A solution of 875 mg (2.6 mmol) of 2-ethyl-4-methoxy-alpha-hydroxy-1-(phenylmethyl)-1H-indole-3-acetamide and 0.51 mL (3.23 mmol) of triethylsilane in 10 mL of trifluoroacetic acid was stirred for 16 hours and concentrated at reduced pressure. The residue was taken up in ethyl acetate and water, the ethyl acetate separated, washed with brine and dried (MgSO4). The residue was chromatographed on silica gel and eluted first with 50% ethyl acetate/hexane and then ethyl acetate to give 521 mg (62% yield) of 2-ethyl-4-methoxy-1-(phenylmethyl)-1H-indole-3-acetamide, mp, 152-154° C.
Reaction SMILES: CCN=C=NCCCN(C)C.[CH3:12][C:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[O:15][C:14]=1[C:22]([OH:24])=O.[C:25]([O:29][C:30](=[O:57])[CH:31]([NH:41][C:42]([C:44]1[CH:49]=[CH:48][C:47]([C:50]2[CH:55]=[CH:54][C:53]([NH2:56])=[CH:52][CH:51]=2)=[CH:46][CH:45]=1)=[O:43])[CH2:32][CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([O:29][C:30](=[O:57])[CH:31]([NH:41][C:42]([C:44]1[CH:45]=[CH:46][C:47]([C:50]2[CH:51]=[CH:52][C:53]([NH:56][C:22]([C:14]3[O:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[C:13]=3[CH3:12])=[O:24])=[CH:54][CH:55]=2)=[CH:48][CH:49]=1)=[O:43])[CH2:32][CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])([CH3:26])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)CCC(NC(=O)c1ccc(-c2ccc(N)cc2)cc1)C(=O)OC(C)(C)C
Reactant: Cc1c(C(=O)O)oc2ccccc12
Agent: CCN=C=NCCCN(C)C
Product: Cc1c(C(=O)Nc2ccc(-c3ccc(C(=O)NC(CCC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc3)cc2)oc2ccccc12
Yield: 12.4 %

Procedure:
EDCI coupling between 3-Methylbenzofuran 2 carboxylic acid (139 mg, 0.79 mmol) and 2-[(4′-Amino-biphenyl-4-carbonyl)-amino]-pentanedioic acid di-tert-butyl ester (358 mg, 0.79 mmol, 1 equiv.) was carried out according to the procedure in step C of Example 5 to give 2-({4′-[(3-Methyl-benzofuran-2-carbonyl)-amino]-biphenyl-4-carbonyl}-amino)-pentanedioic acid di-tert-butyl ester in 12.4% yield (60 mg). MS (ESI) m/z 611.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C@H:13]([CH2:21][CH3:22])[CH2:14][CH:15]([CH3:20])[CH2:16][CH2:17][CH:18]=[CH2:19])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH:56][C@H:57]1[CH2:61][NH:60][C@H:59]([C:62]([O:64][CH3:65])=[O:63])[CH2:58]1>ClCCl>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C@H:13]([CH2:21][CH3:22])[CH2:14][CH:15]([CH3:20])[CH2:16][CH2:17][CH:18]=[CH2:19])[C:10]([N:60]1[CH2:61][C@H:57]([OH:56])[CH2:58][C@H:59]1[C:62]([O:64][CH3:65])=[O:63])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=CCCC(C)C[C@@H](CC)C(NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1
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: ClCCl
Product: C=CCCC(C)C[C@@H](CC)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (3R)-2-(tert-butoxycarbonylamino)-3-ethyl-5-methylnon-8-enoic acid (2 g, 6.38 mmole) in dichloromethane (20 mL) was added DIPEA (1.93 mL, 19.19 mmole), HATU (2.42 g, 6.38 mmole) followed by (2S,4R)-methyl 4-hydroxypyrrolidine-2-carboxylate (1.15 g, 6.38 mmole) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The reaction mass was diluted with DCM and washed with water. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to get crude compound. The crude compound was taken to the next step without further purification (1.5 g, 53.4%). MS: MS m/z 441.6 (M++1)
Reaction SMILES: [Si]([O:8][CH2:9][C:10]([NH:13][C:14]([C:16]1[C:20]2=[N:21][C:22]([C:25]3[C:33]4[C:28](=[CH:29][C:30]([CH3:34])=[CH:31][CH:32]=4)[N:27]([CH2:35][CH2:36][N:37]4[CH2:42][CH2:41][O:40][CH2:39][CH2:38]4)[N:26]=3)=[CH:23][N:24]=[C:19]2[N:18](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:17]=1)=[O:15])([CH3:12])[CH3:11])(C(C)(C)C)(C)C.[ClH:62]>O1CCOCC1>[ClH:62].[OH:8][CH2:9][C:10]([NH:13][C:14]([C:16]1[C:20]2=[N:21][C:22]([C:25]3[C:33]4[C:28](=[CH:29][C:30]([CH3:34])=[CH:31][CH:32]=4)[N:27]([CH2:35][CH2:36][N:37]4[CH2:38][CH2:39][O:40][CH2:41][CH2:42]4)[N:26]=3)=[CH:23][N:24]=[C:19]2[NH:18][CH:17]=1)=[O:15])([CH3:12])[CH3:11]
Reactant: Cc1ccc2c(-c3cnc4c(n3)c(C(=O)NC(C)(C)CO[Si](C)(C)C(C)(C)C)cn4C(c3ccccc3)(c3ccccc3)c3ccccc3)nn(CCN3CCOCC3)c2c1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc2c(-c3cnc4[nH]cc(C(=O)NC(C)(C)CO)c4n3)nn(CCN3CCOCC3)c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 64 %

