Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2](=[CH2:7])[CH2:3][CH2:4][CH2:5][OH:6].C(N(CC)CC)C.[S:15](Cl)([CH3:18])(=[O:17])=[O:16].O>C(Cl)Cl>[CH3:18][S:15]([O:6][CH2:5][CH2:4][CH2:3][C:2]([CH3:1])=[CH2:7])(=[O:17])=[O:16]
Reactant: C=C(C)CCCO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: C=C(C)CCCOS(C)(=O)=O

Procedure:
4-Methyl-4-penten-1-ol (10.0 g, 0.10 mmol) is placed in 100 ml dry methylene chloride and cooled, with stirring and under nitrogen, in an acetone/dry ice bath to 0°. Triethylamine (42 ml, 0.30 mmol) is added all at once, followed by mesyl chloride (12 ml, 0.16 mmol) over a 15 min period. The mixture is stirred at 0° for 2 hr and then water is added, followed by stirring for 5 min. The mixture is worked up by extraction with water and the layers are separated. The aqueous phase is extracted with methylene chloride (2×); the organic layers are combined and washed with sat. NaHCO3, 2 N HCl, water and brine, dried over MgSO4, filtered and evaporated (not to dryness), giving 4-methyl-4-pentenyl methanesulfonate.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[CH3:22])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6].[CH3:23][O:24][C:25]1[N:30]=[CH:29][C:28](B(O)O)=[CH:27][N:26]=1.C([O-])([O-])=O.[Na+].[Na+].O>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.COCCOC.CCO>[CH3:23][O:24][C:25]1[N:30]=[CH:29][C:28]([C:2]2[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=2)=[O:6])=[CH:27][N:26]=1
Reactant: COc1ncc(B(O)O)cn1
Reactant: Cc1ccc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Solvent: O
Product: COc1ncc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)ccc2C)cn1

Procedure:
3-Iodo-4-methyl-N-(4-(trifluoromethoxy)phenyl)benzamide (Stage 13.1, 84 mg, 0.2 mmol), 2-methoxypyrimidin-5-ylboronic acid (61.6 mg, 0.4 mmol), Na2CO3 (63.6 mg, 0.600 mmol), Pd(PPh3)2Cl2 (7.02 mg, 10.00 μmol), water (200 μL), EtOH (133 μL) and DME (1 mL) were added to a vial, which was sealed, evacuated/purged with argon and subjected to MW irradiation at 125° C. for 20 min The RM was diluted with THF (1 mL) and stirred with Si-Thiol (69.4 mg, 0.100 mmol) for a 2 h. The filtrate was evaporated to dryness under reduced pressure to give the crude product which was purified by flash chromatography (Silica gel column, 4 g, DCM/MeOH+1% NH4OH, gradient from 1% to 15% MeOH+1% NH4OH) to afford the title compound as a beige solid. UPLC-MS (Condition 1) tR=2.89 min, m/z=404.1 [M+H]+, m/z=402.2 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.35 (s, 3H) 3.99 (s, 3H) 7.37 (d, J=8.6 Hz, 2H) 7.52 (d, J=8.1 Hz, 1H) 7.88 (d, J=9.3 Hz, 2H), 7.90 (br. s, br. s, 1H) 7.93 (dd, 1H) 8.74 (s, 2H) 10.36 (s, 1H).
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)C=C[CH:4]=[CH:3][CH:2]=1.[NH:21]1C=CC=C1B(O)O>>[NH:21]1[CH:4]=[CH:3][CH:2]=[C:1]1[C:7]1[NH:8][C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=1[C:14]=23
Reactant: O=C1NCCc2c(-c3ccccc3)[nH]c3cccc1c23
Reactant: OB(O)c1ccc[nH]1
Product: O=C1NCCc2c(-c3ccc[nH]3)[nH]c3cccc1c23

