Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N.[Na].[CH3:3][C:4]1[C:14]2[CH2:13][CH2:12][C:11]3[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=3[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1.Cl[CH2:21][CH2:22][CH2:23][NH2:24]>O.C1(C)C=CC=CC=1>[CH3:3][C:4]1[C:14]2[CH2:13][CH2:12][C:11]3[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=3[C:9]([CH2:21][CH2:22][CH2:23][N:24]=[CH:3][C:4]3[CH:14]=[CH:8][CH:7]=[CH:6][CH:5]=3)([OH:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: NCCCCl
Reactant: Cc1cccc2c1CCc1ccccc1C2=O
Agent: N
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cccc2c1CCc1ccccc1C2(O)CCCN=Cc1ccccc1
Temperature: 80 °C

Procedure:
To a 250 ml. 3-neck vessel, equipped with a stirrer, a dropping funnel and an ammonia coolant, are added 75 ml. of liquid ammonia, and it is treated by adding a sodium chip to obtain a stable blue color. A solution containing 22.2 g. of 1-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-one in 50 ml. of dry toluene is added dropwise with stirring. Thereafter, 4.6 g. of sodium are added piece by piece over a 30-minute period. The mixture is stirred for an additional 30 minutes and a solution containing 11.4 g. of freshly distilled 1-chloro-3-aminopropane in 40 ml. of dry toluene is added. The ammonia coolant is replaced by a water-cooler and the mixture is stirred overnight. The following morning, the mixture is cautiously decomposed with 50 ml. of water, whereby the 1-methyl-10,11-dihydro-5-(3-aminopropyl)-5-hydroxy-5H-dibenzo[a,d]cycloheptene partially crystallizes. Its melting point, after recrystallization from benzene/petroleum ether, is 155°-156°C. The crystals are removed by filtration and together with the separated toluene layer are treated with 13 g. of freshly distilled benzaldehyde. The mixture is heated at 80°C. under reduced pressure, so that the toluene and the residual water distil over. After recrystallization of the residue from ethanol, there is obtained 1-methyl-10,11-dihydro-5-(3-benzylideneaminopropyl)-5-hydroxy-5H-dibenzo [a,d]cycloheptene as colorless crystals having a melting point of 130°-131°C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[N:15]([C:16]3[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=3)[N:14]=[C:13](C3C=C([N+]([O-])=O)C=CC=3S([O-])(=O)=O)[CH2:12]2)=[O:10])=[C:4]([C:36](=[O:43])[NH:37][CH:38]([CH:40]2[CH2:42][CH2:41]2)[CH3:39])[CH:3]=1.C(O)(=O)C.[BrH:48].C(OCC)(=O)C.[OH-].[Na+]>C(O)(=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[N:15]([C:16]3[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=3)[N:14]=[C:13]([Br:48])[CH2:12]2)=[O:10])=[C:4]([C:36](=[O:43])[NH:37][CH:38]([CH:40]2[CH2:42][CH2:41]2)[CH3:39])[CH:3]=1
Reactant: Br
Reactant: CC(NC(=O)c1cc(Cl)ccc1NC(=O)C1CC(c2cc([N+](=O)[O-])ccc2S(=O)(=O)[O-])=NN1c1ncccc1Cl)C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(NC(=O)c1cc(Cl)ccc1NC(=O)C1CC(Br)=NN1c1ncccc1Cl)C1CC1
Reaction time: 1 h

