Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[O:14][CH3:15])[CH3:2].Cl[CH2:18][C:19]1[C:20]([CH3:35])=[N:21][C:22]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)=[CH:23][CH:24]=1>>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:18][C:19]2[C:20]([CH3:35])=[N:21][C:22]([C:25]3[CH:26]=[CH:27][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:29][CH:30]=3)=[CH:23][CH:24]=2)=[CH:9][C:8]=1[O:14][CH3:15])[CH3:2]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CCl
Reactant: CCOC(=O)CCc1ccc(O)cc1OC
Product: CCOC(=O)CCc1ccc(OCc2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1OC

Procedure:
In analogy to the procedures described in examples 8A] and 31B], 3-(4-hydroxy-2-methoxy-phenyl)-propionic acid ethyl ester was reacted with 3-chloromethyl-2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine (example 1N]) to give 3-{2-methoxy-4-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmethoxy]-phenyl}-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless solid.
Reaction SMILES: Cl.[CH3:2][N:3]([CH2:5][CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:15]C)[CH:12]=2)[C:7]1([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)O)[CH3:4]>Br.C(O)(=O)C>[CH3:4][N:3]([CH2:5][C:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([OH:15])[CH:12]=2)[C:7]=1[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[CH3:2]
Reactant: COc1ccc2c(c1)CC(CN(C)C)C2(O)c1cccnc1
Agent: Br
Agent: Cl
Solvent: CC(=O)O
Product: CN(C)CC1=C(c2cccnc2)c2ccc(O)cc2C1
Temperature: 105 °C
Reaction time: 3 h
Yield: 92.8 %

Procedure:
0.84 g of 2-dimethylaminomethyl-5-methoxy-1-pyridin-3-yl-indan-1-ol hydrochloride (mixture of the diastereoisomers) was dissolved in about 13 ml of 33% hydrobromic acid in acetic acid and stirred for 3 hours under reflux at 100-110° C. The reaction mixture was concentrated in vacuo, rendered alkaline with 32% sodium hydroxide solution and extracted with ethyl acetate; the combined organic phases were dried over magnesium sulfate, stirred with activated carbon, filtered and concentrated. 0.62 g of 2-dimethylaminomethyl-1-pyridin-3-yl-3H-inden-5-ol was obtained and was dissolved in about 22 ml of 2-butanone/acetone (v/v=1:2) and converted into the corresponding hydrochloride with about 0.04 ml of water and about 0.58 ml of chlorotrimethylsilane, while cooling with ice; the hydrochloride was filtered off with suction, with the exclusion of air, washed with diisopropyl ether and dried in vacuo (about 50 mbar) (yield 0.631 g).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:15]2[C:6]([C:7]3[CH:8]=[C:9]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:10]([C:16]4[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=4)=[N:11][C:12]=3[CH:13]=[CH:14]2)=[N:5][N:4]=1.[NH4+:30].[OH-].II>C1COCC1>[OH:1][CH2:2][C:3]1[N:15]2[C:6]([C:7]3[CH:8]=[C:9]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:10]([C:16]4[CH:17]=[CH:18][C:19]([C:20]#[N:30])=[CH:22][CH:23]=4)=[N:11][C:12]=3[CH:13]=[CH:14]2)=[N:5][N:4]=1
Reactant: O=Cc1ccc(-c2nc3ccn4c(CO)nnc4c3cc2-c2ccccc2)cc1
Reactant: [NH4+]
Agent: II
Agent: [OH-]
Solvent: C1CCOC1
Product: N#Cc1ccc(-c2nc3ccn4c(CO)nnc4c3cc2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred suspension of 14-2 (0.4 g, 1.1 mMol) in anhydrous THF (15 mL) was added 3 mL of concentrated NH4OH. The solution was then treated with iodine (0.4 g, 1.6 mMol) followed by stirring at room temperature overnight. The reaction was quenched with saturated sodium thiosulfate solution (20 mL) and the product was extracted into ethyl acetate three times. The combined organic layers were washed with brine, dried with Na2SO4, filtered and concentrated in vacuo to yield 15-1 as a tan solid. Mass (M+1) calculated: 378.135 observed: 378.1345
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:22]([NH2:25])([CH3:24])[CH3:23]>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:25][CH:22]([CH3:24])[CH3:23])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)N
Reactant: BrCCCCCOc1ccc(OCc2ccccc2)cc1
Product: CC(C)NCCCCCOc1ccc(OCc2ccccc2)cc1

