Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:12])[CH2:7]2.[Cl:13][C:14]1[C:15]([N+:25]([O-:27])=[O:26])=[CH:16][C:17]([O:23][CH3:24])=[C:18]([CH:22]=1)[C:19](O)=[O:20]>>[CH3:12][N:6]1[CH2:5][CH2:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[NH:1][C:19](=[O:20])[C:18]2[CH:22]=[C:14]([Cl:13])[C:15]([N+:25]([O-:27])=[O:26])=[CH:16][C:17]=2[O:23][CH3:24])[CH2:7]1
Reactant: CN1CCc2c(N)cccc2C1
Reactant: COc1cc([N+](=O)[O-])c(Cl)cc1C(=O)O
Product: COc1cc([N+](=O)[O-])c(Cl)cc1C(=O)Nc1cccc2c1CCN(C)C2

Procedure:
The title compound was prepared in an analogous manner to Example 1 from 5-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline and 5-chloro-2-methoxy-4-nitrobenzoic acid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:15]#[N:16])([CH3:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CS(C)=[O:19].[OH-].[Na+].OO>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:15](=[O:19])[NH2:16])([CH3:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(C)=O
Reactant: CC1(C#N)CCN(C(=O)OC(C)(C)C)CC1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(C)(C(N)=O)CC1
Temperature: 50 °C

Procedure:
To a solution of 4-cyano-4-methyl-piperidine-1-carboxylic acid tert-butyl ester (2.24 g, 10 mmol) in methanol (25 mL) was added DMSO (1mL), aqueous 1N NaOH (12mL, 12 mmol) and H2O2 (4 mL) at room temperature. The mixture was heated at 50° C. for 3 hours. After cooling to room temperature, the mixture was partitioned between EtOAc and H2O. The organic layer was washed successively with H2O and brine. After drying (Na2SO4), the solvent was removed to afford the desired product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:15](O)=[O:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.[N:31]1([O:40][P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.Cl.NO.C(N(CC)CC)C>N1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:15]([NH:31][OH:40])=[O:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)C(c1ccccc1)c1ccc(-c2ccc(F)cc2)cc1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: NO
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: O=C(NO)C(c1ccccc1)c1ccc(-c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.9 %

Procedure:
To a solution of 13 (40 mg, 0.14 mmol), BOP (58 mg, 0.13 mmol), and hydroxylamine hydrochloride (9 mg, 0.13 mmol) in pyridine (5 mL) was added triethylamine (0.055 mL, 0.39 mmol) and the reaction mixture was stirred at room temperature for 2 h. The solvents were removed under vacuum and the crude was dissolved in ethyl acetate. The organic layer was washed with water, dried over Na2SO4, filtered and concentrated. The residue was purified via HPLC (Gilson) reverse-phase column with a gradient of methanol (20-75%) in water to afford compound 14 as a white solid (20 mg, 48%). 1H NMR (CD3OD-d4) δ (ppm): 7.62-7.57 (m, 2H), 7.53 (d, J=8.2 Hz, 2H), 7.40-7.22 (m, 7H), 7.14 (t, J=8.8 Hz, 2H), 4.82 (s, 1H). LRMS (ESI): (calc.) 321.1 (found) 320.4 (MH)−.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:12]2[C:13]3[NH:14][C:15]4[CH:16]=[CH:17][C:18]([O:23][CH3:24])=[CH:19][C:20]=4[C:21]=3[O:22][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl.Cl[CH2:31][C:32]1[CH:45]=[CH:44][C:35]([O:36][CH2:37][CH2:38][N:39]([CH2:42][CH3:43])[CH2:40][CH3:41])=[CH:34][CH:33]=1>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:12]2[C:13]3[N:14]([CH2:31][C:32]4[CH:45]=[CH:44][C:35]([O:36][CH2:37][CH2:38][N:39]([CH2:42][CH3:43])[CH2:40][CH3:41])=[CH:34][CH:33]=4)[C:15]4[CH:16]=[CH:17][C:18]([O:23][CH3:24])=[CH:19][C:20]=4[C:21]=3[O:22][C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2[nH]c3c4ccc(OCc5ccccc5)cc4oc3c2c1
Reactant: CCN(CC)CCOc1ccc(CCl)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CC)CCOc1ccc(Cn2c3ccc(OC)cc3c3oc4cc(OCc5ccccc5)ccc4c32)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 7-benzyloxy-3-methoxy-10H-benzo[4,5]furo[3,2-b]indole (102 mg, 0.297 mmol) in DMF (5 mL) was added NaH (37 mg, 60% in mineral oil, 3.0 eq.) followed by [2-(4-chloromethyl-phenoxy)-ethyl]-diethyl-amine hydrochloride salt (99 mg, 0.356 mmol) at 0° C. The mixture was stirred at 0° C. for 30 minutes, warmed to 25° C., and quenched by NH4Cl (solid). EtOAc and water were then added to the mixture. The reaction mixture was then partitioned between EtOAc and water. The aqueous layer was extracted three times with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to yield crude material. The crude material was purified by silica gel (EtOAc to CH2Cl2: MeOH 5:1) to yield the title compound as a brown solid.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[N:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][N:24]([C:27]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[O:28])[CH2:23][CH2:22]2)=[CH:17][CH:16]=1.C(N(CC)CC)C>ClCCl>[F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:32]2[CH2:31][CH2:30][N:29]([C:27]([N:24]3[CH2:25][CH2:26][N:21]([C:18]4[CH:19]=[CH:20][N:15]=[CH:16][CH:17]=4)[CH2:22][CH2:23]3)=[O:28])[CH2:34][CH2:33]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: O=C(N1CCNCC1)N1CCN(c2ccncc2)CC1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(N1CCN(c2ccncc2)CC1)N1CCN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Temperature: 20 °C
Reaction time: 2 h
Yield: 59.9 %

