Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12](Cl)=[O:13])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[Cl-].[Al+3].[Cl-].[Cl-].O>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][C:7]=1[O:8][CH3:9])[C:12](=[O:13])[CH2:11][CH2:10]2
Reactant: COc1ccc(CCC(=O)Cl)cc1Br
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: COc1cc2c(cc1Br)CCC2=O
Reaction time: 2 h

Procedure:
48 g (0.18 mol) of 3-(3-bromo-4-methoxyphenyl)propanoyl chloride are dissolved in 500 ml of dichloromethane. 72 g (0.54 mol) of aluminium chloride are added in small amounts. The reaction medium is stirred for 2 hours and then poured into water and the phases are separated by settling. The organic phase is dried (Na2SO4) and the solvent is evaporated off: (39.8 g). The product is triturated in ethanol, filtered off and dried (25 g; 63%)
Reaction SMILES: [CH:1]1([CH:4]([C:24]2[C:29](=[O:30])[O:28][C:27]3[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:26]=3[C:25]=2[OH:37])[C:5]2[CH:6]=[C:7]([NH:11][S:12]([C:15]3[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=3)[C:18]([OH:20])=[O:19])(=[O:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[CH2:3][CH2:2]1.S(=O)(=O)(O)O.[CH3:43]O>C(OCC)(=O)C>[CH:1]1([CH:4]([C:24]2[C:29](=[O:30])[O:28][C:27]3[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:26]=3[C:25]=2[OH:37])[C:5]2[CH:6]=[C:7]([NH:11][S:12]([C:15]3[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=3)[C:18]([O:20][CH3:43])=[O:19])(=[O:13])=[O:14])[CH:8]=[CH:9][CH:10]=2)[CH2:3][CH2:2]1
Reactant: CO
Reactant: O=C(O)c1cccc(S(=O)(=O)Nc2cccc(C(c3c(O)c4c(oc3=O)CCCCCC4)C3CC3)c2)c1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(S(=O)(=O)Nc2cccc(C(c3c(O)c4c(oc3=O)CCCCCC4)C3CC3)c2)c1

Procedure:
A solution of the title compound from Example 292 (300 mg) and concentrated sulfuric acid (300 μL) in methanol (10 mL) is stirred for 2 days at room temperature, diluted with ethyl acetate, washed with water, brine, dried (anhydrous sodium sulfate), filtered, concentrated, and chromatographed on silica gel to give 225 mg of the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:6]([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:5](C(O)=O)[CH:4]=[N:3]1.CC(O)(C)C.CC[N:24](C(C)C)C(C)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>O1CCOCC1>[CH3:1][N:2]1[C:6]([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:5]([NH2:24])[CH:4]=[N:3]1
Reactant: Cn1ncc(C(=O)O)c1Oc1ccccc1
Reactant: CCN(C(C)C)C(C)C
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CC(C)(C)O
Solvent: C1COCCO1
Product: Cn1ncc(N)c1Oc1ccccc1
Temperature: 110 °C
Reaction time: 3 h

Procedure:
To a stirred mixture of 1-Methyl-5-phenoxy-1H-pyrazole-4-carboxylic acid (16.00 g; 73.32 mmol), t-BuOH (51.20 g; 690.77 mmol) in 1,4-dioxane under argon was added DIPEA (37.44 g; 289.69 mmol) and Diphenylphosphoryl azide (41.60 g; 151.16 mmol). After 10 minutes at ambient temperature it was heated up to 110° C. and stirred there for 3 hours. The solvent was evaporated and the crude material purified by column chromatography. This compound was dissolved in DCM and treated with 4 M HCl in 1,4-dioxane. It was stirred for 2 days at ambient temperature. The solvent was evaporated and the residue dissolved in water and washed with EtOAc. The aqueous layer was basified with NaHCO3 solution and extracted with EtOAc. The organic layer was dried and concentrated to dryness.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[C:5]2[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=2[N:3]=1.[F:12][CH:13]([F:31])[N:14]1[C:22]2[C:17](=[N:18][CH:19]=[CH:20][CH:21]=2)[N:16]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)[C:15]1=[O:30].[H-].[Na+]>CN(C=O)C.CO>[F:31][CH:13]([F:12])[N:14]1[C:22]2[C:17](=[N:18][CH:19]=[CH:20][CH:21]=2)[N:16]([C:23]2[CH:28]=[CH:27][C:26]([O:29][C:2]3[N:6]([CH3:7])[C:5]4[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=4[N:3]=3)=[CH:25][CH:24]=2)[C:15]1=[O:30]
Reactant: O=c1n(-c2ccc(O)cc2)c2ncccc2n1C(F)F
Reactant: Cn1c(Cl)nc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: Cn1c(Oc2ccc(-n3c(=O)n(C(F)F)c4cccnc43)cc2)nc2ccccc21
Temperature: 180 °C
Yield: 46.7 %

