Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:16](=[O:17])[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Ru].COCCO>[CH2:1]([N:8]1[C:16](=[O:17])[CH:15]2[CH:10]([NH:11][CH2:12][CH2:13][CH2:14]2)[C:9]1=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1c2cccnc2C(=O)N1Cc1ccccc1
Agent: [Ru]
Solvent: COCCO
Product: O=C1C2CCCNC2C(=O)N1Cc1ccccc1
Reaction time: 22 h
Yield: 101.4 %

Procedure:
To 10 g of 6-benzyl-5,7-dihydro-5,7-dioxopyrrolo[3.4-b]pyridine were added 84 ml of 2-methoxyethanol and 1.5 g of a ruthenium-on-carbon catalyst, and hydrogenation was conducted under a pressurized hydrogen gas atmosphere at 4.5 kg/cm2 for 22 hours. The catalyst was removed by filtration, and the filtrate was concentrated. To the concentrate were added 84 ml of 2-methoxyethanol and 2 g of a palladium-on-charcoal catalyst, and hydrogenation was conducted under a pressurized hydrogen gas atmosphere at 4.5 kg/cm2 for 7 hours. The catalyst was removed by filtration, and the filtrate was concentrated to yield 10.4 g of the titled compound. Throughout the hydrogenation, the reaction vessel was heated by a tungsten lamp.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][C:15]([OH:17])=O)=[CH:4][CH:3]=1.[CH3:18][CH:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][C:15]([NH:26][CH:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH3:18])=[O:17])=[CH:6][CH:7]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CC(=O)O
Reactant: CC(N)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1noc(-c2ccc(Br)cc2)c1CC(=O)NC(C)c1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
[5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-yl]acetic acid (0.154 g, 0.52 mmol), α-methylbenzylamine (0.07 mL, 0.52 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.120 g, 0.62 mmol), 1-hydroxybenzotriazole (0.087 g, 0.62 mmol), and triethylamine (0.22 mL, 1.56 mmol) were combined in CH2Cl2 (1.5 mL). The reaction was stirred at room temperature for 2.5 hours. After aqueous workup the crude material was purified by silica gel chromatography (0-60% EtOAc in hexanes) to give the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH2:9][C:10]([F:13])([F:12])[F:11])[N:3]=1.[NH4+:14].[OH-]>CC#N>[F:11][C:10]([F:13])([F:12])[CH2:9][S:8][C:4]1[N:3]=[C:2]([NH2:14])[CH:7]=[CH:6][N:5]=1
Reactant: [NH4+]
Reactant: FC(F)(F)CSc1nccc(Cl)n1
Agent: [OH-]
Solvent: CC#N
Product: Nc1ccnc(SCC(F)(F)F)n1
Temperature: 90 °C
Reaction time: 24 h
Yield: 71.3 %

Procedure:
To solution of 4-chloro-2-(2,2,2-trifluoro-ethylsulfanyl)-pyrimidine (22 g, 0.096 mol) in 350 mL of CH3CN was added NH4OH (400 mL). The mixture was stirred for 24 hours at 90° C. in a sealed tube. The mixture was then cooled to room temperature and the solvent was concentrated in vacuo, the residue was extracted with ethyl acetate, dried over MgSO4 and the crude was purified by column chromatography on silica gel to give 2-(2,2,2-trifluoro-ethylsulfanyl)-pyrimidin-4-ylamine (14.3 g, 71.3%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][N:14]=[C:13]([CH3:17])[CH:12]=1)=O.[CH2:18]([CH:20]([CH2:26][CH3:27])[C:21](=O)[CH2:22][C:23]#[N:24])[CH3:19]>>[Cl:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[N:1]=[C:21]([CH:20]([CH2:26][CH3:27])[CH2:18][CH3:19])[C:22]([C:23]#[N:24])=[C:9]2[C:11]1[CH:16]=[CH:15][N:14]=[C:13]([CH3:17])[CH:12]=1
Reactant: CCC(CC)C(=O)CC#N
Reactant: Cc1cc(C(=O)c2cc(Cl)ccc2N)ccn1
Product: CCC(CC)c1nc2ccc(Cl)cc2c(-c2ccnc(C)c2)c1C#N