Procedure:
A solution of 4-trifluoromethylphenylsulphonyl chloride (6.62 g) in dichloromethane (5 mL) was added dropwise over 10 minutes to a stirred solution of 1-[1-(4-pyridyl)piperazin-4-ylcarbonyl]piperazine (5.7 g) (prepared as in Example 1) in dichloromethane (50 mL) containing triethylamine (6 mL) at 20° C. The reaction mixture was stirred for 2 hours at 20° C. The organic phase was washed with water (3×100 mL) and saturated brine solution (2×100 mL) dried and evaporated. The residue was purified by chromatography on silica gel, eluting with a mixture of dichloromethane: methanol (95:5) to give, as a sandy-coloured solid, 1-(4-trifluoromethylphenylsulphonyl)-4-[1-(4-pyridyl)piperazin-4-ylcarbonyl]piperazine (6.0 g): NMR (CDCl3): 3.08(t, 4H), 3.30-3.40 (m, 8H), 3.40-3.45(t, 4H), 6.63(d, 2H), 7.82(d, 2H), 7.90(d, 2H), 8.30(d, 2H); EI-MS m/z 484(M+H).
Reaction SMILES: [F:1][C:2]1[C:3]([F:27])=[C:4]2[O:9][CH2:8][C:7]3([CH2:12][CH2:11][CH2:10]3)[N:6]3[CH:13]=[C:14]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:15](=[O:21])[C:16]([C:17]=1[N+:18]([O-])=O)=[C:5]23.[H][H]>CN(C=O)C.[Pd]>[NH2:18][C:17]1[C:16]2[C:15](=[O:21])[C:14]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:13][N:6]3[C:7]4([CH2:12][CH2:11][CH2:10]4)[CH2:8][O:9][C:4]([C:5]=23)=[C:3]([F:27])[C:2]=1[F:1]
Reactant: [H][H]
Reactant: CCOC(=O)c1cn2c3c(c(F)c(F)c([N+](=O)[O-])c3c1=O)OCC21CCC1
Agent: [Pd]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn2c3c(c(F)c(F)c(N)c3c1=O)OCC21CCC1
Reaction time: 1 h
Yield: 87.3 %

