Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][O:22][CH2:23][C@@H:24]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH3:25].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:21][O:22][CH2:23][C@@H:24]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH3:25])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H](CON)NC(=O)OC(C)(C)C
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: C[C@@H](CONC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.3 %

Procedure:
To a mixture of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.150 g, 0.543 mmol) in DCM (15 mL) were added tert-butyl [(1S)-2-(aminooxy)-1-methylethyl]carbamate 59 (0.176 g, 0.923 mmol), 1-hydroxybenzotriazole (0.110 g, 0.814 mmol) and 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.156 g, 0.814 mmol) sequentially at room temperature. The mixture was stirred at room temperature for 18 h, diluted with DCM, washed with water and brine, dried over sodium sulfate and concentrated to provide a residue which was subjected to chromatography to give 60 (0.237 g, 97%) as a white solid.
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][C:11]([C:17]4[C:25]5[C:24](N)=[N:23][CH:22]=[N:21][C:20]=5[S:19][CH:18]=4)=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C2C=CC3C(=CC(C(=[O:45])C)=CC=3)N=2)C=CC=CC=1.C(CC(OCC)=O)#N>>[C:1]1([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][C:11]([C:17]4[C:25]5[C:24](=[O:45])[NH:23][CH:22]=[N:21][C:20]=5[S:19][CH:18]=4)=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1ncnc2scc(-c3ccc4ccc(-c5ccccc5)nc4c3)c12
Reactant: CC(=O)c1ccc2ccc(-c3ccccc3)nc2c1
Solvent: CCOC(=O)CC#N
Product: O=c1[nH]cnc2scc(-c3ccc4ccc(-c5ccccc5)nc4c3)c12

Procedure:
Following the procedure for the one-pot synthesis of 5-(2-phenylquinolin-7-yl)-thieno[2,3-d]pyrimidin-4-ylamine from 1-(2-phenylquinolin-7-yl)-ethanone, but using ethyl cyanoacetate instead of malononitrile, the title compound was obtained as brown solid. 1H NMR (CDCl3, 400 MHz): δ=7.38 (s, 1H), 7.45-7.56 (m, 3H), 7.76-7.79 (dd, 1H, J=1.6 & 8.4 Hz), 7.86-7.91 (m, 2H), 7.98 (s, 1H), 8.15-8.18 (m, 2H), 8.25-8.27 (d, 1H, J=8.8 Hz), 8.34 (d, 1H, J=2.0 Hz). MS (ES+): 356.2 [MH+]. HPLC: tR=4.3 min (MicromassZQ, polar—15 min).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:23][C:24]1[O:28][N:27]=[C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:25]=1[C:35]([NH:37][NH2:38])=O.P(Cl)(Cl)(Cl)=O.C(=O)([O-])[O-].[Na+].[Na+]>ClC1C=CC=CC=1.C(OCC)(=O)C>[CH3:23][C:24]1[O:28][N:27]=[C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:25]=1[C:35]1[O:8][C:6]([C:5]2[CH:9]=[CH:10][C:2]([NH2:1])=[N:3][CH:4]=2)=[N:38][N:37]=1
Reactant: Nc1ccc(C(=O)O)cn1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NN
Agent: O=C([O-])[O-]
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: Clc1ccccc1
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccc(N)nc2)o1
Temperature: 90 °C
Reaction time: 2 h
Yield: 9.2 %

