Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](O)=[O:12])=[CH:7][C:6]=1[NH:14][C:15](=[O:33])[CH2:16][CH:17]([C:23]1[C:28]([O:29][CH3:30])=[CH:27][CH:26]=[CH:25][C:24]=1[O:31][CH3:32])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])([CH3:4])([CH3:3])[CH3:2].[NH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:12])[NH:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=2)=[CH:7][C:6]=1[NH:14][C:15](=[O:33])[CH2:16][CH:17]([C:23]1[C:28]([O:29][CH3:30])=[CH:27][CH:26]=[CH:25][C:24]=1[O:31][CH3:32])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCCCCC(CC(=O)Nc1cc(C(=O)O)ccc1C(C)(C)C)c1c(OC)cccc1OC
Reactant: Nc1ccccn1
Product: CCCCCC(CC(=O)Nc1cc(C(=O)Nc2ccccn2)ccc1C(C)(C)C)c1c(OC)cccc1OC

Procedure:
Following a similar procedure to that described in Example 8, but using N-(2-t-butyl-5-carboxyphenyl)-3-(2,6-dimethoxyphenyl)octanamide (prepared as described in Preparation 74E) and 2-aminopyridine, the title compound was obtained as a colorless foam-like substance.
Reaction SMILES: [I-].CS[C:4]1[S:5][CH2:6][C@@H:7]2[CH2:16][C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH2:9][N+:8]=12.[NH2:17][C:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[CH:20]=[CH:21][CH:22]=[N:23]2>>[N:23]1[C:24]2[C:19](=[C:18]([N:17]=[C:4]3[N:8]4[CH2:9][C:10]5[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=5[CH2:16][C@H:7]4[CH2:6][S:5]3)[CH:27]=[CH:26][CH:25]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: Nc1cccc2ncccc12
Reactant: CSC1=[N+]2Cc3ccccc3C[C@H]2CS1
Agent: [I-]
Product: c1ccc2c(c1)C[C@H]1CSC(=Nc3cccc4ncccc34)N1C2
Yield: 90.3 %

Procedure:
By following the procedure of Example 2, but using (S)-3-methylthio-1,5,10,10a-tetrahydrothiazolo-[3,4-b]isoquinolinium iodide (18.2 g) and 5-aminoquinoline (14.4 g) as the starting materials, (S)-3-(quinol-5-yl-imino)-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinoline (15.0 g) is obtained in the form of light beige crystals, m.p.=194° C.
Reaction SMILES: [C:1](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[F:15][C:16]1[CH:17]=[C:18]([CH:35]=[CH:36][CH:37]=1)[CH2:19][NH:20][CH2:21][C@@:22]12[CH2:34][CH2:33][CH2:32][N:23]1[C@@H:24]([C:28]([Cl:31])([Cl:30])[Cl:29])[O:25][C:26]2=[O:27].C=O.C(O)(=O)C>ClCCCl>[F:15][C:16]1[CH:17]=[C:18]([CH:35]=[CH:36][CH:37]=1)[CH2:19][N:20]([CH2:21][C@@:22]12[CH2:34][CH2:33][CH2:32][N:23]1[C@@H:24]([C:28]([Cl:30])([Cl:31])[Cl:29])[O:25][C:26]2=[O:27])[CH3:1]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=C1O[C@H](C(Cl)(Cl)Cl)N2CCC[C@@]12CNCc1cccc(F)c1
Agent: C=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CN(Cc1cccc(F)c1)C[C@@]12CCCN1[C@@H](C(Cl)(Cl)Cl)OC2=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium triacetoxyborohydride (889 mg, 4.19 mmol) was added to a mixture of (3R,7aR)-7a-[(3-fluoro-benzylamino)-methyl]-3-trichloromethyl-tetrahydro-pyrrolo[1,2-c]oxazol-1-one (Stage K.2, 400 mg, 1.048 mmol), formaldehyde (37% in H2O, 0.102 mL, 1.36 mmol) and acetic acid (0.150 mL, 2.62 mmol) in DCE (4 mL) under an argon atm. After 2 h stirring at rt the RM was partitioned between DCM and water. The combined organic layers were dried over Na2SO4 and evaporated to give the title compound as a pale brown oil which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[N:9]2[CH2:12][CH:11]([CH:13]([C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=3)[C:14]([CH3:17])(O)[CH3:15])[CH2:10]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[FH:39].[OH-].[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[N:9]2[CH2:12][CH:11]([C@@H:13]([C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=3)[C:14]([F:39])([CH3:17])[CH3:15])[CH2:10]2)=[CH:4][CH:3]=1
Reactant: F
Reactant: CC(C)(O)C(c1cc(F)cc(F)c1)C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(F)[C@H](c1cc(F)cc(F)c1)C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Temperature: 42 °C
Reaction time: 9 h

