Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C@@H:4]3[NH2:11])[CH2:2]1)[CH2:8]2.[OH:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1.N>>[N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C@@H:4]3[NH:11][C:17](=[O:18])[C:16]3[CH:20]=[CH:21][C:13]([OH:12])=[CH:14][CH:15]=3)[CH2:2]1)[CH2:8]2
Reactant: NC1C2CC3CC1CN(C3)C2
Reactant: O=C(O)c1ccc(O)cc1
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1ccc(O)cc1

Procedure:
Prepared from (4s)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine and 4-hydroxybenzoic acid (Aldrich) according to method B; 1H NMR (500 MHz, methanol-d4) δ 1.91-1.98 (m, 5H), 2.14 (s, 1H), 2.27-2.34 (m, 2H), 2.36-2.43 (m, 1H), 3.50 (s, 2H), 3.60 (s, 3H), 4.36 (s, 1H), 6.70-6.98 (m, 2H), 7.56-7.82 (m, 2H); MS (APCI/NH3) m/z 273 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]=1[CH3:13].[CH3:14][C:15]1([CH3:31])[O:20][C:19]2[CH:21]=[C:22]([CH:25]=[CH:26][C:27]([OH:29])=O)[CH:23]=[N:24][C:18]=2[NH:17][C:16]1=[O:30]>>[CH3:31][C:15]1([CH3:14])[O:20][C:19]2[CH:21]=[C:22](/[CH:25]=[CH:26]/[C:27]([N:2]([CH3:1])[CH2:3][C:4]3[C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=4[O:6][C:5]=3[CH3:13])=[O:29])[CH:23]=[N:24][C:18]=2[NH:17][C:16]1=[O:30]
Reactant: CNCc1c(C)oc2ccccc12
Reactant: CC1(C)Oc2cc(C=CC(=O)O)cnc2NC1=O
Product: Cc1oc2ccccc2c1CN(C)C(=O)/C=C/c1cnc2c(c1)OC(C)(C)C(=O)N2
Yield: 81.3 %

Procedure:
According to the procedure of Example 43d, methyl-(2-methyl-benzofuran-3-ylmethyl)-amine (124 mg, 0.71 mmol) and 3-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-acrylic acid (160 mg, 0.64 mmol) were coupled to yield the title compound (211 mg, 81%) as a white solid and as a mixture of amide rotomers. 1H NMR (400 MHz, DMSO-d6) δ 11.39 (1s, 1H), 8.20 (1s, 1H), 7.92 (1s, 1H), 7.54-7.58 (m, 2H), 7.46-7.48 (m, 1H), 7.17-7.25 (m, 3H), 4.72-4.93 (m, 2H), 3.32 (s, 3H), 3.04 (s, 2H), 2.47 (s, 3H), 1.43 (1s, 6H); MS (ESI) m/e 406 (C23H23N3O4+H)+.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[C:9]([N:13]([CH2:17][CH3:18])[C:14](=[O:16])[CH3:15])[CH:10]=[CH:11][CH:12]=1)=O.[NH2:20][C:21]1[C:25]([C:26]#[N:27])=[CH:24][NH:23][N:22]=1>O.Cl>[C:26]([C:25]1[CH:24]=[N:23][N:22]2[CH:3]=[CH:4][C:5]([C:7]3[CH:8]=[C:9]([N:13]([CH2:17][CH3:18])[C:14](=[O:16])[CH3:15])[CH:10]=[CH:11][CH:12]=3)=[N:20][C:21]=12)#[N:27]
Reactant: CCN(C(C)=O)c1cccc(C(=O)C=CN(C)C)c1
Reactant: N#Cc1c[nH]nc1N
Agent: Cl
Solvent: O
Product: CCN(C(C)=O)c1cccc(-c2ccn3ncc(C#N)c3n2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 1.6 %