Procedure:
As described in Example 19, 1-benzyloxy-4-(5-bromopentoxy)benzene was reacted with isopropylamine at 100° (12 hours; 150 psi) to give 1-benzyloxy-4-[5-(1-methylethyl)aminopentoxy]benzene. The distilled product was 95.2% pure by gas chromatography.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([O:10][CH3:11])=[O:9].[Li+].[CH3:13][Si]([N-][Si](C)(C)C)(C)C.IC>C1COCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([CH3:13])[C:8]([O:10][CH3:11])=[O:9]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: COC(=O)Cc1ccccn1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C(C)c1ccccn1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Methyl 2-pyridylacetate (6.81 mL, 50 mmol) was added dropwise to LHMDS (1.0M in THF, 50 mL) and THF (65 mL) cooled to 0° C. After 30 minutes iodomethane (3.97 g, 63.5 mmol) was added to the solution. After stirring for 1 hour at 0° C. the solution was concentrated and the residue was purified by silica gel chromatography using a hexanes/EtOAc gradient to give the indicated product. 1H NMR (400 MHz, CHCl3-d): δ 8.56 (d, J=4.9 Hz, 1H); 7.66 (td, J=7.6, 1.8 Hz, 1H); 7.18 (dd, J=7.6, 4.9 Hz, 1H); 3.96 (q, J=7.2 Hz, 1H); 3.69 (s, 3H). 1.56 (d, J=7.2 Hz, 3H). m/z 166.5 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([Si:13]([CH3:16])([CH3:15])[CH3:14])[C:3]=1[C:4]([NH:6][CH2:7][CH3:8])=[O:5].[Li]C(C)(C)C.CCCCC.C(Br)C[Br:29]>C1COCC1>[Br:29][CH2:16][Si:13]([CH3:15])([CH3:14])[C:9]1[CH:10]=[CH:11][CH:12]=[C:2]([Cl:1])[C:3]=1[C:4]([NH:6][CH2:7][CH3:8])=[O:5]
Reactant: BrCCBr
Reactant: CCNC(=O)c1c(Cl)cccc1[Si](C)(C)C
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: CCNC(=O)c1c(Cl)cccc1[Si](C)(C)CBr
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 17.9 %

Procedure:
To a solution of the compound of example 45 (1.28 g, 5 mmol) in THF (30 mL) at −78° C. was added a 1.7 M solution of t-BuLi in pentane (6.5 mL, 11 mmol, 2.2 eq) such that the temperature was less than −70° C. The reaction was stirred at −78° C. for 1.5 h and ethylene dibromide (0.52 mL, 6.0 mmol, 1.2 eq) was added. The reaction was stirred for 15 min at −78° C. and worked up in the usual manner. The crude product was purified by RC and recrystallized from aq methanol to afford the title compound as white needles (0.30 g, 18%). m.p. 98-99° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[C:16]3[O:15][CH2:14][CH:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)[N:12]4[C:23](=O)[NH:24][C:10]([C:11]=34)=[CH:9][CH:8]=2)=[C:5]([CH3:26])[O:4][N:3]=1.COC1C=CC(P2(=S)SP(C3C=CC(OC)=CC=3)(=S)[S:36]2)=CC=1>O1CCOCC1>[CH3:1][C:2]1[C:6]([C:7]2[C:16]3[O:15][CH2:14][CH:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)[N:12]4[C:23](=[S:36])[NH:24][C:10]([C:11]=34)=[CH:9][CH:8]=2)=[C:5]([CH3:26])[O:4][N:3]=1
Reactant: Cc1noc(C)c1-c1ccc2[nH]c(=O)n3c2c1OCC3c1ccccn1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Product: Cc1noc(C)c1-c1ccc2[nH]c(=S)n3c2c1OCC3c1ccccn1
Temperature: 100 °C

