Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]=[CH:4][CH:3]=1.[Li]C(C)(C)C.CN([CH:23]=[O:24])C>C1COCC1>[F:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:11])([CH3:13])[CH3:12])[C:5]([CH:23]=[O:24])=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: CC(C)(C)C(=O)Nc1cccc(F)n1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1nc(F)ccc1C=O
Temperature: -78 °C
Reaction time: 3 h

Procedure:
N-(6-fluoropyridin-2-yl)pivalamide (1.67 g, 8.5 mmol) was dissolved in THF (15 mL) at room temperature, and the colorless solution was cooled to −78° C., followed by dropwise addition of t-BuLi (10.3 mL, 1.7M in heptane, 17.4 mmol) under nitrogen gas over 10 min. The resulting yellow solution was continued stirring at −78° C. for 3 hr, followed by dropwise addition of DMF (2.0 mL, 25.5 mmol) over 5 min. The light yellow solution was stirred for additional 30 min at −78° C. Thus the mixture was quenched with saturated NH4Cl (30 mL), partitioned between H2O/EtOAc (100 mL/100 mL). After separation, the organic phase was washed with brine (30 mL), dried over MgSO4, concentrated on rotary vacuum, and purified on flash chromatography eluting with 25˜50% EtOAc/hexanes (1400 mL) to afford an expected product, as a white solids (343 mg, 18% yield), plus the recovered starting material (622 mg); 1H NMR (400 MHz, CDCl3) δ ppm 1.23-1.30 (s, 9 H), 8.12 (s, 1 H), 8.18-8.27 (m, 2 H), 10.13 (s, 1 H); Mass spec. 225.13 (MH+), Calc. for C11H13FN2O2224.1
Reaction SMILES: [Si]([O:18][C:19]1[CH:51]=[CH:50][C:22]([O:23][CH2:24][C@@H:25]([OH:49])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([S:36]([CH2:39][C:40]3[N:44]=[C:43]([C:45]([CH3:48])([CH3:47])[CH3:46])[O:42][N:41]=3)(=[O:38])=[O:37])=[CH:32][CH:31]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.[Cl-].[NH4+]>[C:45]([C:43]1[O:42][N:41]=[C:40]([CH2:39][S:36]([C:33]2[CH:34]=[CH:35][C:30]([CH2:29][CH2:28][NH:27][CH2:26][C@H:25]([OH:49])[CH2:24][O:23][C:22]3[CH:21]=[CH:20][C:19]([OH:18])=[CH:51][CH:50]=3)=[CH:31][CH:32]=2)(=[O:37])=[O:38])[N:44]=1)([CH3:48])([CH3:46])[CH3:47]
Reactant: CC(C)(C)c1nc(CS(=O)(=O)c2ccc(CCNC[C@H](O)COc3ccc(O[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)cc3)cc2)no1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)c1nc(CS(=O)(=O)c2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)no1
Reaction time: 6 h
Yield: 63.5 %

Procedure:
To a solution of the amino alcohol of Example 14(0.650 g, 0.90 mmol) in THF (12 mL) was added a 1 M solution of TBAF (0.225 mL, 0.225 mmol). The reaction mixture was stirred for 6 h. TLC showed the absence of starting material, therefore 5 drops of a saturated aqueous ammonium chloride solution was added. The reaction mixture was evaporated in vacuo to dryness and the residue was flash chromatographed (silica gel; dichloromethane/chloroform/methanol: 15/5/3) to afford 0.280 g of the title compound as a white foam.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][NH2:14])=[CH:7][N:6]=1.C1(C)C=CC=CC=1>O>[N:6]1[C:7]2[NH:14][CH2:13][CH2:12][CH2:11][C:8]=2[CH:9]=[CH:10][C:5]=1[CH2:4][CH2:3][CH2:2][NH2:1]
Reactant: NCCCc1ccc(CCCN)nc1
Solvent: Cc1ccccc1
Solvent: O
Product: NCCCc1ccc2c(n1)NCCC2
Reaction time: 15 h
Yield: 94.6 %