Procedure:
N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]-N-ethylacetamide (5.2 g, 0.02 mol) and 3-amino-4cyanopyrazole (2.16 g, 0.02 mol) were dissolved in the mixture of water (50 ml) and concentrated hydrochloric acid (40 ml) and the mixture was stirred at room temperature for 8 h. The reaction mixture was then cooled to 5° C. and the precipitate was removed by filtration. The filtrate was neutralized by concentrated aqueous ammonia solution to precipitate 380 mg of the mixture of zaleplon and its regioisomer 5 which was collected by filtration. The filtrate was extracted with 100 ml of ethylacetate to give 100 mg of the mixture of the above two compounds upon evaporation. The two crops combined were put to a silica gel column (100 g) and the elution was performed by the solvent mixture of chloroform and acetone 3:1 (v/v) to yield as a second crop 240 mg (4%) of 5; mp 194-196° C.; 1H-NMR (CDCl3) δ (ppm) 1.143 (t, 3H), 1.876 (s, 3H), 3.804 (q,2H), 7.361 (d, 1H), 7.532 (d, 1H), 7.613 (t, 1H), 8.018 (s, 1H), 8.159 (d, 1H), 8.375 (s, 1H) 8.805 ((d, 1H); 13C-NMR (CDCl3) δ (ppm) 12.89, 22.68, 43.84, 83.17, 107.71, 112.84, 127.17, 127.48, 130.62, 131.63, 136.67, 137.46, 144.10, 148.31, 149.99, 158.60, 169.90, MS (EI, 70 EV) m/z (%) 305 (M+, 18), 248 (59).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:7][CH3:8])[C:4](=[O:6])[CH3:5].C(O)[C:10]([CH3:13])([CH3:12])[CH3:11]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:11][C:10]([CH3:13])([CH3:12])[CH2:1][O:2][CH:3]([O:7][CH2:8][C:10]([CH3:13])([CH3:12])[CH3:11])[C:4](=[O:6])[CH3:5]
Reactant: CC(C)(C)CO
Reactant: COC(OC)C(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CC(=O)C(OCC(C)(C)C)OCC(C)(C)C
Temperature: 80 °C
Yield: 67.2 %

Procedure:
Add p-toluenesulfonic acid hydrate (1.21 g, 10.58 mmol) to 1,1-dimethoxy-propan-2-one (25.00 g, 211.63 mmol) and neopentyl alcohol (46.64 g, 529.08 mmol) at room temperature. Heat in an open flask in an 80° C. oil bath for 8 hours. Allow to cool to room temperature and stir over the weekend. Purify (silica gel chromatography, eluting with 0:100 to 8:92 ethyl acetate:hexanes) to give the desired compound as a colorless oil (32.78 g 67.2%)
Reaction SMILES: [N:1](CCCCCNCCCCCN=[N+]=[N-])=[N+:2]=[N-:3].[OH:18][C:19]([CH2:21][CH2:22][CH2:23][CH2:24][C@H:25]1[C@@H:33]2[C@@H:28]([NH:29][C:30]([NH:32]2)=[O:31])[CH2:27][S:26]1)=[O:20].C1CN([P+](O[N:51]2[N:59]=[N:58]C3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(CC)CC>CN(C=O)C>[N-:1]=[N+:2]=[N-:3].[N-:58]=[N+:59]=[N-:51].[OH:20][C:19]([CH2:21][CH2:22][CH2:23][CH2:24][C@H:25]1[C@@H:33]2[C@@H:28]([NH:29][C:30]([NH:32]2)=[O:31])[CH2:27][S:26]1)=[O:18]
Reactant: [N-]=[N+]=NCCCCCNCCCCCN=[N+]=[N-]
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: [N-]=[N+]=[N-]
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a solution of di(5-azidopentyl)amine (0.12 g, 0.49 mmol) in anhydrous DMF (5 mL) of were added biotin (0.12 g, 0.41 mmol), PyBOP (0.25 g, 0.49 mmol) and Et3N (0.23 mL, 1.64 mmol). The mixture was stirred for 22 h at room temperature under argon, and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, CH2Cl2/MeOH=13:1) to give biotin-diazide compound 25 (0.15 g, 79%). C20H35N9O2S; pale yellow oil; 1H NMR (CDCl3, 600 MHz) δ 4.48 (dd, J=7, 5 Hz, 1 H), 4.29 (dd, J=7, 5 Hz, 1 H), 3.28 (t, J=7 Hz, 4 H), 3.25 (t, J=7 Hz, 4 H), 3.20 (t, J=7 Hz, 2 H), 2.89 (dd, J=12, 5 Hz, 1 H), 2.71 (d, J=12 Hz, 1 H), 2.29 (t, J=7 Hz, 2H), 1.84 (br s, 3 H), 1.50-1.67 (m, 8 H), 1.43-1.44 (m, 2 H), 1.32-1.38 (m, 4 H); 13C NMR (CDCl3, 150 MHz) δ 172.4, 163.2, 61.8, 60.1, 55.3, 51.2, 47.0, 46.2, 45.6, 40.5, 32.5, 28.7, 28.6, 28.3, 27.3, 26.4, 25.1, 24.1. ESI-HRMS calcd for C20H36N9O2S: 466.2707, found: m/z 466.2703 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](O)=[C:6]([C:8]2([CH2:31][OH:32])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:9]2=[O:30])[CH:7]=1.C1(CCN2C3C(=CC=CC=3)C(C3C(O)=CC4OCOC=4C=3)(CO)C2=O)CC1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:32][CH2:31][C:8]3([C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]([CH:17]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:9]3=[O:30])[C:6]=2[CH:7]=1
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C1(CO)c1cc(Br)ccc1O
Agent: O=C1N(CCC2CC2)c2ccccc2C1(CO)c1cc2c(cc1O)OCO2
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C12COc1ccc(Br)cc12