Procedure:
A solution of ethyl 9′,10′-difluoro-8′-nitro-7′-oxospiro[cyclobutane-1,3′(2′H)-[7H]pyrido[1,2,3-de][1,4]benzoxazine]-6′-carboxylate (580 mg, 1.53 mmol) in DMF (30 mL) was treated with hydrogen under atmospheric pressure over 10% Pd/C (60 mg) at 50° C. for 3 hours. The catalyst was removed by filtration with Celite and the filtrate was poured into ice-water. The resulting precipitate was stirred for 1 hour and collected by filtration, washed with water and dried to yield the title compound (468 mg, 88%) as a pale yellow solid. 1H-NMR (400 MHz, DMSO-d6) δ 1.29 (3H, t, J=7.3 Hz), 1.92-2.02 (2H, m), 2.10-2.19 (2H, m), 2.61-2.69 (2H, m), 4.23 (2H, q, J=7.3 Hz), 4.39 (2H, s), 7.38 (2H, brs), 8.65 (1H, brs). ESIMS (+): 351 [M+H]+.
Reaction SMILES: [OH-].[Li+].[CH:3]1([C:9]2[C:10]3[CH:11]=[CH:12][C:13]([C:32]([O:34][CH3:35])=[O:33])=[CH:14][C:15]=3[N:16]3[CH2:22][C:21]([C:24]([O:26]C)=[O:25])([CH3:23])[CH2:20][C:19]4[CH:28]=[CH:29][CH:30]=[CH:31][C:18]=4[C:17]=23)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Cl>CO.O1CCCC1>[CH:3]1([C:9]2[C:10]3[CH:11]=[CH:12][C:13]([C:32]([O:34][CH3:35])=[O:33])=[CH:14][C:15]=3[N:16]3[CH2:22][C:21]([C:24]([OH:26])=[O:25])([CH3:23])[CH2:20][C:19]4[CH:28]=[CH:29][CH:30]=[CH:31][C:18]=4[C:17]=23)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C)(C(=O)OC)Cc1ccccc1-3
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C)(C(=O)O)Cc1ccccc1-3
Temperature: 65 °C
Yield: 33.5 %

Procedure:
Lithium hydroxide (12 mg, 0.5 mmol) was added to a solution of methyl (±)-13-cyclohexyl-6,7-dihydro-6-carbomethoxy-6-methyl-5H-indolo[2,1-a][2]benzazepine-10-carboxylate (20.0 mg, 0.045 mmol) in methanol (1.0 mL) and tetrahydrofuran (1.0 mL) in a microwave vial. The vial was sealed and the contents heated at 65° C. for 50 min in a microwave apparatus. The solution was acidified with dilute hydrochloric acid to precipitate the crude acid. The solid was collected and was purified on the Shimadzu preparative liquid chromatograph. The product containing fraction was concentrated on a Speed Vac® to leave the titled compound as a white solid (6.5 mg, 34%). ESI-MS m/z 432 (MH+) 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 1.18-1.51 (m, 6 H) 1.62-1.83 (m, 3 H) 1.89-2.14 (m, 4 H) 2.36 (d, J=13.73 Hz, 0.5 H) 2.72 (d, J=13.43 Hz, 0.5 H) 2.89-2.98 (m, 1 H) 3.01 (d, J=13.73 Hz, 0.5 H) 3.19 (d, J=14.04 Hz, 0.5 H) 3.32 (d, J=14.65 Hz, 0.5 H) 3.90 (d, J=14.60 Hz, 0.5 H) 3.94 (d, J=17.70 Hz, 3 H) 4.31 (d, J=14.65 Hz, 0.5 H) 4.89 (d, J=14.65 Hz, 0.5 H) 7.30-7.50 (m, 4 H) 7.75 (dd, J=23.04, 8.39 Hz, 1H) 7.86 (dd, J=24.87, 8.39 Hz, 1 H) 8.11 (s, 0.5 H) 8.28 (s, 0.5 H).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].[C:10]([O:14][C:15]([NH:17][C@@H:18]([CH3:40])[C:19]([NH:21][CH2:22][C:23]1[S:27][CH:26]=[C:25]([N:28]2[C:32]([C:33](O)=[O:34])=[CH:31][C:30]([C:36]([F:39])([F:38])[F:37])=[N:29]2)[CH:24]=1)=[O:20])=[O:16])([CH3:13])([CH3:12])[CH3:11].C(Cl)CCl>ClCCl.CN(C1C=CN=CC=1)C>[CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH:5][C:33]([C:32]1[N:28]([C:25]2[CH:24]=[C:23]([CH2:22][NH:21][C:19](=[O:20])[C@@H:18]([NH:17][C:15](=[O:16])[O:14][C:10]([CH3:13])([CH3:11])[CH3:12])[CH3:40])[S:27][CH:26]=2)[N:29]=[C:30]([C:36]([F:37])([F:39])[F:38])[CH:31]=1)=[O:34]
Reactant: Cc1ccccc1CN
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)NCc1cc(-n2nc(C(F)(F)F)cc2C(=O)O)cs1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: Cc1ccccc1CNC(=O)c1cc(C(F)(F)F)nn1-c1csc(CNC(=O)[C@H](C)NC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 30.9 %