Procedure:
A 100 mL round-bottom flask equipped with a N2 inlet was charged with 1-3 (2.54 g, 13.1 mmol), toluene (65 mL), and freshly grounded NaNH2 (2.69 g, 65.5 mmol). The flask was evacuated and back filled with N2 and placed in a 90° C. oil bath. After 15 h, water (1.18 mL, 65.5 mmol) was added slowly without removing the flask from the oil bath. Caution: an exothermic reaction occurs upon addition of water. After the addition of water, the resulting mixture was filtered while hot, followed by 65 mL of hot toluene (90° C.). The mother liquor was concentrated to yield 2.37 g (94%) of 1-4.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:25])=[C:6]([CH:24]=1)[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=[C:10]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[N:9]=1.[Cl:26][CH2:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1>>[Cl:26][CH2:27][C:28]1[CH:36]=[CH:35][C:31]([C:32]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH3:25])=[C:6]([NH:7][C:8]3[CH:13]=[C:12]([C:14]([F:16])([F:17])[F:15])[N:11]=[C:10]([C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)[N:9]=3)[CH:24]=2)=[O:33])=[CH:30][CH:29]=1
Reactant: Cc1ccc(N)cc1Nc1cc(C(F)(F)F)nc(-c2ccncc2)n1
Reactant: O=C(Cl)c1ccc(CCl)cc1
Product: Cc1ccc(NC(=O)c2ccc(CCl)cc2)cc1Nc1cc(C(F)(F)F)nc(-c2ccncc2)n1

Procedure:
The title compound was prepared from a mixture of 4-(5-amino-2-methylanilino)-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine (80 mg, 0.232 mmol) and 4-chloromethylbenzoyl chloride (53 mg, 0.278 mmol) similar to Example 139 and isolated as a yellow solid (55 mg, 48%). 1H NMR (CDCl3): 8.75 (dd, J=1.8, 4.8 Hz, 2H), 8.29 (dd, J=1.8, 4.8 Hz, 2H), 8.02 (s, 1H), 7.96 (s, 1H), 7.88 (d, J=8.4 Hz, 2H), 7.51 (d, J=8.4 Hz, 2H), 7.37 (dd, J=1.8, 7.5 Hz, 1H), 7.32 (d, J=7.5 Hz, 1H), 7.12 (s, 1H), 6.75 (s, 1H), 4.63 (s, 2H), 2.28 (s, 3H).
Reaction SMILES: Cl.[CH3:2][C:3]1[NH:4][CH:5]=[C:6]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[N:7]=1.[Br:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[CH:24]=[C:23]([S:28]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)(=[O:30])=[O:29])[CH:22]=[CH:21]2>C(O)C.CCCCCC>[Br:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[CH:24]=[C:23]([S:28]([N:31]1[CH2:32][CH2:33][N:34]([C:12](=[O:14])[C:11]3[CH:10]=[CH:9][C:8]([C:6]4[N:7]=[C:3]([CH3:2])[NH:4][CH:5]=4)=[CH:16][CH:15]=3)[CH2:35][CH2:36]1)(=[O:29])=[O:30])[CH:22]=[CH:21]2
Reactant: Cc1nc(-c2ccc(C(=O)O)cc2)c[nH]1
Reactant: O=S(=O)(c1ccc2cc(Br)ccc2c1)N1CCNCC1
Agent: Cl
Solvent: CCO
Solvent: CCCCCC
Product: Cc1nc(-c2ccc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Br)ccc5c4)CC3)cc2)c[nH]1
Yield: 85 %