Procedure:
In a manner similar to that described for Compound 12, the tricyclic bromide (300 mg, 1.13 mmol) and 1-)-t-butoxycarbonyl)pyrrole-2-boronic acid (263 mg, 1.24 mmol) were coupled with concomitant removal of the BOC group to yield 2-(1H-pyrrol-2-yl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one, 81 mg (28% as a greenish grey solid: m.p.>400° C. (dec); 1H NMR (300 MHz, d6-DMSO) δ 3.02 (m, 2H), 3.42 (m, 2H), 6.22 (m, 1H), 6.44 (m, 1H), 6.97 (m, 1H), 7.14 (t, J=7.5 Hz, 1H), 7.49 (dd, J=8.1, 0.9 Hz, 1H), 7.64 (dd, J=7.5, 0.6 Hz, 1H), 7.98 (br t, 1H), 11.01 (br s, 1H), 11.13 (br s, 1H). MS (electrospray, MH+) 252. Anal. (C15H13N3O.0.4 H2O) C, H, N.
Reaction SMILES: CCN(C(C)C)C(C)C.[NH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[C:11]1[C:19]([OH:21])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:44][CH2:45][C:46]([N:48]1[CH2:53][CH2:52][N:51]([C:54](=[O:65])[C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=2[C:61]([F:64])([F:63])[F:62])[CH2:50][CH2:49]1)=[O:47]>CN(C=O)C.O>[O:47]=[C:46]([N:48]1[CH2:49][CH2:50][N:51]([C:54](=[O:65])[C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=2[C:61]([F:64])([F:63])[F:62])[CH2:52][CH2:53]1)[CH2:45][NH:44][C:19]([C:11]1[NH:10][C:18]2[C:13]([CH:12]=1)=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:21]
Reactant: O=C(O)c1cc2ccccc2[nH]1
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 66 %

Procedure:
DIPEA (193 mg, 0.25 mL, 1.11 mmol) was added to a stirred solution of 1H-Indole-2-carboxylic acid (60 mg, 0.37 mmol) in DMF (2 mL). HOBT (60 mg, 0.44 mmol) and EDCI (85 mg, 0.44 mmol) were then added at room temperature. After 2 minutes, 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone hydrochloride salt (157 mg, 0.44 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to afford 112 mg (65.88% yield) of 1H-indole-2-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide. LCMS Purity: 94.15%. 1H NMR (DMSO-d6): δ 11.6 (s, 1H), 8.6 (s, 1H), 7.9-7.4 (m, 6H), 7.2 (m, 2H), 7.1-7.0 (m, 1H), 4.3-4.1 (m, 2H), 3.8-3.4 (m, 6H), 3.2-3.0 (m, 2H).
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[CH:5]=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=1.[CH2:13]([O:15][C:16](=[O:29])[CH:17]=[C:18]1[CH2:21][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:19]1)[CH3:14]>O1CCOCC1.[Cl-].[Na+].O>[Br:3][C:4]1[CH:5]=[C:6]([C:18]2([CH2:17][C:16]([O:15][CH2:13][CH3:14])=[O:29])[CH2:19][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21]2)[CH:7]=[CH:8][CH:9]=1
Reactant: OB(O)c1cccc(Br)c1
Reactant: CCOC(=O)C=C1CN(C(=O)OC(C)(C)C)C1
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)CC1(c2cccc(Br)c2)CN(C(=O)OC(C)(C)C)C1
Yield: 79 %