Procedure:
7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one (50 mg, 0.1 mmol) from Example 13 was stirred in 1,4-dioxane (2 mL) and 2,4-bis(4-methoxyphenyl)-2,4-dithioxo-1,3,2,4-dithiadiphosphetane [Aldrich #: 227439](58 mg, 0.14 mmol) was added. The mixture was heated to 100° C. for 3 h and concentrated. Purification by preparative LCMS (pH 10) afforded the title compound. LCMS calc. for C19H17N4O2S (M+H)+: m/z=365.1. found: 365.1.
Reaction SMILES: [CH2:1]([CH:5]1[CH2:9][O:8][C:7]([CH3:11])([CH3:10])[O:6]1)[CH2:2][C:3]#[CH:4].CN1C(=O)N(C)CCC1.[Li][CH2:22][CH2:23][CH2:24][CH3:25].CCCCCC>C1COCC1>[CH:24]1([CH2:25][C:4]#[C:3][CH2:2][CH2:1][CH:5]2[CH2:9][O:8][C:7]([CH3:11])([CH3:10])[O:6]2)[CH2:22][CH2:23]1
Reactant: [Li]CCCC
Reactant: C#CCCC1COC(C)(C)O1
Solvent: CN1CCCN(C)C1=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC1(C)OCC(CCC#CCC2CC2)O1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of 4-But-3-ynyl-2,2-dimethyl-[1,3]dioxolane (6 mmol, 1.0 g) in 40 ml anhydrous THF and anhydrous DMPU (26 mmol, 3 g) was added a solution of 2.5M BuLi in hexane (9.01 mmol, 3.6 mL) at −78° C. It was stirred at −78° C. for 15 minutes and slowly warmed up to room temperature. The reaction mixture was quenched with sat. NH4Cl and extracted by EtOAc. The combined organic layer was washed with H2O and brine, dried by MgSO4 and concentrated. Silica gel chromatography (2˜10% EtOAc/Hexane) 4-(5-Cyclopropyl-pent-3-ynyl)-2,2-dimethyl-[1,3]dioxolane as a clear oil; 1H NMR (400 MHz, CDCl3): δ 4.22-5.15 (m, 1H), 4.07 (dd, 1H, J1=8.0 Hz, J2=6.0 Hz), 3.57 (dd, 1H, J1=7.9 Hz, J2=7.1 Hz), 2.29-2.23 (m, 2H), 2.20-2.16 (m, 2H), 1.83-1.77 (m, 1H), 1.72-1.65 (m, 1H), 1.40 (s, 3H), 1.35 (s, 3H), 0.91-0.86 (m, 1H), 0.46-0.41(m, 2H), 0.21-0.17 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:25]([O:26][CH3:27])=[CH:24][CH:23]=[CH:22][C:3]=1[O:4][C:5]1[CH2:9][N:8]([CH:10]([CH2:14][CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:11](O)=[O:12])[C:7](=[O:21])[CH:6]=1.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[NH2:49][C:50]1[CH:54]=[CH:53][N:52]([CH2:55][C:56]([CH3:59])([OH:58])[CH3:57])[N:51]=1>ClCCl>[Cl:1][C:2]1[C:25]([O:26][CH3:27])=[CH:24][CH:23]=[CH:22][C:3]=1[O:4][C:5]1[CH2:9][N:8]([CH:10]([CH2:14][CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:11]([NH:49][C:50]2[CH:54]=[CH:53][N:52]([CH2:55][C:56]([OH:58])([CH3:57])[CH3:59])[N:51]=2)=[O:12])[C:7](=[O:21])[CH:6]=1
Reactant: COc1cccc(OC2=CC(=O)N(C(CC3CCOCC3)C(=O)O)C2)c1Cl
Reactant: CC(C)(O)Cn1ccc(N)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COc1cccc(OC2=CC(=O)N(C(CC3CCOCC3)C(=O)Nc3ccn(CC(C)(C)O)n3)C2)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.1 %