Procedure:
By an exactly analogous method to that described in Example 1, starting from 4-(2-methylimidazol-4-yl)benzoic acid hydrochloride and 1-(6-bromonaphth-2-ylsulphonyl)piperazine was prepared 1-(6-bromonaphth-2-ylsulphonyl)-4-[4-(2-methylimidazol-4-yl)benzoyl]piperazine (423 mg, 85% yield), m.p. 215-216° C. (from ethanol/hexane), 1H NMR (d6DMSO) 2.3 ppm (s,3H), 3.0-3.2 ppm (broad s,4H), 3.4-3.7 ppm (broad s,4H), 7.2 ppm (d,2H), 7.5 ppm (s,1H), 7.7 ppm (d,2H), 7.8 ppm (t,2H), 8.2 ppm (t,2H), 8.4 ppm (s,1H), 8.45 ppm (s,1H), 11.8 ppm (broad s,1H), the spectrum also contained signals due to ethanol (˜0.33 mol eq.); microanalysis, found: C, 55.4; H, 4.8; N, 9.9; S, 5.8%; C25H23N4O3BrS requires: C, 55.6; H, 4.5; N, 10.1; S, 5.8%; MS (M+H)+ 539/541.
Reaction SMILES: C(Cl)Cl.[OH:4][CH:5]1[C@@H:9]2[CH:10]([NH:13][C:14](=[O:23])[CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11](=[O:12])[N:8]2[CH:7]([C:24]([O:26][CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[CH:6]1[CH3:40].N1C=CC=CC=1.[C:47](OC(=O)C)(=[O:49])[CH3:48]>CN(C)C1C=CN=CC=1.C(OCC)(=O)C.C(Cl)(Cl)Cl>[C:47]([O:4][CH:5]1[C@@H:9]2[CH:10]([NH:13][C:14](=[O:23])[CH2:15][O:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:11](=[O:12])[N:8]2[CH:7]([C:24]([O:26][CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[O:25])[CH:6]1[CH3:40])(=[O:49])[CH3:48]
Reactant: CC(=O)OC(C)=O
Reactant: CC1C(O)[C@@H]2C(NC(=O)COc3ccccc3)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(=O)OC1C(C)C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)COc3ccccc3)[C@@H]12
Temperature: -10 °C
Reaction time: 1 h

Procedure:
The washed, dried methylene chloride solution of benzhydryl 1-hydroxy-2-methyl-6-(2-phenoxyacetamido)carbapenam-3-carboxylate, freshly prepared according to Example 22 was cooled to -10° C. Pyridine (22 mg., 0.28 mmole), acetic anhydride (29 mg., 0.28 mmole) and 4-dimethylaminopyridine (3.4 mg., 0.028 mmoles) were added in sequence. After stirring for 1 hour at -10° C., tlc (4:1 chloroform:ethyl acetate) indicated acetylation was complete. The reaction mixture was evaporated to dryness in vacuo with toluene chases. Chromatography on silica gel using a methylene chloride-ethyl acetate gradient (0 to 7.5% ethyl acetate) afforded benzhydryl 1-acetoxy-2-methyl-6-(2-phenoxyacetamido)carbapenam-3-carboxylate [18 mg.; Rf 0.56 (4:1 chloroform:ethyl acetate; ir (CHCl3) 1780, 1730, 1680 cm-1 ].
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:22]=[CH:21][C:10]([CH2:11][N:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18]C)[C:13]3=[O:20])=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.B(Br)(Br)Br>C(Cl)Cl>[N:1]1[CH:2]=[CH:3][C:4]([C:7]2[CH:8]=[CH:9][C:10]([CH2:11][N:12]3[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[C:13]3=[O:20])=[CH:21][CH:22]=2)=[CH:5][CH:6]=1
Reactant: COc1cccn(Cc2ccc(-c3ccncc3)cc2)c1=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=c1c(O)cccn1Cc1ccc(-c2ccncc2)cc1
Yield: 83.5 %

