Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](F)[C:3]=1[CH3:9].[CH3:10][S-:11].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:11][CH3:10])[C:3]=1[CH3:9]
Reactant: C[S-]
Reactant: Cc1c(F)cccc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1cccc(Br)c1C
Temperature: 150 °C
Reaction time: 0.25 h
Yield: 57.8 %

Procedure:
To a solution of 1-bromo-3-fluoro-2-methylbenzene (2.0 g, 10.6 mmol) in N,N-dimethylformamide (10 ml) was added sodium methanethiolate (0.85 g, 11.7 mmol) and the mixture was stirred for 15 min at 150° C. After cooling, aqueous sodium carbonate (10%, 50 ml) was added and the phases were separated. The aqueous phase was extracted with ethylacetate (2×50 ml) and the combined organic phases was dried (MgSO4) and evaporated under reduced pressure to give an oil. The residue was purified by flash column chromatography (isooctane) to give the title compound (1.33 g). MS m/z (relative intensity, 70 eV) 218 (M+, 98), 216 (M+, 92), 202 (26), 200 (26), 122 (bp), 121 (56).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:11])[CH2:9][NH2:10])[CH:5]=[CH:6][CH:7]=1.[CH2:12]([C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[CH:18][CH:17]=1)[C:13]([CH3:15])=O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:11])[CH2:9][NH:10][CH:13]([CH3:15])[CH2:12][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(-c2ccc(CC(C)=O)cc2)cc1
Reactant: NCC(O)c1cccc(Cl)c1
Product: COc1ccc(-c2ccc(CC(C)NCC(O)c3cccc(Cl)c3)cc2)cc1
Yield: 20.1 %

Procedure:
Yield: 20.1% of theory, Prepared from 2-(3-chloro-phenyl)-2-hydroxy-ethylamine and 4'-acetonyl-4-methoxy-biphenyl.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].Cl[C:13]1[C:14]2[C:26]([CH3:27])=[C:25]([CH3:28])[S:24][C:15]=2[N:16]=[C:17]([C:19]2[O:23][N:22]=[CH:21][CH:20]=2)[N:18]=1>>[O:23]1[C:19]([C:17]2[N:18]=[C:13]([NH:8][CH2:7][C:6]3[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[C:14]3[C:26]([CH3:27])=[C:25]([CH3:28])[S:24][C:15]=3[N:16]=2)=[CH:20][CH:21]=[N:22]1
Reactant: NCc1cccc([N+](=O)[O-])c1
Reactant: Cc1sc2nc(-c3ccno3)nc(Cl)c2c1C
Product: Cc1sc2nc(-c3ccno3)nc(NCc3cccc([N+](=O)[O-])c3)c2c1C

Procedure:
With the procedure of Example 1, the reaction of 3-nitrobenzylamine with 4-chloro-2-(isoxazol-5-yl)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-(3-nitrobenzylamino)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](Cl)=[O:14])=[CH:10][CH:11]=2)[C:6]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:5]1)(=O)C.[NH2:23][CH2:24][C@@H:25]1[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]1[OH:31]>N1C=CC=CC=1>[OH:31][C@@H:26]1[CH2:27][CH2:28][CH2:29][CH2:30][CH:25]1[CH2:24][NH:23][C:13]([C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][CH:10]=1)[NH:4][N:5]=[C:6]2[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)=[O:14]
Reactant: CC(=O)n1nc(-c2ccc(F)cc2)c2cc(C(=O)Cl)ccc21
Reactant: NC[C@@H]1CCCC[C@H]1O
Solvent: c1ccncc1
Product: O=C(NCC1CCCC[C@H]1O)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 68.8 %

