Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=O.[C:7]([O:11][C:12]([NH:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH:19](C(O)=O)[CH2:18][CH2:17]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].[N-]=[N+]=[N-].[Na+]>C1(C)C=CC=CC=1>[C:7]([O:11][C:12]([NH:14][CH2:15][CH:16]1[CH2:17][CH2:18][CH:19]([NH:14][C:12](=[O:11])[O:5][CH2:1][C:2]2[CH:20]=[CH:21][CH:16]=[CH:17][CH:18]=2)[CH2:20][CH2:21]1)=[O:13])([CH3:8])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)NCC1CCC(C(=O)O)CC1
Reactant: O=C(Cl)C(=O)Cl
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCC1CCC(NC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Oxalyl chloride (1.1 equivalents) was added dropwise to a mixture of 4-[[(tert-butoxycarbonyl)-amino]methyl]-cyclohexanecarboxylic acid (1 equivalent, Maybridge) in toluene. The reaction mixture was stirred at room temperature for 2-6 h. The solvent was removed in vacuo, the residue was dissolved in acetone and the resulting mixture was added dropwise to an aqueous solution of sodium azide (1.2 equivalents) at a rate such as to maintain a temperature of 10-15° C. After the completion of the reaction, the reaction mixture was extracted with ethyl acetate, the combined extracts were dried and concentrated in vacuo. The residue was dissolved in acetone and added slowly to warm (60° C.) benzene. After the completion of the reaction, benzyl alcohol was added to the reaction mixture, stirred for 2 days and the desired product was isolated (For Typical References, See: G. Schroeter Ber. 1909, 42, 3356; and Allen, C. F. H.; Bell, A. Org. Syn. Coll. Vol. 3 (1955) 846.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](I)=[C:5]([O:10][CH3:11])[C:4]=1[O:12][CH3:13].C([Li])CCC.[CH3:19][N:20]([CH3:32])[C:21]1[CH:30]=[C:29]2[C:24]([C:25](=O)[CH2:26][CH2:27][O:28]2)=[CH:23][CH:22]=1>>[CH3:19][N:20]([CH3:32])[C:21]1[CH:30]=[C:29]2[C:24]([C:25]([C:7]3[CH:8]=[C:3]([O:2][CH3:1])[C:4]([O:12][CH3:13])=[C:5]([O:10][CH3:11])[CH:6]=3)=[CH:26][CH2:27][O:28]2)=[CH:23][CH:22]=1
Reactant: COc1ccc(I)c(OC)c1OC
Reactant: CN(C)c1ccc2c(c1)OCCC2=O
Agent: [Li]CCCC
Product: COc1cc(C2=CCOc3cc(N(C)C)ccc32)cc(OC)c1OC

Procedure:
Compounds of this invention having the Formulae I-IV can also be prepared as illustrated by examplary reactions in Scheme V. A phenyl propionitrile is prepared from the condensation of acrylonitrile and dimethylaminophenol. The nitrile was hydrolysed to the acid and the intermediate compound cyclized to yield 7-dimethylamino-chroman-4-one. Trimethoxyiodobenzene was lithiated with butyl lithium and treated with 7-dimethylamino-chroman-4-one to produce dimethyl-[4-(3,4,5-trimethoxy-phenyl)-2H-chromen-7-yl]-amine. Alternatively, 7-dimethylamino-chroman-4-one could be first treated with copper chloride, followed by the addition of lithio trimethoxybenzene, to produce [3-chloro-4-(3,4,5-trimethoxy-phenyl)-2H-chromen-7-yl]-dimethyl-amine.