Procedure:
To a solution of 175 mg (0.368 mmol) of 1-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-1-(3,5-difluorophenyl)-2-methylpropan-2-ol in 3 mL of CH2Cl2. 1 mL of hydrogen fluoride-pyridine was added and the reaction was stirred for 9 h at 42° C. Then the reaction mixture was poured to 7 mL of 5N NaOH, 7 mL of ag NaHCO3 and 30 mL of CH2Cl2. Adjusted pH to 8-9 with 2N NaOH. The water layer was extracted with CH2Cl2 (3×30 mL). The combined organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography with 10% methyl tert-butyl ether-hexane to afford the title compound as a white solid. 1H NMR (CDCl3) δ 1.25 (t, J=22 Hz, 6H), 2.33 (t, J=6.5 Hz, 1H), 2.83-2.89 (m, 2H), 3.09-3.11 (m, 2H), 3.60 (m, 1H), 4.20 (s, 1H), 6.68-6.71 (m, 3H), 7.21-7.33 (m, 8H)
Reaction SMILES: [F:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][C@@H:7]([CH2:11][CH2:12][C@@H:13]([C:17](=[O:35])[NH:18][C@H:19]2[CH2:25][CH2:24][CH2:23][CH2:22][N:21]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])[C:20]2=[O:34])[CH2:14][CH2:15][CH3:16])[C:8](O)=[O:9])=[CH:4][CH:3]=1.[NH2:38][C@H:39]1[CH2:45][CH2:44][S:43][C@H:42]2[CH2:46][CH2:47][CH2:48][C@@H:49]([C:50]#[N:51])[N:41]2[C:40]1=[O:52]>>[C:50]([C@H:49]1[N:41]2[C@@H:42]([S:43][CH2:44][CH2:45][C@H:39]([NH:38][C:8](=[O:9])[C@@H:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:37][CH:36]=3)[CH2:11][CH2:12][C@H:13]([CH2:14][CH2:15][CH3:16])[C:17]([NH:18][C@H:19]3[CH2:25][CH2:24][CH2:23][CH2:22][N:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[O:32][CH3:33])[C:20]3=[O:34])=[O:35])[C:40]2=[O:52])[CH2:46][CH2:47][CH2:48]1)#[N:51]
Reactant: CCC[C@@H](CC[C@H](Cc1ccc(F)cc1)C(=O)O)C(=O)N[C@H]1CCCCN(c2ccccc2OC)C1=O
Reactant: N#C[C@@H]1CCC[C@@H]2SCC[C@H](N)C(=O)N12
Product: CCC[C@@H](CC[C@H](Cc1ccc(F)cc1)C(=O)N[C@H]1CCS[C@H]2CCC[C@@H](C#N)N2C1=O)C(=O)N[C@H]1CCCCN(c2ccccc2OC)C1=O