Procedure:
2-Chloro-1-methyl-1H-benzimidazole (70 mg) was added to a solution of 1-(difluoromethyl)-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (122 mg) and NaH (25.2 mg) in DMF (3 mL) at 100° C. The mixture was heated at 180° C. for 1 h under microwave irradiation. The reaction mixture was diluted with MeOH and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 0%-50% EtOAc in hexane) to give 1-(difluoromethyl)-3-{4-[(1-methyl-1H-benzimidazol-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (80 mg) as white crystals.
Reaction SMILES: [C:1]([O:5]N=O)([CH3:4])([CH3:3])C.[CH2:8](Br)[CH:9]=[CH2:10].CC#N.C([C:18]1[CH:19]=[C:20]([CH:22]=[C:23]([N+:25]([O-:27])=[O:26])C=1)N)(=O)C>>[C:1]([C:3]1[CH:10]=[CH:9][CH:8]=[C:19]([CH2:20][CH:22]=[CH:23][N+:25]([O-:27])=[O:26])[CH:18]=1)(=[O:5])[CH3:4]
Reactant: CC(C)(C)ON=O
Reactant: CC(=O)c1cc(N)cc([N+](=O)[O-])c1
Reactant: C=CCBr
Solvent: CC#N
Product: CC(=O)c1cccc(CC=C[N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of t-butylnitrite (0.24 ml, 2.1 mmol) and allylbromide (1.8 ml, 25.2 mmol) in 3 ml CH3CN 3-acetyl-5-nitroaniline (0.25 g, 1.4 mmol) was added, so that the temperature was maintained between 20 and 25° C., and the mixture was stirred for 10 min at room temperature. The volatile material in the reaction solution was then removed at reduced pressure to give 3-acetyl-5-nitroallylbenzene. 1H-NMR (CDCl3, 300 MHz) δ ppm: 8.61 (s, 1H), 8.25 (s, 1H), 8.10 (s, 1H), 6.03-5.88 (m, 1H), 5.23-5.11 (m, 2H), 3.55 (d, 2H).
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[C:13]([CH2:29][O:30][CH2:31][CH3:32])[N:14]([CH2:15][CH2:16][CH2:17][C:18]3[O:22][N:21]=[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:19]=3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH3:33]>CO>[CH2:31]([O:30][CH2:29][C:13]1[N:14]([CH2:15][CH2:16][CH2:17][C:18]2[O:22][N:21]=[C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:19]=2)[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:33])[C:11]=2[N:12]=1)[CH3:32]
Reactant: N
Reactant: CCOCc1nc2c(Cl)nc3ccccc3c2n1CCCc1cc(-c2ccccc2)no1
Solvent: CO
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CCCc1cc(-c2ccccc2)no1
Temperature: 150 °C