Reaction SMILES: [C:1]([N-:5][CH:6]=[CH:7][N-:8][C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2].[Li+].[Li+].[Cl:15][SiH:16](Cl)Cl>CCCCCC>[Cl:15][SiH:16]1[N:5]([C:1]([CH3:3])([CH3:4])[CH3:2])[CH:6]=[CH:7][N:8]1[C:9]([CH3:12])([CH3:11])[CH3:10]
Reactant: Cl[SiH](Cl)Cl
Reactant: CC(C)(C)[N-]C=C[N-]C(C)(C)C
Agent: [Li+]
Solvent: CCCCCC
Product: CC(C)(C)N1C=CN(C(C)(C)C)[SiH]1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 83 %

Procedure:
In an argon atmosphere, a dilithium(N,N′-di-tert-butyl-1,2-vinylenediaminide) solution prepared according to the procedure and reagent quantities described in Reference Example-9 was added to a hexane (50 mL) solution containing 25.20 g (186.0 mmol) of trichlorosilane, and the mixture was stirred at room temperature for 3 hours. Insoluble matters produced were separated by filtration, and the solvent was removed by distillation from the filtrate under atmospheric pressure. The obtained residue was distilled under reduced pressure (distillation temperature: 80° C./3.8×102 Pa) to obtain 2-chloro-1,3-di-tert-butyl-1,3-diaza-2-silacyclopent-4-ene (Si(tBuNCHCHNtBu)(H)Cl) as a colorless liquid (yielded amount: 35.58 g, yield: 83%).
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.[CH3:13][O:14][C:15](=[O:34])[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:23]=[C:24](Cl)[C:25]3[C:30]([Cl:31])=[C:29]([CH3:32])[S:28][C:26]=3[N:27]=2)=[CH:18][CH:17]=1>>[CH3:13][O:14][C:15](=[O:34])[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:23]=[C:24]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:1][O:2][C:3]=4[CH:4]=3)[C:25]3[C:30]([Cl:31])=[C:29]([CH3:32])[S:28][C:26]=3[N:27]=2)=[CH:18][CH:17]=1
Reactant: NCCc1ccc2c(c1)OCO2
Reactant: COC(=O)c1ccc(-c2nc(Cl)c3c(Cl)c(C)sc3n2)cc1
Product: COC(=O)c1ccc(-c2nc(NCCc3ccc4c(c3)OCO4)c3c(Cl)c(C)sc3n2)cc1

Procedure:
The reaction procedure as above in wherein 3,4-methylenedioxyphenethylamine is reacted with 4-(4-chloro-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-[4-(3,4-methylenedioxyphenethylamino)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidin-2-yl]-benzoic acid methylester.
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]#[C:5][C:6]1[C:7]([NH:16][CH2:17][CH2:18][CH2:19][CH3:20])=[N:8][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:10][CH:11]=1.[Li+].[OH-].Cl>C1COCC1>[CH2:17]([NH:16][C:7]1[C:6]([C:5]#[C:4][C:3]([OH:21])=[O:2])=[CH:11][CH:10]=[C:9]([C:12]([F:15])([F:13])[F:14])[N:8]=1)[CH2:18][CH2:19][CH3:20]
Reactant: CCCCNc1nc(C(F)(F)F)ccc1C#CC(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCNc1nc(C(F)(F)F)ccc1C#CC(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of (2-butylamino-6-trifluoromethyl-pyridin-3-yl)-propynoic acid methyl ester (78 mg, 0.26 mmol) in THF (0.50 ml) was added a solution of 1 N-LiOH (1.0 ml), and the mixture was stirred for 3 hours at room temperature. The reaction mixture was acidified with 1N HCl to pH 1˜2. The solution was extracted three times with methylene chloride and then dried over anhyd. Na2SO4 and concentrated in vacuo to the title compound (50 mg, 65%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C@@H:11]([OH:13])[CH3:12])=[N:9][N:10]=2)[N:7]=1.[C:14]1(B(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[C:14]1([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([C@@H:11]([OH:13])[CH3:12])=[N:9][N:10]=3)[N:7]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C[C@H](O)c1nnc2ccc(Cl)nn12
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@H](O)c1nnc2ccc(-c3ccccc3)nn12
Temperature: 85 °C

Procedure:
A suspension of (1S)-1-(6-chloro[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethanol (0.289 mmol, 1 eq), phenylboronic acid (0.650 mmol, 2.3 eq), Pd(PPh3)4 (45.9 mg, 0.0397 mmol, 14 mol %), and K2CO3 (132.0 mg, 0.9551 mmol, 3.3 eq) in a 4:1 ratio of dioxane (4 mL) to H2O (1 mL) was evacuated and charged with nitrogen several times. The reaction sample was then heated conventionally at 85° C. for 1 h. CH2Cl2 and H2O were added and a standard aqueous workup was performed. The crude material was purified by pTLC [Silicycle, 1000 μM, 20×20 plate], which required two developments in a 3% MeOH in EtOAc solvent system. 1H NMR (400 MHz, CDCl3): δ=1.93 (d, J=6.6 Hz, 3H), 3.00 (br s, 1H), 5.64 (q, J=6.6 Hz, 1H), 7.53-7.61 (m, 3H), 7.66 (d, J=9.9 Hz, 1H), 7.95-8.01 (m, 2H), 8.25 (d, J=9.9 Hz, 1H). MS (ES+): m/z 241.08 (100) [MH+]. HPLC: tR=2.51 min (ZQ3, polar—5 min).
