Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][N:13]([C:16]([C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[NH:24][C:23](=[O:28])[CH2:22][CH2:21]3)=[O:17])[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:31]([Cl:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.Cl>O.CN(C)C=O>[ClH:38].[CH2:31]([N:24]1[C:25]2[C:20](=[CH:19][C:18]([C:16]([N:13]3[CH2:14][CH2:15][N:10]([CH2:9][CH2:8][O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH2:11][CH2:12]3)=[O:17])=[CH:27][CH:26]=2)[CH2:21][CH2:22][C:23]1=[O:28])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C1CCc2cc(C(=O)N3CCN(CCOc4ccccc4)CC3)ccc2N1
Reactant: ClCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1ccc2c(c1)CCC(=O)N2Cc1ccccc1)N1CCN(CCOc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
480 Milligrams of 6-[4-(2-phenoxyethyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyril and 70 ml of 50%-sodium hydride in oil were mixed into 5 ml of dimethylformamide and stirred at a room temperature for 1 hour. Then to this mixture was added a solution of 0.17 ml of benzyl chloride with 3 ml of dimethylformamide was added dropwise slowly and stirred at a room temperature for 4 hours. The reaction mixture was poured in a voluminous amount of water and the organic matters were extracted with chloroform, and the chloroform layer was washed with water, dried and chloroform was removed by distillation. The residue obtained was converted into hydrochloride by adding a concentrated hydrochloric acid and recrystallized from methanol-water to obtain 150 mg of 1-benzyl-6-[4-(2-phenoxyethyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyril monohydrochloride. Colorless powdery crystals. Melting point: 261°-264° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[CH2:10](OC(OCC)CBr)[CH3:11]>>[Br:1][C:2]1[CH:3]=[C:4]([F:9])[C:5]2[N:6]([CH:10]=[CH:11][N:8]=2)[CH:7]=1
Reactant: CCOC(CBr)OCC
Reactant: Nc1ncc(Br)cc1F
Product: Fc1cc(Br)cn2ccnc12
Yield: 88.9 %

Procedure:
Prepared from 5-bromo-3-fluoro-pyridin-2-ylamine (example C.29 step 3) (3.1 g, 15.7 mmol) and bromoacetaldehyde diethyl acetal (90%, 4.86 mL, 31.3 mmol) as described in example C.20 step 1. Obtained the title compound as a light brown solid (3.0 g, 89%). MS (ISP) 215.1 [(M+H)+], 217.1 [(M+2+H)+].
Reaction SMILES: Cl.[NH2:2][CH:3]([C:9](=[O:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(N(CC)CC)C.[CH3:19][O:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1.O>C(Cl)Cl>[CH3:19][O:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:2][CH:3]([C:9](=[O:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:26])=[CH:23][CH:22]=1
Reactant: CCOC(=O)C(N)C(C)=O
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)C(NC(=O)c1ccc(OC)cc1)C(C)=O
Temperature: 25 °C
Yield: 83 %

Procedure:
Ethyl 2-amino-3-oxobutanoate hydrochloride (1 g) was suspended in dry methylene chloride (30 ml) and dissolution was effected with addition of triethylamine (1.69 ml). After adding 4-methoxybenzoyl chloride (0.91 ml) dropwise under cooling, the reaction mixture was allowed to warm up to room temperature and to react for 20 minutes. The mixture was treated with water and extracted with methylene chloride. The extract was washed with water, 1N-HCl, 4% aqueous sodium bicarbonate and saturated aqueous NaCl, dried (anhydrous Na2SO4) and concentrated. The residue was dissolved in developing solvent (benzene:ethyl acetate=4:1) and applied on a silica gel column. The first fraction (unpurities) was discarded and the following fraction was pooled and concentrated to give ethyl 2-(4-methoxybenzamido)-3-oxobutanoate (1.28 g, 83%) as white solid, m.p. 67°-69° C.
Reaction SMILES: [C:1]([O-:4])([O-])=O.[K+].[K+].Cl[C:8]1[C:13](=[O:14])[N:12]([CH3:15])[CH:11]=[C:10]2[CH2:16][N:17]([CH2:20][CH2:21][C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]=3)C(=O)[C:9]=12.[N:32]1[CH:37]=[CH:36][CH:35]=[C:34](B(O)O)[CH:33]=1.O>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:15][N:12]1[C:13](=[O:14])[C:8]([C:34]2[CH:33]=[N:32][CH:37]=[CH:36][CH:35]=2)=[C:9]2[C:1](=[O:4])[N:17]([CH2:20][CH2:21][C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]=3)[CH2:16][C:10]2=[CH:11]1
Reactant: O=C([O-])[O-]
Reactant: OB(O)c1cccnc1
Reactant: Cn1cc2c(c(Cl)c1=O)C(=O)N(CCc1ccc3ccccc3n1)C2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc2c(c(-c3cccnc3)c1=O)C(=O)N(CCc1ccc3ccccc3n1)C2
Temperature: 130 °C
Yield: 89.2 %