Procedure:
The title compound was prepared in analogy to example 101 step B from (2-amino-5-chloro-phenyl)-(2-methyl-pyridin-4-yl)-methanone (prepared in analogy to example 126 step B) and 4-ethyl-3-oxo-hexanenitrile (prepared as described in example 101 step A). Yellow solid. MS (ESI): 350.5 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:44])[C:3]([C:5]1[CH:6]=[C:7]([CH:41]=[CH:42][CH:43]=1)[O:8][C:9]1[N:14]=[C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([NH2:23])=[C:11]([O:24][C:25]2[CH:30]=[C:29]([C:31]#[N:32])[CH:28]=[CH:27][C:26]=2[O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:10]=1)=[O:4].[CH2:45]1COC[CH2:46]1.C(O)C>>[CH3:1][N:2]([CH3:44])[C:3]([C:5]1[CH:6]=[C:7]([CH:41]=[CH:42][CH:43]=1)[O:8][C:9]1[N:14]=[C:13]2[C:12]([N:23]=[C:45]([CH3:46])[N:15]2[CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[C:11]([O:24][C:25]2[CH:30]=[C:29]([C:31]#[N:32])[CH:28]=[CH:27][C:26]=2[O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[N:10]=1)=[O:4]
Reactant: C1CCOC1
Reactant: CN(C)C(=O)c1cccc(Oc2nc(NCc3ccccc3)c(N)c(Oc3cc(C#N)ccc3OCc3ccccc3)n2)c1
Solvent: CCO
Product: Cc1nc2c(Oc3cc(C#N)ccc3OCc3ccccc3)nc(Oc3cccc(C(=O)N(C)C)c3)nc2n1Cc1ccccc1
Temperature: 170 °C

Procedure:
2-(3-Dimethylaminocarbonylphenoxy)-4-(benzyl)amino-5-amino-6-(2-benzyloxy-5-cyanophenoxy)pyrimidine, a compound of formula (J), (0.26 g, 0.44 mmol), was treated with ethyl imidate hydrochloride (0.17 g, 1.3 mmol) in THF/ethanol at 80° C for 6 hours and then concentrated to an oil. The residue was heated in a sand bath under vacuum at 170° C. for 2.0 hours, cooled and filtered through a pad of silica, eluting with 5% methanol in methylene chloride. Evaporation of the volatiles afforded 0.20 g of 2-(3-dimethylaminocarbonylphenoxy)-6-(2-benzyloxy-5-cyanophenoxy)-8-methyl-9-benzylpurine, a compound of formula (L).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[S:14][CH:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=3)[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5])[CH3:2].[C:24](Cl)(=[O:33])[C:25]1[C:26]([O:31][CH3:32])=[CH:27][CH:28]=[CH:29][CH:30]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[S:14][CH:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24](=[O:33])[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[O:31][CH3:32])[CH:18]=3)[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cncc2c(COc3cccc(N)c3)csc12
Reactant: COc1ccccc1C(=O)Cl
Product: CCOC(=O)c1cncc2c(COc3cccc(NC(=O)c4ccccc4OC)c3)csc12

Procedure:
3-[3-(2-Methoxy-benzoylamino)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester was prepared from 3-(3-amino-phenoxymethyl)-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (from Example 3 supra) and o-anisoyl chloride (Aldrich) following the procedure described in Example 10 as an off-white solid.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8](Cl)=[O:9])=[C:6]([N+:11]([O-:13])=[O:12])[C:5]([CH3:14])=[N:4]1)[CH3:2].[OH-].[NH4+:16]>CC(C)=O>[CH2:1]([N:3]1[C:7]([C:8]([NH2:16])=[O:9])=[C:6]([N+:11]([O-:13])=[O:12])[C:5]([CH3:14])=[N:4]1)[CH3:2]
Reactant: CCn1nc(C)c([N+](=O)[O-])c1C(=O)Cl
Reactant: [NH4+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CCn1nc(C)c([N+](=O)[O-])c1C(N)=O
Reaction time: 1 h
Yield: 95 %