Procedure:
400 mg of 5-(4-chloro-2-(1-cyclopropylethylcarbamoyl)phenylcarbamoyl)-1-(3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazol-3-yl4-nitrobenzene sulfonate was dissolved in 0.7 mL of acetic acid, and 0.3 mL of a 33 mass % hydrogen bromide acetic acid solution was dropwise added, followed by stirring for about 1 hour. After completion of the reaction, ethyl acetate, water and 2 mL of 1 N sodium hydroxide were added, followed by stirring and extraction with ethyl acetate. Then, concentration under reduced pressure was carried out to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=3/2) to obtain 310 mg of the desired product in a paste form.
Reaction SMILES: [CH2:1]([C:5]1[N:17]2[C:8]([C:9](=[O:29])[NH:10][C:11]3[C:12]([CH2:27][CH3:28])=[N:13][C:14]([N:18]4[CH:22]=[CH:21][N:20]=[C:19]4CCC=C)=[N:15][C:16]=32)=[CH:7][N:6]=1)[CH2:2][CH:3]=[CH2:4].N1C=CN=C1>>[CH2:1]([C:5]1[N:17]2[C:8]([C:9](=[O:29])[NH:10][C:11]3[C:12]([CH2:27][CH3:28])=[N:13][C:14]([N:18]4[CH:22]=[CH:21][N:20]=[CH:19]4)=[N:15][C:16]=32)=[CH:7][N:6]=1)[CH2:2][CH:3]=[CH2:4]
Reactant: C=CCCc1nccn1-c1nc(CC)c2[nH]c(=O)c3cnc(CCC=C)n3c2n1
Agent: c1c[nH]cn1
Product: C=CCCc1ncc2c(=O)[nH]c3c(CC)nc(-n4ccnc4)nc3n12

Procedure:
Prepared by treatment of the product of Example 9h with excess imidazole at 200° C.
Reaction SMILES: Br[C:2]1[C:3]([CH3:11])=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.C([Li])(C)(C)C.[C:17](=[O:19])=[O:18]>>[CH3:11][C:3]1[C:2]([C:17]([OH:19])=[O:18])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[N:6][NH:7]2
Reactant: Cc1c(Br)ccc2[nH]ncc12
Reactant: O=C=O
Agent: [Li]C(C)(C)C
Product: Cc1c(C(=O)O)ccc2[nH]ncc12

Procedure:
This compound was prepared in a manner similar to the preparation of 88 using commercially available 4-bromo-2,3-dimethylaniline as starting material. After an acylation step, N-(4-bromo-2,3-dimethylphenyl)acetamide was treated with isoamyl nitrite, then 10% aqueous HCl to yield 5-bromo-4-methyl-1H-indazole. 5-bromo-4-methyl-1H-indazole was treated with t-butyl lithium and carbon dioxide to yield 4-methyl-1H-indazole-5-carboxylic acid, which in turn was treated with thiosemicarbazide and polyphosphoric acid to form 5-(4-methyl-1H-indazol-5-yl)-1,3,4-thiadiazol-2-amine. MS (API-ES) m/z (%): 232 (100%, M++1).
Reaction SMILES: [CH2:1]([O:7][C:8]1[C:9](=[O:20])[O:10][C:11]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:12]=2[C:13]=1[OH:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:21]([O:24][CH2:25][CH2:26][CH2:27]Br)(=[O:23])[CH3:22]>>[CH2:1]([O:7][C:8]1[C:9](=[O:20])[O:10][C:11]2[CH:18]=[CH:17][C:16]([O:19][CH2:27][CH2:26][CH2:25][O:24][C:21](=[O:23])[CH3:22])=[CH:15][C:12]=2[C:13]=1[OH:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCOc1c(O)c2cc(O)ccc2oc1=O
Reactant: CC(=O)OCCCBr
Product: CCCCCCOc1c(O)c2cc(OCCCOC(C)=O)ccc2oc1=O

Procedure:
In the same manner as in Reference Example 1, except that an equimolar amount of 3-hexyloxy-4,6-dihydroxy-2H-1-benzopyran-2-one was used in place of 3-ethoxy-4,5-dihydroxy-2H-1-benzopyran-2-one, and 3-bromopropyl acetate was used in place of 2-bromoethyl acetate in Reference Example 1, 3-hexyloxy-4-hydroxy-6-(3-acetoxypropoxy)-2H-1-benzopyran-2-one was obtained.
Reaction SMILES: C(OC([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[C:13]([Cl:17])[CH:14]=2)[CH2:9]1)=O)(C)(C)C.[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28]>>[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28].[Cl:17][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][C:12]=1[O:18][CH:19]1[CH2:20][CH2:21][O:22][CH2:23][CH2:24]1)[CH2:9][NH:8][CH2:16]2
Reactant: CC(C)(C)OC(=O)N1Cc2cc(Cl)c(OC3CCOCC3)cc2C1
Solvent: O=C(O)C(F)(F)F
Product: Clc1cc2c(cc1OC1CCOCC1)CNC2