Reaction SMILES: [Cl:1][C:2]1[C:19]([Cl:20])=[CH:18][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([C:15](O)=[O:16])=[CH:11][CH:10]=3)[NH:8][C:4]=2[CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH3:43][N:44]1[C:49]([CH3:51])([CH3:50])[CH2:48][CH:47]([NH2:52])[CH2:46][C:45]1([CH3:54])[CH3:53]>C1COCC1>[Cl:1][C:2]1[C:19]([Cl:20])=[CH:18][C:5]2[N:6]=[C:7]([C:9]3[CH:10]=[CH:11][C:12]([C:15]([NH:52][CH:47]4[CH2:46][C:45]([CH3:53])([CH3:54])[N:44]([CH3:43])[C:49]([CH3:51])([CH3:50])[CH2:48]4)=[O:16])=[CH:13][CH:14]=3)[NH:8][C:4]=2[CH:3]=1
Reactant: O=C(O)c1ccc(-c2nc3cc(Cl)c(Cl)cc3[nH]2)cc1
Reactant: CN1C(C)(C)CC(N)CC1(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CN1C(C)(C)CC(NC(=O)c2ccc(-c3nc4cc(Cl)c(Cl)cc4[nH]3)cc2)CC1(C)C
Temperature: 25 °C
Yield: 22 %

Procedure:
A mixture of 5,6-dichloro-2-(4-carboxyphenyl)benzimidazole (0.3 g, 0.9 mmol) prepared as described in Preparation 8, 1-hydroxybenzotriazole (0.145 g, 1.08 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.207 g, 1.08 mmol) in THF (10 ml) was heated at 35–40° C. for 1 h. 1,2,2,6,6,-Pentamethyl-4-aminopiperidine in THF (2 ml) was added dropwise and the reaction was refluxed for 1 h. After cooling to room temperature, the solvent was removed under reduced pressure and the residue was treated with 2N NaOH (5 ml). The solid was filtered, washed with water and dried at 50° C. under vacuum. The solid was suspended in isopropyl alcohol and stirred for half an hour, filtered and dried to give 91 mg of the title compound (yield 22%) as an yellow powder, mp>280° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C@@:9]3([CH3:14])[C:11]([CH3:13])([CH3:12])[C@H:6]([CH2:7][CH2:8]3)[C:5]=2[C:4](=[O:15])[NH:3]1.[CH3:16][O:17][C:18]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)=[O:19]>ClCCl.N1C=CC=CC=1.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:16][O:17][C:18](=[O:19])[C:20]1[CH:25]=[CH:24][C:23]([N:3]2[C:4](=[O:15])[C:5]3[C@@H:6]4[C:11]([CH3:12])([CH3:13])[C@@:9]([CH3:14])([CH2:8][CH2:7]4)[C:10]=3[N:2]2[CH3:1])=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: Cn1[nH]c(=O)c2c1[C@]1(C)CC[C@H]2C1(C)C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc(-n2c(=O)c3c(n2C)[C@]2(C)CC[C@H]3C2(C)C)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 29.5 %

Procedure:
A mixture of (4S,7R)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 19; 100 mg, 0.48 mmol), 4-methoxycarbonyl-phenyl-boronic acid (180 mg, 0.97 mmol), and copper(II) acetate (133 mg, 0.73 mmol) in dichloromethane (1 mL) and pyridine (0.8 mL) was stirred at room temperature for 2 days. The reaction mixture was evaporated and purified using an Analogix Intelliflash 280 system (Analogix, Inc., Burlington, Wis.) with an Isco 12 g column, eluting with 10-60% ethyl acetate/hexanes to give 4-((4S,7R)-1,7,8,8-tetramethyl-3-oxo-1,3,4,5,6,7-hexahydro-4,7-methano-indazol-2-yl)-benzoic acid methyl ester (48.2 mg, 29%) as an off-white solid. ES(+)-MS (M+H) 341.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][C:10]2[C:19]3[N:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:13](=O)[NH:12][CH:11]=2)=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:23])=O.Cl>C(#N)C.O1CCOCC1>[Cl:23][C:13]1[N:12]=[CH:11][C:10]([CH2:9][C:6]2[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[C:19]2[C:14]=1[CH:15]=[CH:16][CH:17]=[N:18]2