Procedure:
Following the procedure as described in Example 1, and making non-critical variations using 3-(5-bromo-2-hydroxyphenyl)-1-(diphenylmethyl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one to replace 1-(2-cyclopropylethyl)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one, the title compound was obtained (72%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 7.43-7.25 (m, 11H), 7.14-6.93 (m, 4H), 6.83 (d, 1H), 6.71 (d, 1H), 6.52 (d, 1H), 5.0 (d, 1H), 4.73 (d, 1H); MS (ES+) m/z 484.4 (M+1), 482.4 (M+1).
Reaction SMILES: [C:1]1([C:7]2[N:12]=[N:11][CH:10]=[N:9][C:8]=2[NH2:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23](Cl)=[O:24]>ClCCCl>[C:26]1([C:22]2[N:9]3[CH:10]=[N:11][N:12]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:8]3=[N:13][C:23]=2[OH:24])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)C(Cl)c1ccccc1
Reactant: Nc1ncnnc1-c1ccccc1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: Oc1nc2c(-c3ccccc3)nncn2c1-c1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 42.2 %

Procedure:
To a solution of 6-phenyl-[1,2,4]triazin-5-ylamine (1.1 g, 6.4 mmol) and triethylamine (891 μl, 6.4 mmol) in anhydrous 1,2-dichloroethane (75 ml) under an atmosphere of nitrogen was added dropwise 2-chloro-2-phenylacetyl chloride (1.01 ml, 6.4 mmol). The reaction mixture was stirred at 0° C. for 90 min, then triethylamine (891 μl, 6.4 mmol) was added, and the resulting mixture heated under reflux for 30 min. The cooled reaction mixture was partitioned between CH2Cl2 (100 ml) and water (100 ml). The organic layer was separated, dried over MgSO4 and evaporated in vacuo. The solid residue was triturated with a 1:1 mixture of CH2Cl2 and MeOH (10 ml), filtered and dried to give 780 mg (2.7 mmol, 42%) of 3,8-diphenylimidazo[1,2-d][1,2,4]triazin-2-ol as a pale yellow solid. δH (360 MHz; DMSO-d6) 7.41 (1H, t, J 7.3 and 7.2, aromatic), 7.50-7.63 (5H, m, aromatics), 7.82 (2H, d, J 7.8, aromatics), 8.57 (2H, m, aromatics), 9.65 (1H, s, imidazotriazine H5), 11.72 (1H, br s, OH); m/z (ES+) 289 (M++H, 100%).
Reaction SMILES: C(N(CC)C(C)C)(C)C.Br[C:11]1[S:12][CH:13]=[C:14]([Br:16])[N:15]=1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>CCO>[Br:16][C:14]1[N:15]=[C:11]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[S:12][CH:13]=1
Reactant: C1COCCN1
Reactant: Brc1csc(Br)n1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Brc1csc(N2CCOCC2)n1
Temperature: 140 °C
Yield: 68.5 %