Procedure:
Bis(triphenylphosphine)palladium(II) dichloride (14.88 mg, 0.021 mmol) and K2CO3 (176 mg, 1.27 mmol) were added to a suspension of 7-chloro-5-methyl-2-(2-quinolin-2-yl-ethyl)-3,5-dihydro-2H-pyrrolo[3,4-c]pyridine-1,6-dione (150 mg, 0.424 mmol, see Example c4)) and pyridine-3-ylboronic acid (104 mg, 0.848 mmol) in DMF (3 ml)/water (0.6 ml) and the mixture was heated in a microwave at 130° C. for 30 min. The solvent was removed and the resulting solid was purified by preparative HPLC (system: Gilson 281(PHG008), eluent: MeCN/aqueous 0.1% TFA solution (gradient: 30:70 to 80:20 over 15 min), column: Boston symmetrix ODS-R, C-18, 10 nm, 21.2×250 mm) to afford the title compound (150 mg, 89% yield).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:11][CH2:10][NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=C1N(P(Cl)(N2[CH2:44][CH2:43][O:42]C2=O)=O)CCO1.C(N([CH2:52][CH3:53])CC)C>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:15](=[O:20])[C:16]([F:18])([F:19])[F:17])[CH2:11][CH2:10][N:9]1[C:43](=[O:42])[CH:44]([C:53]1[CH:52]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN[C@H](Cc2ccccc2)C1)C(F)(F)F
Reactant: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Reactant: CCN(CC)CC
Product: O=C(C(Cc1ccccc1)c1ccccc1)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1

Procedure:
300 mg (0.702 mmol) of (2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine are reacted in analogy to Example 4 with 190 mg (0.842 mmol) of (R,S)-2,3-diphenylpropionic acid, 214 mg (0.842 mmol) of bis-(2-oxo-3-oxazolidinyl)phosphinic chloride and 216 μl (1.54 mmol) of triethylamine. The title compound is obtained as white foam. TLC: methylene chloride/methanol/conc. ammonia (700:50:1) Rf =0.74, FD-MS: M+ =635.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[CH:13][C:12]([C:15]2[C:16]([CH3:41])=[N:17][C:18]([CH3:40])=[C:19]([C@H:29]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[C:30]([O:32]CC)=[O:31])[C:20]=2[N:21]2[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH2:22]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-]>CCO.O>[CH2:1]([O:8][C:9]1[N:14]=[CH:13][C:12]([C:15]2[C:16]([CH3:41])=[N:17][C:18]([CH3:40])=[C:19]([C@H:29]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[C:30]([OH:32])=[O:31])[C:20]=2[N:21]2[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH2:22]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(-c2ccc(OCc3ccccc3)nc2)c1N1CCC(C)(C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)O)c(N2CCC(C)(C)CC2)c1-c1ccc(OCc2ccccc2)nc1
Yield: 68 %