Procedure:
To a suspension of 6-aminonicotinic acid (191 mg, 1.38 mmol) in chlorobenzene (2 mL) was added 1,1′-carbonyl-diimidazole (224 mg, 1.38 mmol) and the resulting mixture stirred for 2 h at 90° C. After the suspension was cooled to ambient temperature 5-methyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide (200 mg, 0.92 mmol) was added and stirred for 1 h at 90° C. After the reaction mixture was cooled to ambient temperature phosphorous oxychloride (0.84 mL, 9.20 mmol) was added and stirring was continued for 4 h at 90° C. The cooled reaction mixture was poured carefully onto a mixture of ethyl acetate (20 mL) and aqueous sodium carbonate (saturated, 20 mL) and was stirred for 1 h at ambient temperature. The aqueous layer was separated and extracted with ethyl acetate (20 mL) and the combined organic layers were washed with aqueous sodium carbonate (saturated). Drying over sodium sulfate and purification by chromatography (SiO2, heptane:ethyl acetate:dichloromethane:methanol=40:40:20:0 to 0:75:20:5) afforded the title compound (27 mg, 9%) as a white solid. MS: m/e=320.0 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]([C:8]2[N:9]([CH3:28])[CH:10]=[C:11]([C:13]([C:15]3[C:16](C4C=CC(F)=CC=4)=[N:17][O:18][C:19]=3[CH3:20])=[O:14])[CH:12]=2)=[O:7])C[CH2:2]1.C(NC(C1NC=C(C(C2C([C:48]3[CH:53]=[CH:52][CH:51]=[C:50]([F:54])[CH:49]=3)=NOC=2C)=O)C=1)=O)C#C>>[CH2:4]([NH:5][C:6]([C:8]1[N:9]([CH3:28])[CH:10]=[C:11]([C:13]([C:15]2[C:16]([C:48]3[CH:53]=[CH:52][CH:51]=[C:50]([F:54])[CH:49]=3)=[N:17][O:18][C:19]=2[CH3:20])=[O:14])[CH:12]=1)=[O:7])[C:1]#[CH:2]
Reactant: C#CCNC(=O)c1cc(C(=O)c2c(-c3cccc(F)c3)noc2C)c[nH]1
Reactant: Cc1onc(-c2ccc(F)cc2)c1C(=O)c1cc(C(=O)NCC2CC2)n(C)c1
Product: C#CCNC(=O)c1cc(C(=O)c2c(-c3cccc(F)c3)noc2C)cn1C
Yield: 43 %

Procedure:
According to the procedure described for the synthesis of 4-(5-methyl-3-(4-fluorophenyl)-isoxazole-4-carbonyl)-1-methyl-pyrrole-2-carboxylic acid (cyclopropylmethyl)-amide (Example 229, step 3), the title compound was synthesized from 4-[5-methyl-3-(3-fluorophenyl)-isoxazole-4-carbonyl)-1H-pyrrole-2-carboxylic acid prop-2-ynylamide (example 179) in 43% yield as white solid. (m/e): 366.1 (M+1; 100%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].F[C:9](F)(F)[C:10](O)=[O:11].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:45]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38]([C@@H:40]1[CH2:44][CH2:43][NH:42][CH2:41]1)=[O:39].C(Cl)(=O)C>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:10]([N:42]1[CH2:43][CH2:44][C@@H:40]([C:38]([NH:37][C:29]2[CH:30]=[CH:31][C:32]3[NH:33][C:34]4[N:35]=[C:19]([NH:20][C:21]5[CH:22]=[CH:23][CH:24]=[C:25]([CH:45]=5)[CH2:26][CH2:27][C:28]=2[CH:36]=3)[N:18]=[CH:17][C:16]=4[Cl:15])=[O:39])[CH2:41]1)(=[O:11])[CH3:9]
Reactant: O=C(Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2)[C@@H]1CCNC1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)Cl
Product: CC(=O)N1CC[C@@H](C(=O)Nc2ccc3cc2CCc2cccc(c2)Nc2ncc(Cl)c(n2)N3)C1
Yield: 43 %