Procedure:
(2R,5S)—N1-((4S,7S,10aS)-7-Cyano-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-yl)-2-(4-fluorobenzyl)-N6-((S)-1-(2-methoxyphenyl)-2-oxoazepan-3-yl)-5-propylhexanediamide was synthesized as described in General Procedure H using Intermediate 76 (8.5 mg, 0.017 mmol) and Intermediate 36 (5.0 mg, 0.019 mmol) to give a white solid (5.9 mg, 49% yield). Anal. Calcd. for C39H50FN5O5S m/z 719.7. found: 720.3 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.37 (1H, d, J=6.6 Hz), 7.33-7.25 (1H, m), 7.09-7.02 (3H, m), 7.01-6.94 (3H, m), 6.86 (2H, t, J=8.8 Hz), 5.54-5.32 (3H, m), 5.29 (1H, d, J=4.9 Hz), 5.06-4.86 (2H, m), 4.04-3.89 (1H, m), 3.83 (3H, s), 3.54-3.35 (1H, m), 3.10-2.88 (1H, m), 2.80-2.54 (3H, m), 2.41-2.29 (1H, m), 2.21-1.18 (21H, m), 0.93-0.82 (3H, m).
Reaction SMILES: C([NH:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:19]3[CH:20]=[N:21][CH:22]=[C:18]3[CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)=O)(C)(C)C.P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[C:6]([C:8]1[CH:9]=[CH:10][C:11]([C:14]2[N:19]3[CH:20]=[N:21][CH:22]=[C:18]3[CH:17]=[CH:16][CH:15]=2)=[CH:12][CH:13]=1)#[N:5]
Reactant: CC(C)(C)NC(=O)c1ccc(-c2cccc3cncn23)cc1
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1ccc(-c2cccc3cncn23)cc1

Procedure:
A solution of 0.1 g of 5-(p-tert-butylaminocarbonylphenyl)imidazo[1,5-a]pyridine in 3 ml of toluene is treated with 40 μl of phosphorus oxychloride at 90° for 5 h. The solvent is evaporated and the residue is redissolved in 30 ml of chloroform at 0°. An ice-cold ammonium hydroxide solution is added and the organic phase is separated, dried over sodium sulfate and evaporated. The residue is chromatographed on silica with ethyl acetate to yield the title compound, m.p. 117°-118°.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:7]([CH2:10]O)=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].S(Cl)([Cl:22])=O>>[ClH:19].[CH2:1]([C:5]1[N:6]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:7]([CH2:10][Cl:22])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=S(Cl)Cl
Reactant: CCCCc1ncc(CO)n1Cc1ccccc1Cl
Product: CCCCc1ncc(CCl)n1Cc1ccccc1Cl
Product: Cl

Procedure:
A mixture of 2-n-butyl-1-(2-chlorophenyl)methyl-5-hydroxymethyl-1H-imidazole (1 g) was refluxed with thionyl chloride (20 mL) for 2 hours. The reaction mixture was evaporated in vacuo and the residue was triturated with diethyl ether to give 1.08 g of 2-n-butyl-1-(2-chlorophenyl)methyl-5-chloromethyl-1H-imidazole hydrochloride.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([Br:9])[N:3]=1.N1C=CC=CC=1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>CN(C1C=CN=CC=1)C.C1COCC1.CO>[Br:1][C:2]1[CH:7]=[C:6]([NH:8][C:16](=[O:18])[CH3:17])[CH:5]=[C:4]([Br:9])[N:3]=1
Reactant: Nc1cc(Br)nc(Br)c1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)Nc1cc(Br)nc(Br)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,6-Dibromopyridin-4-amine, DMAP (0.048 g, 0.397 mmol) and pyridine (0.48 ml, 5.95 mmol) were taken-up in THF (7.9 ml) under argon. Acetic anhydride (0.41 ml, 4.37 mmol) was slowly added and the mixture was stirred overnight at room temperature. The reaction was then heated to 65° C. for 5 days and cooled to room temperature, diluted with methanol, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (0-100% EtOAc/hexanes) to afford N-(2,6-dibromopyridin-4-yl)acetamide as a light yellow solid. MS ESI calc'd. for C7H6Br2N2O [M+H]+ 294. found 294.
Reaction SMILES: [Br:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]2[C:8]([CH3:14])([CH3:13])[CH:7](O)[CH2:6][C:5]([CH3:17])([CH3:16])[C:4]=2[CH:3]=1.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[Br:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]2[C:8]([CH3:14])([CH3:13])[CH:7]=[CH:6][C:5]([CH3:17])([CH3:16])[C:4]=2[CH:3]=1
Reactant: Cc1cc2c(cc1Br)C(C)(C)CC(O)C2(C)C
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc2c(cc1Br)C(C)(C)C=CC2(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 86.9 %