Procedure:
To a flask containing 1-acetyl-3-(4-fluorophenyl)-1H-indazole-5-carbonyl chloride (330 mg, 0.95 mmol) dissolved in pyridine (6 mL) was added trans-2-aminomethyl-1-cyclohexanol (135.6 mg, 1.05 mmol). The reaction was allowed to stir under a nitrogen atmosphere overnight. Solvent was removed and the reaction was extracted with ethyl acetate. The organic phase was washed with a saturated aqueous solution of sodium bicarbonate, dried with magnesium sulfate, filtered and concentrated to yield the crude product. The product was purified by column chromatography (SiO2, 5% methanol in dichloromethane). The compound was taken up in a 3% ammonia in methanol solution (8 mL) and allowed to reflux at 60° C. for three hours. The reaction was neutralized with 1 N HCl solution and extracted with ethyl acetate. The organic layer was dried with magnesium sulfate, filtered and concentrated to yield the title compound (240 mg, 69% yield). 1H NMR (DMSO-d6) δ 13.5 (s, 1H), 8.6 (s, 2H), 8.1 (m, 2H), 7.9 (d, 1H), 7.6 (d, 1H), 7.4 (m, 2H), 4.8 (s, 1H), 3.5 (m, 1H), 3.2 (m, 1H), 1.8 (m, 2H), 1.6 (m, 2H), 1.4 (m, 2H), 0.8–1.0 (m, 3H), ES-MS m/z 368 [M+1]+.
Reaction SMILES: [C:1]([C:5]1[C:10]2[CH:11]=[CH:12][O:13][C:9]=2[CH:8]=[CH:7][C:6]=1[OH:14])([CH3:4])([CH3:3])[CH3:2].C1(O)C=CC=CC=1>C(O)(=O)C.[Pd].CCOCC>[C:1]([C:5]1[C:10]2[CH2:11][CH2:12][O:13][C:9]=2[CH:8]=[CH:7][C:6]=1[OH:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1c(O)ccc2occc12
Agent: [Pd]
Solvent: CC(=O)O
Solvent: Oc1ccccc1
Solvent: CCOCC
Product: CC(C)(C)c1c(O)ccc2c1CCO2

Procedure:
To a solution of 4-tert butyl-5-benzofuranol (0,660 g, 3.47 mmol) 41a in acetic acid (20 mL) is added 10% palladium on carbon (0.130 ) and the mixture hydrogenated overnight at 40 psi. The reaction mixture is taken up in ether (25 mL) and filtered through a bed of Celite to remove the catalyst. The filtrate and washing are diluted with water (100 mL) and ether (50 mL) and the layers separated. The aqueous layer is washed with an additional portion of ether (50 mL) and the combined extracts washed sequentially with 5% NaHCO3 (3×50 mL), water (50 mL), and 20% NaCl (50 mL) then dried (MgSO4) and concentrated. Purification by flash chromatography using 5% ethyl acetate in hexane as eluant gives 4-tert-butyl-2,3-dihydro-5-benzofuranol.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([N:11]=[N:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-])=O)[CH:5]=1>[OH-].[Na+].[Zn]>[N:12]1[N:11]([C:6]2[CH:5]=[C:4]([CH2:3][CH2:2][OH:1])[CH:9]=[CH:8][C:7]=2[OH:10])[N:19]=[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=12
Reactant: O=[N+]([O-])c1ccccc1N=Nc1cc(CCO)ccc1O
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Product: OCCc1ccc(O)c(-n2nc3ccccc3n2)c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 80.5 %

Procedure:
5.39 g (18 mmols) of crude 4-(2-hydroxyethyl)-2-[(2-nitrophenyl)azo]phenol synthesized in Example 3 was dissolved in 18 ml of aqueous solution of 2N sodium hydroxide. Subsequently, 9 ml of previously prepared aqueous solution of 25% sodium hydroxide and 5.4 g (83 mmols) of zinc powder were simultaneously added over a period of about 3 hours. The reaction mixture was heated to 70° C. and stirred for about 2 hours. The reaction mixture was then cooled to room temperature and filtered to collect inorganic substance. The obtained mother liquor was acidified with concentrated hydrochloric acid. Precipitated crystals were collected by filtration and recrystalized in toluene, giving 3.70 g of 2-(2H-benzotriazole-2-yl)-4-(2-hydroxyethyl)phenol as yellow crystals (yield 70%, purity 87%).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([CH2:8][PH2:9]=[O:10])=[CH:6][CH:5]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:12]=[CH:11][C:7]([CH2:8][PH2:9]=[O:10])=[CH:6][CH:5]=1
Reactant: O=[PH2]Cc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(C[PH2]=O)cc1
Reaction time: 24 h
Yield: 59.7 %

