Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][C@@H:9]([CH3:26])[C@:10]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[F:25])([OH:17])[CH2:11][N:12]1[CH:16]=[N:15][CH:14]=[N:13]1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].O>C1COCC1>[F:25][C:19]1[CH:20]=[C:21]([F:24])[CH:22]=[CH:23][C:18]=1[C@:10]([OH:17])([C@@H:9]([OH:8])[CH3:26])[CH2:11][N:12]1[CH:16]=[N:15][CH:14]=[N:13]1
Reactant: C[C@H](O[Si](C)(C)C(C)(C)C)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reaction time: 3.5 h
Yield: 868.9 %

Procedure:
To a solution of 0.10 g of (2R,3S)-3-(tert-butyldimethylsilyloxy)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol in 1 mL of THF was added 0.3 mL of TBAF (1 M) at room temperature. Stirring was performed at room temperature for 3.5 hours, and 5 mL of water was added thereto. Then, extraction was performed with ethyl acetate (30 mL). After drying over anhydrous sodium sulfate, concentration was performed under reduced pressure to obtain a crude product. The resulting product was purified by column on silica gel to obtain 0.61 g of the title compound (yield: 87%). 1H-NMR (400 MHz, CDCl3) δ: 0.97 (d, 3H, J=6.3 Hz), 4.31 (q, 1H, J=6.3 Hz), 4.79-4.82 (m, 2H), 6.67-6.81 (m, 2H), 7.32-7.38 (m, 1H), 7.72 (s, 1H), 7.93 (s, 1H).
Reaction SMILES: Br[C:2]1[N:3]([C:19]#[N:20])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH3:21][C:22]1[C:26](B(O)O)=[C:25]([CH3:30])[S:24][N:23]=1.C(=O)([O-])O.[Na+]>COCCOC.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>[CH3:21][C:22]1[C:26]([C:2]2[N:3]([C:19]#[N:20])[C:4]3[C:9]([C:10]=2[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[CH:8][CH:7]=[CH:6][CH:5]=3)=[C:25]([CH3:30])[S:24][N:23]=1
Reactant: COc1ccc(-c2c(Br)n(C#N)c3ccccc23)cc1
Reactant: Cc1nsc(C)c1B(O)O
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: COCCOC
Product: COc1ccc(-c2c(-c3c(C)nsc3C)n(C#N)c3ccccc23)cc1
Temperature: 120 °C
Yield: 50.3 %