Procedure:
To a solution of 15.3 g (51.5 mmol) of 2-bromo-3-methyl-6-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene in 120 ml of pyridine was added 17.9 ml (192 mmol) of phosphorus oxychloride. The reaction mixture was heated to 100°. After 6 h, cooled to room temperature and carefully poured onto ice with stirring. After 1 h, extracted with ethyl acetate, washed with 2 N HCl and brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by gravity chromatography (gradient elution: hexane-10% ethyl acetate/hexane) to afford 12.5 g (87%) of 2-bromo-3,5,5,8,8-pentamethyl-5,8-dihydronaphthalene.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[N:10]([C:26]([CH2:29][CH3:30])=[CH:27][CH:28]=3)[N:11]=[C:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:13]=2[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])[CH:5]=[CH:6][CH:7]=1.F[B-](F)(F)F.[CH3:36][O+](C)C.C(C1C=C(C)C=C(C(C)(C)C)N=1)(C)(C)C>ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[N:10]([C:26]([CH2:29][CH3:30])=[CH:27][CH:28]=3)[N:11]=[C:12]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:13]=2[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH3:36])[CH:5]=[CH:6][CH:7]=1
Reactant: CCc1ccc2c(-c3cccc(Cl)c3)c(CCCCCO)c(-c3ccccc3)nn12
Reactant: C[O+](C)C
Agent: Cc1cc(C(C)(C)C)nc(C(C)(C)C)c1
Agent: F[B-](F)(F)F
Solvent: ClCCCl
Product: CCc1ccc2c(-c3cccc(Cl)c3)c(CCCCCOC)c(-c3ccccc3)nn12
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.3 %

