Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([CH2:12][CH2:13][NH2:14])[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:15][C:16]([F:32])([F:31])[C:17]1[O:21][N:20]=[C:19]([C:22]2[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=2)[C:25](O)=[O:26])[N:18]=1>>[C:1]1([C:7]2[N:11]=[C:10]([CH2:12][CH2:13][NH:14][C:25](=[O:26])[C:24]3[CH:28]=[CH:29][CH:30]=[C:22]([C:19]4[N:18]=[C:17]([C:16]([F:32])([F:31])[F:15])[O:21][N:20]=4)[CH:23]=3)[NH:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: NCCc1nc(-c2ccccc2)n[nH]1
Product: O=C(NCCc1nc(-c2ccccc2)n[nH]1)c1cccc(-c2noc(C(F)(F)F)n2)c1
Yield: 21 %

Procedure:
This compound was synthesized from 2-(3-phenyl-1H-1,2,4-triazol-5-yl)ethanamine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (17 mg, yield 21%). 1H NMR (400 MHz, CDCl3) δ 8.53 (s, 1H), 8.21-8.19 (d, J=7.8 Hz, 1H), 8.06-8.04 (t, J=7.8 Hz, 1H), 8.01-7.99 (m, 2H), 7.89 (m, 1H), 7.58-7.54 (d, J=7.8 Hz, 1H), 7.40-7.39 (m, 3H), 4.00-3.95 (q, J=5.9 Hz, 2H), 3.24-3.21 (d, J=6.1 Hz, 2H). MS (ESI) m/z: Calculated for C20H15F3N6O2: 428.12. found: 429.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[F:30])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([OH:25])[C:10](=[O:24])[N:11]([CH:21]([CH3:23])[CH3:22])[C:12]=2[C:16]([N:18]([CH3:20])[CH3:19])=[O:17])[C:7]1=[O:26].[I:31]NC(=O)CCC(N)=O>FC(F)(F)S(O)(=O)=O.CO>[Cl:1][C:2]1[C:29]([F:30])=[CH:28][C:27]([I:31])=[C:4]([CH:3]=1)[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([OH:25])[C:10](=[O:24])[N:11]([CH:21]([CH3:23])[CH3:22])[C:12]=2[C:16]([N:18]([CH3:20])[CH3:19])=[O:17])[C:7]1=[O:26]
Reactant: NC(=O)CCC(=O)NI
Reactant: CC(C)n1c(C(=O)N(C)C)c2c(c(O)c1=O)C(=O)N(Cc1ccc(F)c(Cl)c1)CC2
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CO
Product: CC(C)n1c(C(=O)N(C)C)c2c(c(O)c1=O)C(=O)N(Cc1cc(Cl)c(F)cc1I)CC2
Reaction time: 0.17 h

Procedure:
A mixture of 6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-isopropyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide (43 mg, 0.10 mmol; Example 13) and N-iodosuccinamide (22 mg, 0.1 mmol) in trifluoromethanesulfonic acid at 0° C. was stirred for 10 minutes. The mixture was diluted with methanol and subjected to preparative HPLC purification on C-18 reverse stationary phase column eluting with a gradient of water—acetonitrile in the presence of 0.1% trifluoroacetic acid. Collection and lyophilization of appropriate fractions provided the titled compound.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C([Li])CCC.C(NC(C)C)(C)C.[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.CN(C)[CH:30]=[O:31]>O1CCCC1>[Cl:21][C:22]1[C:27]([CH:30]=[O:31])=[CH:26][CH:25]=[CH:24][N:23]=1
Reactant: Clc1ccccn1
Reactant: CN(C)C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=Cc1cccnc1Cl
Temperature: -70 °C
Reaction time: 0.33 h