Procedure:
2-bromo-3-(4-methoxyphenyl)-1H-indole-1-carbonitrile (70.0 mg, 0.21 mmol), tetrakis(triphenylphosphine)palladium (24.7 mg, 0.21 mmol) and 3,5-dimethylisothiazol-4-ylboronic acid (102.3 mg, 0.43 mmol) were mixed in 3.5 ml DME and 0.86 ml sodium hydrogen carbonate (1 M) under nitrogen. The resulting mixture was heated at 120° C. for 20 min in microwave. The solvent was evaporated and the residue was dissolved in DCM. Filtering through a short plug of silica gave a crude product which was purified on silica (EtOAc/n-Heptane 1:4). 38.0 mg 2-(3,5-dimethylisothiazol-4-yl)-3-(4-methoxyphenyl)-1H-indole-1-carbonitrile was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C:12]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)([CH2:17][CH3:18])[C:13]([CH3:16])([OH:15])[CH3:14].CN1CCOCC1.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>C(Cl)Cl>[Cl:25][C:22]1[CH:21]=[CH:20][C:19]([C:12]([N:6]2[C:7]3[C:3](=[C:2]([NH:1][S:34]([CH3:33])(=[O:36])=[O:35])[CH:10]=[C:9]([F:11])[CH:8]=3)[CH:4]=[CH:5]2)([CH2:17][CH3:18])[C:13]([OH:15])([CH3:16])[CH3:14])=[CH:24][CH:23]=1
Reactant: CCC(c1ccc(Cl)cc1)(n1ccc2c(N)cc(F)cc21)C(C)(C)O
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCC(c1ccc(Cl)cc1)(n1ccc2c(NS(C)(=O)=O)cc(F)cc21)C(C)(C)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of compound 3-(4-amino-6-fluoro-1H-indol-1-yl)-3-(4-chlorophenyl)-2-methylpentan-2-ol (176 mg, 0.489 mmol) and NMM (145 mg, 1.467 mmol) in DCM (10.0 mL) was added methanesulfonyl chloride (112 mg, 0.978 mmol) dropwise. Then the mixture was stirred at room temperature overnight. The reaction was quenched with saturated ammonium chloride solution, and extracted with ethyl acetate (50 mL). The organic layers was washed with brine, dried over dry sodium sulfate, filtered and evaporated. The residue was purified by Prep-TLC (eluent: ethyl acetate/petroleum=4:1) to obtain the title compound. LC/MS m/z=438.9 [M+H]+. 1H NMR (400 MHz, MeOD) δ 8.02 (s, 1H), 7.57-7.25 (m, 4H), 6.86 (dd, J=10.9, 2.1 Hz, 1H), 6.74 (d, J=3.6 Hz, 1H), 5.85 (d, J=11.1 Hz, 1H), 3.00 (s, 3H), 2.84-2.73 (m, 1H), 2.61-2.47 (m, 1H), 1.31 (s, 3H), 1.27 (s, 3H), 0.64 (t, J=7.3 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:18])[C@:11]([OH:17])([CH3:16])[C:12]([F:15])([F:14])[F:13].[SH:19][CH2:20][CH2:21][OH:22].C[O-].[Na+]>N1C=CC=CC=1.N1C2C(=CC=CC=2)C=CC=1.C(OCC)(=O)C.[Cu]Cl>[Cl:1][C:2]1[CH:7]=[C:6]([S:19][CH2:20][CH2:21][OH:22])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:18])[C@:11]([OH:17])([CH3:16])[C:12]([F:15])([F:14])[F:13]
Reactant: C[C@@](O)(C(=O)Nc1ccc(I)cc1Cl)C(F)(F)F
Reactant: OCCS
Agent: Cl[Cu]
Agent: C[O-]
Agent: [Na+]
Solvent: c1ccc2ncccc2c1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: C[C@@](O)(C(=O)Nc1ccc(SCCO)cc1Cl)C(F)(F)F
Temperature: 190 °C

Procedure:
A solution of (R)-N-[2-chloro-4-iodophenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Example 197) (0.8 g) in pyridine (1 ml) was added to a deoxygenated solution of 2-mercaptoethanol (0.18 ml), sodium methoxide (0.14 g) and copper(I) chloride (0.2 g) in quinoline (2 ml) and pyridine (2 ml). The mixture was heated to 190° C. under argon for 18 hours. The mixture was allowed to cool to room temperature then dissolved in ethyl acetate (100 ml), washed with dilute aqueous hydrochloric acid (2×50 ml) and brine (2×50 ml) then dried. Volatile material was removed by evaporation and the residue was purified by chromatography on a silica gel Mega Bond Elut column eluting with 10-60% ethyl acetate/iso-hexane to give the title compound as a gum. NMR (CDCl3): 1.76 (s, 3H), 3.10 (t, 2H), 3.75-3.80 (m, 2H), 7.31-7.34 (m, 1H), 7.47 (s, 1H), 8.31 (d, 1H), 8.86 (s, 1H); MS (ESPF): 342.
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH2:3][NH:2]1.[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:14]([N:2]1[CH2:3][CH2:4][C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[NH:12][C:13]=2[CH2:1]1)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: c1ccc2c3c([nH]c2c1)CNCC3
Product: O=C(c1ccccc1)N1CCc2c([nH]c3ccccc23)C1