Procedure:
A mixture of 1—(4-nitrobenzyl)phosphorane-1-oxide (1.80 g) and 10% Pd-C (0.2 g) in ethanol (30 ml) was vigorously stirred under hydrogen atmosphere for 24 hours, and the catalyst was filtered off. The filtrate was concentrated and purified with column chromatography (ethanol/ethyl acetate=1:2) and recrystallized from ethanol-diethylether to give 1—(4-aminobenzyl)phosphorane-1-oxide (0.90 g) as colorless crystals.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19](C3ON=CC=3)=[CH:18][CH:17]=2)[C:12]([C:27]([NH2:29])=[O:28])=[CH:11][N:10]=1.[CH3:30][C:31]1[O:35][N:34]=[C:33](C2C=C(C=CC=2)N)[N:32]=1>>[NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:33]3[N:32]=[C:31]([CH3:30])[O:35][N:34]=3)[CH:17]=2)[C:12]([C:27]([NH2:29])=[O:28])=[CH:11][N:10]=1
Reactant: NC(=O)c1cnc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1ccc(-c2ccno2)cc1
Reactant: Cc1nc(-c2cccc(N)c2)no1
Product: Cc1nc(-c2cccc(Nc3nc(N[C@@H]4CCCC[C@@H]4N)ncc3C(N)=O)c2)no1

Procedure:
This compound was synthesised using the synthetic scheme described for the synthesis of compound 122, and using 3-(5-methyl-1,2,4-oxadiazol-3-yl)aniline in step 1. MS: 409.28 (M+H).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[CH2:3][N:4]=[C:5]([NH2:19])[NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][CH2:15][CH2:16][C:17]#[N:18])[N:8]=1.Cl.[CH3:23][OH:24]>C(Cl)(Cl)Cl>[F:21][C:2]([F:1])([F:20])[CH2:3][N:4]=[C:5]([NH2:19])[NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][CH2:15][CH2:16][C:17](=[NH:18])[O:24][CH3:23])[N:8]=1
Reactant: N#CCCCOc1cccc(NC(N)=NCC(F)(F)F)n1
Reactant: CO
Agent: Cl
Solvent: ClC(Cl)Cl
Product: COC(=N)CCCOc1cccc(NC(N)=NCC(F)(F)F)n1
Reaction time: 72 h

Procedure:
A solution of 4-[2-(2-[2,2,2-trifluoroethyl]guanidino)pyrid-6-yloxy]butyronitrile in a mixture of CHCl3 (10 ml.) and MeOH (5 ml.) was saturated with HCl gas at 0° and then kept at 0° for 3 days. The solution was evaporated to dryness and the residue shaken with a mixture of CHCl3 and aqueous K2CO3. The CHCl3 phase was dried and evaporated to dryness to give methyl 4-[2-(2-[2,2,2-trifluoroethyl]guanidino)pyrid-6-yloxy]butyrimidate (0.8 g.) which was used without further purification.
Reaction SMILES: Cl[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[OH:10][N:11]1[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]2[C:12]1=[O:21].C(N(CC)CC)C.CN(C)C=O>O>[C:6]([O:5][C:3]([CH2:2][O:10][N:11]1[C:12](=[O:21])[C:13]2=[CH:20][CH:19]=[CH:18][CH:17]=[C:14]2[C:15]1=[O:16])=[O:4])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)CCl
Reactant: O=C1c2ccccc2C(=O)N1O
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CON1C(=O)c2ccccc2C1=O
Reaction time: 4 h
Yield: 72.1 %