Procedure:
A mixture of 4-chloro-2-(ethoxymethyl)-1-[3-(3-phenylisoxazol-5-yl)propyl]-1H-imidazo[4,5-c]quinoline (2.22 g, 4.97 mmol) in a solution of 7 M ammonia in methanol (25 mL) was heated at 150° C. for 17 hours in a Parr pressure vessel. The volatiles were removed under reduced pressure and the resulting solid was triturated with 1 M aqueous sodium hydroxide and isolated by filtration. The crude product was purified by flash chromatography (silica gel, gradient elution from 10% to 20% CMA in chloroform). The appropriate fractions were combined and concentrated to yield a solid that was triturated with hot diethyl ether and 9:1 dichloromethane/methanol (10 mL). The final material was dried at 80° C. under vacuum to yield 2-(ethoxymethyl)-1-[3-(3-phenylisoxazol-5-yl)propyl]-1H-imidazo[4,5-c]quinolin-4-amine (954 mg) as a white powder, mp 171.0-172.0° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Br[CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:17](=[O:18])[C:16]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]2[C:14]1=[O:23].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[O:1][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:17](=[O:18])[C:16]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]2[C:14]1=[O:23]
Reactant: Oc1ccccn1
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCCCOc1ccccn1
Temperature: 100 °C
Reaction time: 3 h
Yield: 23.5 %

Procedure:
A mixture of 2-hydroxypyridine (6.0 g), N-(4-bromobutyl)phthalimide (17.8 g), potassium carbonate (8.7 g) and N,N-dimethylformamide (DMF) (80 ml) was stirred at 100° C. for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4), then the solvent was distilled off under reduced pressure. The oily residue was subjected to a silica gel column chromatography. From the fraction eluted with chloroform-ethyl acetate (4:1 v/v), N-[4-(2-pyridyloxy)butyl]phthalimide (4.4 g, 23%) was obtained Recrystallization of the product from ether gave colorless prisms, m.p. 77° C. to 78° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[C:8]2[CH2:17][CH:16]([CH3:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=O)=[CH:3][CH:2]=1.[NH2:20][NH2:21].C(Cl)(Cl)Cl>C(O)C>[CH3:18][CH:16]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]2=[N:20][NH:21][CH:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH:8]2[CH2:17]1
Reactant: NN
Reactant: CC1CC(=Cc2ccncc2)C(=O)c2ccccc21
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CC1CC2C(=NNC2c2ccncc2)c2ccccc21

Procedure:
To a mixture of 25 grams of 2-(4-pyridylmethylene)-3,4-dihydro-4-methyl-1 (2H)-naphthalenone and 5 grams of hydrazine in 150 ml of ethanol is added sufficient chlorform to dissolve all the reactants. The solution is refluxed overnight under anhydrous conditions. After cooling, the reaction mixture is filtered and the solvent removed by evaporation to yield 5-methyl-3-(4-pyridyl)-3,3a,4,5-tetrahydro-2H-naphtho[1,2-c]Pyrazole. This is chromatographed on silica using benzene as the eluant to yield 4,5-dihydro-5-methyl-3l -(4-pyridyl)-2H-naphtho[1,2c]pyrazole.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:5]([OH:6])=[CH:4][C:3]=1[OH:10].C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][C:19]([O:21][CH3:22])=[O:20].O>CN(C=O)C>[Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:5]([OH:6])=[CH:4][C:3]=1[O:10][CH2:18][C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)CBr
Reactant: Oc1cc(O)c(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1cc(O)c(Cl)cc1Cl
Temperature: 80 °C
Yield: 23.2 %

Procedure:
A mixture of 4,6-dichlororesorcinol (2 g), potassium carbonate (1.54 g) and methyl bromoacetate (1.71 g) in DMF (10 ml) was heated at 80° C. for 24 h. The resulting mixture was cooled and water (200 ml) added. Solid (bis-alkylated product) was filtered off, then the aqueous was acidified with aq. HCl, which was extracted with ether and the organics were dried and concentrated in vacuo. Purification by RPHPLC (Xterra, gradient 95-5%, ammonia (0.2% aq.) in acetonitrile) gave the subtitle compound (0.65 g) as a solid.
Reaction SMILES: Cl.O1CCOCC1.C(O[C:13](=O)[N:14]([CH2:16][CH2:17][O:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[C:26]([N:28]1[CH2:41][C:31]2=[C:32]3[N:37]([N:38]=[C:30]2[CH2:29]1)[CH:36]=[C:35]([Cl:39])[C:34]([CH3:40])=[N:33]3)=[O:27])C)(C)(C)C>C(Cl)Cl>[ClH:39].[Cl:39][C:35]1[C:34]([CH3:40])=[N:33][C:32]2[N:37]([N:38]=[C:30]3[CH2:29][N:28]([C:26]([C:20]4[CH:21]=[CH:22][C:23]([F:25])=[CH:24][C:19]=4[O:18][CH2:17][CH2:16][NH:14][CH3:13])=[O:27])[CH2:41][C:31]3=2)[CH:36]=1
Reactant: Cc1nc2c3c(nn2cc1Cl)CN(C(=O)c1ccc(F)cc1OCCN(C)C(=O)OC(C)(C)C)C3
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CNCCOc1cc(F)ccc1C(=O)N1Cc2nn3cc(Cl)c(C)nc3c2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.9 %