Procedure:
A mixture of 5-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]-1-pentanol (65 mg), trimethyloxonium tetrafluoroborate (275 mg) and 2,6-di-t-butyl-4-methylpyridine (47.8 mg) in 1,2-dichloroethane (3 mL) was stirred at ambient temperature for 4 hours. The solution was washed with water, 1N hydrochloric acid, water, saturated sodium bicarbonate solution and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of hexane and ethyl acetate (20:1–5:1) to give 4-(3-chlorophenyl)-7-ethyl-3-(5-methoxypentyl)-2-phenylpyrrolo[1,2-b]pyridazine as an yellow oil (60 mg).
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:25]=[CH:24][C:10]([C:11]([NH:13][C:14]2[CH:15]=[CH:16][C:17]3[S:21][CH:20]=[C:19](Br)[C:18]=3[CH:23]=2)=[O:12])=[CH:9][CH:8]=1.[CH:26]1[C:34]2[N:29]([CH:30]=[CH:31][C:32](=O)[CH:33]=2)[CH2:28][CH:27]=1>C(OCC)C>[F:6][C:7]1[CH:25]=[CH:24][C:10]([C:11]([NH:13][C:14]2[CH:15]=[CH:16][C:17]3[S:21][CH:20]=[C:19]([C:32]4[CH2:33][CH:34]5[N:29]([CH2:28][CH2:27][CH2:26]5)[CH2:30][CH:31]=4)[C:18]=3[CH:23]=2)=[O:12])=[CH:9][CH:8]=1
Reactant: O=C(Nc1ccc2scc(Br)c2c1)c1ccc(F)cc1
Reactant: O=c1ccn2c(c1)C=CC2
Agent: [Li]CCCC
Solvent: CCOCC
Product: O=C(Nc1ccc2scc(C3=CCN4CCCC4C3)c2c1)c1ccc(F)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of 1.55 mL n-butyllithium in diethyl ether is cooled to -78° C. under a nitrogen atmosphere. To this cooled solution is added a solution of N-(4-fluorobenzoyl)-3-bromo-5-aminobenzothiophene (0.90 eq.) in diethyl ether. The reaction mixture is stirred at -78° C. for 1 hour and then to it is added dropwise a solution of 7-indolizinone (1.08 eq.) in diethyl ether. The reaction is stirred an additional 2 hours at -78° C. and is then gradually warmed to -20° C. over 55 minutes. The reaction mixture is then quenched with saturated aqueous sodium bicarbonate, diluted with additional diethyl ether and the phases separated. The organic phase is washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. The residue is taken up in aqueous potassium hydroxide (10% in water) and heated to reflux for 15 hours. The mixture is concentrated in vacuo and the residue is subjected to flash silica gel chromatography. Fractions shown to contain product are combined and then concentrated under reduced pressure to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[CH3:17].C(N(CC)CC)C.[C:25](Cl)(Cl)=[O:26].[S:29](Cl)(Cl)(=[O:31])=[O:30]>C(#N)C>[C:25](=[N:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH:12]1[CH2:16][CH2:15][CH2:14][N:13]1[CH3:17])=[O:26].[S:29](=[N:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH:12]1[CH2:16][CH2:15][CH2:14][N:13]1[CH3:17])(=[O:31])=[O:30]
Reactant: O=S(=O)(Cl)Cl
Reactant: CN1CCC[C@@H]1Cc1c[nH]c2ccc(N)cc12
Reactant: O=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CN1CCCC1Cc1c[nH]c2ccc(N=C=O)cc12
Product: CN1CCCC1Cc1c[nH]c2ccc(N=S(=O)=O)cc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred solution of (R)-5-amino-3-(N-methylpyrrolidin-2-ylmethyl) indole (0. 229 g, 1.00 mmol) and triethylamine (0.21 mL, 1.5 mmol, 1.5 eq) in anhydrous acetonitrile (3 mL) at 0° C. under nitrogen was added the appropriate carbonyl chloride or sulfonyl chloride (1.5 mmol, 1.5 eq). The resulting reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was then evaporated under reduced pressure, and the residue was column chromatographed using silica gel (approximately 25 g) and elution with an appropriate solvent system afforded the appropriate 5-carbonylamino-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole or 5-sulfonylamino-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole.
Reaction SMILES: [Br-].[Br:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([NH3+:14])[CH2:10][CH2:9]1.[F:15][C:16]([F:28])([F:27])[C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>C(Cl)Cl.OS([O-])(=O)=O.[K+].CC(OC)(C)C>[Br:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]1[CH2:9][CH2:10][C@H:11]([NH:14][S:23]([C:20]2[CH:19]=[CH:18][C:17]([C:16]([F:15])([F:27])[F:28])=[CH:22][CH:21]=2)(=[O:25])=[O:24])[CH2:12][CH2:13]1
Reactant: [NH3+][C@H]1CC[C@H](CCCCCBr)CC1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Agent: O=S(=O)([O-])O
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Solvent: COC(C)(C)C
Product: O=S(=O)(N[C@H]1CC[C@H](CCCCCBr)CC1)c1ccc(C(F)(F)F)cc1
Reaction time: 1.5 h

Procedure:
A solution of 1.0 g (3.04 mmol) of trans-4-(5-Bromo-pentyl)-cyclohexylammonium bromide in 12 ml CH2Cl2 was first cooled at 0° C., treated with 0.8 g (3.27 mmol) 4-(trifluoromethyl)benzenesulfonylchloride and then with 1.2 ml (7.01 mmol; 2.3 equivalents) of Hünigsbase (during 30 min). After total 1.5 h at 0° C., the mixture was dissolved in aqueous 10% KHSO4/TBME (3×). The organic phases were washed with aqueous saturated NaHCO3 and aqueous 10% NaCl, dried over Na2SO4 and evaporated to give 1.38 g crude product which was crystallized (CH2Cl2/hexane) to give 1.26 g (91%) of pure trans-N-[4-(5-Bromo-pentyl)-cyclohexyl]-4-trifluoromethyl-benzenesulfonamide, MS: 454 (M−H−, 1Br).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[N+:12]([O-])=O.[H][H].[CH3:17]N(C=O)C>[Pd]>[CH3:1][N:2]1[C:3]2[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=2[N:12]=[CH:17]1
Reactant: [H][H]
Reactant: CN(C)C=O
Reactant: CNc1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: [Pd]
Product: Cn1cnc2cc(C(=O)O)ccc21