Procedure:
A solution of 2-[4-(2-chloro-3-methoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-(tetrahydro-pyran-4-yl)-propionic acid (200 mg, 0.51 mmol) in dichloromethane (10 mL) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (86 mg, 0.56 mmol) and 1-hydroxybenzotriazole (72 mg, 0.53 mmol). The reaction mixture was stirred at 25° C. for 2 h followed by the addition of 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in U.S. Pat. Appl. US2008021032 Example 80, 94 mg, 0.61 mmol). The reaction mixture was stirred for 18 h at 25° C., under nitrogen. The reaction mixture was diluted with dichloromethane, washed with 2N aqueous hydrochloric acid, saturated sodium bicarbonate solution, a saturated sodium chloride solution and dried over magnesium sulfate. The organic layer was concentrated, and the crude product was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 12 g; 0% to 10% methanol/dichloromethane) to afford 2-[4-(2-chloro-3-methoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-3-(tetrahydro-pyran-4-yl)-propionamide (166 mg, 62%), as an off-white solid: LR-ES-MS m/z calculated for C26H33ClN4O6 [M]+ 532, observed [M+H]+ 533; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.04 (s, 3H), 1.06 (s, 3H), 1.13-1.30 (m, 2H), 1.37 (br. s., 1H), 1.55-1.73 (m, 3H), 1.72-1.87 (m, 1H), 3.13-3.31 (m, 2H), 3.74-3.87 (m, 2H), 3.89 (br. s., 2H), 3.90 (s, 3H), 4.24 (d, J=18.6 Hz, 1H), 4.60 (d, J=18.6 Hz, 1H), 4.68 (s, 1H), 4.82 (s, 1H), 4.92 (dd, J=10.7, 4.7 Hz, 1H), 6.44 (d, J=2.1 Hz, 1H), 7.09 (d, J=8.5 Hz, 1H), 7.13 (d, J=8.5 Hz, 1H), 7.42 (t, J=8.5 Hz, 1H), 7.54 (d, J=2.1 Hz, 1H), 10.81 (s, 1H).
Reaction SMILES: Cl.[CH2:2](N=C=NCCCN(C)C)C.Cl.[CH2:14]([O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][C:23]=1[O:30][CH3:31])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:32]([O:36][C:37]([N:39]1[CH2:43][CH2:42][C@H:41]([C:44]([OH:46])=O)[CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33].C(N(CC)CC)C>C(Cl)Cl>[CH2:14]([O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH:27][C:44]([C@H:41]2[CH2:2][CH2:42][CH2:43][N:39]([C:37]([O:36][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:38])[CH2:40]2)=[O:46])=[CH:24][C:23]=1[O:30][CH3:31])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COc1cc(CN)ccc1OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](C(=O)O)C1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(CNC(=O)[C@H]2CCCN(C(=O)OC(C)(C)C)C2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 69.4 %