Procedure:
To a solution of 2-methylbenzylamine (0.037 mL, 0.295 mmol) and compound 7 (0.091 g, 0.197 mmol) in dichloromethane (2 mL) under nitrogen was added EDC (0.075 g, 0.394 mmol) followed by DMAP (9.62 mg, 0.079 mmol). The reaction was left to stir for 16 hours at room temperature. The solvent was then removed on the rotary evaporator and the brown material was purified by silica gel chromatography with a 12M Biotage column and a gradient of 0-5% methanol in dichloromethane to give 61.3 mg of a yellow crust. The sample was further purified by preparative HPLC (C18 Aquasil 20×250 mm; 40-85% methanol in water in 45 minutes at 10 mL/min) to afford compound 15a (34.4 mg, 31%) as a white crust. LRMS (ESI): calc. 565.2; found 466.1 (MH-Boc)+, 588.2 (MNa)+.
Reaction SMILES: [N:1]([CH2:4][CH2:5][OH:6])=[N+:2]=[N-:3].CCN(CC)CC.[Br:14][C:15]([CH3:20])([CH3:19])[C:16](Br)=[O:17]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[N:1]([CH2:4][CH2:5][O:6][C:16](=[O:17])[C:15]([Br:14])([CH3:20])[CH3:19])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCCO
Reactant: CC(C)(Br)C(=O)Br
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(Br)C(=O)OCCN=[N+]=[N-]

Procedure:
2-Azidoethanol (17.40 g, 0.2 mol), freshly distilled methylene chloride (150 mL), and Et3N (21.21 g, 0.21 mol) were added into a three-neck round-bottom flask equipped with a condenser and a dropping funnel. Under nitrogen atmosphere and magnetic stirring, freshly distilled anhydrous methylene chloride (150 mL), DMAP (1.7 g, 14 mmol), and freshly distilled anhydrous Et3N (46.5 g, 0.46 mol) were sequentially added. After the flask was immersed into an ice-water bath, 2-bromoisobutyryl bromide (48.28 g, 0.21 mol) was added dropwise into the previous solution. Twenty-four hours later, the reaction mixture was washed successively with 1M HCl (3×200 mL) solution and deionized water (1×200 mL). The organic phase was dried over anhydrous MgSO4 overnight. After filter and removal of methylene chloride on a rotary evaporator, the obtained residues were distilled under reduced pressure to give a colorless viscous liquid. The yield was: 33.4 g, 70%. 1H NMR (CDCl3, δ, ppm): 4.24 (t, 2H, N3CH2CH2), 3.52 (t, 2H, N3CH2), 1.96 (s, 6H, (CH3)2Br).
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:10][C:5]2=[N:4][CH:3]=1.[S:17]1[CH:21]=[CH:20][N:19]=[CH:18]1.CC([O-])=O.[K+].CN(C)C(=O)C>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:11]1([C:9]2[CH:8]=[CH:7][N:6]3[C:2]([C:21]4[S:17][CH:18]=[N:19][CH:20]=4)=[CH:3][N:4]=[C:5]3[CH:10]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Brc1cnc2cc(-c3ccccc3)ccn12
Reactant: c1cscn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: c1ccc(-c2ccn3c(-c4cncs4)cnc3c2)cc1
Temperature: 200 °C