Procedure:
A tetrahydro-β-carboline (II) is reacted with benzoyl chloride to provide a 2-benzoyl-1,2,3,4-tetrahydro-9H-pyrido-(3,4-b)-indole (III). Then compound (III) is reduced to give a 2-benzyl-1,2,3,4-tetrahydro-9H-pyrido-(3,4-b)-indole (IV). Thereafter, compound (IV) is transformed by t-butyl hypochlorite into a chloroindolenine derivative (V) which is immediately treated with a metal dialkylmalonate such as thallium t-butyl methyl malonate to give a dialkyl 3-benzyl-1,2,3,4,5,6-hexahydroazepino-(4,5-b)-indole-5,5-dicarboxylate (VI). Compound (VI) is then partly decarboxylated into a alkyl 3-benzyl-1,2,3,4,5,6-hexahydro-(4,5-b) indole-5-carboxylate (VII). Compound (VII) is hydrogenated to give an alkyl 1,2,3,4,5,6-hexahydroazepino-(4,5-b)-indole 5-carboxylate (VIII). In an alternative embodiment, compound (VI) can be hydrogenated to the corresponding dialkyl 1,2,3,4,5,6-hexahydroazepino-(4,5-b)-indole-5,5-dicarboxylate which is then decarboxylated into compound (VIII). Compound (VIII) is condensed with a functionalised aldehyde, typically a epoxy aldehyde or a haloaldehyde such as 1-bromo-4-formylhexane, to give vincadifformine or similar pentacyclic derivatives.
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:11][CH2:12][C:13](Cl)=[O:14].ClCC(NN)=O>C1(C(C2C=CC=CC=2)CCN2CCCNCC2)C=CC=CC=1.CO.C(Cl)Cl>[C:1]([NH:9][NH:10][C:13](=[O:14])[CH2:12][Cl:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)CCl
Reactant: NNC(=O)c1ccccc1
Agent: NNC(=O)CCl
Agent: c1ccc(C(CCN2CCCNCC2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CO
Product: O=C(CCl)NNC(=O)c1ccccc1
Yield: 54.5 %

Procedure:
1-Benzoyl-2-(chloroacetyl)hydrazine (850 mg, 54%) was prepared from benzhydrazide (1.00 g, 7.34 mmol) and chloroacetyl chloride (0.58 mL, 7.34 mmol, 1 equiv) using general procedure. Compound No. 78 (300 mg, 51%) was prepared from 1-(3,3-diphenyipropyl)homopiperazine (100 mg, 0.34 mmol) and 1-benzoyl-2-(chloroacetylhydrazine (80 mg, 0.38 mmol) employing general alkylation procedure. TLC Rf=0.44 (10% CH3OH—CH2Cl2), RPLC tR=5.85 min (>85%), 220 nm (Method B): ESI/MS m/e 471.3 (M++H, C29H34N4O2).
Reaction SMILES: [CH2:1]([N:3]([CH3:27])[C:4]1[N:26]=[C:7]2[CH:8]=[C:9]([NH:12][C:13]([C:15]3[N:19]([CH3:20])[N:18]=[CH:17][C:16]=3[C:21]([O:23]CC)=[O:22])=[O:14])[CH:10]=[CH:11][N:6]2[N:5]=1)[CH3:2].O.[OH-].[Li+].Cl>CO.O>[CH2:1]([N:3]([CH3:27])[C:4]1[N:26]=[C:7]2[CH:8]=[C:9]([NH:12][C:13]([C:15]3[N:19]([CH3:20])[N:18]=[CH:17][C:16]=3[C:21]([OH:23])=[O:22])=[O:14])[CH:10]=[CH:11][N:6]2[N:5]=1)[CH3:2]
Reactant: CCOC(=O)c1cnn(C)c1C(=O)Nc1ccn2nc(N(C)CC)nc2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCN(C)c1nc2cc(NC(=O)c3c(C(=O)O)cnn3C)ccn2n1
Temperature: 50 °C
Reaction time: 5 h
Yield: 90.5 %