Procedure:
A 4M solution of HCl in 1,4-dioxane (456 μL; 1.83 mmol; 10 eq.) was added to solution of {2-[2-(6-chloro-5-methyl-1H,3H-2,4,7a,8-tetraaza-cyclopenta[a]indene-2-carbonyl)-5-fluoro-phenoxy]-ethyl}-methyl-carbamic acid tert-butyl ester (92 mg; 0.18 mmol; 1 eq.) in DCM (2 mL) and the reaction mixture was stirred at room temperature for 30 minutes then concentrated in vacuo. Purification by mass directed preparative HPLC afforded the title compound (15 mg, 19%) as a yellow solid. 1H NMR (DMSO-d6) δ 9.55-9.45 (d, J=5.0 Hz, 1H), 9.01-8.78 (s, 2H), 7.43 (ddd, J=8.4, 6.7, 4.5 Hz, 1H), 7.19 (dd, J=11.1, 2.3 Hz, 1H), 6.95 (td, J=8.5, 2.3 Hz, 1H), 4.82 (d, J=5.8 Hz, 2H), 4.58 (d, J=12.5 Hz, 2H), 4.36 (t, J=4.5 Hz, 2H), 3.26 (t, J=5.2 Hz, 2H), 2.60 (s, 1.5H), 2.57-2.51 (m, 4.5H). HPLC (max plot) 99.2%, Rt 2.48 min. UPLC/MS: (MS+) 404.3 ([M+H]+).
Reaction SMILES: C([BH3-])#N.[Na+].[Cl:5][C:6]1[CH:7]=[C:8]([CH:24]=[CH:25][C:26]=1[Cl:27])[CH2:9][N:10]1[C:18]2[C:13](=[CH:14][C:15]([NH2:19])=[CH:16][CH:17]=2)[CH:12]=[C:11]1[C:20]([O:22][CH3:23])=[O:21].[C:28]([O:32][CH2:33][CH3:34])(=[O:31])[CH:29]=O.C(O)(=O)C>CO>[Cl:5][C:6]1[CH:7]=[C:8]([CH:24]=[CH:25][C:26]=1[Cl:27])[CH2:9][N:10]1[C:18]2[C:13](=[CH:14][C:15]([NH:19][CH2:29][C:28]([O:32][CH2:33][CH3:34])=[O:31])=[CH:16][CH:17]=2)[CH:12]=[C:11]1[C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)c1cc2cc(N)ccc2n1Cc1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)CNc1ccc2c(c1)cc(C(=O)OC)n2Cc1ccc(Cl)c(Cl)c1
Reaction time: 0.08 h
Yield: 67 %