Procedure:
A microwave vessel was charged with 3-bromo-7-phenylimidazo[1,2-a]pyridine (6-1, 0.050 g, 0.183 mmol), thiazole (0.065 ml, 0.92 mmol), tetrakis(triphenylphosphine)palladium(0) (0.011 g, 0.10 mmol) and KOAc (0.054 g, 0.55 mmol). N,N-dimethylacetamide, 1.5 ml, was added and the reaction was placed in the microwave reactor. The reaction was heated to 200° C. for 10 min. The reaction was diluted with water, and extracted 3× with DCM. The extracts were dried over Na2SO4, filtered and concentrated. The resulting residue was dissolved in DMSO and purified by reverse phase preparative HPLC. The resulting oil was triturated with ether, resulting in the rapid crystallization to a white solid. The solid was filtered and washed with ether. Afforded the pure title compound. 1H NMR (CDCl3) δ 9.11 (s, 1H), 8.47 (s, 1H), 8.37 (d, 1H, J=7.4 Hz), 8.20 (s, 1H), 8.00 (s, 1H), 7.73 (d, 2H, J=7.3 Hz), 7.57–7.52 (m, 4H). LCMS m/z (M+1) Calc: 278.1, found 278.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([C:12](N)=[O:13])=[CH:10][CH:9]=[C:8]2[C:4]=1[C:5](/[CH:15]=[CH:16]/[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[N:6][NH:7]2.[OH-:23].[Li+].Cl>>[CH3:1][O:2][C:3]1[C:11]([C:12]([OH:23])=[O:13])=[CH:10][CH:9]=[C:8]2[C:4]=1[C:5](/[CH:15]=[CH:16]/[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[N:6][NH:7]2
Reactant: [OH-]
Reactant: COc1c(C(N)=O)ccc2[nH]nc(/C=C/c3ccccc3)c12
Agent: Cl
Agent: [Li+]
Product: COc1c(C(=O)O)ccc2[nH]nc(/C=C/c3ccccc3)c12
Temperature: 110 °C
Reaction time: 4 h

Procedure:
22 mg of 4-methoxy-3-(E)-styryl-1H-indazole-5-carboxylic acid amide was added to 3 mL of 4N lithium hydroxide aqueous solution, and stirred at 110° C. for 4 hours. After cooling on ice, the reaction solution was neutralized with 2N hydrochloric acid under ice cooling, and the precipitated crystals were collected by filtration and washed with water. This was then dried under reduced pressure, to afford 20 mg of the title compound as brown crude crystals.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C@@H:10]([OH:15])[C:11]([O:13][CH3:14])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[CH:39](OC)(OC)[O:40][CH3:41]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[C@@H:9]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C@H:10]([C:11]([O:13][CH3:14])=[O:12])[O:15][CH:39]1[O:40][CH3:41])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(OC)OC
Reactant: COC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H]1OC(OC)N(C(=O)OC(C)(C)C)[C@H]1c1ccccc1
Temperature: 20 °C
Yield: 40 %

Procedure:
A solution of 10.0 g of methyl (2R,3S)-3-t-butoxycarbonylamino-2-hydroxy-3-phenylpropionate, 0.334 g of pyridinium p-toluenesulphonate and 3.75 cm3 of trimethyl orthoformate in 70 cm3 of toluene is heated to reflux. 4 cm3 of solvent are distilled off. After cooling to a temperature in the region of 20° C. and filtration, the filtrate is concentrated to dryness under reduced pressure. The residue is taken up with 50 cm3 of hexane. The slurry obtained is filtered, rinsed and drained. 4.6 g of (4S,5R)-3-t-butoxycarbonyl-2-methoxy-4-phenyl-5-methoxycarbonyl-1,3-oxazolidine are thereby obtained in a 40% yield in the form of a mixture of diastereoisomers, the characteristics of which are as follows:
Reaction SMILES: [CH3:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[CH:8]=[C:7]([F:13])[C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:16])=O>>[CH3:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[CH:8]=[C:7]([F:13])[C:3]=1[C:4]([Cl:16])=[O:5]
Reactant: Cc1c(F)c(F)cc(F)c1C(=O)O
Reactant: O=S(Cl)Cl
Product: Cc1c(F)c(F)cc(F)c1C(=O)Cl