Procedure:
To a solution of [RhCl(COD)]2 (63 mg, 0.031 mmol) in dioxane (10 mL) was added aqueous KOH (1.5M, 8.29 mmol, 5.53 mL), followed by (3-bromophenyl)boronic acid (1.67 g, 8.29 mmol). Then a solution of the tert-butyl 3-(2-ethoxy-2-oxoethylidene)azetidine-1-carboxylate in dioxane (7.5 mL) was added. The reaction mixture was microwaved at 100° C. for 5 min at 300 W. Brine was added and the mixture was extracted twice with ethyl acetate. The combined organics were washed with brine and then dried (MgSO4), filtered and concentrated. Purification by column chromatography (4/1 Pet ether/ethyl acetate) gave the Michael adduct (1.31 g, 79%) as a light yellow oil.
Reaction SMILES: [C:1]([O:22][CH:23]1[CH2:28][C:27]([CH3:30])([CH3:29])[NH:26][C:25]([CH3:32])([CH3:31])[CH2:24]1)(=[O:21])[C:2]1[C:3](=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:4]([O:6][CH:7]1[CH2:12][C:11]([CH3:14])([CH3:13])[NH:10][C:9]([CH3:16])([CH3:15])[CH2:8]1)=[O:5].[C:33]([O:37]O)([CH3:36])([CH3:35])C>[Mo](=O)(=O)=O.C1CCCCC1>[C:4]([O:6][CH:7]1[CH2:8][C:9]([CH3:16])([CH3:15])[N:10]([O:37][CH:33]2[CH2:36][CH2:17][CH2:3][CH2:4][CH2:35]2)[C:11]([CH3:13])([CH3:14])[CH2:12]1)(=[O:5])[C:3]1[C:2](=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:1]([O:22][CH:23]1[CH2:24][C:25]([CH3:32])([CH3:31])[N:26]([O:37][CH:33]2[CH2:36][CH2:20][CH2:2][CH2:1][CH2:35]2)[C:27]([CH3:30])([CH3:29])[CH2:28]1)=[O:21]
Reactant: CC(C)(C)OO
Reactant: CC1(C)CC(OC(=O)c2ccccc2C(=O)OC2CC(C)(C)NC(C)(C)C2)CC(C)(C)N1
Agent: O=[Mo](=O)=O
Solvent: C1CCCCC1
Product: CC1(C)CC(OC(=O)c2ccccc2C(=O)OC2CC(C)(C)N(OC3CCCCC3)C(C)(C)C2)CC(C)(C)N1OC1CCCCC1
Temperature: 81 °C
Reaction time: 1.25 h
Yield: 143.3 %

Procedure:
A mixture of 30.0 grams (67.5 mmol) of di-(2,2,6,6-tetramethylpiperidin-4-yl) phthalate, 27.5 grams (214 mmol) of 70% aqueous tert-butyl hydroperoxide, 2.0 grams of molybdenum trioxide and 200 ml of cyclohexane is heated to reflux at 81° C. Water is collected in a Dean-Stark trap. After 75 minutes, the reaction mixture is red. Another portion of tert-butyl hydroperoxide (42.5 grams of 70% aqueous solution, 330 mmol) is added over 30 minutes. After additional water is collected in the trap, the reaction mixture is transferred to a Fischer-Porter bottle and heated at 140° C. for 4.5 hours. The nearly colorless reaction mixture is treated with 6.9 grams (69 mmol) of 90% aqueous tert-butyl hydroperoxide and heated at 140° C. for 90 minutes to remove the last traces of pink color. The reaction mixture is cooled, filtered and stirred with a solution of 43 grams of sodium sulfite in 530 ml of water for 2 hours. Methylene chloride (600 ml) is added and the organic layer is separated, dried over anhydrous magnesium sulfate and concentrated to a crude solid. Purification (Waters Prep. 500A HPLC, 25:1 heptane:ethyl acetate) affords 31.0 grams (72% yield) of the title compound as a white solid, melting at 149°-151° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].Cl.[CH3:7][O:8][C:9](=[O:15])[C@@H:10]1[CH2:14][CH2:13][CH2:12][NH:11]1.C(N(CC)CC)C>C(Cl)Cl.C(OCC)(=O)C>[CH3:1][S:2]([N:11]1[CH2:12][CH2:13][CH2:14][CH:10]1[C:9]([O:8][CH3:7])=[O:15])(=[O:4])=[O:3]
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)C1CCCN1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.6 %