Procedure:
t-Butyl chloroacetate (13.0g, prepared according to Org. Synth., Coll. vol. 4, 263) was added dropwise to a stirred mixture of N-hydroxyphthalimide (14.2g), triethylamine (23.0g), and dimethylformamide (30ml), and the resulting mixture was stirred for 4 hr. The mixture was poured into water (500 ml), and the precipitated solid was collected, washed with water, and dried. Recrystallisation from ethanol gave N-t-butoxycarbonylmethoxyphthalimide (17.26g, 72%); m.p. 145.6°; τ values (DMSO-d6) 2.09 (4 Ar-H), 5.28 (CH2), 8.56 (But).
Reaction SMILES: FC1C=CC=CC=1C1C2C=C([N+]([O-])=[O:20])C=CC=2N(C)C(=O)C(C)(C)N=1.[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]1[C:39]2[CH:40]=[C:41]([N+:44]([O-:46])=[O:45])[CH:42]=[CH:43][C:38]=2[NH:37][C:36](=[O:47])[C:35]([CH3:49])([CH3:48])[N:34]=1>C(Cl)Cl.CCCCCC>[NH2:34][C:35]([CH3:49])([CH3:48])[C:36]([NH:37][C:38]1[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][C:39]=1[C:33](=[O:20])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[Cl:26])=[O:47]
Reactant: CN1C(=O)C(C)(C)N=C(c2ccccc2F)c2cc([N+](=O)[O-])ccc21
Reactant: CC1(C)N=C(c2ccccc2Cl)c2cc([N+](=O)[O-])ccc2NC1=O
Solvent: ClCCl
Solvent: CCCCCC
Product: CC(C)(N)C(=O)Nc1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1Cl

Procedure:
From 76 g (0.21 mol) of 2-amino-2'-(o-chlorobenzoyl)-2-methyl-4'-nitro-propionanilide there is obtained, in analogy to the details in paragraph (b) of Example 1, 5-(o-chlorophenyl)-1,3-dihydro-3,3-dimethyl-7-nitro-2H-1,4-benzodiazepin-2-one of melting point 242° (methylene chloride/n-hexane).
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][C:13]1[C:14]([CH2:31][CH2:32][CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[C:15]([C:24]2[CH:25]=[N:26][CH:27]=[C:28]([CH3:30])[CH:29]=2)[C:16]2[N:17]([C:19]([CH2:22][CH3:23])=[CH:20][CH:21]=2)[N:18]=1.O.NN>C(O)C>[NH2:3][CH2:12][C:13]1[C:14]([CH2:31][CH2:32][CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[C:15]([C:24]2[CH:25]=[N:26][CH:27]=[C:28]([CH3:30])[CH:29]=2)[C:16]2[N:17]([C:19]([CH2:22][CH3:23])=[CH:20][CH:21]=2)[N:18]=1
Reactant: CCOC(=O)CCCCc1c(CN2C(=O)c3ccccc3C2=O)nn2c(CC)ccc2c1-c1cncc(C)c1
Agent: NN
Solvent: CCO
Solvent: O
Product: CCOC(=O)CCCCc1c(CN)nn2c(CC)ccc2c1-c1cncc(C)c1
Yield: 84 %

Procedure:
A mixture of ethyl 5-[2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate (107 mg) and hydrazine monohydrate (51.1 mg) in ethanol (2 mL) was heated under reflux for 2 hours. After evaporation of solvent, the residue was partitioned between chloroform and saturated sodium bicarbonate solution. The organic layer was separated, washed with brine, dried over magnesium sulfate, and evaporated in vacuo to give ethyl 5-[2-(aminomethyl)-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate as yellow oil (67.6 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][C:17]([N:19]3[CH2:26][CH2:25][C:22]4([CH2:24][CH2:23]4)[C@H:21]([OH:27])[CH2:20]3)=[O:18])[C:10](=[O:28])[C@@H:9]2[CH3:29])=[CH:4][C:3]=1[O:30][C:31]([F:34])([F:33])[F:32].CCO>CCCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][C:17]([N:19]3[CH2:26][CH2:25][C:22]4([CH2:24][CH2:23]4)[C@H:21]([OH:27])[CH2:20]3)=[O:18])[C:10](=[O:28])[C@H:9]2[CH3:29])=[CH:4][C:3]=1[O:30][C:31]([F:32])([F:33])[F:34]
Reactant: C[C@H]1C(=O)N(CCCC(=O)N2CCC3(CC3)[C@H](O)C2)CCN1c1ccc(Cl)c(OC(F)(F)F)c1
Solvent: CCO
Solvent: CCCCCCC
Product: C[C@@H]1C(=O)N(CCCC(=O)N2CCC3(CC3)[C@H](O)C2)CCN1c1ccc(Cl)c(OC(F)(F)F)c1
Yield: 25 %