Procedure:
Reaction of 146i (0.10 g, 0.34 mmol) with 1M BBr3 (0.51 mL) in dry CH2Cl2 within 48 h according to procedure 148a afforded pure 148i (79 mg, 83%) as slightly brownish solid. 1H NMR (400 MHz, CDCl3) δ 8.65 (s, 2H), 7.46 (s, 2H), 7.39 (d, J=7.9 Hz, 2H), 6.83 (dd, J=22.5, 7.0 Hz, 2H), 6.16 (t, J=7.0 Hz, 1H), 5.22 (s, 2H). 13C NMR (100 MHz, CDCl3) δ 150.23, 147.62, 146.76, 137.98, 136.87, 128.66, 127.51, 126.64, 121.58, 113.66, 107.13, 52.19. HRMS (FAB) calcd for C17H15N2O2 [M+H]+ 279.1133. found 279.1147.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[S:11]([N:14]2[CH2:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[CH2:18][O:17][CH2:16][C@H:15]2[CH2:26][C:27]([OH:29])=O)(=[O:13])=[O:12])[CH:4]=[CH:3][CH:2]=1.[C:30]([NH:33][NH2:34])(=[O:32])[CH3:31].C(N(CC)CC)C>O=S(Cl)Cl.C(Cl)Cl.O>[C:30]([NH:33][NH:34][C:27](=[O:29])[CH2:26][C@H:15]1[N:14]([S:11]([C:9]2[CH:8]=[CH:7][CH:6]=[C:5]3[C:10]=2[N:1]=[CH:2][CH:3]=[CH:4]3)(=[O:13])=[O:12])[CH2:21][C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[CH2:18][O:17][CH2:16]1)(=[O:32])[CH3:31]
Reactant: O=C(O)C[C@@H]1COCc2ccccc2CN1S(=O)(=O)c1cccc2cccnc12
Reactant: CC(=O)NN
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)NNC(=O)C[C@@H]1COCc2ccccc2CN1S(=O)(=O)c1cccc2cccnc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.4 %

Procedure:
A solution of compound 21a (412 mg, 1 mmol) in SOCl2 (3 mL) was stirred for 1 h at rt and concentrated. Acetohydrazide (148 mg, 2 mmol) and triethylamine (303 mg, 3 mmol) in DCM (5 mL) were added to the above residue. The mixture was stirred at rt for 1 h. The reaction was taken up in H2O (10 mL) and extracted with DCM (30 mL). The combined organic layers were dried over Na2SO4 and concentrated. The crude product was purified by CC to give the compound 27a (400 mg, 85% yield).
Reaction SMILES: [CH:1]1([C:4](=O)[CH2:5][C:6]([CH:8]2[CH2:10][CH2:9]2)=O)[CH2:3][CH2:2]1.O.[NH2:13][NH2:14].O.CCOC(C)=O>C(O)C>[CH:1]1([C:4]2[CH:5]=[C:6]([CH:8]3[CH2:10][CH2:9]3)[NH:14][N:13]=2)[CH2:3][CH2:2]1
Reactant: NN
Reactant: O=C(CC(=O)C1CC1)C1CC1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: c1c(C2CC2)n[nH]c1C1CC1
Temperature: 25 °C

Procedure:
Intermediate 1 (5.3 g, 35 mmol) and hydrazine hydrate (1.8 mL, 38.3 mmol) in ethanol (20 mL) were refluxed overnight. Work-up (H2O/AcOEt) after cooling the mixture to ambient temperature gave the title compound as a brown solid. M. P.: 161-164° C. 1H-NMR (δ ppm, CDCl3, 400 MHz): 15.2 (bs, 1H), 5.65 (s, 1H), 2.16-2.09 (m, 2H), 1.18-1.14 (m, 4H), 0.98-0.94 (m, 4H). MS (m/z): 149.04 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C@H:8]([OH:19])[C@H:9]([CH3:18])[CH2:10][NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH:5]=[CH:6][CH:7]=1.[C:20]([C:22]([OH:29])([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])#[CH:21]>>[F:14][C:13]([F:16])([F:15])[C:12]([NH:11][CH2:10][C@@H:9]([CH3:18])[C@@H:8]([OH:19])[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:21]#[C:20][C:22]([OH:29])([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])[CH:3]=1)=[O:17]
Reactant: C#CC(O)(CCC)CCC
Reactant: C[C@H](CNC(=O)C(F)(F)F)[C@@H](O)c1cccc(Br)c1
Product: CCCC(O)(C#Cc1cccc([C@H](O)[C@H](C)CNC(=O)C(F)(F)F)c1)CCC