Procedure:
A mixture of ethyl 5-(2-(ethyl(methyl)amino)-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylate (366 mg, 985 μmol) and lithium hydroxide hydrate (82.7 mg, 1.97 mmol) in methanol (15 ml) and water (5 ml) was stirred for 5 hours at 50° C. The methanol was evaporated, the residue was diluted with water and was then neutralized with hydrochloric acid 1N (1.97 ml, 1.97 mmol). The precipitated white solid was filtered off, washed with water several times and dried affording 5-[2-(ethyl-methyl-amino)-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl]-1-methyl-1H-pyrazole-4-carboxylic acid (306 mg, 90.4%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32]([C@@H:34]3[CH2:38][CH2:37][CH2:36][N:35]3[C:39](=[O:53])[C@@H:40]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[N:41]3[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]3)=[O:33])=[CH:27][CH:26]=2)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]([C@@H:19]3[CH2:23][CH2:22][CH2:21][NH:20]3)=[O:18])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[CH3:54][O:55][C:56]([NH:58][C@@H:59]([C@H:63]1[CH2:67][CH2:66][O:65][CH2:64]1)[C:60](O)=[O:61])=[O:57]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]([C@@H:19]3[CH2:23][CH2:22][CH2:21][N:20]3[C:60](=[O:61])[C@@H:59]([NH:58][C:56](=[O:57])[O:55][CH3:54])[C@H:63]3[CH2:67][CH2:66][O:65][CH2:64]3)=[O:18])=[CH:12][CH:11]=2)[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32]([C@@H:34]3[CH2:38][CH2:37][CH2:36][N:35]3[C:39](=[O:53])[C@@H:40]([C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=3)[N:41]3[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46]3)=[O:33])=[CH:27][CH:26]=2)=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc(CN(Cc2ccc(NC(=O)[C@@H]3CCCN3C(=O)[C@@H](c3ccccc3)N3CCCCC3)cc2)c2ccc(F)cc2)cc1)[C@@H]1CCCN1
Reactant: COC(=O)N[C@H](C(=O)O)[C@H]1CCOC1
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)Nc1ccc(CN(Cc2ccc(NC(=O)[C@@H]3CCCN3C(=O)[C@@H](c3ccccc3)N3CCCCC3)cc2)c2ccc(F)cc2)cc1)[C@H]1CCOC1

Procedure:
The product from Example 114C (0.040 g, 0.056 mmol) and (S)-2-(methoxycarbonylamino)-2-((R)-tetrahydrofuran-3-yl)acetic acid (0.014 g, 0.067 mmol) were processed as in Example 81A to give the title compound. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.29-1.38 (m, 2 H) 1.39-1.47 (m, 4 H) 1.68-1.78 (m, 1 H) 1.79-1.90 (m, 4 H) 1.93-2.06 (m, 4 H) 2.10-2.22 (m, 1 H) 3.14-3.25 (m, 1 H) 3.41-3.50 (m, 4 H) 3.53 (s, 3 H) 3.58-3.70 (m, 4 H) 3.71-3.79 (m, 2 H) 3.80-3.90 (m, 2 H) 4.20-4.28 (m, 2 H) 4.31 (dd, J=7.64, 4.07 Hz, 1 H) 4.44 (dd, J=7.97, 4.93 Hz, 1 H) 4.56 (s, 4 H) 6.64 (dd, J=9.22, 4.34 Hz, 2 H) 6.91 (t, J=8.95 Hz, 2 H) 7.18 (d, J=8.13 Hz, 4 H) 7.25-7.37 (m, 3 H) 7.42 (d, J=6.83 Hz, 2 H) 7.51 (dd, J=8.57, 1.84 Hz, 4 H) 7.60 (d, J=8.02 Hz, 1 H) 9.96 (s, 1 H) 9.98 (s, 1 H); MS ESI− m/z 900.6 (M−H)−.
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.[CH3:8][O:9][C:10]1[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[C:16]2[C:11]=1[C:12](=[O:24])[N:13]([CH3:23])[C:14](=[O:22])[NH:15]2.[OH-].[K+]>>[CH3:8][O:9][C:10]1[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[C:16]2[C:11]=1[C:12](=[O:24])[N:13]([CH3:23])[C:14](=[O:22])[N:15]2[CH3:5]
Reactant: COS(=O)(=O)OC
Reactant: COc1ccc2[nH]c(=O)n(C)c(=O)c2c1OC
Agent: [K+]
Agent: [OH-]
Product: COc1ccc2c(c1OC)c(=O)n(C)c(=O)n2C