Procedure:
Prepared in analogy to Example A2(c) from 5-chloro-6-(tetrahydro-pyran-4-yloxy)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and trifluoroacetic acid. Yellow oil. 256.3 ([{37Cl}M+H]+, 50%), 254.3 ([{35Cl}M+H]+, 100%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH2:16][CH2:17][NH:18][CH2:19][CH:20]=2)=[CH:11][CH:10]=1.[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(O)C>[CH2:21]([N:18]1[CH2:17][CH:16]=[C:15]([C:12]2[CH:13]=[CH:14][C:9]([F:8])=[CH:10][CH:11]=2)[CH2:20][CH2:19]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: Fc1ccc(C2=CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Fc1ccc(C2=CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.1 %

Procedure:
13.8 g (100 mmol) of potassium carbonate were added to a solution of 10.0 g (46.8 mmol) of 4-(4-fluoro-phenyl)-1,2,3,6-tetrahydro-pyridine hydrochloride in 400 ml of ethanol and the reaction mixture was subsequently heated to reflux temperature. A solution of 5.8 ml (49 mmol) of benzyl bromide in 100 ml of ethanol was added dropwise within one hour and thereafter the mixture was stirred at this temperature for a further 1 hour. The reaction mixture was cooled to room temperature and filtered, the filtrate was extracted with water and ethyl acetate and finally the organic phase was dried over magnesium sulphate. After evaporation in a water-jet vacuum the crude product obtained was chromatographed on silica gel with hexane and ethyl acetate as the eluent. There were obtained 8.90 g (71% of theory) of 1-benzyl-4-(4-fluoro-phenyl)-1,2,3,6-tetrahydro-pyridine; MS: 267 (M)+.
Reaction SMILES: C([C:3]1[CH:4]=[C:5]2[C:11]([C:12]3[CH:13]=[C:14]([CH:35]=[CH:36][CH:37]=3)[CH2:15][NH:16][C:17]([C:19]3[C:20](=[O:34])[N:21]([CH2:25][C:26]4[CH:31]=[CH:30][C:29]([F:32])=[C:28]([F:33])[CH:27]=4)[CH:22]=[CH:23][CH:24]=3)=[O:18])=[CH:10][NH:9][C:6]2=[N:7][CH:8]=1)#N.[F:38]C1C=C(C=CC=1F)CN1C=CC=C(C(NCC2C=C(B(O)O)C=CC=2)=O)C1=O.[B].FC1C=C2C(I)=CNC2=NC=1>>[F:38][C:3]1[CH:4]=[C:5]2[C:11]([C:12]3[CH:13]=[C:14]([CH:35]=[CH:36][CH:37]=3)[CH2:15][NH:16][C:17]([C:19]3[C:20](=[O:34])[N:21]([CH2:25][C:26]4[CH:31]=[CH:30][C:29]([F:32])=[C:28]([F:33])[CH:27]=4)[CH:22]=[CH:23][CH:24]=3)=[O:18])=[CH:10][NH:9][C:6]2=[N:7][CH:8]=1
Reactant: O=C(NCc1cccc(B(O)O)c1)c1cccn(Cc2ccc(F)c(F)c2)c1=O
Reactant: N#Cc1cnc2[nH]cc(-c3cccc(CNC(=O)c4cccn(Cc5ccc(F)c(F)c5)c4=O)c3)c2c1
Agent: Fc1cnc2[nH]cc(I)c2c1
Agent: [B]
Product: O=C(NCc1cccc(-c2c[nH]c3ncc(F)cc23)c1)c1cccn(Cc2ccc(F)c(F)c2)c1=O