Procedure:
Coupling of bromide 97 and 4-ethynylheptan-4-ol was performed following the method used in Example 1 (silica gel, 40% to 60% of EtOAc/hexanes gradient) gave 2,2,2-trifluoro-N-((2R,3R)-3-hydroxy-3-(3-(3-hydroxy-3-propylhex-1-ynyl)phenyl)-2-methylpropyl)acetamide (98) as a light yellow oil. Yield (0.01 g, 25%): 1H NMR (400 MHz, MeOH-d4) δ 7.38 (s, 1H), 7.27-7.30 (m, 3H), 4.40 (d, J=7.2 Hz, 1H), 3.45 (dd, J=13.6, 4.2 Hz, 1H), 3.26 (dd, J=13.6, 8.0 Hz, 1H), 2.03-2.12 (m, 1H), 1.52-1.99 (m, 8H), 0.97 (t, J=7.2 Hz, 6H), 0.76 (d, J=7.2 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[N:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([S:27](O)(=[O:29])=[O:28])[CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1.S(Cl)(Cl)=O.CN(C)C=O.[NH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1>ClCCl.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[N:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([S:27]([N:40]4[CH2:45][CH2:44][O:43][CH2:42][CH2:41]4)(=[O:28])=[O:29])[CH:15]=3)[N:10]=2)=[CH:7][CH:8]=1
Reactant: C1COCCN1
Reactant: COc1ccc(-c2nc3ccc(S(=O)(=O)O)cc3nc2-c2ccc(OC)cc2)cc1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: COc1ccc(-c2nc3ccc(S(=O)(=O)N4CCOCC4)cc3nc2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2,3-bis(4-methoxyphenyl)quinoxaline-6-sulfonic acid (350 mg, 0.83 mmol, 1.00 equiv), thionyl chloride (1.0 g, 8.40 mmol, 10.00 equiv), N,N-dimethylformamide (60 mg, 0.82 mmol, 1.00 equiv) and toluene (10 mL) was heated to reflux for 3 h in an oil bath. The resulting mixture was concentrated in vacuo and diluted with 10 ml of dichloromethane. Then the resulting mixture was added into a solution of morpholine (1.44 g, 16.53 mmol, 20.00 equiv) in dichloromethane (10 mL) at 0° C. The reaction mixture was stirred overnight at room temperature, concentrated in vacuo, and purified by Prep-HPLC with the following conditions (AGILENT Pre-HPLC (UV-Directed)): Column, SunFire Prep C18, 5 um, 19*100 mm; mobile phase, water with 0.05% TFA and CH3CN (10% CH3CN up to 80% in 3 min, hold 80% in 2 min, up to 100% in 0.1 min, hold 100% in 0.9 min); Detector, UV 254 nm. This resulted in 60 mg (34%) of 4-(2,3-bis(4-methoxyphenyl)quinoxalin-6-ylsulfonyl)morpholine as a white solid.
Reaction SMILES: [CH:1]1[C:6]2[CH:7]=[N:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[S:11](=[O:13])(=[O:12])[C:5]=2[CH:4]=[C:3]([C:18]([O:20]C)=[O:19])[CH:2]=1.[OH-].[K+].O.C(O)C>O1CCOCC1>[CH:1]1[C:6]2[CH:7]=[N:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[S:11](=[O:13])(=[O:12])[C:5]=2[CH:4]=[C:3]([C:18]([OH:20])=[O:19])[CH:2]=1
Reactant: COC(=O)c1ccc2c(c1)S(=O)(=O)c1ccccc1N=C2
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCO
Product: O=C(O)c1ccc2c(c1)S(=O)(=O)c1ccccc1N=C2