Procedure:
A solution of 108 g (0.05 mol) of 1-ethyl-3-methyl-4-nitro-pyrazole-5-carbonyl chloride [J. Med. Chem. 16 1346 (1973)] in 100 ml of acetone is added at a fast droprate to 450 ml cold concentrated ammonium hydroxide with stirring. After one hour, the mixture is filtered; the product is washed with water to give 94 g (95%) of 1-ethyl-3-methyl-4-nitropyrazole-5-carboxamide, mp 175°-177° C.
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:17]=[C:16]2[C:12]([NH:13][CH:14]=[N:15]2)=[C:11](Cl)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:20]([NH2:25])[CH2:21][C:22]([CH3:24])=[CH2:23].C(N(CC)CC)C>C(O)CCC>[CH2:1]([S:8][C:9]1[N:17]=[C:16]2[C:12]([NH:13][CH:14]=[N:15]2)=[C:11]([NH:25][CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1nc(SCc2ccccc2)nc2nc[nH]c12
Reactant: C=C(C)CCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: CC(C)=CCNc1nc(SCc2ccccc2)nc2nc[nH]c12
Temperature: 110 °C

Procedure:
A mixture of 2-benzylthio-6-chloropurine (1.2 g) and isopentenylamine hydrochloride (1.04 g) in 1-butanol (25 ml) containing triethylamine (2.2 ml) is heated in a sealed tube at 110° C. for 2 hours. The butanol is removed under vacuum and the mixture shaken with ice-water (100 ml). The product is filtered recrystallized from ethanol with charcoal decolorization and dried under vacuum with phosphorous pentoxide. Yield 0.64 g. Yield 1.3 g of 2-benzyl-thio-N6 -(2-iso-pentyenyl)adenine as a colorless solid. The crude product is used directly in the next step.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([NH:15][CH:16]1[CH2:21][CH2:20][CH2:19][N:18]([C:22]2[CH:23]=[C:24]([CH:29]=[CH:30][CH:31]=2)[C:25]([O:27][CH3:28])=[O:26])[CH2:17]1)=O)(C)(C)C>ClCCl>[NH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][N:18]([C:22]2[CH:23]=[C:24]([CH:29]=[CH:30][CH:31]=2)[C:25]([O:27][CH3:28])=[O:26])[CH2:17]1
Reactant: COC(=O)c1cccc(N2CCCC(NC(=O)OC(C)(C)C)C2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1cccc(N2CCCC(N)C2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
Trifluoroacetic acid (2 mL) was added to methyl 3-[3-(tert-butoxycarbonylamino)piperidin-1-yl]benzoate (451 mg, 1.35 mmol) in dichloromethane (2 mL). The reaction mixture was stirred at room temperature for 1 hour. Subsequently, the mixture was concentrated and a saturated aqueous sodium bicarbonate solution was added to the residue to make it basic. The mixture was extracted with ethyl acetate and the organic layer washed with brine and dried over magnesium sulfate. Evaporation of the solvent gave 158 mg (50%) of the desired compound as a pale yellow oil.
Reaction SMILES: [CH2:1]([O:6][C:7]([NH:9][C@@H:10]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]=[CH2:22])[C:11]([O:13]CC)=[O:12])=[O:8])[CH2:2][CH2:3][CH:4]=[CH2:5].[Li+].[OH-].Cl>C1COCC1.CCO>[CH2:1]([O:6][C:7]([NH:9][C@@H:10]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]=[CH2:22])[C:11]([OH:13])=[O:12])=[O:8])[CH2:2][CH2:3][CH:4]=[CH2:5]
Reactant: C=CCCCCC[C@H](NC(=O)OCCCC=C)C(=O)OCC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: C=CCCCCC[C@H](NC(=O)OCCCC=C)C(=O)O
Yield: 91.7 %