Procedure:
Except where indicated, 1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid 3-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-benzylamide was synthesized as per Example 68, 1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid 3-(5-cyano-1H-pyrrolo[2,3-b]pyridin-3-yl)-benzylamide using 3-({[1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carbonyl]-amino}-methyl)-phenylboronic acid as activated boron species and 5-Fluoro-3-iodo-1H-pyrrolo[2,3-b]pyridine as substituted bicyclic heterocycle, to produce the title compound. 1H NMR (400 MHz, CDCl3) d ppm 12.504 (s, 1H) 10.457 (m, 1H) 8.609 (dd, J=7.3, 2.1 Hz, 1H) 8.541 (d, J=8.1 Hz, 1H) 8.259 (m, 1H) 7.788 (s, 1H) 7.605 (s, 1H) 7.576 (dd, J=6.5, 2.0 Hz, 1H) 7.522-7.366 (m, 3H) 7.221-7.094 (m, 2H) 7.044-6.993 (m, 1H) 6.517 (t, J=6.9 Hz, 1H) 5.178 (s, 2H) 4.739 (d, J=5.7 Hz, 2H); MS m/z=489.33 M+H.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:26]([O:28]CC)=O)[C:5]2[C:6](=O)[CH:7]([C:19]3[N:23]([CH3:24])[N:22]=[CH:21][N:20]=3)[CH:8]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[NH:9][C:10]=2[CH:11]=1.O.[NH2:32][NH2:33]>CO>[F:1][C:2]1[CH:11]=[C:10]2[NH:9][CH:8]([C:12]3[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=3)[CH:7]([C:19]3[N:23]([CH3:24])[N:22]=[CH:21][N:20]=3)[C:6]3=[N:32][NH:33][C:26](=[O:28])[C:4]([CH:3]=1)=[C:5]23
Reactant: CCOC(=O)c1cc(F)cc2c1C(=O)C(c1ncnn1C)C(c1ccc(F)cc1)N2
Reactant: NN
Solvent: O
Solvent: CO
Product: Cn1ncnc1C1c2n[nH]c(=O)c3cc(F)cc(c23)NC1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 84 %

Procedure:
To a solution of ethyl 7-fluoro-2-(4-fluorophenyl)-3-(1-methyl-1H-1,2,4-triazol-5-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (840 mg, 2.04 mmol) in methanol (2 mL) was added hydrazine monohydrate (1 mL), and the mixture was stirred under 25° C. for 10 hr. Then the mixture was filtered to obtain a white solid (650 mg, yield 84%). LC-MS (ESI) m/z: 381 (M+1)+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 3.66 (s, 3H), 4.97-5.04 (m, 2H), 6.91-6.94 (dd, J1=11.2 Hz, J2=2.4 Hz, 1H), 7.06-7.09 (dd, J1=8.8 Hz, J2=2.4 Hz, 1H), 7.14-7.18 (m, 3H), 7.47-7.51 (m, 2H), 7.72 (s, 1H), 7.80 (s, 1H), 12.35 (s, 1H)
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:13]=[C:14]([NH:19][C:20](=[O:32])[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([C:30]#[N:31])([CH3:29])[CH3:28])[CH:22]=3)[CH:15]=[CH:16][C:17]=1[CH3:18])[N:5]=2.[CH3:33][N:34]([CH3:39])[CH2:35][C:36](O)=[O:37].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[C:30]([C:27]([C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=1)[C:20]([NH:19][C:14]1[CH:15]=[CH:16][C:17]([CH3:18])=[C:12]([O:11][C:6]2[N:5]=[C:4]3[S:3][C:2]([NH:1][C:36](=[O:37])[CH2:35][N:34]([CH3:39])[CH3:33])=[N:10][C:9]3=[CH:8][CH:7]=2)[CH:13]=1)=[O:32])([CH3:29])[CH3:28])#[N:31]
Reactant: CN(C)CC(=O)O
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc2nc(N)sc2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: c1ccncc1
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc2nc(NC(=O)CN(C)C)sc2n1
Temperature: 100 °C
Reaction time: 15 h
Yield: 14 %