Procedure:
Methanesulfonyl chloride (2.3 mL, 30 mmol) was slowly added to a stirring solution of D/L-proline methyl ester hydrochloride (5.0 g, 30.2 mmol) and triethylamine (8.4 mL, 60 mmol) in anhydrous methylene chloride (75 mL). The reaction was stirred overnight at ambient temperature and then diluted with ethyl acetate. The organic layer was successively washed with water, 1N aqueous hydrochloric acid twice, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride solutions, dried (anhydrous sodium sulfate), and filtered. The solution was concentrated under reduced pressure to give the desired product as a tan liquid (4.45 g, 72%). 1H NMR (CDCl3, 300 MHz) δ 4.53-4.49 (dd, 1H, J=8.7, 3.6 Hz), 3.75 (s, 3H), 3.57-3.54 (m, 1H), 3.52-3.42 (m, 1H), 3.01 (s, 3H), 2.32-2.22 (m, 1H), 2.11-1.98 (m, 3H).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[C:4]#[C:5][CH3:6].Cl[C:9]1[CH:14]=[C:13]([CH:15]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)[CH3:16])[N:12]=[CH:11][N:10]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:3]([O:7][C:9]1[CH:14]=[C:13]([CH:15]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)[CH3:16])[N:12]=[CH:11][N:10]=1)[C:4]#[C:5][CH3:6]
Reactant: CC(c1cccc(F)c1)c1cc(Cl)ncn1
Reactant: CC#CCO
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC#CCOc1cc(C(C)c2cccc(F)c2)ncn1
Temperature: 25 °C
Yield: 91.9 %

Procedure:
In 2 ml of tetrahydrofuran was suspended 0.05 g of sodium hydride (60% in oil), to which 0.6 ml of a tetrahydrofuran solution containing 0.07 g of 2-butyn-1-ol was slowly added dropwise with stirring at room temperature. The mixture was stirred at room temperature for 20 minutes, to which 0.6 ml of a tetrahydrofuran solution containing 0.2 g of 4-chloro-6-(1-(3-fluorophenyl)ethyl)pyrimidine was slowly added dropwise at room temperature, followed by stirring for 4 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution and extracted three times with chloroform. The chloroform layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.21 g of 4-(2-butynyloxy)-6-(1-(3-fluorophenyl)ethyl)pyrimidine (the present compound (116)).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:15]([OH:17])=O)[CH2:10][O:11][CH2:12][CH:13]=[CH2:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:18][O:19][C:20](=[O:33])[C@H:21]([CH:30]([CH3:32])[CH3:31])[NH:22][C:23](=[O:29])[C@H:24]([CH:26]([CH3:28])[CH3:27])[NH2:25].FC(F)(F)C(O)=O.COC(=O)[C@H](C(C)C)NC(=O)[C@H](C(C)C)N.C(N(CC)C(C)C)(C)C.C1C=C2N=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[CH3:18][O:19][C:20](=[O:33])[C@H:21]([CH:30]([CH3:32])[CH3:31])[NH:22][C:23](=[O:29])[C@H:24]([CH:26]([CH3:27])[CH3:28])[NH:25][C:15](=[O:17])[C@H:9]([CH2:10][O:11][CH2:12][CH:13]=[CH2:14])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7]
Reactant: C=CCOC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)[C@@H](NC(=O)[C@@H](N)C(C)C)C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: C=CCOC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)N[C@H](C(=O)OC)C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 22 h
Yield: 94 %

