Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][SH:21])[C:10]=1[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:2].[Br:30][C:31]1[CH:32]=[C:33]([N+]([O-])=O)[CH:34]=[C:35]([Br:37])[CH:36]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][S:21][C:33]2[CH:32]=[C:31]([Br:30])[CH:36]=[C:35]([Br:37])[CH:34]=2)[C:10]=1[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:2]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCS)c1CCC(=O)OCC
Reactant: O=[N+]([O-])c1cc(Br)cc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCOc1cccc(CCCCCCSc2cc(Br)cc(Br)c2)c1CCC(=O)OCC
Temperature: 90 °C
Reaction time: 3 h
Yield: 70.5 %

Procedure:
To a solution of 4-[2-(2-ethoxycarbonyl-ethyl)-3-(6-mercapto-hexyl)-phenoxy]-butyric acid ethyl ester (162 mg, 0.388 mmol) in DMSO (5 mL), 3,5-dibromonitrobenzene (129 mg, 0.46 mmol) and Cs2CO3 (150 mg, 0.46 mmol) were added and stirred at 90° C. for 3 hrs. At this time, the reaction mixture was diluted with EtOAc (200 mL) and washed with water (100 mL). The EtOAc layer was washed), brine and then dried over Na2SO4. This mixture was filtered and the filtrate was concentrated. The solvent was removed in vacuo to afford an oil. This oil was purified using FCC (15% EtOAc/Hex) to provide a colorless oil (180 mg, yield 72%). 1H NMR (CDCl3): □ 7.42 (s, 1H), 7.32 (s, 2H), 7.09 (dd, 1H), 6.75 (d, 1H), 6.69 (d, 1H), 4.14 (m, 4H), 3.99 (t, 2H), 2.98-2.89 (m, 4H), 2.64-2.46 (m, 6H), 2.13 (m, 2H), 1.67-1.39 (m, 8H), 1.27 (m, 6H).
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]=[C:7]([S:9]([NH2:12])(=[O:11])=[O:10])[S:8][C:4]=2[CH:3]=1.C(N(CC)CC)C.[C:22](Cl)(=[O:34])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].Cl>CN(C)C1C=CN=CC=1.CN(C)C=O>[C:22]([O:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]=[C:7]([S:9](=[O:11])(=[O:10])[NH2:12])[S:8][C:4]=2[CH:3]=1)(=[O:34])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: NS(=O)(=O)c1nc2ccc(O)cc2s1
Reactant: CCCCCCCCCCCC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCC(=O)Oc1ccc2nc(S(N)(=O)=O)sc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 6-hydroxy-2-benzothiazolesulfonamide (6.9 g., 0.03 mole), triethylamine (4.2 ml., 0.03 mole) and 4-dimethylaminopyridine (100 mg.) in dimethylformamide (30 ml.) is added lauroyl chloride (7 ml.) during a 1/2 hour period. The reaction mixture is stirred for 2 hours at room temperature, poured into ice water and hydrochloric acid, extracted into ether, washed with water, ammonium hydroxide (3 ml. diluted with water) dilute hydrochloric acid and dried over magnesium sulfate. The ether is evaporated at reduced pressure to give 2.2 g of 2-sulfamoyl-6-benzothiazolyl dodecanoate which melts at 112°-114° C. after recrystallization from butyl chloride.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:9])=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[CH2:10]([O:12][C:13](=[O:17])[C:14]#[C:15][CH3:16])[CH3:11].N12CCCN=C1CCCCC2>O1CCCC1>[CH2:10]([O:12][C:13](=[O:17])/[CH:14]=[C:15](/[O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[C:3]=1[F:9])\[CH3:16])[CH3:11]
Reactant: CC#CC(=O)OCC
Reactant: Oc1cccc(Br)c1F
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(\C)Oc1cccc(Br)c1F
Yield: 69.5 %