Procedure:
The title compounds were prepared by chiral separation of (S)-4-(4-chloro-3-trifluoromethoxy-phenyl)-1-[4-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-4-oxo-butyl]-3-methyl-piperazin-2-one (61% ds) on a Reprosil Chiral NR, (40% EtOH in n-heptane) to give 25% of (R)-4-(4-chloro-3-trifluoromethoxy-phenyl)-1-[4-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-4-oxo-butyl]-3-methyl-piperazin-2-one (example 63) as white foam, MS: 504.19 (MH+, Cl) and 33% of (S)-4-(4-chloro-3-trifluoromethoxy-phenyl)-1-[4-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-4-oxo-butyl]-3-methyl-piperazin-2-one (example 62) as white foam, MS: 504.19 (MH+, Cl).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:14])[C:5]2[S:10][CH2:9][CH2:8][C:7](=[O:11])[C:6]=2[C:12]=1[CH3:13].[CH2:15](O)[CH2:16][OH:17].C(OC)(OC)OC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(OCC)C>[Br:1][C:2]1[CH:3]=[C:4]([CH3:14])[C:5]2[S:10][CH2:9][CH2:8][C:7]3([O:17][CH2:16][CH2:15][O:11]3)[C:6]=2[C:12]=1[CH3:13]
Reactant: Cc1cc(Br)c(C)c2c1SCCC2=O
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: O
Solvent: COC(OC)OC
Product: Cc1cc(Br)c(C)c2c1SCCC21OCCO1

Procedure:
26.06 g (0.096 mol) of the title compound of Step C, 250 mL of ethylene glycol, 170 mL of trimethyl orthoformate (purchased from Aldrich Chemical Company), and 0.06 g of p-toluenesulfonic acid monohydrate were stirred together at 80° C. under nitrogen overnight. The mixture was diluted with 400 mL of diethyl ether. The resulting mixture was washed with a 1:1 mixture of 1N sodium hydroxide:saturated aqueous NaCl (2×600 mL) and then with saturated aqueous NaCl (1×600 mL). The organic layer was dried (Na2SO4), filtered, and evaporated to dryness. The crude product was chromatographed over silica gel eluting with a mixture of ethyl acetate:hexane (1:9) to yield 24.73 g of the title compound of Step D as a solid melting at 97° C. (dec). 1H NMR (CDCl3): δ2.2 (s,3H), 2.3 (m,2H), 2.4 (s,3H), 3.0 (m,2H), 4.15 (m,2H), 4.3 (m,2H), 7.3 (s,1H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[C:18]([C:29]([NH2:31])=[O:30])[CH:19]=[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:21]=3)[NH:16][N:15]=2)[CH2:10][CH2:9]1)(=[O:7])=[O:6].C([O-])([O-])=O.[K+].[K+].[OH:38][CH:39]1[CH2:44][CH2:43][CH:42]([NH2:45])[CH2:41][CH2:40]1.[I-].[Na+]>CN(C=O)C>[OH:38][CH:39]1[CH2:44][CH2:43][CH:42]([NH:45][CH2:2][CH2:3][CH2:4][S:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[C:22]4[C:17](=[C:18]([C:29]([NH2:31])=[O:30])[CH:19]=[C:20]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH:21]=4)[NH:16][N:15]=3)[CH2:10][CH2:9]2)(=[O:7])=[O:6])[CH2:41][CH2:40]1
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)n[nH]c12
Reactant: NC1CCC(O)CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(S(=O)(=O)CCCNC4CCC(O)CC4)CC3)n[nH]c12
Temperature: 120 °C
Reaction time: 0.02 h
Yield: 54.7 %