Procedure:
1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.12 g) was added to a mixture of 4-benzyloxy-3-methoxybenzylamine hydrochloride (1.26 g), (S)-1-(t-butoxycarbonyl)pyrrolidine-3-carboxylic acid (0.97 g), triethylamine (0.82 ml) and methylene chloride (20 ml). After stirring the reaction mixture at room temperature for 20 hours, the mixture was washed with saturated ammonium chloride aqueous solution and then saturated brine, the organic layer was dried over sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: hexane/ethyl acetate=100/0 to 0/100 gradient) to obtain 1.42 g of t-butyl (S)-3-(4-benzyloxy-3-methoxybenzylcarbamoyl)-piperidine-1-carboxylate.
Reaction SMILES: [CH2:1]([C@H:8]1[C:37](=[O:38])[N:36]([CH3:39])[C@@H:35]([CH2:40][CH:41]([CH3:43])[CH3:42])[C:34](=[O:44])[NH:33][C@@H:32]([C@H:45]([OH:47])[CH3:46])[C:31](=[O:48])[N:30]([CH3:49])[CH2:29][C:28](=[O:50])[N:27]([CH3:51])[C@@H:26]([CH2:52][CH:53]([CH3:55])[CH3:54])[C:25](=[O:56])[NH:24][C@@H:23]([CH2:57][O:58][C:59]([CH3:62])([CH3:61])[CH3:60])[C:22](=[O:63])[N:21]([CH3:64])[C@@H:20]([C@H:65]([CH2:67][CH3:68])[CH3:66])[C:19](=[O:69])[NH:18][C@H:17]([C:70]([N:72]2[CH2:77][CH2:76][CH2:75][CH2:74][CH2:73]2)=[O:71])[CH2:16][S:15][CH2:14][C:13](=[O:78])[N:12]([CH3:79])[C@@H:11]([CH3:80])[C:10](=[O:81])[N:9]1[CH3:82])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH:84]OS([O-])=O.[K+].CS(C)=O>CO>[CH2:1]([C@H:8]1[C:37](=[O:38])[N:36]([CH3:39])[C@@H:35]([CH2:40][CH:41]([CH3:42])[CH3:43])[C:34](=[O:44])[NH:33][C@@H:32]([C@H:45]([OH:47])[CH3:46])[C:31](=[O:48])[N:30]([CH3:49])[CH2:29][C:28](=[O:50])[N:27]([CH3:51])[C@@H:26]([CH2:52][CH:53]([CH3:55])[CH3:54])[C:25](=[O:56])[NH:24][C@@H:23]([CH2:57][O:58][C:59]([CH3:60])([CH3:62])[CH3:61])[C:22](=[O:63])[N:21]([CH3:64])[C@@H:20]([C@H:65]([CH2:67][CH3:68])[CH3:66])[C:19](=[O:69])[NH:18][C@H:17]([C:70]([N:72]2[CH2:73][CH2:74][CH2:75][CH2:76][CH2:77]2)=[O:71])[CH2:16][S:15](=[O:84])[CH2:14][C:13](=[O:78])[N:12]([CH3:79])[C@@H:11]([CH3:80])[C:10](=[O:81])[N:9]1[CH3:82])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S([O-])OO
Reactant: CC[C@H](C)[C@H]1C(=O)N[C@H](C(=O)N2CCCCC2)CSCC(=O)N(C)[C@@H](C)C(=O)N(C)[C@@H](Cc2ccccc2)C(=O)N(C)[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N(C)CC(=O)N(C)[C@@H](CC(C)C)C(=O)N[C@@H](COC(C)(C)C)C(=O)N1C
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: CO
Product: CC[C@H](C)[C@H]1C(=O)N[C@H](C(=O)N2CCCCC2)CS(=O)CC(=O)N(C)[C@@H](C)C(=O)N(C)[C@@H](Cc2ccccc2)C(=O)N(C)[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N(C)CC(=O)N(C)[C@@H](CC(C)C)C(=O)N[C@@H](COC(C)(C)C)C(=O)N1C
Yield: 89.3 %