Procedure:
N-tert-butoxycarbonyl O-allyl L-serine (3) (11.31 g, 46.10 mmol) was dissolved in 40 mL DMF. A solution of L-valyl L-valine methyl ester.trifluoroacetate 6 (15.87 g, 46.09 mmol) and N,N-diisopropylethyl amine (5.96 g, 46.1 mmol) in 60 mL DMF was added in one portion and the solution cooled to 0° C. (icebath). HOBt hydrate (7.06 g, 46.1 mmol) was added. Finally, EDC hydrochloride (9.72 g, 50.7 mmol) was added together with 30 mL DMF. The reaction mixture was stirred for 22 hours before the solvent was evaporated. The residue was taken up in 250 mL EtOAc and washed with 2 M aqueous H2SO4 (3×100 mL), 7.5% (w/w) aqueous K2CO3 (3×100 mL) and saturated brine (100 mL). The solution was dried with anhydrous MgSO4 and the solvent evaporated affording an off-white solid (19.82 g, 94%); δH (300 MHz; d6-DMSO) 8.18 (1H, d, J 8, NH(Valx), 7.62 (1H, d, J 9, NH(Valy)), 7.03 (1H, d, J 8, NH(Ser(All))), 5.83 (1H, ddt, J 5, 10 and 17, CH═CH2), 5.23 (1H, ddt, J 1, 3 and 17, CH═CHH), 5.11 (1H, ddt, J 1, 3 and 10, CH═CHH), 4.34 (1H, dd, J 7 and 9, CαH(Valy)), 4.22-4.17 (1H, m, CαH(Ser(All))), 4.13 (1H, dd, J 6 and 8, CαH(Valx)), 3.92 (2H, dt, J 1 and 5, CH2CH═CH2), 3.61 (3H, s, OCH3), 3.53-3.49 (2H, m, CH2), 2.11-1.86 (2H, m, CH(CH3)2), 1.38 (9H, s, (CH3)3), 0.90-0.79 (12H, m, CH3); δC (75 MHz; d6-DMSO) 171.6, 171.0, 169.5, 155.1, 134.9, 116.3, 78.2, 70.9, 69.5, 57.4, 56.8, 54.5, 51.4, 31.1, 29.5, 28.0, 18.9, 18.8, 18.1, 17.7; m/z (ESI) 480.2666 ([M+Na]+; C22H39N3O7Na requires 480.2685)
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH:15]=[C:14]([C:19]2[NH:23][C:22]([C@@H:24]4[CH2:28][CH2:27][CH2:26][N:25]4[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[N:21][CH:20]=2)[CH:13]=[CH:12]3)O1.Br[C:38]1[CH:43]=[CH:42][C:41]([C:44]2[NH:48][C:47]([C@@H:49]3[CH2:57][C:52]4([O:56][CH2:55][CH2:54][O:53]4)[CH2:51][N:50]3[C:58](=[O:68])[C@@H:59]([NH:63][C:64](=[O:67])[O:65][CH3:66])[CH:60]([CH3:62])[CH3:61])=[N:46][CH:45]=2)=[CH:40][CH:39]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:66][O:65][C:64]([NH:63][C@@H:59]([CH:60]([CH3:62])[CH3:61])[C:58]([N:50]1[C@H:49]([C:47]2[NH:48][C:44]([C:41]3[CH:40]=[CH:39][C:38]([C:9]4[CH:10]=[C:11]5[C:12](=[CH:17][CH:18]=4)[CH:13]=[C:14]([C:19]4[NH:23][C:22]([C@@H:24]6[CH2:28][CH2:27][CH2:26][N:25]6[C:29]([O:31][C:32]([CH3:34])([CH3:35])[CH3:33])=[O:30])=[N:21][CH:20]=4)[CH:15]=[CH:16]5)=[CH:43][CH:42]=3)=[CH:45][N:46]=2)[CH2:57][C:52]2([O:56][CH2:55][CH2:54][O:53]2)[CH2:51]1)=[O:68])=[O:67]
Reactant: COC(=O)N[C@H](C(=O)N1CC2(C[C@H]1c1ncc(-c3ccc(Br)cc3)[nH]1)OCCO2)C(C)C
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2ccc3cc(B4OC(C)(C)C(C)(C)O4)ccc3c2)[nH]1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)N[C@H](C(=O)N1CC2(C[C@H]1c1ncc(-c3ccc(-c4ccc5cc(-c6cnc([C@@H]7CCCN7C(=O)OC(C)(C)C)[nH]6)ccc5c4)cc3)[nH]1)OCCO2)C(C)C
Temperature: 110 °C