Procedure:
A solution of (S)-ethyl 2-(6′-(benzyloxy)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethyl-[3,3′-bipyridin]-5-yl)-2-(tert-butoxy)acetate (0.014 g, 0.025 mmol) and LiOH (5.99 mg, 0.250 mmol) in 9:1 EtOH/H2O (2 mL) was refluxed for 3 h. Then, cooled and purified by prep-HPLC to afford (S)-2-(6′-(benzyloxy)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethyl-[3,3′-bipyridin]-5-yl)-2-(tert-butoxy)acetic acid (0.0089 g, 0.017 mmol, 66.9% yield) as white solid. 1H NMR (500 MHz, CDCl3) δ 8.08 (d, J=2.2 Hz, 0.5H), 7.99 (d, J=1.7 Hz, 0.5H), 7.46-7.54 (m, 3H), 7.33-7.45 (m, 3H), 6.94 (dd, J=5.8, 8.4 Hz, 1H), 5.93 (br. s., 1H), 5.40-5.55 (m, 2H), 3.40-3.70 (m, 0.5H), 2.74-3.11 (m, 0.5H), 2.67 (s, 3H), 2.28 (s, 1.5H), 2.25 (s, 1.5H), 1.94-2.20 (m, 1H), 1.27-1.40 (m, 4H), 1.25 (s, 4.5H), 1.24 (s, 4.5H), 0.80 (br.s., 6H). LCMS (M+H)=532.4.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([N+:17]([O-:19])=[O:18])=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[N:12][CH:11]=[CH:10]2)(=O)=O.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:25][CH:24]=1>>[C:32]([O:31][C:30](=[O:36])[NH:29][C:26]1[CH:25]=[CH:24][C:23]([NH:22][C:7]2[C:8]([N+:17]([O-:19])=[O:18])=[C:9]3[C:14](=[CH:15][CH:16]=2)[CH:13]=[N:12][CH:11]=[CH:10]3)=[CH:28][CH:27]=1)([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)cc1
Reactant: O=[N+]([O-])c1c(OS(=O)(=O)C(F)(F)F)ccc2cnccc12
Product: CC(C)(C)OC(=O)Nc1ccc(Nc2ccc3cnccc3c2[N+](=O)[O-])cc1
Yield: 26.3 %

Procedure:
By using 5-nitroisoquinolin-6-yl trifluoromethanesulfonate (258 mg, 0.8 mmol), and tert-butyl 4-aminophenylcarbamate (250 mg, 1.2 mmol), the title compound (80 mg, yield 26%) was obtained as red crystals in the same manner as that of Example 1, (1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:40]=[C:41]([F:43])[CH:42]=1)[CH2:5][C@H:6]([NH:20][C:21]([C:23]1[CH:24]=[C:25]([C:29]2[O:30][C:31]([CH2:34][CH2:35][C:36]([O:38]C)=[O:37])=[CH:32][N:33]=2)[CH:26]=[CH:27][CH:28]=1)=[O:22])[C@H:7]([OH:19])[CH2:8][NH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH3:18])[CH:12]=1.O.[OH-].[Li+]>O1CCCC1.CO.O>[F:1][C:2]1[CH:3]=[C:4]([CH:40]=[C:41]([F:43])[CH:42]=1)[CH2:5][C@H:6]([NH:20][C:21]([C:23]1[CH:24]=[C:25]([C:29]2[O:30][C:31]([CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[CH:32][N:33]=2)[CH:26]=[CH:27][CH:28]=1)=[O:22])[C@H:7]([OH:19])[CH2:8][NH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH3:18])[CH:12]=1
Reactant: CCc1cccc(CNC[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cccc(-c3ncc(CCC(=O)OC)o3)c2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCc1cccc(CNC[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cccc(-c3ncc(CCC(=O)O)o3)c2)c1

Procedure:
Methyl 3-(2-{3-[({(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}amino)carbonyl]phenyl}-1,3-oxazol-5-yl)propanoate (70 mg, 0.12 mmol) and lithium hydroxide monohydrate (10 mg, 0.24 mmol) in 2:1:1 tetrahydrofuran/methanol/water (6 mL) is stirred at room temperature 1.5 h. The reaction is concentrated under reduced pressure. The residue is washed with 1N hydrochloric acid (aq), then chloroform, and the solid is dried under reduced pressure to give the title compound. ESI MS m/z 578.2 [M+H]+.
Reaction SMILES: [C:1]([O:9][C@@H:10]1[C@H:14]([O:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([CH2:24][O:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:12][C@H:11]1[N:34]1[C:41](=[O:42])[CH:40]=[C:38]([NH2:39])[NH:37][C:35]1=[O:36])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:43]([O-])=O.[Na+].C(O)(=O)C>C(O)(C)=O.O.[Zn]>[NH2:43][C:40]1[C:41](=[O:42])[N:34]([C@@H:11]2[O:12][C@H:13]([CH2:24][O:25][C:26](=[O:33])[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C@@H:14]([O:15][C:16](=[O:23])[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:10]2[O:9][C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:35](=[O:36])[NH:37][C:38]=1[NH2:39]
Reactant: O=N[O-]
Reactant: Nc1cc(=O)n([C@@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H]2OC(=O)c2ccccc2)c(=O)[nH]1
Agent: [Na+]
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: Nc1[nH]c(=O)n([C@@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H]2OC(=O)c2ccccc2)c(=O)c1N
Temperature: -5 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
To a solution of 49 (238 mg, 0.42 mmol) in AcOH—H2O (5: 0.5 mL) was added NaNO2 over 10 min at −5° C. The resulting mixture was stirred at −5° C. for 1 hr, concentrated, and co-evaporated with toluene to give a purple solid, which was treated with acetic acid (5 mL) and Zn dust (460 mg, 7.04 mmol), and heated at 70° C. for 30 mm. The mixture was filtered through a Celite pad, and the filtrate concentrated to a slightly green solid, which was purified by silica gel column chromatography (CHCl3:MeOH=10:1 v/v) to give compound 50 (217 mg, 88%).
Reaction SMILES: [CH3:1][S:2]([O:5][CH2:6][CH2:7][C:8]([CH3:11])([CH3:10])[CH3:9])(=[O:4])=[O:3].[C:12]1([P:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH3:1][S:2]([O-:5])(=[O:4])=[O:3].[CH3:9][C:8]([CH3:11])([CH3:10])[CH2:7][CH2:6][P+:18]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)(C)CCOS(C)(=O)=O
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: CS(=O)(=O)[O-]
Yield: 98.2 %