Procedure:
To a stirred mixture of 3-bromo-2-fluoro-phenol (19.5 g, 0.102 mol) and ethyl-2-butynoate (22.0 g, 0.196 mol) in tetrahydrofuran (100 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (15.6 g, 0.102 mol) slowly. After addition was complete the mixture was stirred at reflux for overnight. Upon completion of the reaction the tetrahydrofuran was removed in vacuo and the residue was diluted in diethyl ether and washed first with 1N aqueous hydrochloric acid, then 10% aqueous sodium hydroxide solution, a saturated sodium chloride solution and dried over magnesium sulfate. The mixture was filtered and evaporated, and the residue dried under high vacuum which afforded (E)-3-(3-bromo-2-fluoro-phenoxy)-but-2-enoic acid ethyl ester as a brown oil (21.5 g, 69%) and used without further purification.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[Cl:33][C:34]1[NH:42][C:41]2[C:40](=[O:43])[N:39]([CH2:44][CH2:45][CH2:46][CH2:47][C:48](=[NH:51])[NH:49]O)[C:38](=[O:52])[N:37]([CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])[C:36]=2[N:35]=1>CS(C)=O>[Cl:33][C:34]1[NH:42][C:41]2[C:40](=[O:43])[N:39]([CH2:44][CH2:45][CH2:46][CH2:47][C:48]3[N:49]=[C:1]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[O:9][N:51]=3)[C:38](=[O:52])[N:37]([CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])[C:36]=2[N:35]=1
Reactant: CCCCCn1c(=O)n(CCCCC(=N)NO)c(=O)c2[nH]c(Cl)nc21
Reactant: O=C(O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CS(C)=O
Solvent: O
Product: CCCCCn1c(=O)n(CCCCc2noc(-c3ccccc3)n2)c(=O)c2[nH]c(Cl)nc21
Temperature: 40 °C
Reaction time: 5 h
Yield: 25.1 %

Procedure:
Benzoic acid (18 mg, 0.15 mmol) was treated with a solution of 1H-1,2,3-benzotriazol-1-ol hydrate (25 mg, 0.19 mmol) in DMSO (0.3 ml). To this was added a solution/suspension of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (29 mg, 0.15 mmol) in DMSO (0.3 ml) followed by a solution of 5-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-hydroxypentanimidamide (55 mg, 0.15 mmol) in DMSO (0.3 ml). The mixture was heated at 40° C. for 1 h, then at 80° C. for 5 h and then cooled. The mixture was subjected to purification by MDAP. Product-containing fractions were blown to dryness by a stream of nitrogen to yield the title compound as a white solid (17.2 mg, 25%).
Reaction SMILES: [C:1]([O-:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+].[CH2:11]([O:13][CH:14]([O:17][CH2:18][CH3:19])[CH2:15]Br)[CH3:12].CN(C)C=O>O>[CH2:11]([O:13][CH:14]([O:17][CH2:18][CH3:19])[CH2:15][O:9][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH3:12]
Reactant: O=C([O-])c1ccccc1
Reactant: CCOC(CBr)OCC
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(COCc1ccccc1)OCC
Temperature: 25 °C
Yield: 94.8 %

Procedure:
To a 2-L, three-necked, round-bottomed flask fitted with a mechanical stirrer, a reflux condenser and a glass stopper is added sodium benzoate (0.579 mol, 83.44 g, 1.1 equiv.), bromoacetaldehyde diethyl acetal (0.526 mol, 103.74 g, 1.0 equiv.) and N,N-dimethylformamide (1.0 L). The reaction was heated to reflux and stirred while monitoring progress by thin layer chromatography (TLC). When determined to be complete, the reaction was allowed to cool to ambient temperature and diluted with water (2.0 L). The product was extracted with methyl tert-butyl ether. The organic phase was dried over magnesium sulfate and concentrated by rotary evaporation to give 2-(benzyloxy)acetaldehyde diethyl acetal (111.85 g, 81.1% yield). The crude product was advanced to the next reaction step without further purification.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]([OH:14])=O)=[CH:11][C:6]=2[N:5]=[C:4]1[NH:15][C:16]1[S:17][C:18]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:19]=2[N:20]=1)[CH3:2].CN.[CH3:31][N:32](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:31][NH:32][C:12]([C:10]1[CH:9]=[CH:8][C:7]2[N:3]([CH2:1][CH3:2])[C:4]([NH:15][C:16]3[S:17][C:18]4[CH:24]=[C:23]([C:25]([F:27])([F:28])[F:26])[CH:22]=[CH:21][C:19]=4[N:20]=3)=[N:5][C:6]=2[CH:11]=1)=[O:14]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CCn1c(Nc2nc3ccc(C(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCn1c(Nc2nc3ccc(C(F)(F)F)cc3s2)nc2cc(C(=O)NC)ccc21
Yield: 48.4 %