Procedure:
To a solution of 3-{1-[(3-chloropropyl)sulfonyl]-4-piperidinyl}-5-phenyl-1H-indazole-7-carboxamide (Intermediate 22) (19 mg, 0.0413 mmol) in DMF (1 mL) was added K2CO3 (25 mg, 0.165 mmol), 4-hydroxycyclohexylamine (33 mg, 0.2065 mmol) and sodium iodide (1.0 mg). The reaction mixture was heated to 120° C. for 14 hrs. The solution was filtered and concentrated. The residue was purified by using a Gilson semi-preparative HPLC system with a YMC ODS-A (C-18) column 50 mm by 20 mm ID, eluting with 10% B to 80% B in 10 min, hold for 1 min where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) pumped at 25 mL/min to afford the title compound (12.2 mg, 55%).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH:12]2[CH2:15][C:14]3([CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16]3)[CH2:13]2)[CH2:8][CH2:7]1)=[O:5])C.[Li+].[OH-].Cl>C1COCC1>[CH2:23]([O:22][C:20]([N:17]1[CH2:18][CH2:19][C:14]2([CH2:15][CH:12]([N:9]3[CH2:8][CH2:7][CH:6]([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]3)[CH2:13]2)[CH2:16]1)=[O:21])[CH3:24]
Reactant: CCOC(=O)C1CCN(C2CC3(CCN(C(=O)OCC)C3)C2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOC(=O)N1CCC2(CC(N3CCC(C(=O)O)CC3)C2)C1
Temperature: 25 °C

Procedure:
Ethyl 2-[4-(ethoxycarbonyl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate (2.474 g, 7.32 mmol) was dissolved in THF (25 mL) at rt and 1 M LiOH sol. (7.32 mL) was added. The reaction mixture was stirred at rt over the weekend. The reaction mixture was adjusted to pH 5 by addition of 1 M HCl sol. and solvents were removed in vacuo, to give 1-[6-(ethoxycarbonyl)-6-azaspiro[3.4]oct-2-yl]piperidine-4-carboxylic acid which was used directly without further purification.
Reaction SMILES: N[CH:2]([CH2:6][C:7]([F:10])([F:9])[F:8])[C:3]([OH:5])=[O:4].S(=O)(=O)(O)[OH:12].N([O-])=O.[Na+].[Cl-].[Na+]>O>[F:8][C:7]([F:10])([F:9])[CH2:6][CH:2]([OH:12])[C:3]([OH:5])=[O:4]
Reactant: O=S(=O)(O)O
Reactant: NC(CC(F)(F)F)C(=O)O
Agent: O=N[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: O=C(O)C(O)CC(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 2-amino-4,4,4-trifluorobutanoic acid (12-1) (1 g, 6.37 mmol) in 1 N aqueous sulfuric acid (10.00 ml, 10 mmol) was cooled to 0° C. To the cooled reaction mixture was added a solution of sodium nitrite (1.1 g, 15.9 mmol) in water (5 mL) dropwise over 40 minutes via addition funnel. The reaction mixture was then warmed to room temperature and stirred for 16 h. Sodium chloride was added to the reaction until complete saturation was achieved. The resulting aqueous mixture was washed with ethyl acetate (3×50 mL) and the combined organic layer was dried over sodium sulfate, filtered and concentrated to dryness to afford 12-2 as a white crystalline solid. 1H NMR (500 MHz, DMSO-d6) δ 2.51 (m, 1H), 2.67 (m, 1H), 4.24 (dd, J=8.60, 3.60 Hz, 1H), 5.74 (br s, 1H), 12.89 (br s, 1H).
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[CH3:5][NH:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[CH:11]=1.ClCCl>O.Cl>[CH3:5][N:6]([N:1]=[O:3])[CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:21][CH:22]=2)[CH:11]=1
Reactant: CNCCCc1cccc(Oc2ccc(C(F)(F)F)cc2)c1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CN(CCCc1cccc(Oc2ccc(C(F)(F)F)cc2)c1)N=O
Reaction time: 1 h
Yield: 85.3 %