Procedure:
Sodium cyanoborohydride (0.2 g) was added in a single portion to methyl N-(3,4-dichlorobenzyl)-5-aminoindole-2-carboxylate (0.16 g), ethyl glyoxalate (0.2 ml of 50 wt % solution in toluene) and acetic acid (0.1 ml) in methanol (3 ml). The reaction was stirred for 5 mins then partitioned between ethyl acetate and 2M HCl. Combined organic extracts were dried (MgSO4) and concentrated to give an oil which crystallised upon trituration with i-hexane. Filtration yielded the desired end product as an off-white powder (0.136 g, 67%); NMR δ (CD3SOCD3) 1.18 (t, 3H), 3.79 (s, 3H), 3.82 (d, 2H), 4.08 (q, 2H), 5.72 (s, 2H), 6.60-7.50 (in, 7H); M/z (+) 435 (M+), 133.
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1.[CH:20]1([CH2:25][CH2:26][NH2:27])[CH2:24][CH2:23][CH2:22][CH2:21]1.[BH4-].[Na+]>CO>[CH:20]1([CH2:25][CH2:26][NH:27][CH2:18][C:16]2[CH:15]=[CH:14][C:3]([O:4][C:5]3[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=3)=[C:2]([F:1])[CH:17]=2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2F)cn1
Reactant: NCCC1CCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1ccc(Oc2ccc(CNCCC3CCCC3)cc2F)cn1
Reaction time: 8 h
Yield: 9.5 %

Procedure:
Place 5-(2-fluoro-4-formylphenoxy)pyridine-2-carboxamide (Example 403, Part B) (0.650 g, 2.50 mmol), 2-cyclopentylethylamine (0.792 g, 2.75 mmol) and 3 {acute over (Å)} molecular sieves in a vial. Add methanol (12 mL), cap and stir overnight. Add NaBH4 (slight excess) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 25 g ISCO® pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting through a 40 g ISCO® column with 0% to 10% (2.0 M NH3 in methanol) in ethyl acetate to give the title compound (0.0850 g, 10%): TOF MS ES+ 358.2 (M+H)+, HRMS calcd for C20H25N3O2F 358.1931 (M+H)+, found 358.1925, time 0.48 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18], tR=11.8 min, 94.2% purity.
Reaction SMILES: C(N(CC)CC)C.[N:8]#[C:9]Br.[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([OH:22])=[C:16]([CH:21]=1)[C:17]([O:19][CH3:20])=[O:18]>CC(C)=O>[O:22]([C:15]1[CH:14]=[CH:13][C:12]([Cl:11])=[CH:21][C:16]=1[C:17]([O:19][CH3:20])=[O:18])[C:9]#[N:8]
Reactant: COC(=O)c1cc(Cl)ccc1O
Reactant: N#CBr
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(Cl)ccc1OC#N
Temperature: -20 °C
Reaction time: 0.08 h

Procedure:
At −20° C., 20.0 g (0.198 mol) of triethylamine were added with stirring to 21.0 g (0.198 mol) of cyanogen bromide in 200 ml of acetone. After 5 min, 36.9 g (0.198 mol) of methyl 5-chloro-2-hydroxybenzoate were added, and the mixture was stirred at −20° C. for 30 min. The mixture was filtered, the filter was washed with 200 ml of acetone and the combined organic phases were concentrated under reduced pressure. This gave 34.4 g of the title compound as a yellow solid which was directly reacted further.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[Li]CCCC.[B:26](OC(C)C)([O:31]C(C)C)[O:27]C(C)C.P(=O)(O)(O)O>C1(C)C=CC=CC=1.O1CCCC1>[C:17]([O:16][C:14]([N:11]1[CH2:12][CH2:13][N:8]([C:4]2[CH:3]=[C:2]([B:26]([OH:31])[OH:27])[CH:7]=[CH:6][CH:5]=2)[CH2:9][CH2:10]1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(Br)c2)CC1
Agent: O=P(O)(O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(B(O)O)c2)CC1
Temperature: -70 °C