Procedure:
Stir a mixture 2.04 gm (6.77 mmole) of the ester from Example 17. 2.24 gm (20 mmole) of 85% aqueous potassium hydroxide, 11 ml of water, 55 ml of ethanol and 5.5 ml of dioxane under argon at room temperature for 1 hour. Evaporate to a syrup and dilute with 25 ml of water. Charcoal and filter twice. Acidify with acetic acid. Separate the precipitate by filtration, wash with water and dry to obtain the title product (m.p. 302° C. dec.).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:13]([OH:16])([CH3:15])[CH3:14])[C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[F:18][C:19]([F:23])([F:22])[CH2:20][NH2:21].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl.C(OCC)(=O)C>[C:4]([O:3][C:1]([NH:8][C@@H:9]([C:10]([NH:21][CH2:20][C:19]([F:23])([F:22])[F:18])=[O:12])[C:13]([OH:16])([CH3:15])[CH3:14])=[O:2])([CH3:5])([CH3:6])[CH3:7]
Reactant: NCC(F)(F)F
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C(C)(C)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)NCC(F)(F)F)C(C)(C)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a vial was added (R)—N-Boc-2-amino-3-hydroxy-3-methylbutanoic acid (CA, 500 mg, 2.144 mmol), 2,2,2-trifluoroethanamine hydrochloride (581 mg, 4.29 mmol), EDC (493 mg, 2.57 mmol), and HOBT (328 mg, 2.144 mmol). The reactants were dissolved in DCM (10 mL) and then DIEA (1.497 mL, 8.57 mmol) was added. The mixture was allowed to stir at RT overnight. The mixture was diluted with ethyl acetate, washed 2× with aqueous sodium hydrogen carbonate and 1× with brine. Aqueous layers were back extracted once with ethyl acetate, combined organic layers were dried with Na2SO4, filtered and the solvent was evaporated under reduced pressure. The material I-27a was used directly in the subsequent step without purification.
Reaction SMILES: [C:1](=[O:12])([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])OC(C)(C)C.[OH:13][CH:14]1[CH2:19][CH2:18][CH2:17][NH:16][CH2:15]1.CC(C)(N)CN>O.C(O)(C)(C)C>[C:8]([O:7][C:1]([N:16]1[CH2:17][CH2:18][CH2:19][CH:14]([OH:13])[CH2:15]1)=[O:12])([CH3:9])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: OC1CCCNC1
Agent: CC(C)(N)CN
Solvent: CC(C)(C)O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC(O)C1
Reaction time: 16 h

Procedure:
Di-t-butyl carbonate (11.9 g.) was added to a solution of 3-hydroxypiperidine (5.0 g.) in water (10 ml.) and t-butanol (5 ml.) at ambient temperature, and the mixture was stirred for 16 hr. at ambient temperature. 1,1-Dimethylethylenediamine (1.5 ml.) was added and the mixture was stirred at ambient temperature for 1 hr. The solution was poured into water (150 ml.) and extracted with diethyl ether (3×50 ml.). The diethyl ether extract was washed successively with 1 M-hydrochloric acid (50 ml.), saturated sodium carbonate solution (50 ml.) and brine (50 ml.), and then dried (MgSO4). The solvent was evaporated to give 1-t-butoxycarbonyl-3-hydroxypiperidine, which was used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:54](O)[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1.CCOC(/N=N/C(OCC)=O)=O.C1(C)C=CC=CC=1>C1COCC1>[CH2:54]([O:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34])[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: OCc1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OCc3ccccc3)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 73.3 %

Procedure:
In a similar manner to Step 1 of Example 149, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (80.0 mg, 0.173 mmol) was dissolved in THF (4.0 mL), and the solution was treated with triphenylphosphine (137 mg, 0.519 mmol), benzylalcohol (0.0534 mL, 0.519 mmol) and 40% DEAD-toluene solution (0.237 mL), followed by purification by flash column chromatography (chloroform/methanol=100/0 to 90/10) to obtain 4-benzyloxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (70 mg, yield 73%).
Reaction SMILES: Cl[Si](C)(C)C.[I-].[Na+].[Br:8][C:9]1[CH:10]=[CH:11][C:12]([Cl:21])=[C:13]([CH2:15][NH:16]C(=O)OC)[CH:14]=1.[OH-].[Na+]>C(#N)C>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([Cl:21])=[C:13]([CH2:15][NH2:16])[CH:14]=1
Reactant: COC(=O)NCc1cc(Br)ccc1Cl
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: NCc1cc(Br)ccc1Cl
Temperature: -20 °C
Reaction time: 1 h