Procedure:
To 2-methyl-3,4,6-trifluorobenzoic acid (3.2 g) is added thionyl chloride (7 ml) and the mixture is refluxed for 1 hour. After concentrating, 2-methyl-3,4,6-trifluorobenzoyl chloride (3.3 g) is obtained.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH2:14])=[O:13])=[C:6]2[S:15]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)(=[O:17])=[O:16].B(Br)(Br)Br.CCOC(C)=O.C([O-])(O)=O.[Na+]>ClCCl>[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH2:14])=[O:13])=[C:6]2[S:15]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)(=[O:17])=[O:16]
Reactant: COc1ccc2[nH]c(C(N)=O)c(S(=O)(=O)N3CCOCC3)c2c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: NC(=O)c1[nH]c2ccc(O)cc2c1S(=O)(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a suspension of 5-methoxy-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide from Example 4 (416 mg, 1.23 mmol) in 15 mL of dichloromethane at −78° C. was added boron tribromide solution (1 M in dichloromethane, 6.13 mmol). After 10 minutes the mixture was allowed to warm to room temperature, and stir for an additional 60 hours. The reaction was poured into a mixture of EtOAc and saturated aqueous NaHCO3 solution. The organic phase was washed with water and brine, dried with Na2SO4, filtered, and concentrated in vacuo. Purification by flash chromatography through silica gel (3-10% MeOH/dichloromethane) provided the titled compound. Proton NMR for the product was consistent with the titled compound. HRMS (ES) exact mass calculated for C13H16N3O5S (M+H+). 326.0805. Found 326.0808.
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([CH2:17]C#N)[CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[C:25](=[O:28])(O)[O-:26].[Na+]>O.C(O)(=O)C>[C:1]1([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([CH2:17][C:25]([OH:26])=[O:28])[CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C([O-])O
Reactant: N#CCc1ccc2nc(-c3ccccc3)ccc2c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)Cc1ccc2nc(-c3ccccc3)ccc2c1

Procedure:
A mixture of 10 g of 2-phenyl-6-quinolineacetonitrile, 19 ml of water, 19 ml of concentrated sulphuric acid and 19 ml of glacial acetic acid is kept under reflux for 2 hours. Thereafter, ice and water are added and the pH is adjusted to 5-6 with solid sodium bicarbonate. The crystals which thereupon precipitate are filtered off and rinsed with water. Recrystallisation from methanol-ether-petroleum ether yields 2-phenyl-6-quinolineacetic acid of melting point 176°-179°C. 2-(p-Chlorophenyl)-6-quinoline-acetic acid and 2-(p-fluorophenyl)-6-quinolineacetic acid are obtained analogously.
Reaction SMILES: ClC1C(F)=C(C=CC=1)CNC([C@@H]1C[C@]2(CO)[C@@H](C2)N1C(=O)CN1C2=NC=CC=C2C(C(=O)C)=C1)=O.C(O[C:41]([N:43]1[CH2:48][C@H:47]2[C@H:45]([CH2:46]2)[C@H:44]1[C:49](=[O:62])[NH:50][C@@H:51]([C:54]1[CH:59]=[CH:58][CH:57]=[C:56]([Cl:60])[C:55]=1[F:61])[CH2:52][OH:53])=[O:42])(C)(C)C.[C:63]([C:66]1[C:74]2[C:69](=[CH:70][CH:71]=[CH:72][CH:73]=2)[N:68]([CH2:75]C(O)=O)[CH:67]=1)(=[O:65])[CH3:64]>CCOC(C)=O>[Cl:60][C:56]1[C:55]([F:61])=[C:54]([C@H:51]([NH:50][C:49]([C@H:44]2[N:43]([C:41](=[O:42])[CH2:75][N:68]3[C:69]4[C:74](=[CH:73][CH:72]=[CH:71][CH:70]=4)[C:66]([C:63](=[O:65])[CH3:64])=[CH:67]3)[CH2:48][C@H:47]3[C@@H:45]2[CH2:46]3)=[O:62])[CH2:52][OH:53])[CH:59]=[CH:58][CH:57]=1
Reactant: CC(=O)c1cn(CC(=O)O)c2ccccc12
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@@H]2[C@H]1C(=O)N[C@H](CO)c1cccc(Cl)c1F
Agent: CC(=O)c1cn(CC(=O)N2[C@H](C(=O)NCc3cccc(Cl)c3F)C[C@@]3(CO)C[C@@H]23)c2ncccc12
Solvent: CCOC(C)=O
Product: CC(=O)c1cn(CC(=O)N2C[C@@H]3C[C@@H]3[C@H]2C(=O)N[C@H](CO)c2cccc(Cl)c2F)c2ccccc12