Procedure:
A solution of ethyl (2S)-2-{[(pent-4-en-1-yloxy)carbonyl]amino}non-8-enoate (0.96 g, 3.08 mmol) in THF (20 mL), EtOH (1 mL) and 1 M aqueous LiOH (21.58 mL, 21.58 mmol) was stirred at RT for 2 hours. The reaction mixture was acidified to pH 5 with 1 N aqueous HCl and extracted with ether (3×100 mL). The combined ether layers were washed with water (100 mL), brine (50 mL), dried over Na2SO4, filtered and concentrated to give title compound (0.80 g). LRMS (ESI) m/z 284.4 [(M+H)+; calcd for C15H26NO4: 284.2].
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:31]1[CH:36]=[CH:35][N:34]=[CH:33][N:32]=1)[S:7]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C@H:17]2[CH2:22][CH2:21][CH2:20][CH2:19][C@@H:18]2[C:23]2[N:27]([CH2:28][CH3:29])[N:26]=[CH:25][CH:24]=2)=[CH:12][C:11]=1[F:30])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[CH2:28]([N:27]1[C:23]([C@H:18]2[CH2:19][CH2:20][CH2:21][CH2:22][C@@H:17]2[O:16][C:13]2[CH:14]=[CH:15][C:10]([S:7]([NH:6][C:31]3[CH:36]=[CH:35][N:34]=[CH:33][N:32]=3)(=[O:8])=[O:9])=[C:11]([F:30])[CH:12]=2)=[CH:24][CH:25]=[N:26]1)[CH3:29]
Reactant: CCn1nccc1[C@H]1CCCC[C@@H]1Oc1ccc(S(=O)(=O)N(Cc2ccc(OC)cc2OC)c2ccncn2)c(F)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCn1nccc1[C@H]1CCCC[C@@H]1Oc1ccc(S(=O)(=O)Nc2ccncn2)c(F)c1
Yield: 88 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-4-{[(1S*,2R*)-2-(1-ethyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide (0.51 g, 0.85 mmol) prepared in Example 45a, triethylsilane (0.68 mL), trifluoroacetic acid (0.85 mL) and dichloromethane (8.5 mL), to yield the title compound (333.4 mg, 88%) as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:10]([C:22]34[CH2:31][CH:26]5[CH2:27][CH:28]([CH2:30][CH:24]([CH2:25]5)[CH2:23]3)[CH2:29]4)[CH:9]=2)=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41]>CC(C)=O>[C:22]12([C:10]3[CH:9]=[C:8]([C:5]4[N:6]=[CH:7][C:2]([NH:1][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:3][N:4]=4)[CH:13]=[CH:12][C:11]=3[O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:23][CH:24]3[CH2:30][CH:28]([CH2:27][CH:26]([CH2:25]3)[CH2:31]1)[CH2:29]2
Reactant: CCOC(=O)CBr
Reactant: Nc1cnc(-c2ccc(OCc3ccccc3)c(C34CC5CC(CC(C5)C3)C4)c2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CNc1cnc(-c2ccc(OCc3ccccc3)c(C34CC5CC(CC(C5)C3)C4)c2)nc1
Temperature: 25 °C
Yield: 88.8 %