Procedure:
The desired compound was prepared according to the procedure of Example A20, using (3R)—N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]pyrrolidine-3-carboxamide bis(trifluoroacetate) and acetyl chloride as starting materials in 43% yield. LCMS for C25H26ClN6O2 (M+H)+: m/z=477.2.
Reaction SMILES: [SH2:1].[Na].Cl[C:4]1[C:8]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[N:7][S:6][N:5]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[CH2:22][CH2:23][CH2:24][CH3:25]>CN(C=O)C.O>[CH2:21]([S:1][C:4]1[C:8]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[N:7][S:6][N:5]=1)[CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: Clc1nsnc1-c1cccnc1
Reactant: S
Reactant: CCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCSc1nsnc1-c1cccnc1
Reaction time: 0.5 h

Procedure:
Sodium hydrogen sulfide (0.25 g, 3.3 mmol) was added to a solution of 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (0.59 g, 3 mmol) in DMF (20 ml) at room temperature and the reaction mixture was stirred for 30 min. Potassium carbonate (1.24 g, 9 mmol) and pentyl bromide (700 mg, 4.5 mmol) were added and the reaction mixture was stirred for additionally 10 min. Water (50 ml) was added and extracted with ether. The combined ether phases were dried and evaporated to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:18]([NH:20][CH2:21][C:22]([NH:24][CH2:25][C:26]([NH:28][C@H:29]([C:37]([OH:39])=O)[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:27])=[O:23])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:55][C@H:56]([C:62]([OH:64])=[O:63])[CH2:57][CH2:58][S:59]([CH3:61])=[O:60]>CN(C)C=O.O>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:18]([NH:20][CH2:21][C:22]([NH:24][CH2:25][C:26]([NH:28][C@H:29]([C:37]([NH:55][C@H:56]([C:62]([OH:64])=[O:63])[CH2:57][CH2:58][S:59]([CH3:61])=[O:60])=[O:39])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:27])=[O:23])=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)NCC(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CS(=O)CC[C@H](N)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)CC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)CNC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)O
Temperature: -15 °C
Reaction time: 2 h