Procedure:
A mixture of N-{3-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-4-methylphenyl}-3-(1-cyano-1-methylethyl)benzamide (153 mg, 0.344 mmol) produced in Example C12(iv), N,N-dimethylglycine (79.5 mmol, 0.771 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (321 mg, 0.843 mmol) and pyridine (3 mL) was stirred at 100° C. for 15 hr. To the reaction mixture was added aqueous sodium hydrogen carbonate solution (5 mL), and the mixture was extracted with ethyl acetate (5 mL×4). The organic layers were combined, and dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=50/50→0/100), and crystallized from diisopropyl ether/ethyl acetate to give the title compound (25.4 mg, 14%) as pale-orange crystals.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=4[CH3:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([CH:26]2[CH2:28][CH2:27]2)[OH:25])=[CH:4][CH:3]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[F:60][C:61]([F:65])([F:64])[CH2:62]O>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=4[CH3:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([CH:26]2[CH2:28][CH2:27]2)[O:25][CH2:62][C:61]([F:65])([F:64])[F:60])=[CH:4][CH:3]=1
Reactant: COc1ccc(N2CCCn3c2nc2c(Cl)ccc(C(O)C4CC4)c23)c(C)c1
Reactant: OCC(F)(F)F
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COc1ccc(N2CCCn3c2nc2c(Cl)ccc(C(OCC(F)(F)F)C4CC4)c23)c(C)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 35.7 %

Procedure:
To a solution of [9-chloro-1-(4-methoxy-2-methylphenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl](cyclopropyl)methanol (82 mg, 0.21 mmol) and tributyl phosphine (0.10 mL, 0.41 mmol) in tetrahydrofuran (0.84 mL) was added 1,1′-(azodicarbonyl) dipiperidine (104 mg, 0.41 mmol), and the mixture was stirred at room temperature for 10 min. To the reaction mixture was added 2,2,2,-trifluoroethanol (0.15 mL, 2.06 mmol), and the mixture was stirred at 60° C. for 1 h. The reaction mixture was cooled at room temperature and concentrated in vacuo. The residue was diluted with diethyl ether. The residual solid was removed by filtration. The filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 40% ethyl acetate/n-hexane mixture. The desired fractions were concentrated in vacuo. The residual oil was crystallized from ethyl acetate/diisopropyl ether to give the title compound as a colorless crystal (35.8 mg, 0.075 mmol, 36%).
Reaction SMILES: C([O:3][C:4](=[O:39])[CH2:5][C:6]1[CH:7]=[C:8]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=2[CH2:25][N:26]2[C@@H:30]([CH3:31])[C@@H:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[O:28][C:27]2=[O:38])[C:9]([O:12][CH2:13][CH3:14])=[CH:10][CH:11]=1)C.[OH-].[Li+]>CO>[CH2:13]([O:12][C:9]1[C:8]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][C:16]=2[CH2:25][N:26]2[C@@H:30]([CH3:31])[C@@H:29]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[O:28][C:27]2=[O:38])=[CH:7][C:6]([CH2:5][C:4]([OH:39])=[O:3])=[CH:11][CH:10]=1)[CH3:14]
Reactant: CCOC(=O)Cc1ccc(OCC)c(-c2ccc(C(F)(F)F)cc2CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CCOc1ccc(CC(=O)O)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2ccccc2)[C@@H]1C
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To [6-ethoxy-2′-((4S,5R)-4-methyl-2-oxo-5-phenyl-oxazolidin-3-ylmethyl)-4′-trifluoromethyl-biphenyl-3-yl]-acetic acid ethyl ester (0.18 mmol) in MeOH (3 mL) was added aqueous lithium hydroxide (1N; 1 mL), and the reaction was stirred overnight at 70° C. After acidification with 1N aqueous HCl, the aqueous layer was separated and extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated, and the crude material was purified by preparative HPLC to give the desired product. M+H is 514.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([CH:12]2[CH:16]=[N:15][N:14]=[N:13]2)=[CH:8][C:4]=1[C:5](O)=[O:6].C(Cl)(=O)C([Cl:20])=O>CN(C)C=O.ClCCl>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([CH:12]2[CH:16]=[N:15][N:14]=[N:13]2)=[CH:8][C:4]=1[C:5]([Cl:20])=[O:6]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1ccc(C2C=NN=N2)cc1C(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(C2C=NN=N2)cc1C(=O)Cl
Reaction time: 4 h