Procedure:
To a suspension of 5-amino-2-[3-(1-adamantyl)-4-benzyloxyphenyl]pyrimidine (49 mg, 0.12 mmol) and K2CO3 (69 mg, 0.50 mmol) in acetone (5 mL) was added ethyl bromoacetate (53 μl, 0.48 mmol). The mixture was heated at reflux under argon for 19 h and cooled to room temperature. After removal of acetone at reduced pressure, the residue was diluted with water (8 mL) and extracted with EtOAc (60 mL). The extract was washed (H2O and brine) and dried. After solvent removal at reduced pressure, the residue was chromatographed (14% EtOAc/hexane) to give 53 mg (89%) of 2-[3-(1-adamantyl)-4-benzyloxyphenyl]-5-(carbethoxymethylamino)pyrimidine as a pale-tan solid, mp 153-156° C. IR 3455, 2901, 1710, 1179 cm−1; 1H NMR (CDCl3) δ 1.33 (t, J=7.2 Hz, 3H, OCH2CH3), 1.75 (bs, 6H, AdCH2), 2.07 (bs, 3H, AdCH), 2.24 (m, 6H, AdCH2), 4.31 (q, J=7.2 Hz, 2H, OCH2CH3), 4.60 (m, 1H, NH), 4.73 (s, 2H, NHCH2CO), 5.20 (s, 2H, C6H5CH2), 7.03 (d, J=8.4 Hz, 1H, 5′-ArH), 7.32-7.55 (m, 5H, C6H5), 8.17 (dd, J=8.4 Hz, 2.1 Hz, 1H, 6′-ArH), 8.32 (d, J=2.1 Hz, 1H, 2′-ArH), 8.46 ppm (s, 2H, 4-ArH, 6-ArH). HRMS calcd C31H35N3O3 [M+H]+ 498.2757. found 498.2762.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([OH:10])[CH2:8][CH2:7][N:6]([CH3:9])[CH2:5][CH2:4]1.[C:11](OC(=O)C)(=[O:13])[CH3:12]>C(Cl)(Cl)Cl>[C:11]([NH:1][CH2:2][C:3]1([OH:10])[CH2:8][CH2:7][N:6]([CH3:9])[CH2:5][CH2:4]1)(=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: CN1CCC(O)(CN)CC1
Solvent: ClC(Cl)Cl
Product: CC(=O)NCC1(O)CCN(C)CC1
Reaction time: 0.5 h

Procedure:
4-Aminomethyl-4-hydroxy-1-methylpiperidine (0.83 g., 5.7 mmole) was dissolved in 10 ml. chloroform, and acetic anhydride (0.58 g., 5.7 mmole) was added. The reaction mixture warmed spontaneously to 40°-50° C. After 30 minutes, the solvent was evaporated and the crude residue was chromatographed on a silica gel column (Merck 7734), using 33:67 2% aqueous ammonia-methanol as eluent.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[C:18]([NH2:20])=[O:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[CH2:22][C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:22][C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=2)[C@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[C:18]([NH2:20])=[O:19])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: NC(=O)[C@@H]1CCCC[C@@H]1NS(=O)(=O)c1ccc(Cl)cc1
Product: N#Cc1ccc(CN([C@H]2CCCC[C@H]2C(N)=O)S(=O)(=O)c2ccc(Cl)cc2)cc1
Yield: 49 %

Procedure:
The titled compound (133 mg) was prepared in 49% yield from cis-2-(4-chlorobenzenesulfonylamino)-cyclohexanecarboxylic acid amide and 4-bromomethyl-benzonitrile according to the procedure described in Example 11: 1H NMR (DMSO-d6) δ 7.84 (d, 2 H, J=8.0 Hz), 7.73 (d, 2 H, J=8.0 Hz), 7.66 (d, 2 H,J=8.0 Hz), 7.48 (d, 2 H,J=8.0 Hz), 7.29 (s, 1 H), 6.60 (s, 1 H), 4.63 (AB2,2 H,Δv=16,Jab=76 Hz), 3.84 (m, 1 H), 2.79 (m, 1 H), 2.41 (m, 1 H), 1.64 (m, 2 H), 1.27 (m, 3 H), 0.85 (m, 1 H); MS m/e 454.02 (M+Na)+.
Reaction SMILES: O=[C:2]1[CH2:6][CH2:5][S:4][CH:3]1[C:7]([O:9][CH3:10])=[O:8].[CH3:11][CH:12]([C:31]1[CH:32]=C(O)[CH:34]=[C:35]([CH:37]=1)[OH:36])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>>[CH3:11][CH:12]([C:31]1[CH:37]=[C:35]([OH:36])[C:34]2[C:2]3[CH2:6][CH2:5][S:4][C:3]=3[C:7](=[O:8])[O:9][C:10]=2[CH:32]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: COC(=O)C1SCCC1=O
Reactant: CCCCCCCCCCCCCCCCCCC(C)c1cc(O)cc(O)c1
Product: CCCCCCCCCCCCCCCCCCC(C)c1cc(O)c2c3c(c(=O)oc2c1)SCC3