Procedure:
3,3-Dimethylbutyl methanesulfonate (36.5 g) and triphenylphosphine (53.1 g) were stirred at 120° C. for 15 hr to give the title compound (88.0 g) as a white gummy substance.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrCC[OH:46]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH2:15][OH:46])[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Reactant: OCCBr
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(CCO)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-bromoethanol and isolated as white solid (5.8 mg, 43%). MS(m/e): 327.3 (MH+).
Reaction SMILES: CC1C=CC(S([O:11][CH2:12][CH:13]2[CH2:17][CH2:16][CH2:15][O:14]2)(=O)=O)=CC=1.C1(O)C=CC=CC=1.[OH:25][C@@H:26]([C:37]1[CH:42]=[CH:41][CH:40]=[C:39](O)[CH:38]=1)[CH2:27][CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33]>CCOC(C)=O>[OH:25][C@@H:26]([C:37]1[CH:38]=[CH:39][CH:40]=[C:41]([O:11][CH2:12][CH:13]2[CH2:17][CH2:16][CH2:15][O:14]2)[CH:42]=1)[CH2:27][CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33]
Reactant: Cc1ccc(S(=O)(=O)OCC2CCCO2)cc1
Reactant: CC(C)(C)OC(=O)NCC[C@@H](O)c1cccc(O)c1
Solvent: CCOC(C)=O
Solvent: Oc1ccccc1
Product: CC(C)(C)OC(=O)NCC[C@@H](O)c1cccc(OCC2CCCO2)c1

Procedure:
tert-Butyl ((3R)-3-hydroxy-3-(3-((tetrahydrofuran-2-yl)methoxy)phenyl)propyl)-carbamate was prepared by the reaction between rac-(tetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate and phenol (7, Intermediate I) at +100° C. following the method used in Example 12 with the following exception. After the reaction was complete (as judged by TLC), the reaction mixture was diluted with EtOAc, dried over anhydrous Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography (EtOAc:hexane 10-40% gradient) gave the product as an off-white semi-solid. Yield (0.36 g, 66%); 1H NMR (400 MHz, CDCl3): δ 7.23 (t, J=8.0 Hz, 1H), 6.95 (s, 1H), 6.91 (d, J=8.0 Hz, 1H), 6.82 (d, 1H), 4.88 (bs, 1H), 4.71 (bs, 1H), 4.28-4.25 (m, 1H), 3.96-3.90 (m, 3H), 3.85-3.82 (m, 1H), 3.49 (bs, 1H), 3.19-3.13 (m, 2H), 1.97-1.92 (m, 2H), 1.83-1.74 (m, 3H), 1.60 (s, 1H), 1.45 (s, 9H); MS: m/z 352.8 [M+H]+.
Reaction SMILES: [Mn]([O-])(=O)(=O)=[O:2].[K+].[CH3:7][O:8][C:9]1[CH:10]=[C:11]2[O:32][C:31]([CH3:34])([CH3:33])[CH:30]=[CH:29][C:12]2=[C:13]2[C:22]=1[C:21](=[O:23])[C:20]1[CH:19]=[C:18]3[CH:24]=[CH:25][CH:26]=[CH:27][C:17]3=[CH:16][C:15]=1[N:14]2[CH3:28].[OH2:35]>CC(C)=O>[O:35]=[C:29]1[C:12]2=[C:13]3[C:22](=[C:9]([O:8][CH3:7])[CH:10]=[C:11]2[O:32][C:31]([CH3:34])([CH3:33])[CH:30]1[OH:2])[C:21](=[O:23])[C:20]1[CH:19]=[C:18]2[CH:24]=[CH:25][CH:26]=[CH:27][C:17]2=[CH:16][C:15]=1[N:14]3[CH3:28]
Reactant: O
Reactant: COc1cc2c(c3c1c(=O)c1cc4ccccc4cc1n3C)C=CC(C)(C)O2
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc2c(c3c1c(=O)c1cc4ccccc4cc1n3C)C(=O)C(O)C(C)(C)O2
Reaction time: 2 h