Procedure:
Combine 2-methoxy-5-(4H-triazol-4-yl)benzoic acid (5 mmol) and dichloromethane (40 mL). Add dropwise oxalyl chloride (0.72 mL, 8.25 mmol) followed by dimethylformamide (3 drops). After 4 hours, evaporate in vacuo and dry to give the title compound.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[N+:9]([O-:11])=[O:10].[BrH:12]>C1(C)C=CC=CC=1>[Br:12][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[N+:9]([O-:11])=[O:10]
Reactant: Br
Reactant: COc1ccncc1[N+](=O)[O-]
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cnccc1Br
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To 4-methoxy-3-nitropyridine (3.5 g) was added 48% hydrobromic acid (30 ml), and the solution was stirred overnight at 80° C. Toluene was added thereto followed by stirring. The solvent was evaporated in vacuo. To the total amount of the resulting 3-nitropyridin-4-ol (crude product) were added phosphorous oxybromide (20 g) and chloroform (30 ml), and the solution was stirred for 2 hours at 110° C. To the reaction mixture was added an ice, the solution was neutralized with aqueous ammonia, extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, then filtered through silica gel, and the solvent was evaporated in vacuo to provide the title compound (2.6 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].[CH3:10][O:11][CH2:12][CH2:13]Br.C([O-])([O-])=O.[Cs+].[Cs+].C(=O)([O-])O.[Na+]>CN(C=O)C>[CH3:9][C:8]1[CH:7]=[CH:6][C:4]([NH2:5])=[CH:3][C:2]=1[O:1][CH2:13][CH2:12][O:11][CH3:10]
Reactant: Cc1ccc(N)cc1O
Reactant: COCCBr
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COCCOc1cc(N)ccc1C
Temperature: 40 °C
Reaction time: 8 h
Yield: 101.6 %

Procedure:
22.0 g of 3-hydroxy-4-methylaniline, 24.9 g of 2-bromoethyl methyl ether and 233 g of Cs2CO3 are dissolved in 570 ml of DMF and stirred at 40° C. for 8 h. 3 l of a 10% aqueous sodium hydrogencarbonate solution are added, and the mixture is extracted 6 times with 750 ml of EA each time and washed twice with 1 l of a 10% aqueous sodium hydrogencarbonate solution each time. It is dried over sodium sulfate and the solvent is removed in vacuo. 32.9 g of a yellow oil are obtained, which is employed further as such.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]2[CH2:11][CH2:12][N:13]([C:16]3[CH:24]=[C:23]4[C:19]([CH:20]=[CH:21][N:22]4[CH2:25][C:26]([O:28]C(C)(C)C)=[O:27])=[CH:18][CH:17]=3)[C:14](=[O:15])[C:3]=12.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]2[CH2:11][CH2:12][N:13]([C:16]3[CH:24]=[C:23]4[C:19]([CH:20]=[CH:21][N:22]4[CH2:25][C:26]([OH:28])=[O:27])=[CH:18][CH:17]=3)[C:14](=[O:15])[C:3]=12
Reactant: CC(C)(C)OC(=O)Cn1ccc2ccc(N3CCn4c(c(Cl)c5ccccc54)C3=O)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)Cn1ccc2ccc(N3CCn4c(c(Cl)c5ccccc54)C3=O)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
tert-Butyl 2-(6-(10-chloro-1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1H-indol-1-yl)acetate (2.22 mmol, 1.0 equiv.) was dissolved in DCM (15 ml); TFA (3 ml) was added, and the mixture was stirred for 2 h at 25° C. The solvent was concentrated under reduced pressure, and the residue was taken up in DCM (60 ml), washed with water (25 ml) and sat. NaCl solution (25 ml), dried over Na2SO4 and concentrated to dryness under reduced pressure. Yield: 91%
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[CH:14]=[C:13]([C:16]([OH:18])=[O:17])[CH:12]=[CH:11]2.[BrH:19]>OS(O)(=O)=O.CC(O)=O.O>[Br:19][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[CH:14]=[C:13]([C:16]([OH:18])=[O:17])[CH:12]=[CH:11]2
Reactant: Br
Reactant: Nc1cccc2ccc(C(=O)O)cc12
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1ccc2cccc(Br)c2c1
Temperature: 10 °C
Yield: 55 %