Procedure:
To a microwave vial was added N,N-diisopropylethylamine (0.86 ml, 4.9 mmol), 2,4-dibromothiazole (1.00 g, 4.1 mmol), and morpholine (0.43 ml, 4.9 mmol) in EtOH (4 mL). The mixture was heated under microwave irradiation at 140° C. for 35 minutes. The reaction mixture was concentrated in vacuo. The crude material was dissolved in minimal DCM/MeOH and purified via MPLC (eluting with 0-30% EtOAc in hexnaes) to yield 4-(4-bromothiazol-2-yl)morpholine (0.700 g, 68% yield) as a white solid.
Reaction SMILES: CS[C:3]1[CH2:4][CH2:5][C@@H:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[N:7]=1.[NH4+:15].[Cl-:16]>CO>[ClH:16].[NH2:15][C:3]1[CH2:4][CH2:5][C@@H:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[N:7]=1
Reactant: [NH4+]
Reactant: CSC1=N[C@H](C(=O)OC(C)(C)C)CC1
Reactant: [Cl-]
Solvent: CO
Product: CC(C)(C)OC(=O)[C@@H]1CCC(N)=N1
Product: Cl
Reaction time: 0.33 h
Yield: 79.7 %

Procedure:
To a solution of 1c (10.17 g, 47.2 mmol) in 100 mL MeOH, was added NH4Cl (2.65 g, 49.6 mmol). The mixture was refluxed for 2 h, then concentrated. The residue was taken up in 200 mL CHCl3 and stirred for 20 min until only a fine suspension persisted. The mixture was filtered and the filtrate concentrated. The solid was suspended in hexanes, sonicated, and then filtered and dried to afford 8.30 g (80%) of 1d as an off-white solid. 1H NMR (300 MHz, CDCl3) δ4.44 (dd, J=8.8, 5.1, 1H), 3.11-3.05 (m, 2H), 2.58-2.45 (m, 1H), 2.28-2.15 (m,1H), 1.48 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:30])[CH2:24][O:25][CH2:26][C:27](O)=[O:28])=[C:18]([C:31]([O:33]C)=[O:32])[CH:17]=1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:30])[CH2:24][O:25][CH2:26][C:27]([NH:14][C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:9][CH:10]=2)=[O:28])=[C:18]([CH:17]=1)[C:31]([OH:33])=[O:32]
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)COCC(=O)O
Reactant: Nc1ccc(-c2ccc(F)cc2)cc1
Product: O=C(COCC(=O)Nc1ccc(Cl)cc1C(=O)O)Nc1ccc(-c2ccc(F)cc2)cc1

Procedure:
Using the same method as in Example 1-(ii), 4′-fluorobiphenyl-4-yl amine was reacted with the (2-([4-chloro-2-(methoxycarbonyl)phenyl]amino)-2-oxoethoxy)acetic acid obtained in Example 1-(i) to give 5-chloro-2-[((2-[(4′-fluorobiphenyl-4-yl)amino]-2-oxoethoxy)acetyl)amino]benzoic acid.methyl ester (yield: 86%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[C:14]([O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[F:25])[C:13](=[O:26])[N:12]([CH3:27])[C:11]=2[C:10](I)=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].[Cl:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1B(O)O>C1C=CC=CC=1.CO.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>[C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[C:14]([O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[F:25])[C:13](=[O:26])[N:12]([CH3:27])[C:11]=2[C:10]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[Cl:35])=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccccc1Cl
Reactant: Cn1c(=O)c(Oc2ccc(F)cc2F)cc2c1c(I)nn2C(=O)OC(C)(C)C
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: [Na+]
Solvent: c1ccccc1
Solvent: CO
Product: Cn1c(=O)c(Oc2ccc(F)cc2F)cc2c1c(-c1ccccc1Cl)nn2C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
To a solution of 6-(2,4-difluorophenoxy)-3-iodo-4-methyl-5-oxo-4,5-dihydro-pyrazolo[4,3-b]pyridine-1-carboxylic acid tert-butyl ester (18 mg) in benzene (1.3 mL) and methanol (0.26 mL) was added I M aqueous solution of sodium carbonate (76 μL, 2 eq), 2-chlorophenylboronic acid (12 mg, 2 eq), and Pd(PPh3)4 (13 mg, 0.3 eq). The mixture was purged with argon, heated at reflux for 2 hours, cooled to room temperature, and diluted with ethyl acetate (35 mL) and water (25 mL). The organic layer was separated, washed with brine (1×25 mL), dried over magnesium sulfate, filtered and concentrated to give the crude product ((M+H)+=488) which was used without purification for the following step.
Reaction SMILES: ClC1N=C2[C:5]([N:6]=CN2)=[C:4]([NH:11][CH2:12][CH:13]([C:20]2[CH:25]=[CH:24]C=CC=2)C2C=CC=CC=2)N=1.Cl[C:27]1[N:35]=[C:34]2[C:30]([N:31]=[CH:32][N:33]2[C@@H:36]2[CH2:40][C@H:39]([NH:41][C:42]([C:44]3[O:48]N=CC=3)=[O:43])[C@@H:38]([OH:49])[C@H:37]2[OH:50])=[C:29]([NH:51][CH2:52][CH:53]([C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[N:28]=1.[NH2:66][CH2:67][CH2:68][N:69]1[CH2:74][CH2:73][CH2:72][CH2:71][CH2:70]1.[I-].[Na+]>>[C:60]1([CH:53]([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[CH2:52][NH:51][C:29]2[N:28]=[C:27]([NH:66][CH2:67][CH2:68][N:69]3[CH2:74][CH2:73][CH2:72][CH2:71][CH2:70]3)[N:35]=[C:34]3[C:30]=2[N:31]=[CH:32][N:33]3[C@@H:36]2[CH2:40][C@H:39]([NH:41][C:42](=[O:43])[C:44]([NH:6][CH2:5][CH2:4][N:11]3[CH2:12][CH2:13][CH2:20][CH2:25][CH2:24]3)=[O:48])[C@@H:38]([OH:49])[C@H:37]2[OH:50])[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=1
Reactant: NCCN1CCCCC1
Reactant: Clc1nc(NCC(c2ccccc2)c2ccccc2)c2nc[nH]c2n1
Reactant: O=C(N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O)c1ccno1
Agent: [I-]
Agent: [Na+]
Product: O=C(NCCN1CCCCC1)C(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(NCCN4CCCCC4)nc32)[C@H](O)[C@@H]1O