Procedure:
Form a solution of lithium diisopropylamide by the adding n-butyl lithium (37.5 mL, 0.06 mol, 1.6 M in hexanes) to diisopropylamine (8.39 mL, 0.06 mol) in tetrahydrofuran (200 mL) at −10 to −20° C. under a nitrogen atmosphere. After stirring for 20 min., cool the mixture to −70° C. and add 2-chloropyridine (4.96 mL, 0.05 mol) dropwise via syringe and stir the mixture for 1 hour at this temperature. Add N,N-dimethylformamide (7.73 mL, 0.10 mol) dropwise via syringe and stir for 1 hour near −70° C. after which time remove the cooling bath and add a solution of aqueous 5N hydrochloric acid/tetrahydrofuran (5 ml125 mL) in a dropwise manner. Add water (200 mL) and warm the mixture to −10° C. Extract with ethyl acetate. Dry the combined extracts over sodium sulfate and concentrate in vacuo. Elute the resulting residue over silica gel using 10% ethyl acetate/hexanes allowing for isolation of the desired aldehyde (2.86 g, 40%) as a solid. MS(EI): (M)+ 140.2, 141.3, 143.3 m/z.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][C:8]([O:17][CH3:18])=[CH:7][C:5]=2[N:6]=1.C(N(CC)CC)C.[CH3:26][C:27]1[S:31][C:30]([C:32](Cl)=[O:33])=[CH:29][CH:28]=1.[OH-].[Na+]>ClCCl>[CH3:18][O:17][C:8]1[CH:9]=[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:4]2[S:3][C:2]([NH:1][C:32]([C:30]3[S:31][C:27]([CH3:26])=[CH:28][CH:29]=3)=[O:33])=[N:6][C:5]=2[CH:7]=1
Reactant: COc1cc(-c2ccccc2)c2sc(N)nc2c1
Reactant: Cc1ccc(C(=O)Cl)s1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(-c2ccccc2)c2sc(NC(=O)c3ccc(C)s3)nc2c1
Reaction time: 6 h
Yield: 14.6 %

Procedure:
2-Amino-5-methoxy-7-phenylbenzothiazol (45 mg, 0.18 mmol) is dissolved in dichloromethane (2 ml) and subsequently treated with triethylamine (0.073 ml, 0.53 mmol) and 5-methyl-thiophene-2-carbonyl chloride (56 mg, 0.35 mmol). After 6 h, further 0.073 ml, 0.53 mmol) and 5-methyl-thiophene-2-carbonyl chloride (56 mg, 0.35 mmol) are added and the mixture is stirred for additional 18 h at ambient. After addition of 0.1M aqueous sodium hydroxide, the mixture is stirred for additional 16 h. The organic layer is separated, dried and evaporated to dryness. Flash chromatography (silica, eluent ethyl acetate/cyclohexane 1:1, containing 0.5% of 25% aqueous ammonia) affords (10 mg, 5%) of the product as white solid. MS: m/e=380 (M+).
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4](=[O:18])[C@H:5]([CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:17])[CH:15]=2)[NH:10][CH:9]=1)[NH2:6].C=O.[CH3:21]COCC>CO>[ClH:1].[F:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]1[CH2:21][NH:6][C@H:5]([C:4]([O:3][CH3:2])=[O:18])[CH2:7][C:8]2=1
Reactant: CCOCC
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccc(F)cc12
Agent: C=O
Agent: Cl
Solvent: CO
Product: COC(=O)[C@@H]1Cc2c([nH]c3ccc(F)cc23)CN1
Temperature: 25 °C
Reaction time: 20 h
Yield: 68 %