Reactant: COc1ccc(Cc2c[nH]c(=O)c3cccnc23)cn1
Reactant: O=P(Cl)(Cl)Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CC#N
Product: COc1ccc(Cc2cnc(Cl)c3cccnc23)cn1
Temperature: 25 °C

Procedure:
396 mg (1.48 mmol) of 8-[(6-methoxy-pyridin-3-yl)-methyl]-6H-[1,6]naphthyridin-5-one in 24 ml of acetonitrile are mixed, whilst excluding air, with 1.4 ml (15 mmol) of phosphorus oxychloride and 0.78 ml of 4 N HCl in dioxan and stirred for 96 h at 65° C. After cooling to RT, partial concentration by evaporation takes place on a RE, then 40 ml of ice water and 10 ml of NH3 solution are added and extraction carried out 3 times with EtOAc. The organic phases are washed with water and brine, dried (Na2SO4) and concentrated by evaporation to form 5-chloro-8-[(6-methoxy-pyridin-3-yl)-methyl]-[1,6]naphthyridine (contaminated with a little 5-chloro-8-[(6-chloro-pyridin-3-yl)-methyl]-[1,6]naphthyridine); FAB-MS: (M+H)+=286; HPLC(gradients20-100) tRef=10.2.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][C:11]([C:17]([OH:20])([CH3:19])[CH3:18])([C:14]([OH:16])=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:21][C:22]([F:36])([F:35])[C:23]1[CH:28]=[CH:27][N:26]=[C:25]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:24]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[OH:20][C:17]([C:11]1([C:14]([N:32]2[CH2:33][CH2:34][N:29]([C:25]3[CH:24]=[C:23]([C:22]([F:36])([F:21])[F:35])[CH:28]=[CH:27][N:26]=3)[CH2:30][CH2:31]2)=[O:16])[CH2:12][CH2:13][CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10]1)([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC(C(=O)O)(C(C)(C)O)C1
Reactant: FC(F)(F)c1ccnc(N2CCNCC2)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1CCC(C(=O)N2CCN(c3cc(C(F)(F)F)ccn3)CC2)(C(C)(C)O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.2 %

Procedure:
To a suspension of (3S)-3-[(tert-butoxycarbonyl)amino]-1-(1-hydroxy-1-methylethyl)cyclopentanecarboxylic acid (150 mg, 0.52 mmol) and 1-[4-(trifluoromethyl)pyridin-2-yl]piperazine (130 mg, 0.57 mmol) in methylene chloride (3 mL) under N2 was added triethylamine (0.16 g, 1.6 mol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (0.25 g, 0.57 mmol). After being stirred at room temperature overnight, the reaction was quenched by saturated NaHCO3 solution and extracted with methylene chloride three times. The combined extracts were dried (MgSO4), filtered, concentrated and purified by flash column chromatography to yield the desired product (76 mg, 29%).