Procedure:
10.84 Parts N-t-butoxycarbonyl-L-tyrosylglycylglycyl-L-phenylalanine and 2.0 parts N-methylmorpholine are dissolved in 200 parts dimethylformamide and cooled to -15° C. Then, 2.9 parts isobutyl chloroformate is added dropwise over a thirty minute period while keeping the temperature between -15° C. to -10° C. After the addition is completed, a solution of 3.3 parts L-methionine sulfoxide in 15 parts dimethylformamide is slowly added. The mixture is stirred for a further thirty minutes at -15° C. and then warmed to room temperature and stirred thereat for an additional 2 hours. The product is isolated by diluting the reaction mixture with 10 volumes water and extracting with ethyl acetate. The ethyl acetate extracts are combined, dried over anhydrous sodium sulfate and stripped of solvent under reduced pressure. The residue is purified by low-pressure chromatography to afford N-t-butoxycarbonyl-L-tyrosyl-glycylglycyl-L-phenylalanyl-L-methionine sulfoxide.
Reaction SMILES: C(O[C:9]([NH:11][C:12]1[CH:20]=[C:19]2[C:15]([C:16]3[C:24]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[F:31])=[CH:23][N:22]=[C:21]([C:32]([OH:34])=O)[C:17]=3[NH:18]2)=[CH:14][CH:13]=1)=[O:10])C1C=CC=CC=1.[Cl-].[NH4+].C([NH:40]C(C)C)(C)C.F[P-](F)(F)(F)(F)F.[N:51]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:55]2C=[CH:57][CH:58]=[CH:59][C:54]=2N=N1.CN1CCOCC1>CN(C=O)C.O>[F:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:24]1[C:16]2[C:15]3[C:19](=[CH:20][C:12]([NH:11][C:9](=[O:10])[C:59]4[CH:58]=[CH:57][N:51]=[CH:55][CH:54]=4)=[CH:13][CH:14]=3)[NH:18][C:17]=2[C:21]([C:32]([NH2:40])=[O:34])=[N:22][CH:23]=1
Reactant: CC(C)NC(C)C
Reactant: O=C(Nc1ccc2c(c1)[nH]c1c(C(=O)O)ncc(-c3ccccc3F)c12)OCc1ccccc1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: O
Product: NC(=O)c1ncc(-c2ccccc2F)c2c1[nH]c1cc(NC(=O)c3ccncc3)ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
A mixture of 7-(benzyloxycarbonylamino)-4-(2-fluorophenyl)-9H-pyrido[3,4-b]indole-1-carboxylic acid (214 mg, 0.470 mmol), ammonium chloride (101 mg, 1.880 mmol), N,N-diisopropylamine (0.394 mL, 2.255 mmol), BOP (270 mg, 0.611 mmol), N-methylmorpholine (0.201 mL, 1.833 mmol) in DMF (2 mL) was stirred at rt for 1 hr. To the reaction solution was added water (20 mL), and the precipitating product (213 mg, 0.422 mmol, 90% yield) was collected as a beige solid by suction filtration and dried over Drierite under vacuum.
Reaction SMILES: Cl.[NH2:2][CH:3]1[C:33](=[O:34])[N:5]2[C:6]([C:17]([O:19][CH:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[S:18])=[C:7]([CH2:10][CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[CH2:8][S:9][C@H:4]12.[C:35]([NH:54][C:55]1[S:56][CH:57]=[C:58](/[C:60](=[N:64]/[O:65][C:66]([C:79]2[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=2)([C:73]2[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=2)[C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)/[C:61](O)=[O:62])[N:59]=1)([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[C:35]([NH:54][C:55]1[S:56][CH:57]=[C:58](/[C:60](=[N:64]/[O:65][C:66]([C:79]2[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=2)([C:73]2[CH:74]=[CH:75][CH:76]=[CH:77][CH:78]=2)[C:67]2[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=2)/[C:61]([NH:2][CH:3]2[C:33](=[O:34])[N:5]3[C:6]([C:17]([O:19][CH:20]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[S:18])=[C:7]([CH2:10][CH:11]4[CH2:16][CH2:15][CH2:14][CH2:13][O:12]4)[CH2:8][S:9][C@H:4]23)=[O:62])[N:59]=1)([C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: O=C(O)/C(=N\OC(c1ccccc1)(c1ccccc1)c1ccccc1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: NC1C(=O)N2C(C(=S)OC(c3ccccc3)c3ccccc3)=C(CC3CCCCO3)CS[C@H]12
Agent: Cl
Product: O=C(NC1C(=O)N2C(C(=S)OC(c3ccccc3)c3ccccc3)=C(CC3CCCCO3)CS[C@H]12)/C(=N\OC(c1ccccc1)(c1ccccc1)c1ccccc1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Yield: 57.7 %

Procedure:
Diphenylmethyl 7-amino-3-(tetrahydropyran-2-yl)methylthio-3-cephem-4-carboxylate hydrochloride (300 mg) was reacted with (Z)-2-(2-tritylaminothiazol-4-yl)-2-trityloxyiminoacetic acid (403 mg) in accordance with the procedure of Example 1(d). The crude reaction product was purified by a column chromatography on a silica gel column (30 g) with elution using benzene-ethyl acetate (7:1 by volume) as eluent to collect fractions containing the titled compound. Concentration of the fractions so collected gave the titled compound (380 mg; 60%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Br:23][CH:24]([CH2:28][CH2:29][Br:30])[C:25](Cl)=[O:26].O>ClCCl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([NH:13][C:25](=[O:26])[CH:24]([Br:23])[CH2:28][CH2:29][Br:30])=[CH:14][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(OCc2ccccc2)cc1
Reactant: O=C(Cl)C(Br)CCBr
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=C(Nc1ccc(OCc2ccccc2)cc1)C(Br)CCBr
Reaction time: 0.25 h
Yield: 22.2 %