Procedure:
(S)-tert-butyl 2-(5-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (150 mg, 0.296 mmol) and methyl (S)-1-((S)-8-(5-(4-bromophenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-3-methyl-1-oxobutan-2-ylcarbamate (174 mg, 0.355 mmol) were weighed out in a microwave vessel and dissolved in 1,4-dioxane (3 mL), followed by 2M potassium carbonate (444 uL, 0.888 mmol) and Pd(dppf)Cl2 (21 mg, 0.03 mmol). The mixture was sonicated for 2 minutes and then bubbled with nitrogen gas for 3 min to degas. The vessel was sealed and the content was heated in microwave at 110° C. for 30 min. The crude reaction mixture was then diluted with EtOAc and washed twice with brine and saturated NaHCO3 and once with brine again and dried over MgSO4. The crude solution was then filtered and concentrated down. (233 mg, 99%).
Reaction SMILES: C([O:3][C:4](=O)[C:5]([OH:23])([C:19]([F:22])([F:21])[F:20])[CH2:6][C:7]([C:10]1[CH:15]=[C:14]([Br:16])[CH:13]=[CH:12][C:11]=1[O:17][CH3:18])([CH3:9])[CH3:8])C.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(=O)(O)[O-].[Na+]>C(OCC)C>[Br:16][C:14]1[CH:13]=[CH:12][C:11]([O:17][CH3:18])=[C:10]([C:7]([CH3:9])([CH3:8])[CH2:6][C:5]([OH:23])([C:19]([F:22])([F:21])[F:20])[CH2:4][OH:3])[CH:15]=1
Reactant: CCOC(=O)C(O)(CC(C)(C)c1cc(Br)ccc1OC)C(F)(F)F
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: COc1ccc(Br)cc1C(C)(C)CC(O)(CO)C(F)(F)F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3 g (7.25 mmol) of 4-(5-bromo-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanoic acid ethyl ester is dissolved in 120 ml of diethyl ether, and the reaction mixture is cooled to 0° C. 426.5 mg (10.89 mmol) of lithium aluminum hydride is added in portions. After two hours of stirring at room temperature, starting material is no longer present. The batch is mixed with saturated sodium bicarbonate solution while being cooled in an ice bath, the precipitate is suctioned off, and it is washed with diethyl ether. After spinning-in, the residue is chromatographed on a Flashmaster. In addition to 540.5 mg of 4-(5-bromo-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal, 1.14 g of the desired alcohol (which, however, also contains the Desbrom compound) is isolated.
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][C:10](=O)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.C1C=[N+:30]([C@@H]2O[C@H](COP(OP(OC[C@H]3O[C@@H](N4C5N=CN=C(N)C=5N=C4)[C@H](O)[C@@H]3O)(O)=O)(O)=O)[C@@H](O)[C@H]2O)C=C(C(N)=O)C=1.N[C@@H](C(O)=O)C.CC1N=CC(COP(O)(O)=O)=C(C=O)C=1O.[OH-].[Na+]>>[C:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([NH2:30])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Agent: C[C@@H](N)C(=O)O
Agent: Cc1ncc(COP(=O)(O)O)c(C=O)c1O
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: CC(C)(C)OC(=O)N1CC[C@@H](N)C1