Reaction SMILES: [CH3:1][C:2]([CH2:6][CH2:7][CH:8]=[C:9]([CH3:47])[CH2:10][CH2:11][CH:12]=[C:13]([CH3:46])[CH2:14][CH2:15][CH:16]=[C:17]([CH3:45])[CH2:18][CH2:19][CH:20]=[C:21]([CH3:44])[CH2:22][CH2:23][C:24](=[O:43])[CH:25]([CH3:42])[CH2:26][CH2:27][CH:28]=[C:29]([CH3:41])[CH2:30][CH2:31][CH:32]=[C:33]([CH3:40])[CH2:34][CH2:35][CH:36]=[C:37]([CH3:39])[CH3:38])=[CH:3][CH2:4][OH:5].[CH3:48][C:49](OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=[O:50].CCOCC>N1C=CC=CC=1>[C:49]([O:5][CH2:4][CH:3]=[C:2]([CH3:1])[CH2:6][CH2:7][CH:8]=[C:9]([CH3:47])[CH2:10][CH2:11][CH:12]=[C:13]([CH3:46])[CH2:14][CH2:15][CH:16]=[C:17]([CH3:45])[CH2:18][CH2:19][CH:20]=[C:21]([CH3:44])[CH2:22][CH2:23][C:24](=[O:43])[CH:25]([CH3:42])[CH2:26][CH2:27][CH:28]=[C:29]([CH3:41])[CH2:30][CH2:31][CH:32]=[C:33]([CH3:40])[CH2:34][CH2:35][CH:36]=[C:37]([CH3:39])[CH3:38])(=[O:50])[CH3:48]
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)C(=O)CCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCO
Reactant: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(=O)OCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC(=O)C(C)CCC=C(C)CCC=C(C)CCC=C(C)C
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To a solution of 3,7,11,15,19,23,27,31,35-nonamethyl-2,6,10,14,18,26,30,34-hexatriacontaoctaen-22-on-1-ol 6.5 g) in pyridine (1 g), acetic anhdyride (3.0 g) is added, and the resulting mixture is allowed to stand at room temperature for 5 hours. The reaction mixture is poured into ice water and shaken with ether. The ether layer is washed with water, dried and evaporated. The residual material (6.5 g) is chromatographed on silica gel (70 g) using benzene to give 1-acetoxy-3,7,11,15,19,23,27,31,35-nonamethyl-2,6,10,14,18,26,30,34-hexatriacontaoctaen-22-one (6.1 g). A solution of this compound in ethanol (6 ml) is dropwise added to a solution of sodium borohydride (0.1 g) in ethanol (10 ml) while cooling with ice, and stirring is continued for 3 hours. The reaction mixture is poured into an aqueous saturated solution of ammonium chloride and extracted with ether. The ether extract is washed with water, dried and concentrated. The residual material (4.8 g) is treated as in Example 1 (5) a) to give 1-acetoxy-3,7,11,15,19,23,27,31, 35-nonamethyl-2,6,10,14,18,26,30,34-hexatriacontaoctaen- 22-ol (2.1 g) as a fraction (1) and 3,7,11,15,19,23,27,31,35-nonamethyl-2,6,10,14,18,26,30,34-hexatriacontaoctaene-1,22-diol (0.9 g) as a fraction (2). The latter is treated with acetic anhydride as above to give 1-acetoxy-3,7,11,15,19,23,27,31,35-nonamethyl-2,6,10,14,18,26,30,34-hexatriacontaoctaen-22-ol (0.82 g).