Procedure:
Following a procedure similar to that described in Example 1B hereinabove, methyl 3-oxo-2,3,4,5-tetrahydrothiophene-2-carboxylate is reacted with 5-(2-eicosyl)resorcinol to give 1,2-dihydro-7-(2-eicosyl)-9-hydroxy-4-oxo-4H-thieno [2,3-c] [1]benzopyran.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[N:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][CH2:12][O:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:27][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCCCCCCOCCOCCc1ccccn1
Reactant: NCc1ccccc1
Product: c1ccc(CNCCCCCCOCCOCCc2ccccn2)cc1
Yield: 82.5 %

Procedure:
A solution of 2-[2-[2-[(6-bromohexyl)oxy]ethoxy]ethyl]pyridine (1.55 g) in benzylamine (3.1 g) was heated at 125° under nitrogen for 3 h. The solution was allowed to cool and then partitioned between 8% sodium bicarbonate (100 ml) and diethyl ether (2×100 ml). The solvent was evaporated in vacuo and the residual oil distilled (Kugelrohr) to remove excess benzylamine. Purification by FCC eluting with System G 92:8:1) gave the title compound (1.38 g) as a colourless oil. T.l.c. (System G 95:5:1) Rf 0.14
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]([OH:20])=O)=[C:13]3[N:12]=[CH:11][C:10]=2[C:21]([N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:25][CH2:24]2)=[O:22])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:35]([S:37]([NH2:40])(=[O:39])=[O:38])[CH3:36]>>[CH3:1][C:2]1[C:7]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]([NH:40][S:37]([CH2:35][CH3:36])(=[O:39])=[O:38])=[O:20])=[C:13]3[N:12]=[CH:11][C:10]=2[C:21]([N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:25][CH2:24]2)=[O:22])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Cc1ncccc1Nc1c(C(=O)N2CCC(c3ccccc3)CC2)cnc2c(C(=O)O)cnn12
Reactant: CCS(N)(=O)=O
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3cccnc3C)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Yield: 31.5 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(2-methyl-3-pyridylamino)-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.05 g, 0.11 mmol) obtained in step 2 and ethanesulfonamide (0.052 g, 0.55 mmol), the title compound (0.019 g, 31%) was obtained.
Reaction SMILES: [OH:1][C@H:2]1[C@@H:6]([OH:7])[C@H:5]([N:8]2[CH:13]=[CH:12][C:11](=[O:14])[N:10]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[C:9]2=[O:24])[O:4][CH:3]1[C@H:25]([OH:57])[C@@H:26]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[NH:27][CH2:28][CH2:29][CH2:30][NH:31][C:32](=[O:49])[C@H:33]([CH2:45][CH:46]([CH3:48])[CH3:47])[NH:34]C(=O)OCC1C=CC=CC=1>CO.[Pd]>[NH2:34][C@@H:33]([CH2:45][CH:46]([CH3:48])[CH3:47])[C:32]([NH:31][CH2:30][CH2:29][CH2:28][NH:27][C@@H:26]([C@H:25]([CH:3]1[C@@H:2]([OH:1])[C@@H:6]([OH:7])[C@H:5]([N:8]2[CH:13]=[CH:12][C:11](=[O:14])[N:10]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[C:9]2=[O:24])[O:4]1)[OH:57])[C:50]([O:52][C:53]([CH3:54])([CH3:56])[CH3:55])=[O:51])=[O:49]
Reactant: COc1ccc(Cn2c(=O)ccn([C@@H]3OC([C@H](O)[C@H](NCCCNC(=O)[C@H](CC(C)C)NC(=O)OCc4ccccc4)C(=O)OC(C)(C)C)[C@@H](O)[C@H]3O)c2=O)cc1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(Cn2c(=O)ccn([C@@H]3OC([C@H](O)[C@H](NCCCNC(=O)[C@@H](N)CC(C)C)C(=O)OC(C)(C)C)[C@@H](O)[C@H]3O)c2=O)cc1
Yield: 90.4 %