Procedure:
1-Ethyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid methylamide (75.0 mg) was prepared by following General Procedure F starting from 1-ethyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (150.0 mg), methylamine (2.0 M solution in THF, 1.0 mL), HBTU (200.0 mg) and DIEA (0.2 mL) in DMF (1.0 mL). LCMS: m/z 421.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([C:10](=[O:26])[C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]4)=[CH:13][CH:12]=3)=[C:8]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH:34](C)C)=[CH:29][CH:28]=3)[S:7][C:6]=2[CH:37]=1.[C:38]([O-])(=O)CCC([O-])=O>>[CH3:38][O:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([C:10](=[O:26])[C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]4)=[CH:13][CH:12]=3)=[C:8]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[S:7][C:6]=2[CH:37]=1
Reactant: CC(C)Oc1ccc(-c2sc3cc(O)ccc3c2C(=O)c2ccc(OCCN3CCCCC3)cc2)cc1
Reactant: O=C([O-])CCC(=O)[O-]
Product: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(OCCN3CCCCC3)cc2)cc1

Procedure:
6-hydroxy-2-(4-isopropoxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]thiophene, succinate
Reaction SMILES: CON(C)[C:4]([C:6]1[C:7]([NH2:15])=[N:8][C:9]([S:12][CH2:13]C)=[N:10][CH:11]=1)=[O:5].Br[C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[CH2:25][CH3:26]>>[NH2:15][C:7]1[C:6]([C:4]([C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[CH2:25][CH3:26])=[O:5])=[CH:11][N:10]=[C:9]([S:12][CH3:13])[N:8]=1
Reactant: CCSc1ncc(C(=O)N(C)OC)c(N)n1
Reactant: CCc1ccc(F)cc1Br
Product: CCc1ccc(F)cc1C(=O)c1cnc(SC)nc1N

Procedure:
The compound was prepared from 4-amino-2-ethylsulfanyl-pyrimidine-5-carboxylic acid methoxy-methyl-amide, Example 1, and 2-bromo-1-ethyl-4-fluoro-benzene (prepared from 2-bromo-4-fluoroacetophenone, WO0015634) in an analogous manner as described in Example 169.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH2:14].[CH:15]([C:17]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]2[C:18]=1[CH:19]=[CH:20][CH:21]=[N:22]2)=O>C1C=CC=CC=1>[CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]=[CH:15][C:17]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]2[C:18]=1[CH:19]=[CH:20][CH:21]=[N:22]2
Reactant: NCCCCCCC1CC2C=CC1C2
Reactant: O=Cc1ccc(O)c2ncccc12
Solvent: c1ccccc1
Product: Oc1ccc(C=NCCCCCCC2CC3C=CC2C3)c2cccnc12
Yield: 99.8 %

Procedure:
Amine 4 (0.726 g, 0.00376 mol) and 5-formyl-8-hydroxyquinoline 6 (0.650 g, 0.00376 mol) were dissolved in 40 mL of benzene and refluxed for 18 hours. After cooling, the solvent was removed under reduced pressure to yield the product as an orange solid (1.308 g, 100%). 1H NMR (300 MHz, CDCl3) δ9.75 (1H, dd J=8.79, 1.64); 8.81 (1H, dd, J=1.64, 4.39); 8.59 (1H, s); 7.69 (1H, d, J=8.24); 7.56 (1H, dd, J=4.39, 8.79); 7.19 (1H, d, J=7.69); 6.10 (1H endo, dd, J=2.74, 5.49); 6.06–5.99 (2H exo, m); 5.91 (1H endo, dd, J=2.74, 5.94); 3.67 (2H, t, J=7.14); 2.74 (2H, s); 1.99–1.69 (4H, m); 1.42–1.01 (12H, m); 0.50–0.44 (1H, m). 13C NMR (75 MHz, CDCl3) δ160.8; 154.2; 148.1; 138.4; 137.0; 135.3; 133.0; 132.6; 127.0; 123.3; 123.2; 109.2; 62.9; 49.7; 45.6; 42.7; 38.9; 34.9; 32.6; 31.4; 29.9; 28.8; 27.6. HRMS (EI): calcd for C23H28N2O1 [M]+348.2201, found 348.2186.
Reaction SMILES: [Br:1]/[CH:2]=[CH:3]/[CH:4]([OH:12])[CH2:5][C:6]([CH3:11])([CH3:10])[CH2:7][CH2:8][CH3:9].[C:13]1([C:19](Br)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[Br:1]/[CH:2]=[CH:3]/[CH:4]([O:12][C:19]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH2:5][C:6]([CH3:11])([CH3:10])[CH2:7][CH2:8][CH3:9]
Reactant: BrC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCC(C)(C)CC(O)/C=C/Br
Product: CCCC(C)(C)CC(/C=C/Br)OC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
Treatment of 3.53 g. (15 moles) of 1-bromo-5,5-dimethyl-trans-1-octen-3-ol (Example 1177) with 4.85 g. (15 moles) of triphenylmethyl bromide in 35 ml. of pyridine and purification on Florisil®, all as described in Example 728 gives the title compound.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].CCOCC.[C:17](O)(=[O:35])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].CS(O)(=O)=O>>[C:17]([O:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)(=[O:35])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: Oc1ccc2ccccc2c1
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Agent: CS(=O)(=O)O
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCCCC(=O)Oc1ccc2ccccc2c1
Temperature: 220 °C