Procedure:
0.93 g of 5-fluoro-L-tryptophan methyl ester hydrochloride is dissolved in 14 ml of methanol. 0.52 g of 35% formalin is added thereto and the mixture is stirred at room temperature for 20 hours. Ether is added to the mixture and crystalline precipitates are collected by filtration, washed with ether and dried, whereby 0.66 g of methyl (3S)-6-fluoro-1,2,3,4-tetrahydro-β-carboline-3-carboxylate hydrochloride are obtained as colorless needles. Yield: 68%
Reaction SMILES: C(OCC)C.C([Li])CCC.Br[C:12]1[CH:13]=[N:14][CH:15]=[N:16][CH:17]=1.[CH:18]([C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1)=[O:19]>O1CCCC1>[N:14]1[CH:13]=[CH:12][CH:17]=[N:16][C:15]=1[C:25]1[CH:26]=[CH:27][CH:28]=[C:29]2[C:24]=1[CH:23]=[CH:22][CH:21]=[C:20]2[CH2:18][OH:19]
Reactant: Brc1cncnc1
Reactant: O=Cc1cccc2ccccc12
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: OCc1cccc2c(-c3ncccn3)cccc12
Temperature: -120 °C
Reaction time: 0.75 h

Procedure:
To a 500 ml 3-neck flask round bottom flask equipped with an addition funnel, septum, thermometer and an argon inlet is added 100 ml of anhydrous diethyl ether and 62.5 ml of 1.6 molar butyllithium solution (in hexane). The system is cooled to -120° C. and 15.90 gm of 5-bromopyrimidine in 50 ml of tetrahydrofuran is added over 2 hours. After addition of the 5-bromopyrimidine, the system is stirred for an additional 45 minutes. At this time, 15.60 gm of 1-formylnaphthalene in 50 ml of tetrahydrofuran is added to the system while still maintaining a temperature of -120° C. The system is kept at -120° C. for an additional 3 hours after addition of the 1-formylnaphthalene and afterwards is allowed to come to room temperature. After 10 hours at room temperature, the system is quenched with saturated ammonium chloride (in water). The system is adjusted to pH2 with HCl solution. The product is extracted with methylene chloride. The methylene chloride is washed with a 10% NaOH solution and then is dried over sodium sulfate. The methylene chloride is removed by stripping and the residue is triturated with hexane to give the 5-pyrimidyl-1-naphthylcarbinol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:30][CH3:31])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[O:27][CH2:28][CH3:29])=[N:13][C:14]=1[CH2:15][CH3:16].[CH2:32](Br)C#C>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:30][CH3:31])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[O:27][CH2:28][C:29]#[CH:32])=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Reactant: C#CCBr
Product: C#CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine but substituting propargylbromide and making non-critical variations provided the title compound as a white solid. IR (diffuse reflectance) 3451, 3293, 2964, 2932, 1563, 1493, 1469, 1390, 1204, 1184, 1087, 1076, 820, 742, 646 cm−1; OAMS supporting ions at: ESI+ 465.8; MS (EI) m/z 465 (M+); HRMS (FAB) calcd for C26H25CL2N3O+H1 466.1453, found 466.1455. [α]25D=−56 (c 0.83, methylene chloride). Anal. Calcd for C26H25Cl2N3O: C, 66.96; H, 5.40; N, 9.01. Found: C, 66.96; H, 5.49 N, 8.93.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[O:3][C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][CH2:10][CH2:11][NH2:12])=[CH:6][CH:5]=1.CCN(C(C)C)C(C)C.[Cl:26][C:27]1[N:32]=[C:31](Cl)[CH:30]=[CH:29][N:28]=1>C(O)(C)C>[Cl:26][C:27]1[N:32]=[C:31]([NH:12][CH2:11][CH2:10][CH2:9][O:8][C:7]2[CH:13]=[CH:14][C:4]([O:3][C:2]([F:15])([F:16])[F:1])=[CH:5][CH:6]=2)[CH:30]=[CH:29][N:28]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: NCCCOc1ccc(OC(F)(F)F)cc1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)(F)Oc1ccc(OCCCNc2ccnc(Cl)n2)cc1
Temperature: 80 °C
Reaction time: 24 h
Yield: 60.2 %