Procedure:
The title compound was prepared in 2 steps according to the procedure described for the preparation of Example 610 (1R,3S,5S)-2-[2-(3-acetyl-pyrrolo[2,3-b]pyridin-1-yl)-acetyl]-5-hydroxymethyl-2-aza-bicyclo[3.1.0]hexane-3-carboxylic acid 3-chloro-2-fluoro-benzylamide from (1S,2S,5R)-2-[(S)-1-(3-chloro-2-fluoro-phenyl)-2-hydroxy-ethylcarbamoyl]-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (prepared using similar protocols as described in Scheme B9) and (3-acetyl-indol-1-yl)-acetic acid. White powder. TLC, Rf (EtOAc)=0.10; MS (UPLC/MS): 498.3/500.4 [M+H]+, 542.4/544.3 [M+HCOO]−; tR (HPLC conditions a): 3.10 min.
Reaction SMILES: Cl.[C:2]([C@:5]12[C@@:12]3([CH3:30])[CH2:13][C@H:14]([OH:29])[C@@:15]4([F:28])[C@H:24]([C@@H:11]3[CH2:10][C@H:9]1[CH2:8][NH:7][CH2:6]2)[CH2:23][C@H:22]([F:25])[C:21]1[C@:16]4([CH3:27])[CH:17]=[CH:18][C:19](=[O:26])[CH:20]=1)(=[O:4])[CH3:3].[CH3:31][C:32]1[O:38][C:35]([CH:36]=O)=[CH:34][CH:33]=1.C(O)=O>C(#N)C>[C:2]([C@:5]12[C@@:12]3([CH3:30])[CH2:13][C@H:14]([OH:29])[C@@:15]4([F:28])[C@H:24]([C@@H:11]3[CH2:10][C@H:9]1[CH2:8][N:7]([CH2:36][C:35]1[O:38][C:32]([CH3:31])=[CH:33][CH:34]=1)[CH2:6]2)[CH2:23][C@H:22]([F:25])[C:21]1[C@:16]4([CH3:27])[CH:17]=[CH:18][C:19](=[O:26])[CH:20]=1)(=[O:4])[CH3:3]
Reactant: CC(=O)[C@@]12CNC[C@@H]1C[C@H]1[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]12C
Reactant: Cc1ccc(C=O)o1
Agent: Cl
Solvent: CC#N
Solvent: O=CO
Product: CC(=O)[C@@]12CN(Cc3ccc(C)o3)C[C@@H]1C[C@H]1[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]12C
Temperature: 140 °C
Yield: 68.2 %

Procedure:
In a closed vessel, a mixture of compound 177 (306 mg, 0.692 mmol), 5-methylfurfural (344 μl, 3.46 mmol), TEA (97 μl, 0.692 mmol) and formic acid (266 μl, 6.92 mmol) in acetonitrile (15 ml) is heated under microwave irradiation for 15 minutes at 140° C. LC-MS shows that the reaction is complete. The solution is partitioned between AcOEt and a saturated solution of NaHCO3, the aqueous phase is extracted with AcOEt and the combined organic layers are washed with brine, dried over Na2SO4 and filtered. The solvent is evaporated to give a oil which is purified by silica gel chromatography (eluent AcOEt/petroleum ether 1/1). Trituration with petroleum ether affords the title compound (236 mg, 0.472 mmol, 68.2% yield).