Procedure:
To a four neck round bottom flask fitted with nitrogen inlet, mechanical stirrer, temperature probe and condenser is charged 1100.40 g (1.84 moles) of the Alkoxylate from example 15 and 499.60 g (1.76 moles) of Stearic Acid. A catalytic amount of Methanesulfonic Acid (1.6 g) is charged and the reaction mixture is heated to 220° C. under nitrogen sparge. The reaction is monitored by measuring the acid value to an AV of preferably less than 5. Once the AV is reached, the temperature is cooled to 85° C. and the catalyst is neutralized with an equivalent molar amount of 45% KOH and washed once with water. The reaction is dried under vacuum yielding the desired product.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[O:15]1[CH2:20][CH2:19][N:18]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH2:17][CH2:16]1>>[O:15]1[CH2:16][CH2:17][N:18]([CH:21]2[CH2:26][CH2:25][N:24]([C:2]3[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=3[C:11]([F:14])([F:13])[F:12])[CH2:23][CH2:22]2)[CH2:19][CH2:20]1
Reactant: O=[N+]([O-])c1ccc(Cl)c(C(F)(F)F)c1
Reactant: C1CC(N2CCOCC2)CCN1
Product: Nc1ccc(N2CCC(N3CCOCC3)CC2)c(C(F)(F)F)c1

Procedure:
By the reaction and treatment in the same manner as in Starting Material Synthesis Example 40 using 4-chloro-3-trifluoromethylnitrobenzene and 4-morpholinopiperidine, the title compound was obtained, melting point: 118–120° C.
Reaction SMILES: [Cr](Cl)([O-])(=O)=[O:2].[NH+]1C=CC=CC=1.OCC[CH2:15][C:16]1[CH:34]=[CH:33][C:19]([CH2:20][CH2:21][NH:22][S:23]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)(=[O:25])=[O:24])=[CH:18][CH:17]=1>C(Cl)Cl>[CH:15]([C:16]1[CH:34]=[CH:33][C:19]([CH2:20][CH2:21][NH:22][S:23]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)(=[O:25])=[O:24])=[CH:18][CH:17]=1)=[O:2]
Reactant: O=S(=O)(NCCc1ccc(CCCO)cc1)c1ccc(Cl)cc1
Reactant: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=Cc1ccc(CCNS(=O)(=O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C

Procedure:
Into a solution of 12.8 g. (59.4 mmole) pyridinium chlorochromate and 250 ml. methylene chloride are introduced, with stirring at ambient temperature, 14.0 g. (39.6 mmole) 4-chlorobenzenesulphonic acid-[4-(3-hydroxypropyl)-phenethylamide]. The reaction mixture is stirred for a further hour and then poured off from insolubles. The methylene chloride phase is chromatographed with a short column (silica gel/methylene chloride) and evaporated. Yield 10.8 g. (78% of theory); m.p. 65°-66° C. Oxime: m.p. 156°-158° C. (recrystallised from toluene).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18](O)=[O:19])[CH2:16][C:15]2[CH:14]=[C:13]3[O:21][CH2:22][C@H:23]([C:25]4[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH:33]5[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]5)=[CH:27][CH:26]=4)[O:24][C:12]3=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.Cl.Cl.[CH3:63][O:64][C:65](=[O:83])[C@@H:66]([NH2:82])[CH2:67][C:68]1[CH:73]=[CH:72][C:71]([C:74]2[CH:79]=[CH:78][N:77]=[C:76]([CH3:80])[C:75]=2[CH3:81])=[CH:70][CH:69]=1.CN1CCOCC1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18](=[O:19])[NH:82][C@H:66]([C:65]([O:64][CH3:63])=[O:83])[CH2:67][C:68]2[CH:69]=[CH:70][C:71]([C:74]3[CH:79]=[CH:78][N:77]=[C:76]([CH3:80])[C:75]=3[CH3:81])=[CH:72][CH:73]=2)[CH2:16][C:15]2[CH:14]=[C:13]3[O:21][CH2:22][C@H:23]([C:25]4[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH:33]5[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]5)=[CH:27][CH:26]=4)[O:24][C:12]3=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1Cc2cc3c(cc2C[C@H]1C(=O)O)OC[C@H](c1ccc(OCC2CCCCC2)cc1)O3
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccnc(C)c2C)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@H](c1ccc(OCC2CCCCC2)cc1)CO3
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.2 %