Procedure:
To a solution of 3-(4-(trifluoromethoxy)phenoxy)propan-1-amine (450 mg, 1.91 mmol) in isopropanol (8 mL, 3 mL/mmol) was added DIPEA (0.5 mL, 2.86 mmol) and 2,4-dichloropyrimidine (340 mg, 2.29 mmol) and the mixture was stirred at 80° C. for 24 h. Then reaction mixture was concentrated under reduced pressure and extracted with EtOAc (2×30 mL) and water (2×30 mL). The EtOAc layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. Purification by column chromatography provided 2-chloro-N-(3-(4-(trifluoromethoxy)phenoxy)propyl)pyrimidin-4-amine (400 mg, 60%) as a solid. Observed mass (M+1): 348.1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:31](=[CH:32][CH:33]=1)[O:30][C:29]([CH3:35])([CH3:34])[C:25]1([CH2:28][O:27][CH2:26]1)[C:5]12[CH2:9][O:8][C:7]([N:10](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=[N:6]1.[Cl:36][C:37]1[CH:38]=[C:39](B(O)O)[CH:40]=[C:41]([F:43])[CH:42]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[Cl:36][C:37]1[CH:38]=[C:39]([C:2]2[CH:3]=[C:4]3[C:31](=[CH:32][CH:33]=2)[O:30][C:29]([CH3:35])([CH3:34])[C:25]2([CH2:28][O:27][CH2:26]2)[C:5]23[CH2:9][O:8][C:7]([NH2:10])=[N:6]2)[CH:40]=[C:41]([F:43])[CH:42]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=NC2(CO1)c1cc(Br)ccc1OC(C)(C)C21COC1
Reactant: OB(O)c1cc(F)cc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC1(C)Oc2ccc(-c3cc(F)cc(Cl)c3)cc2C2(COC(N)=N2)C12COC2
Temperature: 100 °C
Reaction time: 12 h
Yield: 45.8 %

Procedure:
A mixture of di-tert-butyl (6′-bromo-2′,2′-dimethyldispiro[1,3-oxazole-4,4′-chromene-3′,3″-oxetan]-2-yl)imidodicarbonate (13.8 mg), 3-chloro-5-fluorophenylboronic acid (8.7 mg), Pd(PPh3)4 (2.9 mg) and 1M aqueous Na2CO3 (0.063 mL) in dioxane (0.25 mL) was stirred for 12 hours at 100° C. The mixture was filtered by using Chem Elut cartridges and washed with CHCl3. The filtrate was evaporated. The residue was purified with HPLC (Column: Waters SunFire™ Prep C18 OBD™ 5 micrometer, 19×100 mm; MeOH/0.1% aqueous HCOOH 11/89 to 95/5(v/v)) and afforded 6′-(3-chloro-5-fluorophenyl)-2′,2′-dimethyldispiro[1,3-oxazole-4,4′-chromene-3′,3″-oxetan]-2-amine (4.6 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](=O)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C:5]([Cl:17])=[CH:4][C:3]=1[O:18][CH3:19].Cl.[NH2:21][OH:22]>N1C=CC=CC=1>[F:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1/[C:8](=[N:21]/[OH:22])/[C:6]1[CH:7]=[C:2]([Cl:1])[C:3]([O:18][CH3:19])=[CH:4][C:5]=1[Cl:17]
Reactant: COc1cc(Cl)c(C(=O)c2ccccc2F)cc1Cl
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: COc1cc(Cl)c(/C(=N\O)c2ccccc2F)cc1Cl