Procedure:
A solution of 12.8 g (64.2 mmol) 4-benzyloxyaniline and 9.74 g (96.3 mmol) triethylamine in 125 ml dichloromethane is cooled to 0° C. 20.4 g (77.1 mmol) of 2,4-dibromobutyryl chloride [Ikuta et al., J. Med. Chem. 30:1995 (1987)] is slowly added over a period of 45 min. The reaction mixture is stirred for additional 15 min, then hydrolysed with 100 ml of water. The insoluble precipitate is filtered off and the organic phase is washed successively with a saturated solution of sodium hydrogencarbonate and water. After drying and evaporation, the crude product is subjected to chromatography (silica gel, dichloromethane) to yield 6.1 g (22%) of a colorless solid. Mp=139.5–142° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:5]([NH:16][C:17](=[O:35])[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:20][CH:19]=2)[CH:4]=1.[C:36]([O:42][CH2:43][C:44]1[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[CH:46][CH:45]=1)(=[O:41])[CH2:37][C:38]([O-])=[O:39].C1(N=C=NC2CCCCC2)CCCCC1>N1C=CC=CC=1>[CH3:51][O:50][C:47]1[CH:46]=[CH:45][C:44]([CH2:43][O:42][C:36]([CH2:37][C:38]([NH:2][C:3]2[CH:15]=[CH:14][C:6]([O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:5]([NH:16][C:17](=[O:35])[C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)=[CH:20][CH:19]=3)[CH:4]=2)=[O:39])=[O:41])=[CH:49][CH:48]=1
Reactant: CCOC(=O)COc1ccc(N)cc1NC(=O)c1ccc(OCCCCc2ccccc2)cc1
Reactant: COc1ccc(COC(=O)CC(=O)[O-])cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)COc1ccc(NC(=O)CC(=O)OCc2ccc(OC)cc2)cc1NC(=O)c1ccc(OCCCCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 200 mg of ethyl 4-amino-2-[p-(4-phenylbutoxy)benzamido]phenoxyacetate hydrochloride, 107 mg of mono-p-methoxybenzyl malonate and 5 ml of pyridine was added 90 mg of dicyclohexylcarbodiimide. The mixture was stirred at room temperature overnight. The reaction mixture was treated in a manner similar to Example 68. Thereafter the system was applied to silica gel column chromatography and eluted with a toluene-ethyl acetate (4:1) mixture to obtain 110 mg of caramel-like ethyl 4-(p-methoxybenzyloxycarbonyl)acetamido-2-[p-(4-phenylbutoxy)benzamido]phenoxyacetate.
Reaction SMILES: CCN(C(C)C)C(C)C.CC1C=CC(S(O)(=O)=O)=CC=1.[NH:21]1[CH2:25][CH2:24][CH2:23][C@H:22]1[C:26]#[N:27].[C:28]([O:32][C:33]([NH:35][C@H:36]([CH2:40][O:41][Si:42]([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43])[C:37](O)=[O:38])=[O:34])([CH3:31])([CH3:30])[CH3:29].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.CN(C=O)C>[Si:42]([O:41][CH2:40][C@@H:36]([NH:35][C:33](=[O:34])[O:32][C:28]([CH3:31])([CH3:30])[CH3:29])[C:37]([N:21]1[CH2:25][CH2:24][CH2:23][C@H:22]1[C:26]#[N:27])=[O:38])([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43]
Reactant: N#C[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)N[C@H](CO[Si](C)(C)C(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H](CO[Si](C)(C)C(C)(C)C)C(=O)N1CCC[C@H]1C#N