Procedure:
Dimethyl sulfate (2.5 ml, 3.33 g, 26.40 mM) was added to 5,6-dimethoxy-3-methylquinazolin-2,4(1H, 3H)-dione (2.0 g, 8.47 mM). The mixture was heated at 80°-85° C. (oil bath temperature) for five minutes. Aqueous KOH (7.9 ml of a 5N solution) was added gradually until the pH of the reaction mixture remained basic. The reaction mixture was cooled and the resulting solid filtered, washed with a small amount of H2O and dried to afford the title compound as a white solid; 1.74 g (80.6%); mp 136°-139° C.; CF3COOH(TMS) 7.75 (d, 1H, J7,8 =9.0Hz, 7-H), 7.33 (d, 1H, J8,7 =9.0Hz, 8-H), 4.28 (s, 3H, 5 or 6-OCH3), 4.07 (s, 3H, 5 or 6-OCH3), 3.80 (s, 3H, 1 or 3-N-CH3), 3.73 (s, 3H, 1 or 3-N-CH3); M+ 250.
Reaction SMILES: [NH2:1][C:2]1[N:21]=[C:20]2[CH:22]=[C:4]([C:5]3[CH:28]=[C:9]([C:10](=[O:27])[NH:11][C@H:12]([C:24]([OH:26])=O)[CH2:13][CH2:14][NH:15][C:16](=[O:23])[CH2:17][CH2:18][S:19]2)[C:8]([CH3:29])=[CH:7][C:6]=3[CH3:30])[N:3]=1.O[N:32]1[C:36]2C=CC=CC=2N=N1.CN.Cl.C(N=C=NCCCN(C)C)C.C(N(C(C)C)CC)(C)C>CN(C)C=O.C(OCC)(=O)C>[CH3:36][NH:32][C:24]([C@H:12]1[NH:11][C:10](=[O:27])[C:9]2=[CH:28][C:5](=[C:6]([CH3:30])[CH:7]=[C:8]2[CH3:29])[C:4]2=[CH:22][C:20](=[N:21][C:2]([NH2:1])=[N:3]2)[S:19][CH2:18][CH2:17][C:16](=[O:23])[NH:15][CH2:14][CH2:13]1)=[O:26]
Reactant: On1nnc2ccccc21
Reactant: Cc1cc(C)c2cc1C(=O)N[C@H](C(=O)O)CCNC(=O)CCSc1cc-2nc(N)n1
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CNC(=O)[C@@H]1CCNC(=O)CCSc2cc(nc(N)n2)-c2cc(c(C)cc2C)C(=O)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.3 %

Procedure:
(S)-4-Amino-18,20-dimethyl-10,16-dioxo-7-thia-3,5,11,15-tetraazatricyclo[15.3.1.12,6]docosa-1(20),2(22),3,5,17(21),18-hexaene-14-carboxylic acid (25 mg, 0.058 mmol) obtained in Example 2-13 and 1-hydroxybenzotriazole (24 mg, 0.175 mmol) were dissolved in N,N-dimethylformamide (580 μl). Methylamine (2.0 M tetrahydrofuran solution, 88 μl, 0.175 mmol), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (34 mg, 0.175 mmol), and diisopropylethylamine (0.073 ml, 0.42 mmol) were added to the solution. The resulting mixture was stirred overnight at room temperature. The reaction solution was diluted with ethyl acetate, and sequentially washed with a saturated aqueous sodium bicarbonate solution, water (three times), and a saturated aqueous sodium chloride solution. The washed organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting crude product was purified by preparative thin layer silica gel chromatography (developing solvent: dichloromethane:methanol=10:1) to yield (S)-4-amino-18,20-dimethyl-10,16-dioxo-7-thia-3,5,11,15-tetraazatricyclo[15.3.1.12,6]docosa-1(20),2(22),3,5,17(21),18-hexaene-14-carboxylic acid methylamide (Compound 65) (7 mg) was obtained as a white solid material.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][C:5](=[O:8])[NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:17]1[C:22]([N+:23]([O-:25])=[O:24])=[N:21][CH:20]=[CH:19][N:18]=1>C(O)(C)C.C(Cl)(Cl)Cl>[N+:23]([C:22]1[C:17]([N:1]2[CH2:7][CH2:6][C:5](=[O:8])[NH:4][CH2:3][CH2:2]2)=[N:18][CH:19]=[CH:20][N:21]=1)([O-:25])=[O:24]
Reactant: O=C1CCNCCN1
Reactant: O=[N+]([O-])c1nccnc1Cl
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: O=C1CCN(c2nccnc2[N+](=O)[O-])CCN1
Reaction time: 20 h