Procedure:
To a flask containing 0.5 g of a substrate N-Boc-3-pyrrolidinone, 0.73 g of D-glucose, 4 mg of NAD+, 1.44 g of D-alanine, and 3.3 mg of pyridoxal phosphate, a culture fluid of the recombinant E. coli HB101 (pNTASPAG), obtained in Example 11, which expresses TAS, PALDH, and GDH was added so that total volume was 25 ml. The resultant product was stirred at 30° C. while being adjusted to a pH of 6.8 by drippage of 5 N aqueous solution of sodium hydroxide. After nine hours in reaction, 0.25 g of N-Boc-3-pyrrolidinone, 0.37 g of D-glucose, 0.37 g of D-alanine, and 3 mg of pyridoxal phosphate were added.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:30]=[CH:29][C:8]([CH2:9][N:10]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([O:27][CH3:28])=[O:26])=[CH:21][CH:20]=2)[C:11](=[O:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]Br)=[CH:7][CH:6]=1)=[O:4].[CH2:31]([O:41][C:42]1[CH:43]=[C:44]([OH:59])[CH:45]=[C:46]([O:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])[CH:47]=1)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40].C([O-])([O-])=O.[K+].[K+]>C1(=O)CCCCC1>[CH3:1][O:2][C:3]([C:5]1[CH:30]=[CH:29][C:8]([CH2:9][N:10]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([O:27][CH3:28])=[O:26])=[CH:21][CH:20]=2)[C:11](=[O:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:59][C:44]2[CH:45]=[C:46]([O:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])[CH:47]=[C:42]([O:41][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH:43]=2)=[CH:7][CH:6]=1)=[O:4]
Reactant: CCCCCCCCCCOc1cc(O)cc(OCCCCCCCCCC)c1
Reactant: COC(=O)c1ccc(CN(C(=O)CCCCCBr)c2ccc(C(=O)OC)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C1CCCCC1
Product: CCCCCCCCCCOc1cc(OCCCCCCCCCC)cc(OCCCCCC(=O)N(Cc2ccc(C(=O)OC)cc2)c2ccc(C(=O)OC)cc2)c1
Yield: 84.7 %

Procedure:
A mixture of compound 19b (540 mg, 1.13 mmol), phenol 9 (461 mg, 1.13 mmol), K2CO3 (392 mg, 2.83 mmol), and a catalytic amount of KI in cyclohexanone (6.50 ml) is reacted in analogy to the already described reaction instructions for the synthesis of compound 20a. The subsequent purification through column chromatography (silica gel, ethyl acetate/petroleum ether 1:2) produced 768 mg (85%) of compound 20b as colorless oil. IR (film) 2900, 2830, 1710, 1650, 1590 cm−1; 1H-NMR (CDCl3) δ 8.00 (d, 8.6 Hz, 2H), 7.94 (d, 8.4 Hz, 2H), 7.25 (d, 8.4 Hz, 2H), 7.05 (d, 8.6 Hz, 2H), 6.05 (t, 1.9 Hz, 1H), 6.02 (d, 1.9 Hz, 2H), 4.95 (s, 2H), 3.92 (s, 3H), 3.91-3.82 superimposed signals (3.90, s, 3H and m, 6H), 2.12 (t, 7.4 Hz, 2H), 1.80-1.61 (m, 8H), 1.47-1.20 (m, 30H), 0.88 (t, 6.7 Hz, 6H); MS (FD) m/z 802 (M+). Anal. calc. for C49H71NO8: C, 73.37; H, 8.92; N, 1.75. Found C, 73.25; H, 8.78; N, 1.87.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].[N:10]([O-])=O.[Na+].[Sn](Cl)Cl>Cl.O>[F:1][C:2]1[CH:3]=[C:4]([NH:5][NH2:10])[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: Nc1ccc(F)c(F)c1
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: NNc1ccc(F)c(F)c1
Temperature: 10 °C
Reaction time: 2 h
Yield: 56.3 %

Procedure:
A stirred mixture of 3,4-difluoroaniline (12.9 g, 0.1 mol) in concentrated hydrochloric acid (60 mL) was chilled to 10° C. with an ice/methanol bath. A solution of sodium nitrite (6.9 g, 0.1 mol) in water (30 mL) was added at a rate which maintained the temperature of the reaction mixture below 10° C. After stirring for 2 hours, the reaction mixture was cooled to 0° C. and a solution of tin(II) chloride. (56.88 g, 0.3 mol) in concentrated hydrochloric acid (50 mL) was added dropwise with vigorous stirring. Additional concentrated hydrochloric acid (150 mL) was added to the reaction mixture and stirring was continued for 2 hours. The reaction mixture was filtered to collect the precipitated hydrochloride salt of the title compound. This precipitate was dissolved in water (75 mL) and the resulting solution was basified with 50% aqueous sodium hydroxide and extracted with ethyl acetate. The organic extracts were dried (Na2SO4) and filtered. The filtrate was concentrated in vacuo to provide the title intermediate as a brown oil (8.11 g, 57.4%).