Reaction SMILES: [OH:1][CH:2]([CH:41]1[CH2:45][O:44]C(C)(C)[O:42]1)[CH2:3][NH:4][C:5](=[O:40])[C:6]1[CH:24]=[C:23]([S:25](=[O:39])(=[O:38])[NH:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=2[C:34]([F:37])([F:36])[F:35])[CH:22]=[C:8]([C:9]([NH:11][CH2:12][CH:13]([OH:21])[CH:14]2[CH2:18][O:17]C(C)(C)[O:15]2)=[O:10])[CH:7]=1.Cl>C(O)C.O>[OH:1][CH:2]([CH:41]([OH:42])[CH2:45][OH:44])[CH2:3][NH:4][C:5](=[O:40])[C:6]1[CH:24]=[C:23]([S:25](=[O:38])(=[O:39])[NH:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=2[C:34]([F:37])([F:35])[F:36])[CH:22]=[C:8]([C:9]([NH:11][CH2:12][CH:13]([OH:21])[CH:14]([OH:15])[CH2:18][OH:17])=[O:10])[CH:7]=1
Reactant: CC1(C)OCC(C(O)CNC(=O)c2cc(C(=O)NCC(O)C3COC(C)(C)O3)cc(S(=O)(=O)Nc3ccc(F)cc3C(F)(F)F)c2)O1
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=C(NCC(O)C(O)CO)c1cc(C(=O)NCC(O)C(O)CO)cc(S(=O)(=O)Nc2ccc(F)cc2C(F)(F)F)c1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
3.79 g (5.46 mmol) of 5-[N-(4-fluoro-2-trifluoromethylphenyl)sulfamoyl]-isophthalic acid-bis[2-hydroxy-2-(2,2-dimethyl-1,3-dioxolan-4-yl)-ethylamide] is dissolved in a mixture of 40 ml of ethanol and 10 ml of water and the solution is acidified with dilute hydrochloric acid to pH 1. It is stirred at this pH for 4 hours at 60° C. The solution is then adjusted to pH 6.1 with the anion exchanger Amberlite IRA 67, filtered and evaporated to dryness in a vacuum. The solid amorphous residue is dried in a vacuum at 50° C. 2.55 g (4.16 mmol) =76.12% of the theoretical yield is obtained as an amorphous solid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:15]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:16]=2[CH:17]=[CH:18][CH2:19]3)[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].CS(C)=O.[Br:28]N1C(=O)CCC1=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[Br:28][C:18]1[CH2:19][C:20]2[C:16]([CH:17]=1)=[C:15]([C:7]1[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[CH:6]=1)[CH:23]=[CH:22][CH:21]=2
Reactant: CC(C)(C)c1cc(-c2cccc3c2C=CC3)cc(C(C)(C)C)c1
Reactant: O=C1CCC(=O)N1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)c1cc(-c2cccc3c2C=C(Br)C3)cc(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.4 %

Procedure:
A cold solution (5° C.) of compound 5 (49 g, 161 mmol, 1 equiv), dimethyl sulfoxide (500 mL) and water (5 mL) was treated in one portion with N-bromosuccinimide (43 g, 241 mmol, 1.5 equiv). The bath was removed and the reaction allowed to stir at room temperature overnight. The reaction was poured into water (1 L) and the mixture extracted with ethyl acetate (2×500 mL). The combined organic layers were washed with saturated brine (1 L), dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was dissolved in toluene (500 mL) and p-toluenesulfonic acid (6.2 g, 32.6 mmol, 0.2 equiv) was added. The mixture was refluxed for 20 hours while removing water with a Dean-Stark trap. The reaction was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified over silica gel (1 Kg) eluting with heptanes to give compound 6 (41 g, 66% yield) as a white solid.