Procedure:
To a solution of hexahydro-1H-1,4-diazepin-5-one (1.14 g, 10 mmol) and triethylamine (1.01 g, 10 mmol) in isopropanol (30 ml) cooled in an ice bath, was added over 30 minutes a solution of 2-chloro-3-nitropyrazine (1.59 g, 10 mmol) in chloroform (20 ml). After addition was complete, the reaction mixture was allowed to warm to 20°-25° and was stirred at this temperature for 20 hours. Solvents were removed under reduced pressure and the residue was partitioned between a saturated aqueous solution of sodium chloride and ethyl acetate. The ethyl acetate extract was dried over anhydrous sodium sulfate, filtered and concentrated to an oil. Flash chromatography over silica gel and elution with 2% methanol -98% chloroform gave pure 1-(3-nitro-2-pyrazinyl)hexahydro-1H-1,4-diazepin-5-one. ##STR3##
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([NH:13][CH2:14][CH2:15][O:16][CH3:17])[C:7]([CH2:18]O)=[CH:6]2.O=S(Cl)[Cl:22]>C(Cl)Cl>[ClH:22].[Cl:22][CH2:18][C:7]1[C:8]([NH:13][CH2:14][CH2:15][O:16][CH3:17])=[N:9][C:10]2[C:5]([CH:6]=1)=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2
Reactant: O=S(Cl)Cl
Reactant: COCCNc1nc2ccc(OC)cc2cc1CO
Solvent: ClCCl
Product: COCCNc1nc2ccc(OC)cc2cc1CCl
Product: Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
To a stirred solution of (6-methoxy-2-(2-methoxyethylamino)quinolin-3-yl)methanol SLA 47064A (0.90 g, 3.43 mmol) in dry CH2Cl2 (30 mL) in a 100 mL round-bottomed flask equipped with a magnetic stirrer was added dropwise SOCl2 (4.98 mL, 68.6 mmol). The mixture was stirred for 1.5 h at RT then concentrated to dryness at 40° C. under vacuum. The residue was then taken up in CH2Cl2 (20 mL) before concentration back to dryness at 40° C. under vacuum (done 3 times) to give 3-(chloromethyl)-6-methoxy-N-(2-methoxyethyl)quinolin-2-amine hydrochloride SLA 47064 as a yellow solid (1.13 g, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:10]([O-])=O)[CH:5]=[C:6]([CH2:8][CH3:9])[CH:7]=1>C(O)(=O)C.C(O)C.[Fe]>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([CH2:8][CH3:9])[CH:7]=1)[NH2:10]
Reactant: CCc1cc(Br)cc([N+](=O)[O-])c1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Product: CCc1cc(N)cc(Br)c1

Procedure:
Dissolve 3-bromo-5-ethylnitrobenzene (6.21g, 27mmol) in acetic acid (40mL) and ethanol (30mL) and treat with iron powder (2.7g). Reflux for 3 hours, filter through Celite and evaporate the solvent in vacuo. Purify by silica gel chromatography to give 3-bromo-5-ethylaniline.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]([CH:16]=1)=[C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[O:8][N:9]=2.C(O)(=O)C>[Zn].O>[NH2:9][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:16][C:6]=1[C:7]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:8]
Reactant: Brc1ccc2noc(-c3ccccc3)c2c1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: Nc1ccc(Br)cc1C(=O)c1ccccc1
Temperature: 80 °C
Yield: 94 %