Procedure:
(5S,8S,11S,14S,20S,23S,26S,29R)-8-Benzyl-23-(tert-butoxymethyl)-26-((S)-sec-butyl)-14-((R)-1-hydroxyethyl)-11,20-diisobutyl-4,5,7,10,16,19,25-heptamethyl-29-(piperidine-1-carbonyl)-1-thia-4,7,10,13,16,19,22,25,28-nonaazacyclotriacontane-3,6,9,12,15,18,21,24,27-nonone (Compound P-109) (9.5 mg, 8.11×10−3 mmol) was dissolved in methanol (0.5 ml), and water (0.25 ml) was added. The solution was cooled in an ice bath with stirring, and oxone (5.5 mg, 8.92×10−3 mmol) was added. The reaction mixture was stirred under ice-cooling for 25 minutes, and DMSO (80 μl) was then added. The mixture was purified by reverse-phase silica gel column chromatography (10 mM aqueous ammonium acetate solution/methanol=60/40→0/100) to afford (5S,8S,11S,14S,20S,23S,26S,29R)-8-benzyl-23-(tert-butoxymethyl)-26-((S)-sec-butyl)-14-((R)-1-hydroxyethyl)-11,20-diisobutyl-4,5,7,10,16,19,25-heptamethyl-29-(piperidine-1-carbonyl)-1-thia-4,7,10,13,16,19,22,25,28-nonaazacyclotriacontane-3,6,9,12,15,18,21,24,27-nonone 1-oxide (Compound P-114) (8.6 mg, 90%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.[F:24][C:25]([F:34])([F:33])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1Br>>[F:1][C:2]1[CH:7]=[C:6]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[C:25]([F:34])([F:33])[F:24])[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Reactant: FC(F)(F)c1ccccc1Br
Product: Nc1cnc(-c2ccc(-c3ccccc3C(F)(F)F)cc2F)cn1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 1 utilizing 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amine and 2-trifluoromethylbromobenzene. MS (ESI): mass calcd. for C17H11F4N3, 333.09; m/z found, 334.1 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.40 (s, 1H), 8.09 (s, 1H), 7.91 (m, 1H), 7.81 (d, J=7.6, 1H), 7.69 (m, 1H), 7.59 (m, 1H), 7.44 (d, J=7.8, 1H), 7.23 (d, J=8.7, 1H), 7.17 (d, J=11.8, 1H).
Reaction SMILES: Cl.[CH:2]([O:5][C:6](=[O:10])[C@@H:7]([CH3:9])[NH2:8])([CH3:4])[CH3:3].N(C(OCC1C=CC=CC=1)=O)[C@H](C(O)=O)CC(=O)OCC1C=CC=CC=1.COC(=O)[C@H](CC1C=CC=CC=1)N[C:42](=[O:55])[C@:43]([NH2:54])([CH2:50][C:51](=[O:53])[OH:52])[NH:44][C:45](=[O:49])[CH:46]([CH3:48])[CH3:47]>>[CH:2]([O:5][C:6](=[O:10])[C@@H:7]([CH3:9])[NH:8][C:42](=[O:55])[C@:43]([NH2:54])([CH2:50][C:51](=[O:52])[OH:53])[NH:44][C:45](=[O:49])[CH:46]([CH3:48])[CH3:47])([CH3:4])[CH3:3]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@](N)(CC(=O)O)NC(=O)C(C)C
Reactant: CC(C)OC(=O)[C@@H](C)N
Agent: Cl
Agent: O=C(C[C@H](NC(=O)OCc1ccccc1)C(=O)O)OCc1ccccc1
Product: CC(C)OC(=O)[C@@H](C)NC(=O)[C@](N)(CC(=O)O)NC(=O)C(C)C

Procedure:
This compound was prepared from 1.7 g D-alanine isopropyl ester hydrochloride, 3.6 g Z-Asp(OBzl) and 1.8 g N-t-butoxycarbonyl-α-aminoisobutyric acid N-hydroxysuccinimide ester in a manner similar to Example 20 (A), (C), (D) and (E). Yield: 1.2 g, m.p.: 176°-178° C.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:21])=[C:4]2[C:9]3=[C:10]([C:12](=[O:19])[C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:14][N:8]3[N:7]([CH3:20])[CH2:6][CH2:5]2)[CH:11]=1.N1C=CC=CC=1.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(Cl)(Cl)Cl>[F:1][C:2]1[C:3]([O:21][S:29]([CH3:28])(=[O:31])=[O:30])=[C:4]2[C:9]3=[C:10]([C:12](=[O:19])[C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:14][N:8]3[N:7]([CH3:20])[CH2:6][CH2:5]2)[CH:11]=1
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1cn2c3c(c(O)c(F)cc3c1=O)CCN2C
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: COC(=O)c1cn2c3c(c(OS(C)(=O)=O)c(F)cc3c1=O)CCN2C
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.5 %

Procedure:
304 mg of the compound (167) obtained in Example 44 was added to 2 ml of pyridine, and 120 mg of methane-sulfonyl chloride was added to the solution. The solution was stirred for 3 hours at room temperature. 50 ml of chloroform was added to the solution, and the solution was washed with aqueous 5% citric acid solution. The organic layer was separated, and after drying over magnesium sulfate, the solvent was removed by distillation. To the residue, ethanol was added, and the solid matter was filtered off and washed with isopropyl ether to obtain 260 mg of the subject compound (168).
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:16])[C:4](=[O:15])[C:5]1[CH:10]=[C:9]([CH:11]=[O:12])[CH:8]=[CH:7][C:6]=1[O:13][CH3:14].[CH2:17](O)[CH2:18][OH:19]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[CH3:1][O:2][N:3]([CH3:16])[C:4](=[O:15])[C:5]1[CH:10]=[C:9]([CH:11]2[O:19][CH2:18][CH2:17][O:12]2)[CH:8]=[CH:7][C:6]=1[O:13][CH3:14]
Reactant: COc1ccc(C=O)cc1C(=O)N(C)OC
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(C2OCCO2)cc1C(=O)N(C)OC
Yield: 84 %