Procedure:
Into a 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of tert-butyl 4-(3-bromophenyl)piperazine-1-carboxylate (3.8 g, 11.14 mmol, 1.00 equiv) in toluene/tetrahydrofuran=1:1 (40 mL). This was followed by the addition of n-BuLi (4.9 mL, 2.5M/L) dropwise with stirring at −70° C. The resulting solution was stirred for 30 min at −70° C. To this was added triisopropyl borate (2.5 g, 13.30 mmol, 1.19 equiv)dropwise with stirring at −70° C. The mixture was warmed to 0° C., the reaction was then quenched by the addition of 13 mL of saturated ammonium chloride and 3.4 mL of water. Phosphoric acid (85 wt %, 1.5 g, 1.2 equiv) was added and the mixture was stirred for 30 min. The organic layer was separated and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was dissolved in 20 mL of toluene. The product was precipitated by the addition of 80 mL of heptane. The solids were washed with 20 mL of heptane and collected by filtration. This resulted in 2.9 g (85%) of 3-(4-(tert-butoxycarbonyl)piperazin-1-yl)phenylboronic acid as a white solid.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH:9]1[CH:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH2:12][N:11]([C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:10]1)C)(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH:13]2[CH:9]([NH:7][CH3:6])[CH2:10][N:11]([C:21]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[O:28])[CH2:12]2)=[CH:15][CH:16]=1
Reactant: CN(C(=O)OC(C)(C)C)C1CN(C(=O)c2ccccc2)CC1c1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC1CN(C(=O)c2ccccc2)CC1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 107 %

Procedure:
To a stirred solution of [(3RS,4SR)-1-benzoyl-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid tert-butyl ester (80 mg, 0.19 mmol) in CH2Cl2 (1 ml) was added TFA (0.2 ml). The reaction mixture was stirred at RT for 2 hours, aqueous NaHCO3 was added until pH=8 and the product was extracted with CH2Cl2. The combined organic phase were dried over Na2SO4. Concentration under vacuo gave 64 mg (95%) of the title product as a colorless oil. ES-MS m/e: 315.1 (M+H+).
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]4[N:24]([CH2:29][CH3:30])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])=[CH:16][CH:15]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:31].[NH2:32][C:33]1[CH:34]=[CH:35][C:36]([CH3:40])=[C:37]([OH:39])[CH:38]=1>C1COCC1>[OH:39][C:37]1[CH:38]=[C:33]([NH:32][CH:2]=[C:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]([C:14]4[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]5[N:24]([CH2:29][CH3:30])[N:25]=[C:26]([CH3:28])[CH:27]=5)=[O:22])=[CH:16][CH:15]=4)=[O:13])=[CH:9][CH:10]=3)[NH:5][C:4]2=[O:31])[CH:34]=[CH:35][C:36]=1[CH3:40]
Reactant: CCn1nc(C)cc1C(=O)Nc1ccc(C(=O)c2ccc3c(c2)NC(=O)C3=CO)cc1
Reactant: Cc1ccc(N)cc1O
Solvent: C1CCOC1
Product: CCn1nc(C)cc1C(=O)Nc1ccc(C(=O)c2ccc3c(c2)NC(=O)C3=CNc2ccc(C)c(O)c2)cc1
Temperature: 65 °C
Reaction time: 24 h
Yield: 40665.4 %