Procedure:
The title compound is prepared using a method that is analogous to that used to prepare the compound of Example 22 using isoxazole-5-carboxylic acid {(1S,2R,3S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-amide, 1-(2-aminoethyl)-piperidine (51 mg, 0.4 mmol) and sodium iodide (6 mg, 0.04 mmol). LCMS (electrospray): m/z [MH+] 739.55
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[C:12]([CH:23]([CH3:25])[CH3:24])=[CH:11][C:10]=1[C:26]1[N:27]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[C:34]([N:40]([CH3:44])[CH2:41][CH2:42][CH3:43])[CH:33]=2)[C:28]([OH:31])=[N:29][N:30]=1)C1C=CC=CC=1>CO.[Pd]>[OH:31][C:28]1[N:27]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[C:34]([N:40]([CH3:44])[CH2:41][CH2:42][CH3:43])[CH:33]=2)[C:26]([C:10]2[CH:11]=[C:12]([CH:23]([CH3:24])[CH3:25])[C:13]([OH:15])=[CH:14][C:9]=2[OH:8])=[N:30][N:29]=1
Reactant: CCCN(C)c1cc(-n2c(O)nnc2-c2cc(C(C)C)c(OCc3ccccc3)cc2OCc2ccccc2)ccc1OC
Agent: [Pd]
Solvent: CO
Product: CCCN(C)c1cc(-n2c(O)nnc2-c2cc(C(C)C)c(O)cc2O)ccc1OC
Reaction time: 16 h
Yield: 90.9 %