Procedure:
To a stirred solution of N-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-2-(6-methyl-1-(2-morpholinoethyl)-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (167 mg, 0.2 mmol) in dioxane (20 mL) was bubbled HCl gas until saturation and then stirred at room temperature for 16 hours. Reaction mixture was concentrated and the residue was triturated with methanol (1 mL) then decanted and dried to afford N-(1-hydroxy-2-methylpropan-2-yl)-2-(6-methyl-1-(2-morpholinoethyl)-1H-indazol-3-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide hydrochloride (76 mg, 64%) as a white solid. LCMS: (M+H)+=478; 1H NMR (300 MHz, CD3OD): δ 9.15 (s, 1H), 8.49 (d, 1H, J=8.4 Hz), 8.29 (s, 1H), 7.56 (s, 1H), 7.22 (d, 1H, J=8.1 Hz), 5.00-4.96 (m, 2H), 4.08-3.85 (m, 12H), 2.59 (s, 3H), 1.56 (s, 6H).
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[C:37]([N:38]2[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]2)=[CH:36][C:12]2[NH:13][C:14]([C:16]3[C:20]([NH:21][C:22]([N:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)=[O:23])=[CH:19][N:18](C4CCCCO4)[N:17]=3)=[N:15][C:11]=2[CH:10]=1>ClCCl>[F:8][C:9]1[C:37]([N:38]2[CH2:39][CH2:40][N:41]([CH3:44])[CH2:42][CH2:43]2)=[CH:36][C:12]2[NH:13][C:14]([C:16]3[C:20]([NH:21][C:22]([N:24]4[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]4)=[O:23])=[CH:19][NH:18][N:17]=3)=[N:15][C:11]=2[CH:10]=1
Reactant: CN1CCN(c2cc3[nH]c(-c4nn(C5CCCCO5)cc4NC(=O)N4CCCCC4)nc3cc2F)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCN(c2cc3[nH]c(-c4n[nH]cc4NC(=O)N4CCCCC4)nc3cc2F)CC1
Temperature: 22 °C
Reaction time: 48 h
Yield: 55.3 %

Procedure:
0.6 mL of trifluoroacetic acid is added to a solution of 260 mg of piperidine-1-carboxylic acid [3-[5-fluoro-6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-yl]amide in solution in 1.5 mL of dichloromethane. The reaction medium is stirred at 22° C. for 48 hours. The reaction medium is concentrated under vacuum in a rotary evaporator. After evaporation, the reaction crude is purified by flash chromatography in an Intelliflash apparatus on an Analogix RS-12 cartridge. The elution is carried out in pure dichloromethane for 20 min and then in dichloromethane containing 10% of ammoniacal methanol. 120 mg of N-{3-[5-fluoro-6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl}piperidine-1-carboxamide are obtained in the form of a beige solid. 1H NMR (400 MHz, DMSO-d6, δ in ppm): from 1.45 to 1.70 (m, 6H); 2.90 (s, 3H); 3.07 (m, 2H); 3.29 (m, 2H); 3.45 (m, 4H); 3.55 (m, 4H); 7.31 (d, J=8.0 Hz, 1H); 7.57 (d, J=11.5 Hz, 1H); 8.02 (s, 1H). EI mass spectrum: m/z=426, M+., m/z=341 (M−C5H11N)+; m/z=114 CF3CO2H+. relative to TFA; m/z=84 C5H10N+; m/z=69 CF3+ relative to TFA; m/z=45 CO2H+ relative to TFA base peak, m/z=43 C2H5N+.; m/z=41 C3H5+
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([PH:17](=[O:19])[OH:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N([Si](C)(C)C)[Si](C)(C)C.[C:29]([O:34][CH3:35])(=[O:33])[C:30]([CH3:32])=[CH2:31]>CCO>[CH3:35][O:34][C:29](=[O:33])[CH:30]([CH3:32])[CH2:31][P:17]([C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([OH:18])=[O:19]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[PH](=O)O
Reactant: C=C(C)C(=O)OC
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: CCO
Product: COC(=O)C(C)CP(=O)(O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 110 °C
Reaction time: 2 h