Procedure:
According to the procedure of W. Adcock, et al. Aust. J. Chem. 18, 1351 (1965) and H. H. Hodgson, et al. J. Chem. Soc., 1620 (1933), to a cooled (10° C.), stirred solution of NaNO2 (1.24 g, 0.0179 mol) in H2SO4 (16.1 mL) and HOAc (14.9 mL) [prepared by adding NaNO2 to cooled (10° C.) H2SO4, heating to dissolve, recooling, and adding HOAc] was added a solution of 8-amino-2-naphthoic acid (2.80 g, 0.0150 mol) in HOAc (50 mL) over 10 minutes. The resulting solution was added slowly (over 10 minutes) to a heated (60° C.), stirred solution of CuBr (9.44 g, 0.0658 mol) in concentrated HBr (90 mL). The mixture was warmed to 90° C. for 10 minutes, cooled, diluted with H2O (200 mL) and filtered to give a green solid, 3.4 g. The crude product was combined with similarly prepared material (450 mg) and recrystallized from EtOH to give an off-white solid (2.3 g, 55%), m.p. 265°-266° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH2:18][C:19]4[S:20][CH:21]=[CH:22][N:23]=4)=[CH:14][CH:15]=3)[C:10]([CH2:24][CH2:25][O:26][N:27]=[CH:28][C:29]([OH:31])=[O:30])=[C:9]2[CH3:32])[CH:2]=1.FC(F)(F)C(O)=O.[NH:40]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46]C=2)C=C1.N1C=CC=C(CCl)C=1.[H-].[Na+]>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH2:18][C:19]4[S:20][CH:21]=[CH:22][N:23]=4)=[CH:14][CH:15]=3)[C:10]([CH2:24][CH2:25][O:26][N:27]=[CH:28][C:29]([OH:31])=[O:30])=[C:9]2[CH3:32])[CH:2]=1.[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH2:18][C:19]4[S:20][CH:21]=[CH:22][N:23]=4)=[CH:14][CH:15]=3)[C:10]([CH2:24][CH2:25][O:26][N:27]=[CH:28][C:29]([O:31][C:43]3[CH:48]=[N:40][CH:46]=[CH:45][CH:44]=3)=[O:30])=[C:9]2[CH3:32])[CH:2]=1
Reactant: c1ccc2[nH]ccc2c1
Agent: Cc1c(CCON=CC(=O)O)c2cc(OCc3nccs3)ccc2n1Cc1cccnc1
Agent: ClCc1cccnc1
Agent: [H-]
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(CCON=CC(=O)Oc2cccnc2)c2cc(OCc3nccs3)ccc2n1Cc1cccnc1

Procedure:
The title compound is prepared by reaction of glyoxylic acid-O-2-[1-(3-pyridylmethyl)-5-(thiazol-2-ylmethoxy)-2-methylindol-3-yl]ethyl oxime with trifluoroacetic acid to remove the t-BOC group followed by reaction of the indole intermediate with two equivalents of 3-pyridylmethyl chloride in the presence of a suitable base such as NaH to provide the intermediate glyoxylic acid 3-pyridyl ester-O-2-[1-(3-pyridylmethyl)-5-(thiazol-2-ylmethoxy)-2-methylindol-3-yl]ethyl oxime which is subsequently saponified.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[CH3:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]=O)[CH:23]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C1(C2C=CC=CC=2)C=CC=CC=1CN1CCN(C2C=CC=CC=2)CC1>>[CH3:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][N:12]2[CH2:13][CH2:14][N:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[CH2:10][CH2:11]2)[CH:23]=1
Reactant: COc1ccccc1N1CCNCC1
Reactant: Cc1ccccc1-c1cccc(C=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: c1ccc(-c2ccccc2CN2CCN(c3ccccc3)CC2)cc1
Product: COc1ccccc1N1CCN(Cc2cccc(-c3ccccc3C)c2)CC1

Procedure:
77 mg of the target compound (0.21 mmol, 40.5%) was obtained using 1-(2-methoxyphenyl)piperazine (196 mg, 1.02 mmol), 2′-methylbiphenyl-3-carbaldehyde (100 mg, 0.51 mmol) and NaBH(OAc)3 (329 mg, 1.53 mmol) according to the synthesis method of Compound 1.