Procedure:
5-(2,4-Bis-benzyloxy-5-isopropyl-phenyl)-4-[4-methoxy-3-(methylpropylamino)phenyl]-4H-[1,2,4]triazol-3-ol (240 mg, 0.4 mmol) was dissolved in methanol (10 mL) then 10% palladium on charcoal (200 mg) was added and the reaction was stirred under an atmosphere of hydrogen for 16 hrs. Filtration was carried out through a silca gel plug and removal of the solvent under reduced pressure produced the desired compound as a white solid (150 mg, 94%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[C@H:15]([CH3:16])[N:14]([O:17][C:18]([CH3:23])([CH3:22])[C:19]([OH:21])=[O:20])[C:13]1=[O:24])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25]N(C1C=CC=CN=1)C.CO.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[C@H:15]([CH3:16])[N:14]([O:17][C:18]([CH3:23])([CH3:22])[C:19]([O:21][CH3:25])=[O:20])[C:13]1=[O:24])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H]1[C@H](NC(=O)OCc2ccccc2)C(=O)N1OC(C)(C)C(=O)O
Reactant: CN(C)c1ccccn1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)C(C)(C)ON1C(=O)[C@@H](NC(=O)OCc2ccccc2)[C@@H]1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred suspension of (3S-trans)-2-[[3-(benzyloxycarbonyl)amino4-methyl-2-oxo-1-azetidinyl]oxy]-2-methylpropanoic acid (1.68 g, 5.0 mmol) (see example 29) in 10 ml of dry dichloromethane were added 4 dimethylaminopyridine (30 mg), dry methanol 0.81 ml, 210 mmol) and dicyclohexylcarbodiimide (1.13 g, 5.5 mmol) at 0° C. The reaction mixture was stirred for 3 hours at room temperature. The precipitate (dicyclohexylurea) was removed by filtration and the filtrate was evaporated in vacuo. The residue was taken up in ether, filtered, washed with aqueous buffer solution pH 4 (citrate/HCl), NaHCO3 solution, dried over MgSO4 and filtered. Evaporation in vacuo gave the title compound.
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[CH:9]2.[CH:13]1([C:16]([C:19]2[CH:29]=[CH:28][C:22]3[O:23][C:24]([F:27])([F:26])[O:25][C:21]=3[CH:20]=2)(O)[CH3:17])[CH2:15][CH2:14]1.C1(C(C2C3C(=C(CSC)C=CC=3)NC=2)(C2C=CC(OC)=C(F)C=2)C)CC1>>[CH:13]1([C:16]([C:9]2[C:8]3[C:12](=[C:4]([CH2:3][S:2][CH3:1])[CH:5]=[CH:6][CH:7]=3)[NH:11][CH:10]=2)([C:19]2[CH:29]=[CH:28][C:22]3[O:23][C:24]([F:26])([F:27])[O:25][C:21]=3[CH:20]=2)[CH3:17])[CH2:15][CH2:14]1
Reactant: CC(O)(c1ccc2c(c1)OC(F)(F)O2)C1CC1
Reactant: CSCc1cccc2cc[nH]c12
Agent: COc1ccc(C(C)(c2c[nH]c3c(CSC)cccc23)C2CC2)cc1F
Product: CSCc1cccc2c(C(C)(c3ccc4c(c3)OC(F)(F)O4)C3CC3)c[nH]c12

Procedure:
The title compound was prepared starting from 32 mg (0.18 mmol) of the compound from Example 8A and 43 mg (0.18 mmol) of the compound from Example 144A in analogy to the synthesis of the compound from Example 186. 38 mg (53% of theory) of the target compound were obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[C:12]([CH3:16])([CH3:15])[C:13]#[CH:14].Br[C:19]1[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][C:20]=1[NH:27][S:28]([CH3:31])(=[O:30])=[O:29]>[Cu](I)I.CN(C=O)C>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[C:12]([C:13]1[N:27]([S:28]([CH3:31])(=[O:30])=[O:29])[C:20]2[C:19]([CH:14]=1)=[CH:24][CH:23]=[C:22]([C:25]#[N:26])[CH:21]=2)([CH3:15])[CH3:16]
Reactant: C#CC(C)(C)c1cc(OC)ccc1C(=O)OC
Reactant: CS(=O)(=O)Nc1cc(C#N)ccc1Br
Agent: I[Cu]I
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC)cc1C(C)(C)c1cc2ccc(C#N)cc2n1S(C)(=O)=O
Temperature: 90 °C
Reaction time: 2 h
Yield: 61.8 %