Procedure:
25.0 g of 4-methylamino-3-nitrobenzoic acid, dissolved in 200 ml DMF, are hydrogenated for 5 hours at a hydrogen pressure of 30 psi with the addition of 2.5 g of palladium on activated charcoal (10%). The catalyst is suction filtered and the solvent is distilled off. The residue is stirred with diethyl ether, suction filtered and dried. The crude product thus obtained (19.7 g) is refluxed for 2 hours in 250 ml formic acid. After the solvent has been distilled off the residue is stirred with diethyl ether, suction filtered and dried.
Reaction SMILES: [CH2:1]([N:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([CH3:14])[C:8]1=[O:15])[CH2:2][CH2:3]CC=C.C[N+]1([O-])CC[O:20]CC1.S(S([O-])=O)([O-])=O.[Na+].[Na+].[C:32]([OH:36])(C)([CH3:34])[CH3:33]>[Os](=O)(=O)(=O)=O.CC(C)=O.O>[OH:36][CH:32]([CH2:34][OH:20])[CH2:33][CH2:3][CH2:2][CH2:1][N:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([CH3:14])[C:8]1=[O:15]
Reactant: CC(C)(C)O
Reactant: C=CCCCCn1c(=O)ccn(C)c1=O
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: Cn1ccc(=O)n(CCCCC(O)CO)c1=O
Yield: 66 %

Procedure:
A solution of 3-(5-hexenyl)-1-methyluracil (598 mg, 2.9 mmol), 4-methylmorpholine-N oxide (408 mg, 3.5 mmol), and a 2.5% solution in t-butanol of osmium tetroxide (3 drops) in acetone (15 mL) and water (5 mL) was stirred for 3 days. After addition of a saturated solution of sodium hydrosulfite (10 mL) and 15 minutes, the reaction mixture was added to water (15 mL) and extracted with 20% ethanol/dichloromethane (4×40 mL). The combined organic layers were dried over sodium sulfate and the solvent is evaporated under vacuum to give 461 mg (66%) 3-(5,6-dihydroxyhexyl)-1-methyluracil (inventive compound no. 1811) as a colorless oil.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH2:4][CH:3]([C:11]([OH:13])=O)[CH2:2]1.[CH2:14]([NH2:17])[CH:15]=[CH2:16]>C(O)C>[CH2:14]([NH:17][C:11]([CH:3]1[CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[O:1][CH2:2]1)=[O:13])[CH:15]=[CH2:16]
Reactant: C=CCN
Reactant: O=C(O)C1COc2ccccc2C1
Solvent: CCO
Product: C=CCNC(=O)C1COc2ccccc2C1

Procedure:
A solution of 5 g of 2A and 5.7 g of 2-propenamine in 50 ml of ethanol was refluxed for 6 days. Stripping of the solvent, followed by charcoal treatment of the product and recrystallization of the treated product from ether-hexane, gave 2, as white crystals, mp: 114.5°-115.5° C.
Reaction SMILES: [CH2:1]([C:5]1[N:13]2[C:8]([C:9]([CH2:31][C:32]([O:34]C(C)(C)C)=[O:33])=[CH:10][CH2:11][CH:12]2[C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[NH:30][N:29]=[N:28][N:27]=3)=[CH:16][CH:15]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].C(O)(C(F)(F)F)=O>C(Cl)(Cl)Cl>[CH2:1]([C:5]1[N:13]2[C:8]([C:9]([CH2:31][C:32]([OH:34])=[O:33])=[CH:10][CH2:11][CH:12]2[C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[NH:27][N:28]=[N:29][N:30]=3)=[CH:16][CH:15]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc2n1C(c1ccc(-c3ccccc3-c3nnn[nH]3)cc1)CC=C2CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CCCCc1ccc2n1C(c1ccc(-c3ccccc3-c3nnn[nH]3)cc1)CC=C2CC(=O)O
Temperature: 25 °C