Procedure:
A mixture of DIPEA (0.542 ml, 3.11 mmol) and (S)-pyrrolidine-2-carbonitrile 4-methylbenzenesulfonate (0.269 g, 1.002 mmol) in DCM was added to a mixture of (R)-2-(tert-butoxycarbonylamino)-3-(tert-butyldimethylsilyloxy)propanoic acid (0.320 g, 1.002 mmol) and HATU (0.381 g, 1.002 mmol) in DMF. After 3 h the mixture was washed with 1N citric acid and saturated sodium bicarbonate and brine. The organic layer was dried sodium sulfate, filtered and purified by column chromatography using hexane-ethylacetate as eluents.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C@H:11]([CH2:16][CH:17]=[CH2:18])[C:12](OC)=[O:13])([O-])=O.Cl[Sn]Cl.O>CO>[CH2:16]([C@H:11]1[NH:10][C:5]2[C:4](=[CH:9][CH:8]=[CH:7][CH:6]=2)[NH:1][C:12]1=[O:13])[CH:17]=[CH2:18]
Reactant: C=CC[C@@H](Nc1ccccc1[N+](=O)[O-])C(=O)OC
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CO
Product: C=CC[C@H]1Nc2ccccc2NC1=O
Yield: 47 %

Procedure:
To a solution of 2-fluroronitrobenzene (3.70 g, 26.06 mmol) and (2R)-2-aminopent-4-enoic acid (3.00 g, 26.06 mmol) in MeOH (30 mL), was added NaHCO3 (4.82 g, 57.33 mmol), and the reaction mixture was refluxed overnight. After cooling, concentrating, and chasing with benzene (3×30 mL), the crude product was dried on high vacuum pump overnight to give (2R)-2-[(2-nitrophenyl)amino]-pent-4-enoic acid, which was then dissolved in MeOH, cooled to 0° C. and saturated with HCl(g). The reaction was capped and the reaction mixture was stirred at room temperature overnight, concentrated, and then subjected to silica gel chromatography eluting with 40%-60% CH2Cl2 in hexanes to give methyl (2R)-2-[(2-nitrophenyl)amino]pent-4-enoate (3.75 g, 57% overall yield for 2 steps). Methyl (2R)-2-[(2-nitrophenyl)amino]pent-4-enoate was dissolved in MeOH (70 mL) and SnCl2.H2O (16.84 g, 74.63 mmol) was added After refluxing overnight, the reaction mixture was cooled and concentrated under reduced pressure. The crude material was poured into EtOAc and saturated NaHCO3 and extracted with EtOAc (3×100 mL). The combined organics were then washed with NaHCO3 (1×50 mL) and brine (1×50 mL), dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel, eluting with 25%-40% EtoAc in Hexanes to give 1.31 g (47%) of (3R)-3-allyl-3,4-dihydroquinoxalin-2(1H)-one. LCMS (ES) m/z 189.3 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[Br:11][CH:12]([CH:15]=O)[CH:13]=O.CC1C=CC(S(O)(=O)=O)=CC=1>C(O)CCC>[Br:11][C:12]1[CH:13]=[N:10][C:8]2[N:7]([N:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:9]=2)[CH:15]=1
Reactant: CC(C)(C)c1cc(N)[nH]n1
Reactant: O=CC(Br)C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCO
Product: CC(C)(C)c1cc2ncc(Br)cn2n1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
3-tert-Butyl-1H-pyrazol-5-amine (9 g, 64.7 mmol) was dissolved in BuOH (100 ml). 2-Bromomalonaldehyde (9.76 g, 64.7 mmol) and p-TsOH*H2O (615 mg, 3.23 mmol) were added at room temperature. The mixture was stirred for 16 hours at 100° C. The reaction mixture was evaporated to dryness and the residue was purified by flash chromatography on silica gel (120 gr, 0% to 40% EtOAc in heptane) and crystallization with a small volume of diisopropylether. The crystals were washed with diisopropylether and dried for 1 hour at 50° C. and <20 mbar. The desired compound was obtained as a light yellow solid (9.5 g, 58% yield), MS: m/e=256.1/254.1 (M+H+).
Reaction SMILES: O.[NH2:2][NH2:3].[CH3:4][O:5][C:6](=[O:27])[CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:26])[C:22](OC)=[O:23])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1>CCO>[NH:2]([C:22](=[O:23])[C:21]([NH:20][C:17]1[CH:18]=[CH:19][C:14]([C@H:11]2[CH2:12][CH2:13][C@H:8]([CH2:7][C:6]([O:5][CH3:4])=[O:27])[CH2:9][CH2:10]2)=[CH:15][CH:16]=1)=[O:26])[NH2:3]
Reactant: NN
Reactant: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)C(=O)OC)cc2)CC1
Solvent: O
Solvent: CCO
Product: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)C(=O)NN)cc2)CC1
Reaction time: 1 h