Procedure:
To a solution of chlorotrimethylsilane (3.55 mL, 27.2 mmol) in acetonitrile (70 mL) was added sodium iodide (3.91 g, 27.2 mmol), and the reaction mixture was stirred at −20° C. for 1 h. Then methyl N-[(5-bromo-2-chlorophenyl)methyl]carbamate (3 g, 7.7 mmol; prepared according to U.S. Pat. No. 6,313,071) was added, and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was then basified with 1 N aqueous sodium hydroxide solution and extracted with ethyl acetate (3×). The organic layers were combined, washed with water and brine and then dried (Na2SO4). The solvent was evaporated to provide the title product (1.4 g).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[C:11]2[C:24]([CH3:25])=[CH:23][S:22][C:12]=2[N:13]=[C:14]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[N:15]=1>>[N:19]1[CH:18]=[CH:17][C:16]([C:14]2[N:15]=[C:10]([NH:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:11]3[C:24]([CH3:25])=[CH:23][S:22][C:12]=3[N:13]=2)=[CH:21][CH:20]=1
Reactant: Cc1csc2nc(-c3ccncc3)nc(Cl)c12
Reactant: NCc1ccccc1
Product: Cc1csc2nc(-c3ccncc3)nc(NCc3ccccc3)c12

Procedure:
With the procedure of Example 1, the reaction of benzylamine with 4-chloro-2-(pyridin-4-yl)-5-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-benzylamino-5-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:28][CH:29]([CH2:39]O)[CH2:30][NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35].N1C=CC=CC=1>ClCCl>[Br:8][CH2:39][CH:29]([F:28])[CH2:30][NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)NCC(F)CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NCC(F)CBr
Reaction time: 0.17 h

Procedure:
To a suspension of NBS (20 g, 110 mmol, 3.0 equiv) in dichloromethane (250 mL) was added dropwise triphenylphosphine (28 g, 110 nmol, 3.0 equiv) in dichloromethane (100 mL). After addition was complete, the reaction mixture was stirred for 10 min and a solution of tert-butyl 2-fluoro-3-hydroxypropylcarbamate (1-8) (7.0 g, 36 mmol, 1 equiv) in dichloromethane (100 mL) followed by pyridine (3.5 g, 44 mmol, 1.2 equiv) were added. The resulting mixture was stirred at 23° C. under nitrogen for 16 h. The reaction solution was concentrated and purified by silica gel chromatography (100% hexanes to 100% ethyl acetate over 1 h, analysis by Ninhydrin stain) to yield tert-butyl 3-bromo-2-fluoropropylcarbamate (1-9) as a clear oil. 1H NMR (500 MHz, CDCl3) δ 4.89-4.68 (m, 2H), 3.55-3.40 (m, 2H), 1.45 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:14](O)([CH3:16])[CH3:15])=[CH:5][C:6]2[CH2:7][CH2:8][CH2:9][CH:10]([CH3:13])[C:11]=2[CH:12]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:14]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:3]=1[O:2][CH3:1])[CH:10]([CH3:13])[CH2:9][CH2:8][CH2:7]2)([CH3:16])[CH3:15]
Reactant: COc1cc2c(cc1C(C)(C)O)CCCC2C
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(cc1C(C)C)CCCC2C
Temperature: 25 °C
Reaction time: 5 h
Yield: 61 %

Procedure:
To a stirred solution of 2-(3-methoxy-5-methyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-propan-2-ol (5.38 g, 22.96 mmol) in methylene chloride (100 mL) at room temperature under nitrogen atmosphere, was added triethyl silane (36.6 mL, 229.6 mmol) followed by trifluoroacetic acid (17.7 mL, 229.6 mmol). The reaction mixture was stirred for five hours at room temperature, then was concentrated under reduced pressure. The residue was partitioned between methylene chloride and saturated aqueous potassium carbonate solution. The organic layer was separated, washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified with flash chromatography on silica (10:0.1 hexanes/dichloromethane) to give 3.06 g of 6-isopropyl-7-methoxy-1-methyl-1,2,3,4-tetrahydro-naphthalene.