Procedure:
N-Methoxy-N-methyl-5-formyl-2-methoxybenzamide (6.56 g, 29.4 mnmol), ethylene glycol (8.20 mL, 147 mmol), p-toluenesulfonic acid monohydrate (110 mg, 0.578 mmol) and toluene (100 mL) were mixed, and, while removing water generated using dean-stark apparatus, the mixture was refluxed for 4 hours. After allowed to stand for cooling, ethyl acetate was added, which was washed with saturated aqueous solution of sodium hydrogencarbonate and water in sequence. Then, the organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluate n-hexane:ethyl acetate=1:2 v/v) to obtain 6.60 g (84%) of the title compound as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20])(=[O:13])=[O:12].[CH2:21]([Sn](CCCC)(CCCC)C=C)[CH2:22]CC>CC#N>[CH3:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[S:11]([N:6]1[C:7]2[C:3](=[C:2]([CH:21]=[CH2:22])[CH:10]=[CH:9][CH:8]=2)[CH:4]=[CH:5]1)(=[O:13])=[O:12]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1ccccc1S(=O)(=O)n1ccc2c(Br)cccc21
Solvent: CC#N
Product: C=Cc1cccc2c1ccn2S(=O)(=O)c1ccccc1C
Yield: 70.5 %

Procedure:
4-Bromo-1-[(2-methylphenyl)sulfonyl]-1H-indole (500 mg, 1.43 mmol; Intermediate 14) was dissolved in dry MeCN (8 mL) and distributed into two microwave vials. Tributyl(vinyl)stannane (0.417 mL, 1.43 mmol) and Pd(PPh3)2OAc2 (27 mg, 0.036 mmol) was added to each vial. The reaction mixtures were irradiated with microwaves at 180° C. for 720 s. The mixtures were combined, filtered and concentrated. Purification was performed by flash chromatography (30% hexane in DCM). This afforded the product (300 mg, 71%) as a yellow sticky oil. MS (ESI+) for C17H15NO2S m/z 298 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[NH2:11][C:12]1[CH:13]=[CH:14][C:15]([F:35])=[C:16]([C@:18]23[O:26][CH2:25][CH2:24][C@H:23]2[CH2:22][S:21][C:20]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[N:19]3)[CH:17]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[F:35][C:15]1[CH:14]=[CH:13][C:12]([NH:11][C:8](=[O:10])[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=2)=[CH:17][C:16]=1[C@:18]12[O:26][CH2:25][CH2:24][C@H:23]1[CH2:22][S:21][C:20]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[N:19]2
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc(N)ccc3F)OCC[C@H]2CS1
Reactant: O=C(O)c1ccc(F)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: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc(NC(=O)c4ccc(F)cn4)ccc3F)OCC[C@H]2CS1
Yield: 40 %

Procedure:
A solution of 5-fluoropicolinic acid (6.34 mg, 0.045 mmol), tert-butyl ((4aR,7aR)-7a-(5-amino-2-fluorophenyl)-4a,5,6,7a-tetrahydro-4H-furo[2,3-d][1,3]thiazin-2-yl)carbamate (11 mg, 0.030 mmol), HATU (17.07 mg, 0.045 mmol), Hunig's Base (10.46 μL, 0.060 mmol) in DMF (299 μL) was stirred at rt for 10 h. The crude reaction mixture was purified by reverse phase preparative HPLC on a Luna C18 column (10 μM, 30×100 mm) eluting with 0-100% B (A: 95% eater/5% MeCN/10 nM NH4OAc, B: 5% water/95% MeCN/10 mM NH4OAc) over 12 min to give tert-butyl ((4aR,7aR)-7a-(2-fluoro-5-(5-fluoropicolinamido)phenyl)-4a,5,6,7a-tetrahydro-4H-furo[2,3-d][1,3]thiazin-2-yl)carbamate (6 mg, 0.012 mmol, 40.9% yield) as a white solid.