Procedure:
A solution of sodium nitrite (7.2 g) in water (50 ml) was added slowly to a solution of N-methyl-3-[4-(trifluoromethyl)phenoxy]benzenepropanamine (30 g) and dichloromethane (100 ml) in 10% hydrochloric acid (200 ml). After one hr, the reaction mixture was separated, and the aqueous phase was extracted with dichloromethane. The organic extracts were dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated. The residue was chromatographed on silica (eluted with 50% hexanes-dichloromethane). The appropriate fractions were collected and evaporated to give 28 g (95.4%) of product, mp 75°-76° C. Recrystallization from hexanes gave the analytical sample, mp 76°-77° C.
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:14])[C:6]1=[O:15].[N+:20]([CH3:23])([O-:22])=[O:21]>O>[Br:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([OH:14])([CH2:23][N+:20]([O-:22])=[O:21])[C:6]1=[O:15]
Reactant: O=C1C(=O)N(Cc2ccccc2Br)c2ccccc21
Reactant: C[N+](=O)[O-]
Solvent: O
Product: O=C1N(Cc2ccccc2Br)c2ccccc2C1(O)C[N+](=O)[O-]
Temperature: 30 °C
Reaction time: 30 h

Procedure:
1-(2-bromobenzyl)indoline-2,3-dione (0.158 g) and nitromethane (0.15 ml) were added to water and the reaction mixture was vigorously stirred at a temperature of 30° C. for 30 hours. The obtained product was extracted with ethyl acetate and purified by silica gel column chromatography using ethyl acetate/hexane as eluents to afford pure product.
Reaction SMILES: [C:1](=[O:4])([OH:3])[O-:2].[ClH:5].[NH2:6][CH2:7][CH2:8][NH:9][CH2:10][CH2:11][NH2:12].[C:13](=[O:16])([O-:15])[O-:14]>>[Cl-:5].[NH2:6][CH2:7][CH2:8][NH:9][CH2:10][CH2:11][NH2:12].[C:1](=[O:2])([O-:4])[O-:3].[C:13](=[O:14])([OH:16])[O-:15]
Reactant: Cl
Agent: NCCNCCN
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Product: [Cl-]

Procedure:
The invention further discloses a process of making colestipol carbonate and/or bicarbonate salt comprising: (a) reacting diethylene triamine hydrochloride with carbonate and/or bicarbonate ions to form diethylene triamine chloride, carbonate and/or bicarbonate salt; (b) reacting and copolymerizing the diethylene triamine chloride, carbonate and/or bicarbonate salt obtained in step (a) with a copolymerizing agent, in the presence of sodium hydroxide to form a wet gel; (c) reducing the particle size of the wet gel obtained in step (b); (d) purifying the wet gel particles obtained in step (c) with water to significantly remove the chloride ions; and (e) drying the purified gel particles obtained in step (d).
Reaction SMILES: [CH:1]1([S:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N+:15]([O-])=O)(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[Sn]Cl>CCO>[CH:1]1([S:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH2:15])(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)C1CCCC1
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Nc1ccccc1S(=O)(=O)C1CCCC1
Yield: 64.9 %

Procedure:
A solution of 1-cyclopentanesulfonyl-2-nitrobenzene (0.66 g, 2.6 mmol) and SnCl2 (2.4 g, 10.34 mmol) in EtOH (10 ml) was heated under reflux for 2 h. The solvent was removed under reduced pressure and the resulting crude was dissolved in AcOEt (100 ml) and washed with sodium hydroxide 2N (30 ml) and brine (10 ml). The organic layer was dried (MgSO4) and the solvents removed under reduced pressure to give the title compound (0.38 g, 66%) as a white solid.