Procedure:
A mixture of 2,5-dichloro-4-(2-fluorobenzoyl)anisole (3 g) and hydroxylamine hydrochloride (1.4 g) in pyridine (25 ml) is refluxed for several hours until no ketone remains. The pyridine is removed under high vacuum and the residue diluted with water, then extracted with chloroform. The chloroform solution is dried and the chloroform removed to give a solid which is recrystallized from ether to afford (z)-2'-fluoro-2,5-dichloro-4-methoxybenzophenone oxime, mp 188° C.
Reaction SMILES: [OH:1][CH:2]1[C:7]2[NH:8][C:9]3[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][C:14]=3[C:6]=2[C:5](=[O:16])[N:4]([CH3:17])[CH2:3]1.[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]=[CH2:26])=[CH:21][N:20]=1.[OH-].[K+]>CN1C(=O)CCC1>[OH:1][CH:2]1[C:7]2[N:8]([CH2:26][CH2:25][C:22]3[CH:21]=[N:20][C:19]([CH3:18])=[CH:24][CH:23]=3)[C:9]3[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][C:14]=3[C:6]=2[C:5](=[O:16])[N:4]([CH3:17])[CH2:3]1
Reactant: C=Cc1ccc(C)nc1
Reactant: Cc1ccc2[nH]c3c(c2c1)C(=O)N(C)CC3O
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(C)nc2)C(O)CN(C)C1=O

Procedure:
The title compound is prepared from a mixture of 3,4-dihydro-4-hydroxy-2,8-dimethyl-2H-pyrido[4,3-b]indol-1(5H)-one, 2-methyl-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH3:35][C:36]1[CH:37]=[C:38]([CH:40]=[CH:41][C:42]=1[CH3:43])[NH2:39]>CN(C=O)C.O>[CH3:35][C:36]1[CH:37]=[C:38]([NH:39][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:2]([OH:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=2)[CH:40]=[CH:41][C:42]=1[CH3:43]
Reactant: Cc1ccc(N)cc1C
Reactant: O=C(O)c1ccc(O)c([N+](=O)[O-])c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(NC(=O)c2ccc(O)c([N+](=O)[O-])c2)cc1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of 4-hydroxy-3-nitrobenzoic acid (732 mg), EDCI (768 mg) and HOBt (540 mg) in DMF (8 mL) was added 3,4-dimethylaniline (484 mg) and the mixture was stirred at room temperature for 18 h. The mixture was poured into water and was extracted with EtOAc. The organic phase was washed with water (3×) and dried over sodium sulfate. The solvent was concentrated until crystallization occurred. The mixture was cooled to room temperature and the solid filtered, washed with EtOAc and dried under reduced pressure to give N-(3,4-dimethyl-phenyl)-4-hydroxy-3-nitrobenzamide as a pale-yellow solid, mp=209-212° C.; MS (m/z) 285 (M−1).
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[NH:4][C:3]1=[O:20].[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[C:22]1[C:30](Cl)=[O:31].C(N(CC)CC)C>C(Cl)Cl>[F:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:7]1[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[NH:4][C:3](=[O:20])[CH:2]([NH:1][C:30]([C:22]2[NH:21][C:29]3[C:24]([CH:23]=2)=[CH:25][CH:26]=[CH:27][CH:28]=3)=[O:31])[N:8]=1
Reactant: NC1N=C(c2ccccc2F)c2ccccc2NC1=O
Reactant: O=C(Cl)c1cc2ccccc2[nH]1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC1N=C(c2ccccc2F)c2ccccc2NC1=O)c1cc2ccccc2[nH]1
Reaction time: 0.17 h