Procedure:
(3S,8S)-3-(4-Cyclohexylmethoxy-phenyl)-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7,8-dicarboxylic acid 7-tert-butyl ester (72 mg), EDCl (33 mg), HOBt (24 mg), and (S)-2-amino-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester bis hydrochloride (59 mg) were suspended in 3 mL DCM and NMM (0.067 mL) added. The mixture was stirred at room temperature for 3 hours and the mixture was directly purified over silica (hexanes to 1:1 hexanes/EtOAc to 1:1 hexanes/EtOAc+1% MeOH) to give (3S,8S)-3-(4-cyclohexylmethoxy-phenyl)-8-{(S)-2-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-1-methoxycarbonyl-ethylcarbamoyl}-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7-carboxylic acid tert-butyl ester (86 mg). LCMS: (m/z) 791.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][N:3]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C@@H:27]([NH2:29])[CH3:28])=[CH:23][CH:22]=1.CCN(C(C)C)C(C)C>CCCCO>[CH:14]1([C:12]2[NH:11][N:10]=[C:9]([NH:8][C:6]3[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][N:3]=[C:2]([NH:29][C@H:27]([C:24]4[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=4)[CH3:28])[N:7]=3)[CH:13]=2)[CH2:16][CH2:15]1
Reactant: C[C@H](N)c1ccc(F)cc1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Nc1cc(C2CC2)[nH]n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@H](Nc1ncc([N+](=O)[O-])c(Nc2cc(C3CC3)[nH]n2)n1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
A mixture of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-5-nitropyrimidin-4-amine (Method 76; 1.0 g, 3.6 mmol), (S)-1-(4-fluorophenyl)ethanamine (0.5 g, 3.6 mmol), and DIEA (0.6 g, 4.6 mmol) in n-BuOH (15 ml) was stirred at 25° C. for 1 hour and then concentrated. The resulting oil was purified by column chromatography (DCM:MeOH=50:1) to give the title compound (0.8 g, 60%). MS: Calcd.: 383; Found: [M+H]+ 384.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]=[C:11]=[O:12])=[CH:6][CH:5]=1)[CH3:2].[ClH:13].Cl.Cl.[NH2:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][N:23]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[CH2:22][CH2:21]1.C(N(CC)CC)C>C(Cl)Cl>[ClH:33].[ClH:13].[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][N:23]2[CH2:22][CH2:21][N:20]([CH2:19][CH2:18][CH2:17][NH:16][C:11]([NH:10][C:7]3[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=3)=[O:12])[CH2:25][CH2:24]2)=[CH:28][CH:29]=1
Reactant: CCOc1ccc(N=C=O)cc1
Reactant: NCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1ccc(NC(=O)NCCCN2CCN(Cc3ccc(Cl)cc3)CC2)cc1
Yield: 135.7 %

Procedure:
The procedure described in Example 29 was followed, using 4-ethoxyphenyl isocyanate (1.63 g; 10 mmole), 1-(3-aminopropyl)-4-(4-chlorobenzyl)piperazine trihydrochloride (3.77 g; 10 mmole), methylene chloride (16 ml), and triethylamine (4.3 ml; 31 mmole). Recrystallization from ethanol provided the title compound (3.42 g; 68% yield) as colorless crystals, m.p. 225°-227° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([CH2:19][C:20]4([CH3:24])[CH2:23][O:22][CH2:21]4)=[C:14]([C:16]([NH2:18])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:25]=1.[CH3:26][C:27]1[O:31][N:30]=[C:29]([C@:32]([OH:36])([C:34]#[CH:35])[CH3:33])[CH:28]=1>>[OH:36][C@:32]([C:29]1[CH:28]=[C:27]([CH3:26])[O:31][N:30]=1)([CH3:33])[C:34]#[C:35][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]3[CH2:10][CH:9]([CH2:12]3)[N:8]3[C:13]([CH2:19][C:20]4([CH3:24])[CH2:23][O:22][CH2:21]4)=[C:14]([C:16]([NH2:18])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:25]=1
Reactant: CC1(Cc2c(C(N)=O)nc3n2C2CC(C2)c2ccc(Br)cc2-3)COC1
Reactant: C#C[C@@](C)(O)c1cc(C)on1
Product: Cc1cc([C@](C)(O)C#Cc2ccc3c(c2)-c2nc(C(N)=O)c(CC4(C)COC4)n2C2CC3C2)no1