Procedure:
To the DMF (2 ml) solution of 2-(1,1-dimethylprop-2-ynyl)-4-methoxy-benzoic acid methyl ester (Compound AA3, 134 mg, 0.577 mmol) and N-(2-bromo-5-cyanophenyl)methanesulfonamide (Compound AA5, 167 mg, 1.05 eq.), copper iodide (9 mg, 0.08 eq.) and TEA (129 μl, 1.6 eq.) were added, degassed and flushed with nitrogen gas, added with dichlorobis(triphenylphosphine) palladium (20 mg, 0.05 eq.), and then degassed and flushed again with nitrogen gas. After stirring for 2 hr at 90° C., the reaction solution was added with water, extracted with ethyl acetate. The organic layer was washed with an brine and dried over magnesium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (white solid, 152 mg, 62%).
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[C:3]=1[CH:4]=[CH:5][C@H:6]1[O:11][CH2:10][C@@H:9]([CH2:12][OH:13])[N:8]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:7]1.C(C1NC=CN=1)(C1NC=CN=1)=[O:29].[N:40]1[CH:45]=CC=CC=1>>[C:45]([O:13][CH2:12][C@H:9]1[N:8]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:7][C@@H:6](/[CH:5]=[CH:4]/[C:3]2[C:21]([N+:25]([O-:27])=[O:26])=[CH:22][CH:23]=[CH:24][C:2]=2[F:1])[O:11][CH2:10]1)(=[O:29])[NH2:40]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](C=Cc2c(F)cccc2[N+](=O)[O-])OC[C@H]1CO
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: c1ccncc1
Product: CC(C)(C)OC(=O)N1C[C@@H](/C=C/c2c(F)cccc2[N+](=O)[O-])OC[C@H]1COC(N)=O
Temperature: 60 °C

Procedure:
To a solution of (2R,5R)-tert-butyl 2-[(E)-2-fluoro-6-nitrostyryl)-5-(hydroxymethyl)]morpholine-4-carboxylate (5 g, 13 mmol) from step 2 of Example 99 in pyridine (15 mL) was added carbonyl diimidazole (8.4 g, 52 mmol) and the mixture was heated in sealed tube at 60° C. for 2 h. The reaction mixture was cooled to ambient temperature, then purged with NH3 gas for 5 min and heated in a sealed tube at 60° C. for 16 h. The mixture was cooled to ambient temperature and the solvent was concentrated under reduced pressure. The residue was purified on an 80 g SiO2 column using gradient elution of 0-50% EtOAc in hexanes. Fractions containing product were combined and the solvents were removed under reduced pressure to give the product (5.50 g,) a pale yellow gum.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[C:8](=O)[N:7]2[CH2:10][CH2:11][NH:12][CH2:13][CH:6]2[C:5](=O)[NH:4]1.B.C1COCC1.Cl>CO>[CH2:5]1[NH:4][C@@H:3]([CH2:2][OH:1])[CH2:8][N:7]2[CH2:10][CH2:11][NH:12][CH2:13][CH:6]12
Reactant: O=C1NC(CO)C(=O)N2CCNCC12
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: OC[C@H]1CN2CCNCC2CN1
Temperature: 80 °C

Procedure:
To a flask containing (3S,9aS or 9aR)-3-(hydroxymethyl)tetrahydro-2H -pyrazino[1,2-a]pyrazine-1,4(3H,6H)-dione and (3S,9aR or 9aS)-3-(hydroxymethyl)tetrahydro-2H-pyrazino[1,2-a]pyrazine-1,4(3H,6H)-dione (D83, Diastereoisomer 1 plus D84,Diastereoisomer 2, 976 mg, 4.9 mmol) was added 1M BH3-THF solution (49 mL) under nitrogen and the reaction was brought to reflux (80° C.) overnight. The reaction flask was cooled to 0° C. and treated with 25 mL of MeOH. Conc. HCl was added and the resulting solution was heated to 60° C. for 5 h. The reaction was checked by direct MS (m/z=184 (M+BH3) ). The reaction mixture was purified by SCX, obtaining 528 mg of product.
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH2:3]1.[CH2:12]([O:15][C:16](Cl)=[O:17])[CH2:13][CH3:14].C(NC(=O)[C@H](C)C[C@H](O)[C@@H](NC(OC(C)(C)C)=O)CC(C)(C)CC(N1C2C(=CC=CC=2)N(C(=O)C)C(C(NC)=O)C1)=O)CCC>>[CH2:12]([O:15][C:16]([NH:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH2:3]1)=[O:17])[CH2:13][CH3:14]
Reactant: CCCOC(=O)Cl
Reactant: NC1CNc2ccccc2C1
Agent: CCCCNC(=O)[C@H](C)C[C@H](O)[C@H](CC(C)(C)CC(=O)N1CC(C(=O)NC)N(C(C)=O)c2ccccc21)NC(=O)OC(C)(C)C
Product: CCCOC(=O)NC1CNc2ccccc2C1

Procedure:
Analogously to the method described in Example 108b) from 3(R,S)-amino-1,2,3,4-tetrahydroquinoline and propylchloroformate: Rf (P)=0.84; MS: M+ =234.