Procedure:
A solution of 8.1 g of potassium permanganate diluted in 30 ml of water is slowly added at room temperature to a solution of 3.5 g of the product of Example 2 in 50 ml of acetone. After 2 hours, the solution is concentrated under reduced pressure. The residue is then mixed with silica and then chromatographed on silica gel (dichloromethane/methanol: 98/2), allowing the compound of Example 4, which is present in a small amount, to be isolated from the expected product.
Reaction SMILES: [C:1]([C:4]1[CH:8]=[C:7]([C:9]([NH:11][CH2:12][CH2:13][C:14]2[O:15][C:16]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=3)=[CH:17][CH:18]=2)=[O:10])[NH:6][N:5]=1)(=O)[CH3:2].[NH2:27][CH2:28][CH2:29][OH:30].[BH4-].[Na+].Cl>C1(C)C=CC=CC=1.O.C1COCC1>[Cl:26][C:21]1[CH:20]=[C:19]([C:16]2[O:15][C:14]([CH2:13][CH2:12][NH:11][C:9]([C:7]3[NH:6][N:5]=[C:4]([CH:1]([NH:27][CH2:28][CH2:29][OH:30])[CH3:2])[CH:8]=3)=[O:10])=[CH:18][CH:17]=2)[CH:24]=[CH:23][C:22]=1[Cl:25]
Reactant: NCCO
Reactant: CC(=O)c1cc(C(=O)NCCc2ccc(-c3ccc(Cl)c(Cl)c3)o2)[nH]n1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(NCCO)c1cc(C(=O)NCCc2ccc(-c3ccc(Cl)c(Cl)c3)o2)[nH]n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 25.6 %

Procedure:
3-Acetyl-N-(2-(5-(3,4-dichlorophenyl)furan-2-yl)ethyl)-1H-pyrazole-5-carboxamide (78 mg; 0.20 mmol) and 2-aminoethanol (10 mg; 0.17 mmol) were dissolved in 5 ml of dry toluene and 5 ml of dry THF and stirred for 6.5 h at 75° C. under nitrogen atmosphere and then overnight at RT. Sodium tetrahydroborate (18.8 mg; 0.50 mmol) was added, stirred for 3 days at RT and then 4.5 h at 75° C. 10 mg of sodium tetrahydroborate was added and the mixture was heated for 5 h at 50° C. to complete the reaction. 0.1 ml of water was added at 0° C. and pH adjusted to 1 with 1 M HCl. Solution was evaporated to dryness, 15 ml of DCM was added and the mixture was washed with 10 ml of water. pH was adjusted to 12 with 1 M NaOH and 15 ml of DCM was added. After Na2SO4 drying the compound was purified by chromatography (CombiFlash, Silica column, 2.5-10% MeOH/DCM) to obtain 19 mg (26%) of the title compound. 1H-NMR (400 MHz; d1-CDCl3): δ 1.43 (d, 3H), 2.55-2.70 (m, 1H), 2.74-2.85 (m, 1H), 2.97 (t, 2H), 3.60-3.76 (m, 4H), 4.02-4.12 (m, 1H), 6.16 (d, 1H), 6.53 (d, 1H), 6.65 (s, 1H), 7.33-7.41 (m, 3H), 7.67 (d, 1H).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][C:10]=2[CH3:19])O1.[Cl:21][C:22]1[CH:23]=[C:24]([CH2:28][N:29]2[CH:33]=[CH:32][N:31]=[C:30]2[CH3:34])[N:25]=[N:26][CH:27]=1>>[ClH:21].[CH3:34][C:30]1[N:29]([CH2:28][C:24]2[N:25]=[N:26][CH:27]=[C:22]([C:9]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH:12]=[CH:11][C:10]=3[CH3:19])[CH:23]=2)[CH:33]=[CH:32][N:31]=1
Reactant: Cc1ccc2ccccc2c1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1nccn1Cc1cc(Cl)cnn1
Product: Cc1ccc2ccccc2c1-c1cnnc(Cn2ccnc2C)c1
Product: Cl