Procedure:
3-(RS)-Amino-1,3-dihydro-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one (1.5 gm, 5.57 mmol), indole-2-carbonyl chloride (1.05 gm, 5.85 mmol) and triethylamine (0.814 ml, 5.85 mmol) were combined in CH2Cl2 (15 ml) and stirred 10 min. The reaction was concentrated and chromatographed on silica gel (5% MeOH in CH2Cl2) to give the title compound as a white solid from CH2Cl2 : (m.p. 290°-291°).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[NH:9][CH:8]=[C:7]([CH2:10][CH2:11][OH:12])[C:5]=2[CH:6]=1.[C:13]([NH:16][CH2:17][C:18](=O)[CH3:19])(=[O:15])[CH3:14]>C1C=CC=CC=1>[C:13]([NH:16][CH2:17][C:18]1([CH3:19])[C:8]2[NH:9][C:4]3[C:5]([C:7]=2[CH2:10][CH2:11][O:12]1)=[CH:6][CH:1]=[CH:2][CH:3]=3)(=[O:15])[CH3:14]
Reactant: CC(=O)CNC(C)=O
Reactant: OCCc1c[nH]c2ccccc12
Solvent: c1ccccc1
Product: CC(=O)NCC1(C)OCCc2c1[nH]c1ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of tryptophol (3.86 g; II, R2, R3, R4, R5, R6 = H and X1 =OH) and acetamidoacetone (3.0 g), see R. H. Wileg and O. H. Borum, J. Amer. Chem. Soc., 70, 2005 (1948), in 300 ml of dry benzene is stirred and heated to reflux. Water is collected in a Dean-Stark trap. After removal of the water five drops of boron trifluoride-etherate is added and the mixture refluxed 30 min. using the water-separator again. After stirring at room temperature overnight, the reaction mixture is evaporated to dryness. The solid residue is dissolved in chloroform and washed successively with 10% aqueous sodium bicarbonate, water, and brine. The chloroform solution is dried over magnesium sulfate, filtered, and evaporated. The residue is crystallized from benzene to yield 1-(acetamidomethyl)-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole, m.p. 100° - 102° C. This product is dried under reduced pressure at 27° C. Spectroscopic and analytical data show that the compound is solvated with one mole of benzene which can be removed completely only by melting. Rf values of the amide and tryptophol are equal.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH3:14]>>[Cl:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:14])=[O:5]
Reactant: N
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1Cl
Product: NC(=O)c1ccc([N+](=O)[O-])cc1Cl
Yield: 90 %

Procedure:
Thereafter, 2-chloro-4-nitrobenzoyl chloride (450 g, 2.1 m) was added dropwise to a stirred 28% ammonia solution (2,000 ml) at below room temperature between 9° and 16° C. The precipitated reaction mixture was washed with water and 30% methanol and then vacuum-dried to yield 2-chloro-4-nitrobenzamide (379 g, 90%, mp 168°-170° C.).
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH3:17])[CH:15]=2)[N:10]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=[CH:20][CH:19]=2)[CH:9]=1)=[O:7]>O1CCCC1.O>[C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH3:17])[CH:15]=2)[N:10]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=[CH:20][CH:19]=2)[CH:9]=1)([OH:7])=[O:5]
Reactant: COC(=O)c1cn(-c2ccnc3ccccc23)c2ccc(C)cc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)c(C(=O)O)cn2-c1ccnc2ccccc12
Reaction time: 22 h
Yield: 98.3 %

Procedure:
0.422 g (10.05 mmol) of lithium hydroxide monohydrate and 50 cm3 of water are added at 25° C. to 1.06 g (3.35 mmol) of 3-methoxycarbonyl-5-methyl-1-(quinol-4-yl)-1H-indole dissolved in 50 cm3 of tetrahydrofuran. After stirring at the reflux point of the solvent for 22 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is taken up in 25 cm3 of water and then triturated with 10 cm3 of N hydrochloric acid. After filtering off and drying the solid residue under reduced pressure (2.7 kPa) at 40° C., 0.996 g of 3-carboxy-5-methyl-1-(quinol-4-yl)-1H-indole is obtained in the form of a white solid. Mass spectrum (EI): m/e 302 (M+·).
Reaction SMILES: F[C:2]([C:4]([O:10][C:11]([C:14]([C:17]([F:20])([F:19])[F:18])([F:16])[F:15])([F:13])[F:12])([C:6]([F:9])([F:8])[F:7])[F:5])=[O:3].[F:21][S:22]([CH2:25][CH2:26][O:27][CH2:28][CH2:29][OH:30])(=[O:24])=[O:23]>>[F:21][S:22]([CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][C:2]([C:4]([O:10][C:11]([C:14]([C:17]([F:18])([F:19])[F:20])([F:15])[F:16])([F:12])[F:13])([C:6]([F:9])([F:8])[F:7])[F:5])=[O:3])(=[O:24])=[O:23]
Reactant: O=C(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Reactant: O=S(=O)(F)CCOCCO
Product: O=C(OCCOCCS(=O)(=O)F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F