Procedure:
Hydrazine hydrate (0.361 mL) was added to a stirred solution of methyl ({4-[trans-4-(2-methoxy-2-oxoethyl)cyclohexyl]phenyl}amino)(oxo)acetate (2260 mg) in EtOH (50 mL). The mixture was stirred for 1 hour. The precipitate was filtered off, washed with Et2O, and dried under vacuum overnight to give the title compound (Intermediate 43, 1845 mg) as a solid; 1H NMR δ 10.44 (1H, s), 10.20 (1H, s), 7.70 (2H, d), 7.21 (2H, d), 4.60 (2H, s), 3.60 (3H, s), 2.42 (1H, m), 1.79 (5H, m), 1.45 (2H, m), 1.11 (2H, m); MS m/e MH+ 334.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[CH:6]=[C:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=1.[Cl:21][C:22]1[CH:26]=[CH:25][S:24][C:23]=1[C:27]([C:29]1[N:30]([CH3:34])[CH:31]=[N:32][CH:33]=1)=[O:28]>>[Cl:20][C:16]1[CH:15]=[C:14]([C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([C:27]([C:23]4[S:24][CH:25]=[CH:26][C:22]=4[Cl:21])([C:29]4[N:30]([CH3:34])[CH:31]=[N:32][CH:33]=4)[OH:28])[CH:3]=3)[N:8]=[C:7]([O:12][CH3:13])[CH:6]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: COc1cc(-c2cccc(Cl)c2)c2cc(Br)ccc2n1
Reactant: Cn1cncc1C(=O)c1sccc1Cl
Product: COc1cc(-c2cccc(Cl)c2)c2cc(C(O)(c3sccc3Cl)c3cncn3C)ccc2n1
Yield: 51.2 %

Procedure:
Following the same procedure as described in example 1E, 6-bromo-4-(3-chloro-phenyl)-2-methoxy-quinoline (300 mg, 0.859 mmol) and (3-chloro-thiophen-2-yl)-(3-methyl-3H-imidazol-4-yl)-methanone (230 mg 1.032 mmol) generated the title compound of 21A as a yellow solid (218.5 mg, 51% yield).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]1[NH:11][C:12]2[C:17]([N:18]=1)=[C:16]([NH2:19])[N:15]=[C:14]([O:20][CH2:21][CH2:22][O:23][CH3:24])[N:13]=2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>CN(C=O)C>[CH3:8][O:9][C:10]1[N:11]([CH2:32][CH:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[C:12]2[C:17]([N:18]=1)=[C:16]([NH2:19])[N:15]=[C:14]([O:20][CH2:21][CH2:22][O:23][CH3:24])[N:13]=2
Reactant: COCCOc1nc(N)c2nc(OC)[nH]c2n1
Reactant: BrCC1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: COCCOc1nc(N)c2nc(OC)n(CC3CCOCC3)c2n1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
8-(Methoxy)-2-{[2-(methoxy)ethyl]oxy}-9H-purin-6-amine trifluoroacetate salt (0.30 g) was heated with anhydrous potassium carbonate (0.4698 g) in anhydrous DMF (5 mL) at 60° C. for 1 hour. The reaction mixture was cooled to room temperature before 4-(bromomethyl) tetrahydro-2H-pyran (0.1669 g) was added in anhydrous DMF (1 mL). The reaction mixture was then stirred overnight at 50° C. The reaction mixture was quenched into water (20 mL) and extracted into ethyl acetate (20 mL, 3 times).