Procedure:
A mixture of 5.00 g of ((R)-1-tert-butoxycarbonylamino-2-phenyl-ethyl)-phosphinic acid and 18.3 ml of HN(TMS)2 was heated to 110° C. for 1 h. To the solution was added 2.5 ml of methyl methacrylate and heating was continued at 110° C. for 2 h. The solution was cooled to 70° slowly diluted with 10 ml of EtOH and evaporated. The residue was chromatographed on silica using a gradient of CH2Cl2/MeOH (9:1)→CH2Cl2/MeOH/AcOH (10:1:0.3) to give 4.10 g of the title compound. MS: 386.5 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[C:4]([N:11]2[CH:15]=[CH:14][CH:13]=[N:12]2)[N:3]=1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:48][C@H:49]([C:62]1[CH:67]=[CH:66][C:65]([F:68])=[CH:64][CH:63]=1)[C:50]1[CH:55]=[CH:54][C:53]([P:56]([CH3:61])(=[O:60])[O:57][CH2:58][CH3:59])=[CH:52][CH:51]=1>CC#N>[F:68][C:65]1[CH:64]=[CH:63][C:62]([C@@H:49]([NH:48][C:8]([C:7]2[C:2]([OH:1])=[N:3][C:4]([N:11]3[CH:15]=[CH:14][CH:13]=[N:12]3)=[N:5][CH:6]=2)=[O:10])[C:50]2[CH:55]=[CH:54][C:53]([P:56]([CH3:61])(=[O:60])[O:57][CH2:58][CH3:59])=[CH:52][CH:51]=2)=[CH:67][CH:66]=1
Reactant: CCOP(C)(=O)c1ccc([C@H](N)c2ccc(F)cc2)cc1
Reactant: O=C(O)c1cnc(-n2cccn2)nc1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOP(C)(=O)c1ccc([C@H](NC(=O)c2cnc(-n3cccn3)nc2O)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 65.7 %

Procedure:
To a stirred solution of 4-hydroxy-2-(1H-pyrazol-1-yl)pyrimidine-5-carboxylic acid, 8-b, (5.15 g, 25 mmol) and Et3N (6.9 g, 68 mmol) in MeCN (100 ml) was added HATU (9.5 g, 25 mmol). The mixture was stirred for 5 min at room temperature and then compound 18-e (7 g, 23 mmol) was added. The resulting mixture was stirred at room temperature for 1 hour. Then it was concentrated under vacuum and the residue was taken into ethyl acetate followed by washing with 1N HCl. The organic layer was dried over sodium sulfate and concentrated under vacuum. The residue was purified on silica gel chromatography (petroleum ether:ethyl acetate=2/1) to provide the product, 18-f, (8.1 g, 65.7%).
Reaction SMILES: [F:1]C(F)(F)C1C=CC(OC2C=CC=CC=2CC2CCNCC2)=CC=1.Cl.C([C:34]1[CH:53]=[CH:52][C:37]([O:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[CH2:45][CH:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)=[CH:36][CH:35]=1)(=O)C1C=CC=CC=1>>[F:1][C:34]1[CH:53]=[CH:52][C:37]([O:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[CH2:45][CH:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)=[CH:36][CH:35]=1
Reactant: O=C(c1ccccc1)c1ccc(Oc2ccccc2CC2CCNCC2)cc1
Reactant: FC(F)(F)c1ccc(Oc2ccccc2CC2CCNCC2)cc1
Agent: Cl
Product: Fc1ccc(Oc2ccccc2CC2CCNCC2)cc1

Procedure:
(−)-4-[(4-trifluoromethylphenoxy)phenyl]methyl-piperidine, sulfate (96% ee, m.p.=85° C. (d), [α]365−15.5, c=0.508, CHCl3)
Reaction SMILES: [O:1]([C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][S:17][CH2:18][CH2:19][NH2:20]>>[CH3:16][S:17][CH2:18][CH2:19][NH:20][CH2:12][C:11]1[CH:14]=[CH:15][C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:9][CH:10]=1
Reactant: O=Cc1ccc(Oc2ccccc2)cc1
Reactant: CSCCN
Product: CSCCNCc1ccc(Oc2ccccc2)cc1
Yield: 92.5 %

Procedure:
Following the procedure described in Example 68A, 4-phenoxybenzaldehyde (1.98 g, 10 mmol) and 2-methylthioethylamine (0.912 g, 10 mmol) were combined to give the title compound (2.53 g, 93%) 1H NMR (300 MHz, CDCl3) δ 7.32 (m, 4 H), 7.09. (t, 1 H), 6.97 (m, 4 H), 3.80 (s, 2 H), 2.84 9t, 2 H), 2.68 (t, 2 H), 2.10 (s, 3 H).