Procedure:
The title compound, MS: m/e=315.3 (M+H+), was prepared from 4,4,5,5-tetramethyl-2-(2-methyl-naphthalen-1-yl)-[1,3,2]dioxaborolane and 5-chloro-3-(2-methyl-imidazol-1-yl-methyl)-pyridazine.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][C:29](C(O)=O)=[CH:28][CH:27]=1.[NH2:35][CH2:36][CH:37]([C:39]1[CH:40]=[C:41]([OH:45])[CH:42]=[CH:43][CH:44]=1)[OH:38]>>[OH:38][CH:37]([C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([OH:45])[CH:40]=1)[CH2:36][NH:35][C:16]([C@@H:9]1[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]1[C:6]([C:29]1[CH:28]=[CH:27][C:26]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH3:19])=[CH:31][CH:30]=1)=[O:7])=[O:18]
Reactant: Cc1ccccc1-c1ccc(C(=O)O)cc1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: NCC(O)c1cccc(O)c1
Product: CON=C1C[C@@H](C(=O)NCC(O)c2cccc(O)c2)N(C(=O)c2ccc(-c3ccccc3C)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, and 3-[(1RS)-2-amino-1-hydroxyethyl]phenol, the title compound was obtained in 70% purity by HPLC. MS(ESI+): m/z=488.
Reaction SMILES: [CH3:1][CH:2]1[CH2:4][NH:3]1.C(N(CC)CC)C.[CH2:12]([O:19][C:20](Cl)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[C:20]([N:3]1[CH2:4][CH:2]1[CH3:1])([O:19][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:21]
Reactant: CC1CN1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1CN1C(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
2-Methyl aziridine is dissolved in CH2Cl2 and triethylamine under argon at 0° C. Benzylchloroformate is added and the contents of the flask are at room temperature overnight. The mixture is poured into 10% citric acid and is extracted with CHCl3. The organic layer is washed with dilute aqueous NaHCO3 and dried over MgSO4. The solution is evaporated to yield N-Cbz-2-methyl aziridine.
Reaction SMILES: [C:1]1([C:14](O)=[O:15])[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.CN(C)C=O.[N:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[CH:35]=[C:36]([NH2:40])[CH:37]=[CH:38][CH:39]=2)[N:29]=1>ClCCl.N1C=CC=CC=1>[N:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[CH:35]=[C:36]([NH:40][C:14]([C:1]3[C:13]4[CH2:12][C:11]5[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=5)[C:5]=4[CH:4]=[CH:3][CH:2]=3)=[O:15])[CH:37]=[CH:38][CH:39]=2)[N:29]=1
Reactant: Nc1cccc(-c2cccnn2)c1
Reactant: O=C(O)c1cccc2c1Cc1ccccc1-2
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(Nc1cccc(-c2cccnn2)c1)c1cccc2c1Cc1ccccc1-2
Reaction time: 2 h
Yield: 13.8 %

Procedure:
To a suspension of 1-fluorenecarboxylic acid (184 mg) and oxalyl chloride (0.2 ml) in dichloromethane (4 ml) was added N,N-dimethylformamide (0.01 ml), and the mixture was stirred for 2 hours. The resultant solution was evaporated to give a crude acid chloride. To a suspension of 3-pyridazin-3-yl-phenylamine (150 mg) and pyridine (0.21 ml) in dichloromethane (2 ml) was dropwise added a solution of the acid chloride obtained above in dichloromethane. (5 ml) followed by stirring for an hour. The mixture was diluted with dichloromethane and washed with an aqueous solution of sodium hydrogen carbonate and brine. The separated organic layer was dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by a silica gel column chromatography eluting with 2% methanol in dichloromethane to give N-(3-(pyridazin-3-yl)phenyl)-9H-fluorene-1-carboxamide (44 mg, 13.8%).