Reaction SMILES: O1CCCCC1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([NH:16][C@H:17]3[CH2:22][CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18]3)=[CH:13][CH:14]=2)[CH:9]=[N:8]1.[ClH:30].O1CCOCC1>C(O)C>[ClH:30].[ClH:30].[NH:19]1[CH2:20][CH2:21][CH2:22][C@H:17]([NH:16][C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[NH:7][N:8]=[CH:9]3)[CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](Nc2ccc3c(cnn3C3CCCCO3)c2)C1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: c1cc2[nH]ncc2cc1N[C@H]1CCCNC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
A 1 L round bottom flask was charged with (3S)-tert-butyl 3-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-ylamino)piperidine-1-carboxylate (32.4 g, 0.0809 mol, 1.00 eq) and EtOH (500 mL). To the ethanol solution was added 4N HCl in dioxane (40.0 mL, 0.160 mol, 2.0 eq), and the solution was stirred at room temperature for 2 h, giving an inhomogeneous dark brown solution. The solution was then heated to 75° C. with a mechanical stirrer and maintained at that temperature for 2 h, after which it was cooled to room temperature. A large amount of fine white solid was observed to form and was collected by filtration, and the filter cake was washed with isopropyl acetate (500 mL). The solid was dried in a vacuum oven at 45° C. for 3 days to give the title compound as an off-white powder (18.1 g, 77%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][C:16]([O:22][CH2:23][CH:24]4[CH2:26][O:25]4)=[CH:17][CH:18]=3)[O:13][CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][C:16]([O:22][CH2:23][CH:24]([OH:25])[CH2:26][N:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)=[CH:17][CH:18]=3)[O:13][CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: C1CNCCN1
Reactant: COc1ccc(-c2coc3cc(OCC4CO4)ccc3c2=O)cc1OC
Solvent: CCO
Product: COc1ccc(-c2coc3cc(OCC(O)CN4CCNCC4)ccc3c2=O)cc1OC
Yield: 56.8 %

Procedure:
A mixture of compound 4 (obtained from example 2) (0.35 g, 1 mmol), piperazine (0.43 g, 5 mmol), and ethanol (30 mL) was refluxed for 6 hrs (TLC monitoring). After removal of solvent in vaccuo, the residue was treated with H2O (50 mL). The resulting precipitate was collected and purified by column chromatography (MeOH/CH2Cl2=1:25) to give the title compound 6b (0.25 g, 56% yield). M.p.: 84-85° C.
Reaction SMILES: [CH3:1][C:2]1([CH2:15][N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH2:6][C:5]2[C:7]([CH3:14])=[C:8]([NH2:13])[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1.[C:22]1([CH2:28][CH2:29][C:30](O)=[O:31])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH3:1][C:2]1([CH2:15][N:16]2[CH2:21][CH2:20][N:19]([C:30](=[O:31])[CH2:29][CH2:28][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:18][CH2:17]2)[CH2:6][C:5]2[C:7]([CH3:14])=[C:8]([NH2:13])[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1
Reactant: O=C(O)CCc1ccccc1
Reactant: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CCNCC1)O2
Product: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CCN(C(=O)CCc3ccccc3)CC1)O2
Yield: 73 %

Procedure:
Using 2,3-dihydro-2,4,6,7-tetramethyl-2-[(1-piperazinyl)methyl]-5-benzofuranamine and 3-phenylpropionic acid, the procedure of Example 10 was otherwise repeated to provide the title compound. Yield 73%.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[Br-:17].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>Br.CC(O)=O>[Br:17][CH2:2][C:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])[CH:7]=[CH:8][CH:9]=1)=[O:3]
Reactant: [Br-]
Reactant: CC(=O)c1cccc(NC(=O)C(C)(C)C)c1
Agent: Br
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Product: CC(C)(C)C(=O)Nc1cccc(C(=O)CBr)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 78.3 %

Procedure:
To a stirred solution of N-(3acetylphenyl)pivalamide 8z (0.30 g, 1.37 mmol) in 33% HBr in HOAc (5 mL) was added pyridinium tribromide (0.48 g, 1.51 mmol) and the mixture was stirred at room temperature for 24 h then poured into ice-cold water. The organic layer was extracted with DCM, washed with sat. aq. NaHCO3 and brine, dried over anhydrous MgSO4, and filtered. Evaporation of the solvent afforded 9z (0.32 g, 78%) which was used in the next step without further purification. 1H NMR (600 MHz, CDCl3): δ 8.08 (t, J=1.8 Hz, 1H), 7.94 (br s, 1H), 7.82 (dt, J=8.4, 1.2 Hz, 1H), 7.60 (dd, J=7.2 Hz, 1.2 Hz, 1H), 7.32 (t, J=7.8 Hz, 1H), 4.30 (s, 2H), 1.27 (s, 9H). 13C NMR (150 MHz, CDCl3): δ 191.2, 177.3, 139.0, 134.4, 129.3, 125.8, 124.4, 120.4, 39.7, 31.4, 27.5. MS m/z (ESI) 298.06 [M+H]+, 300.02 [(M+2)+H]+.