Procedure:
By using an analogous procedure to that described for Example 45, tert-butyl (5S,12S)-12-[(R)-[(3S,4R,5R)-3,4-dihydroxy-5-(3-(4-methoxybenzyl)-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)tetrahydro-2-furanyl](hydroxy)methyl]-5-isobutyl-3,6-dioxo-1-phenyl-2-oxa-4,7,11-triazatridecan-13-oate (20 mg, 0.025 mmol, obtained from Example 51) was hydrogenated in methanol (1 ml) using 10% palladium on carbon (8 mg) for 4 hours to provide tert-butyl (2S,3R)-2-[(3-{[(2S)-2-amino-4-methylpentanoyl]amino}propyl)amino]-3-[(3S,4R,5R)-3,4-dihydroxy-5-(3-(4-methoxybenzyl)-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)tetrahydro-2-furanyl]-3-hydroxypropanoate (15 mg, 90%) as a white solid.
Reaction SMILES: [Br-:1].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.[S:34]1[C:38]([C:39](=[O:41])[CH3:40])=[CH:37][C:36]2[CH:42]=[CH:43][CH:44]=[CH:45][C:35]1=2>O1CCCC1>[S:34]1[C:38]([C:39](=[O:41])[CH2:40][Br:1])=[CH:37][C:36]2[CH:42]=[CH:43][CH:44]=[CH:45][C:35]1=2
Reactant: CC(=O)c1cc2ccccc2s1
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: O=C(CBr)c1cc2ccccc2s1
Temperature: 25 °C
Reaction time: 5 h
Yield: 193.5 %

Procedure:
Phenyltrimethylammonium tribromide (32.04 g) was added in portions under nitrogen at 0° C. over 10 minutes to a stirred solution of 1-(benzo[b]thiophen-2-yl]ethan-1-one (15.0 g) in tetrahydrofuran (400 ml), the mixture was stirred at ambient temperature for 5 hours, then it was filtered and the solvent was removed in vacuo. The residue was triturated with a 9:1 mixture of petroleum ether (b.p. 60-80° C.) and ethyl acetate (50 ml) and the resulting solid was collected by filtration and dried in vacuo to give 1-(benzo[b]thiophen-2-yl)-2-bromoethan-1-one (24.40 g) as a brown solid which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:3]=1[C:4]([OH:6])=[O:5].[C:14](Cl)(=O)C(Cl)=O>ClCCl.CN(C)C=O>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:3]=1[C:4]([O:6][CH3:14])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1c(Cl)cccc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1c(Cl)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.9 %

Procedure:
To a suspension containing 3.0 g (15 mmol) of 2-chloro-6-nitrobenzoic acid in 150 ml of dichloromethane was added 2.8 g (22 mmol) of oxalyl chloride followed by 0.055 ml (0.75 mmol) of N,N-dimethylformamide. The reaction was allowed to stir at room temperature for 2 h, quenched with 50 ml of methanol and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate. The organic phase was dried over magnesium sulfate. Filtration, removal of solvent and purification of the residue via biotage eluting with 10% ethyl acetate/hexanes gave 3.1 g (9-7%) of product.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([NH:12][C:13]1[NH:21][C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]=2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].Br[CH2:26][CH2:27][CH2:28][CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][O:31]1>>[CH2:8]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:26][CH2:27][CH2:28][CH2:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][O:31]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCNc1nc(N)c2nc(OC)nc-2[nH]1
Reactant: BrCCCCC1CCCCO1
Solvent: O=C(O)C(F)(F)F
Product: CCCCNc1nc(N)c2nc(OC)n(CCCCC3CCCCO3)c2n1

Procedure:
Prepared similarly to Intermediate 220 from N2-butyl-8-(methyloxy)-3H-purine-2,6-diamine trifluoroacetate and 2-(4-bromobutyl)tetrahydro-2H-pyran.