Procedure:
5-Bromo-3-phenyl-2,1-benzisoxazole (7.5 g, 28.6 mmol), water (14.6 ml), and zinc dust (9.3 g, 143 mmol) were combined. Acetic acid (8.6 ml, 143 mmol) was added and the mixture was stirred and heated at 80° C. for 90 minutes. After cooling to room temperature, both the liquid and solid portion of the reaction were extracted with methylene chloride. The combined methylene chloride solutions was washed once with sodium hydroxide solution (10%) and several times with water. Drying (sodium sulfate) and evaporation yielded the desired product (7.42 g) of mp. 92°-102° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[NH:6][CH2:5][CH:4]([CH2:7][O:8][CH3:9])[O:3]1.[Br:11][CH:12]([CH2:16][Br:17])[C:13](Cl)=[O:14].C(N(CC)CC)C>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:10])[N:6]([C:13](=[O:14])[CH:12]([Br:11])[CH2:16][Br:17])[CH2:5][CH:4]([CH2:7][O:8][CH3:9])[O:3]1
Reactant: O=C(Cl)C(Br)CBr
Reactant: COCC1CNC(C)(C)O1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: COCC1CN(C(=O)C(Br)CBr)C(C)(C)O1

Procedure:
To 11.6 milliliters of 25 percent w/v, 2,2-dimethyl-5-methoxymethyl oxazolidine solution in 50 milliliters of benzene with 5.0 grams of 2,3-dibromopropionyl chloride was added dropwise 2.1 grams of triethylamine. After the reaction was complete the mixture was washed with water, separated, dried and the organic solvent removed in vacuo. There was obtained 2.7 grams of the title compound, nD30 1.4887. Analytical data supports the structure.
Reaction SMILES: [N+:1]([CH:4]=[C:5](SC)[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[S:12][CH:13]=[CH:14][N:15]=1)([O-:3])=[O:2].[CH3:18][NH2:19]>>[N+:1]([CH:4]=[C:5]([NH:19][CH3:18])[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[S:12][CH:13]=[CH:14][N:15]=1)([O-:3])=[O:2]
Reactant: CN
Reactant: CSC(=C[N+](=O)[O-])NCCSCc1nccs1
Product: CNC(=C[N+](=O)[O-])NCCSCc1nccs1

Procedure:
Reaction of 1-nitro-2-methylthio-2-[2-(2-thiazolylmethylthio)ethylamino]ethylene with methylamine according to the process of Example 8(ii) yielded the title compound, m.p. 103°-104°. (from ethanol ether). (Found: C, 39.4; H, 5.2; N, 20.2% C9H14N4O2S2 requires: C, 39.4; H, 5.1; N, 20.4%).
Reaction SMILES: [CH2:1]([N:7]1[C:15]2[C:10](=[CH:11][C:12]([OH:16])=[CH:13][CH:14]=2)[C:9]([CH2:17][C:18]([NH2:20])=[O:19])=[C:8]1[CH3:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[H-].[Na+].Br[CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>CN(C=O)C.O>[CH2:31]([O:30][C:28](=[O:29])[CH2:27][CH2:26][CH2:25][O:16][C:12]1[CH:11]=[C:10]2[C:15](=[CH:14][CH:13]=1)[N:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:8]([CH3:21])=[C:9]2[CH2:17][C:18]([NH2:20])=[O:19])[CH3:32]
Reactant: CCCCCCn1c(C)c(CC(N)=O)c2cc(O)ccc21
Reactant: CCOC(=O)CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCn1c(C)c(CC(N)=O)c2cc(OCCCC(=O)OCC)ccc21
Reaction time: 1 h
Yield: 53 %

Procedure:
1-Hexyl-5-hydroxy-2-methyl-1H-indole-3-acetamide (230 mg, 0.8 mmol) was dissolved in 10 mL of DMF and 26 mg (0.8 mmol) of 60% NaH/mineral oil added. The mixture was stirred for 1 hour, 0.115 mL (0.8 mmol) of ethyl 4-bromobutyrate added and stirring continued for 96 hours. The mixture was diluted with water, extracted with ethyl acetate, the ethyl acetate washed with water and dried (Na2SO4). The solution was concentrated at reduced pressure and the residue chromatographed on silica gel (eluted with 3% MeOH/methylene chloride) to give 170 mg (53% yield of [4-[[3-(2-amino-2-oxoethyl)-1-hexyl-2-methyl-1-H-indol-5-yl]oxy]butanoic acid ethyl ester, mp, 69-71° C.