Procedure:
Similar to as described in General Procedure E, 10-bromo-3-((3-methyloxetan-3-yl)methyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide was reacted with (R)-2-(5-methylisoxazol-3-yl)but-3-yn-2-ol to give the titled compound.
Reaction SMILES: [ClH:1].C([N:9]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][N:16]=[N:15]2)[CH2:10]1)C1C=CC=CC=1.Cl>CO.[Pd]>[ClH:1].[CH2:22]([O:21][C:19]([C:18]1[N:14]([CH:11]2[CH2:12][CH2:13][NH:9][CH2:10]2)[N:15]=[N:16][CH:17]=1)=[O:20])[CH3:23]
Reactant: CCOC(=O)c1cnnn1C1CCN(Cc2ccccc2)C1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCOC(=O)c1cnnn1C1CCNC1
Reaction time: 20 h

Procedure:
To a solution of N-benzyl-3-(5-ethoxy carbonyl -1,2,3-triazol-1-yl)pyrrolidine hydrochloride (2 g, 0.0061 mol) in methanol (100 ml) was added 10% Pd/C (200 mg) and concentrated HCl (1 ml). The suspension was hydrogenated at r.t. and 50 psi pressure for 20 hrs. The Pd/C was removed by filtration and the solution was concentrated. The residue was crystallized from methanol/ether to obtain crystalline white compound. Yield: 135 mg (93.29%). 1H NMR (D2O) δ: 1.42 (t, 3H), 2.52-2.86 (m, 2H), 3.65-3.75 (m, 2H), 3.87-4.08 (m, 2H), 3.47 (q, 2H), 5.58-5.69 (m, 1H), 8.69 (s, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12].[OH-].[Na+].[Cl:16][C:17]1[CH:25]=[C:24]([Cl:26])[CH:23]=[C:19]([C:20]([O-])=[O:21])[C:18]=1[OH:27].Cl>O1CCOCC1>[Cl:16][C:17]1[CH:25]=[C:24]([Cl:26])[CH:23]=[C:19]([C:20]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[O:21])[C:18]=1[OH:27]
Reactant: O=C([O-])c1cc(Cl)cc(Cl)c1O
Reactant: NCCCCCCCCCC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)CCCCCCCCCNC(=O)c1cc(Cl)cc(Cl)c1O
Temperature: 90 °C

Procedure:
A slurry of 3.0 g of (16.0 mmol, 1.1 eq) 10-aminodecanoic acid, 9 ml (18.0 mmol, 1.13 eq) of 2 N aqueous sodium hydroxide and 30 ml of dioxane was added to a white slurry of 3.97 g (20.8 mmol, 1.3 eq) of oligo (3,5-dichlorosalicylate) and 30 ml of dioxane in a 250 mL round bottom flask equipped with a magnetic stir bar and reflux condenser. The reaction mixture was heated to 90° C. for 20 hours (at which time no further change was observed, by HPLC). The reaction mixture was cooled to 25° C. and acidified to pH=1 with 2N aqueous hydrochloric acid. The mixture was concentrated in vacuo (60° C., 50 mm). The resulting solid was recrystallized twice from ethanol-water decolorized with charcoal but was not yet clean. Column chromatography using 5:1 hexanes/ethyl acetate-1% acetic acid as eluant gave one fraction as acid and another as ethyl ester. The ethyl ester was hydrolyzed to the acid using 4 ml of 2N aqueous sodium hydroxide and acidified with 2N aqueous hydrochloric acid. The acid was isolated by filtration. The combined acid portions were triturated with methylene chloride and hexanes to give 1.22 g of N-(3,5-dichlorosalicyloyl)-10-aminodecanoic acid.