Procedure:
A small screw cap test tube was charged with 2-Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid [4-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 15, 100 mg, 0.240 mmol) and THF (2 mL). To the resulting solution was added 5-amino-2-methylphenol (32.5 mg, 0.1082 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature. The solid precipitate that formed was washed with ˜1 mL of i-prOH yielding 44% (55 mg, 44 mmol) of the title compound.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[N:7]=[C:8]([NH:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:9]([CH3:15])=[N:10]2)=[O:4].[C:21]([O:25][C:26]([NH:28][C:29]1([C:32](=[O:39])[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:31][CH2:30]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].C([O-])([O-])=O.[K+].[K+]>C1COCC1.CN(C=O)C.CCOC(C)=O>[C:21]([O:25][C:26]([NH:28][C:29]1([C:32]([CH:33]([CH2:2][C:3]([C:5]2[CH:14]=[CH:13][CH:12]=[C:11]3[C:6]=2[N:7]=[C:8]([NH:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:9]([CH3:15])=[N:10]3)=[O:4])[C:34]([O:36][CH2:37][CH3:38])=[O:35])=[O:39])[CH2:31][CH2:30]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]
Reactant: CCOC(=O)CC(=O)C1(NC(=O)OC(C)(C)C)CC1
Reactant: Cc1nc2cccc(C(=O)CBr)c2nc1NC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC(=O)c1cccc2nc(C)c(NC(C)(C)C)nc12)C(=O)C1(NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
At RT, a mixture of 2-bromo-1-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)ethanone (606) (1.01 g, 3.00 mmol) and ethyl 3-(1-((tert-butoxycarbonyl)amino)cyclopropyl)-3-oxopropanoate (604) (0.978 g, 3.60 mmol) in 5 mL of THF and 5 mL of DMF was treated with K2CO3 (1.04 g, 7.51 mmol). After the reaction mixture was stirred at RT for 18 h, it was diluted with 100 mL of EtOAc and filtered. The filtrate was washed with sat. NH4Cl (2×15 mL) followed by brine (10 mL), and concentrated. The crude material was purified by silica gel chromatography (25-50% EtOAc in hexanes) to afford ethyl 2-(1-((tert-butoxycarbonyl)amino)cyclopropanecarbonyl)-4-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-4-oxobutanoate as a yellow amorphous solid (324a). m/z (ESI, +ve) 527.3 (M+H)+. In a glass tube, a solution of ethyl 2-(1-((tert-butoxycarbonyl)amino)cyclopropanecarbonyl)-4-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-4-oxobutanoate as a yellow amorphous solid (324a) in 5 mL of EtOH and 2.5 mL of AcOH was treated with NH4OAc (1.39 g, 18.02 mmol). The glass tube was sealed, and heated in an oil bath at 55° C. for 8 h. The reaction mixture was concentrated to half of its volume. The residue was diluted with 150 mL of EtOAc and washed sequentially with 15 mL of water, 10 mL of 0.5 N NaOH and 10 mL of brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The crude material was purified by silica gel chromatography (25-50% EtOAc in hexanes) to provide ethyl 2-(1-((tert-butoxycarbonyl)amino)cyclopropyl)-5-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylate (1.4 g, 2.76 mmol, 92% yield) as a yellow amorphous solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.21 (1H, br.), 7.87 (1H, d, J=7.2 Hz), 7.61 (1H, dd, J=8.0, 1.4 Hz), 7.40 (1H, d, J=2.7 Hz), 7.35 (1H, t, J=7.8 Hz), 6.92 (1H, br.), 5.90 (1H, s), 4.25 (2H, q, J=7.1 Hz), 2.56 (3H, s), 1.58 (9H, s), 1.26-1.39 (14H, m), 1.13 (2H, m). m/z (ESI, +ve) 508.3 (M+H)+.
Reaction SMILES: P(=O)(O)(O)O.C([O-])([O-])=[O:7].[K+].[K+].[CH3:12][C:13]([OH:16])([CH3:15])[CH3:14].[CH3:17][C:18]([C:20]1C=CC=[CH:22][CH:21]=1)=C>O=[Os](=O)(=O)=O.O>[C:12]1([C@:13]([OH:16])([CH3:15])[CH2:14][OH:7])[CH:22]=[CH:21][CH:20]=[CH:18][CH:17]=1
Reactant: CC(C)(C)O
Reactant: O=C([O-])[O-]
Reactant: C=C(C)c1ccccc1
Agent: O=[Os](=O)(=O)=O
Agent: O=P(O)(O)O
Agent: [K+]
Solvent: O
Product: C[C@](O)(CO)c1ccccc1
Reaction time: 4 h
Yield: 94.5 %

Procedure:
The cathode compartment of a divided glass H-cell as described in Example 6.1 is charged with 40 mL of 10% phosphoric acid, and the anode compartment is charged with Na4Fe(CN)6.10H2O (3.9 g, 8.0 mmol), K2CO3 (8.3 g, 60 mmol) and t-BuOH (50 mL)/water (50 mL), the chiral ligand, PHAL-DHQD (878 mg. 0.10 mmol), OsO4 (0.196 M in toluene, 0.05 mL, 0.01 mmol) and α-methylstyrene (2.4 g, 20 mmol). The mixture is electrolyzed at 0.4 V (vs ref. Ag/AgCl) at 15° C. until about 4253 coulombs of electricity is consumed. After stirring without electricity for 4 hours, the reaction is worked up as in Example 6.I to give (R)-2-phenyl-1,2-propanediol (2.87 g, 94.5% yield and 92.6% ee).