Procedure:
FCOCF(CF3)OCF2CF2CF3 obtained in Example 4 was reacted with FSO2CH2CH2OCH2CH2OH under the same conditions as in the above esterification to obtain FSO2CH2CH2OCH2CH2OCOCF(CF3)OCF2CF2CF3. The obtained FSO2CH2CH2OCH2CH2OCOCF(CF3)OCF2CF2CF3 was fluorinated under the same conditions as in the above fluorination step to obtain FSO2CF2CF2OCF2CF2OCOCF(CF3)OCF2CF2CF3. The obtained FSO2CF2CF2OCF2CF2OCOCF(CF3)OCF2CF2CF3 was decomposed under the same conditions as in the above decomposition step to obtain FSO2CF2CF2OCF2COF and FCOCF(CF3)OCF2CF2CF3.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](I)=[N:6][CH:7]=1.[NH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16]>CCOC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:9][CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[N:6][CH:7]=1
Reactant: Brc1ccc(I)nc1
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCNc1ccc(Br)cn1
Temperature: 170 °C
Reaction time: 3 h

Procedure:
A mixture of 8.86 g (31.20 mmol) of 5-bromo-2-iodopyridine and 10.00 g (62.42 mmol) of tert-butyl (2-aminoethyl)carbamate was stirred for 3 hours at 170° C. The reaction mixture was cooled to RT and diluted with EtOAc. The organic phase was washed with saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, and evaporated down in vacuo. The crude product was purified by chromatography (silica gel, cyc/EtOAc 4:1). Yield: 2.37 g (24% of theoretical); C12H18BrN3O2 (M=316.194); calc.: molpeak (M+H)+:316/318 (Br); found: molpeak (M+H)+:316/318 (Br); Rf value: 0.22 (silica gel, cyc/EtOAc 2:1).
Reaction SMILES: [OH:1][CH:2]([CH:9]([CH3:13])[CH2:10][CH2:11][CH3:12])[CH:3]([CH3:8])[C:4]([O:6][CH3:7])=[O:5].[O:14]1[CH:19]=[CH:18][CH2:17][CH2:16][CH2:15]1.C(Cl)Cl>O1CCCC1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[CH3:8][CH:3]([CH:2]([O:1][CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][O:14]1)[CH:9]([CH3:13])[CH2:10][CH2:11][CH3:12])[C:4]([O:6][CH3:7])=[O:5]
Reactant: CCCC(C)C(O)C(C)C(=O)OC
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCC(C)C(OC1CCCCO1)C(C)C(=O)OC
Reaction time: 8 h
Yield: 121.2 %

Procedure:
200 mg (1.06 mmol) of methyl (+)-3-hydroxy-2,4-dimethylheptanoate was dissolved in 4 ml of tetrahydrofuran, and 134 mg (1.59 mmol) of dihydropyran and 1 mg of pyridinium p-toluenesulfonate were added, and the mixture was reacted overnight at room temperature. Since TLC showed that the starting materials still remained, 5 mg of pyridinium p-toluenesulfonate and 3 ml of methylene chloride were added, and the reaction was further carried out overnight at room temperature. The reaction mixture was extracted with ether. The ethereal layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and then with an aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate, filtered, and concentrated to give 350 mg of crude methyl (+)-2,4-dimethyl-3-tetrahydropyranyloxy-1heptanoate (6).