Procedure:
To a solution of biphenyl indolizinyl tert-butyl ester (0.039 mmol, the title compound of Example 1949) in 0.5 mL of chloroform is added 0.25 mL of TFA, and the progress of the reaction is monitored by 1H NMR. The resulting solution is stirred at room temperature until the reaction is complete. The mixture is quenched with methanol and concentrated in vacuo. The residue is purified to give the title compound of Example 1950.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.Cl[C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH2:25])=[O:24])=[CH:21][N:20]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C1(C)C=CC=CC=1>[OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:19]2[CH:27]=[CH:26][C:22]([C:23]([NH2:25])=[O:24])=[CH:21][N:20]=2)=[CH:13][CH:12]=1
Reactant: Oc1ccc(CCNC2CCCCC2O)cc1
Reactant: NC(=O)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: NC(=O)c1ccc(Oc2ccc(CCNC3CCCCC3O)cc2)nc1
Temperature: 25 °C

Procedure:
Heat a mixture of 4-[2-(2-hydroxycyclohexylamino)ethyl]phenol (152.6 mg, 0.65 mmol), 6-chloronicotinamide (84.6 mg, 0.54 mmol) and K2CO3 (186.7 mg, 1.35 mmol) in 3:1 DMF/toluene (4.0 mL) at 160° C. for 2 hours. Cool to room temperature and filter with thorough MeOH and CH2Cl2 wash. Concentrate the filtrate and remove DMF azeotropically with xylenes. Purify by flash chromatography, eluting with 75:15:10 EtOAc/CH2Cl2/2.0 M NH3 in MeOH (56.3 mg, 29%): MS ES+ 356.1 (M+H)+, HRMS calcd for C20H26N3O3 356.1974 (M+H)+, found 356.1966, time 0.37 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), acetonitrile in water containing 0.01% concentrated HCl at 1.0 mL/min, 30-99% over 19 min], tR=1.23 min, 100% purity; Chiralpak AD 225 nm, 60:40 EtOH/heptane at 1.0 mL/min, tR=5.55 min, 50% and tR=7.17 min, 50%; Anal. Calcd for C20H25N3O3.0.2CH2Cl2.0.2MeOH: C, 64.68; H, 6.97; N, 11.09. Found: C, 64.46; H, 6.84; N, 11.11.
Reaction SMILES: [CH2:1]([N:5]1[CH2:9][C:8]([CH3:11])([CH3:10])[S:7][C:6]1=[NH:12])[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[C:20]12([C:30](Cl)=[O:31])[CH2:29][CH:24]3[CH2:25][CH:26]([CH2:28][CH:22]([CH2:23]3)[CH2:21]1)[CH2:27]2>C1COCC1>[CH2:1]([N:5]1[CH2:9][C:8]([CH3:11])([CH3:10])[S:7]/[C:6]/1=[N:12]\[C:30]([C:20]12[CH2:29][CH:24]3[CH2:23][CH:22]([CH2:28][CH:26]([CH2:25]3)[CH2:27]1)[CH2:21]2)=[O:31])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1CC(C)(C)SC1=N
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCN1CC(C)(C)S/C1=N\C(=O)C12CC3CC(CC(C3)C1)C2
Yield: 9 %

Procedure:
To a solution of Example 2A (149 mg, 0.8 mmol) in THF (10 mL) was added triethylamine (0.4 mL) and adamantane-1-carbonyl chloride (0.2 g, 1 mmol). The mixture was heated to reflux overnight and then concentrated under reduced pressure. The residue was diluted with ethyl acetate, washed with 1 M NaHCO3, dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography (SiO2, 0-100% ethyl acetate:hexanes) to provide 25 mg of the title compound. MS (ESI+) m/z 349 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.92 (t, J=7.3 Hz, 3H), 1.19-1.36 (m, 2H), 1.39 (s, 6H), 1.51-1.61 (m, 2H), 1.61-1.73 (m, 6H), 1.74-1.81 (m, 6H), 1.89-2.02 (m, 3H), 3.40-3.44 (m, 2H), 3.55-3.64 (m, 2H); Anal. Calculated for C20H32N2OS: C, 68.92; H, 9.25; N, 8.04. Found: C, 68.94; H, 8.73; N, 8.02.