Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Mg]Cl.[CH:4]1[C:9]([OH:10])=[CH:8][CH:7]=[C:6]([CH3:11])[CH:5]=1.C1(C)C=CC=CC=1.[CH2:19]=[O:20]>O1CCCC1.CN1CCCN(C)C1=O>[OH:10][C:9]1[CH:8]=[CH:7][C:6]([CH3:11])=[CH:5][C:4]=1[CH:19]=[O:20]
Reactant: C=O
Reactant: Cc1ccc(O)cc1
Agent: C[Mg]Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: Cc1ccc(O)c(C=O)c1
Reaction time: 2 h
Yield: 18 %

Procedure:
Methylmagnesium chloride solution in tetrahydrofuran (100 mL, 3.0M, 300 mmol) at room temperature was treated dropwise over 30 minutes with a solution of 32.3 g (300 mmol) of p-cresol in 30 mL of tetrahydrofuran. An additional 70 mL of tetrahydrofuran was added to moderate the exothermic reaction. The mixture was aged at room temperature for 2 hours then treated with 400 mL of toluene, 41mg of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone and 23 g of paraformaldehyde. The reaction mixture was heated at reflux for 18 hours, then cooled and washed with 200 mL of 2N aqueous hydrochloric acid and 200 mL of water. The organic layer was removed, filtered through Celite, dried over magnesium sulfate, filtered and solvents removed under vacuum. Crystallization of the crude residue from cold hexanes gave 7.4 g (54 mmol, 18%) of the product. The mother liquors were further purified by column chromatography on silica gel, eluting with methylene chloride, to give an additional 17.5 g (128 mmol, 43%) of the product. 1H NMR (200 MHz,CDCl3): 2.33 (s,3H), 6.89 (d,10 Hz,1H), 7.33 (m,2H), 9.83 (s,1H), 10.80 (s,1H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.N([O-])=O.[Na+].[N-:15]=[N+:16]=[N-].[Na+]>FC(F)(F)C(O)=O.O>[N:1]([C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)=[N+:15]=[N-:16]
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: [N-]=[N+]=[N-]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: [N-]=[N+]=Nc1ccc(C(=O)O)cc1
Reaction time: 0.5 h
Yield: 72.7 %

Procedure:
To a solution of 4-aminobenzoic acid (2.00 g, 14.00 mmol) in trifluoroacetic acid (10 ml) at 5° C., was added sodium nitrite (3.50 g) portionwise, and the mixture allowed to stir for 30 min. Sodium azide (3.79 g,) was then added portionwise and the mixture stirred for a further 30 min at 0° C. The mixture was diluted with water, and a white solid precipitated. The solid was filtered, washed with cold water and dried, to afford the title compound (1.66 g, 73%).
Reaction SMILES: O.O.S([O-])([O-])(=O)=O.[Ca+2].CC(N)[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O[C@H]3OC[C@@](O)(C)[C@H](NC)[C@H]3O)[C@H](N)C[C@@H]2N)[C@H](N)CC1.CC(NC)[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O[C@H]3OC[C@@](O)(C)[C@H](NC)[C@H]3O)[C@H](N)C[C@@H]2N)[C@H](N)CC1.C[C@@]1(O)[C@H](NC)[C@@H](O)[C@@H](O[C@@H]2[C@@H](O)[C@H](O[C@H]3O[C@H](CN)CC[C@H]3N)[C@@H](N)C[C@H]2N)OC1.OS(O)(=O)=O.[Na+].[O-:111][C:112]([CH:114]([C:116]1[CH:125]=[CH:124][C:119]([CH2:120][CH:121]([CH3:123])[CH3:122])=[CH:118][CH:117]=1)[CH3:115])=[O:113]>>[OH:113][C:112]([CH:114]([C:116]1[CH:117]=[CH:118][C:119]([CH2:120][CH:121]([CH3:122])[CH3:123])=[CH:124][CH:125]=1)[CH3:115])=[O:111]
Reactant: CC(C)Cc1ccc(C(C)C(=O)[O-])cc1
Agent: CNC(C)[C@@H]1CC[C@@H](N)[C@@H](O[C@H]2[C@H](O)[C@@H](O[C@H]3OC[C@](C)(O)[C@H](NC)[C@H]3O)[C@H](N)C[C@@H]2N)O1
Agent: CN[C@@H]1[C@@H](O)[C@@H](O[C@@H]2[C@@H](O)[C@H](O[C@H]3O[C@H](C(C)N)CC[C@H]3N)[C@@H](N)C[C@H]2N)OC[C@]1(C)O
Agent: CN[C@@H]1[C@@H](O)[C@@H](O[C@@H]2[C@@H](O)[C@H](O[C@H]3O[C@H](CN)CC[C@H]3N)[C@@H](N)C[C@H]2N)OC[C@]1(C)O
Solvent: O
Product: CC(C)Cc1ccc(C(C)C(=O)O)cc1

Procedure:
A mixture of 1,000.0 mg calcium sulfate dihydrate (Fluka), 250.0 mg poly-L-lactide (M-10,000 g/mol), 49.7 mg gentamicin sulfate (AK 628) and 78.5 mg ibuprofen sodium salt (produced through the neutralization of ibuprofen (Fluka)) is ground up. 200 mg of this mixture, respectively, are pressed with a press at a pressure of 5 tons within a period of two minutes into disk-shaped molded bodies with a diameter of 13 mm.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[CH:9]2)([O-:5])=[O:4].Br[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=1>CN(C=O)C>[F:23][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[CH2:16][N:11]1[C:12]2[C:8](=[CH:7][C:6]([N+:3]([O-:5])=[O:4])=[CH:14][CH:13]=2)[CH:9]=[N:10]1
Reactant: Fc1cccc(CBr)c1
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2c(cnn2Cc2cccc(F)c2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (NaH) 95% (0.81 g, 34.1 mmol) was added to a solution of 5-nitro-1H-indazole Compound 4a (5.3 g, 32.5 mmol) in DMF (33 mL) at 0° C. under nitrogen. The mixture was stirred for 1 hour at RT, then 1-bromomethyl-3-fluoro-benzene Compound 4b (6.14 g, 32.5 mmol) was added dropwise at 0° C. After stirring at RT for 12 hours, the reaction mixture was partitioned between ethyl acetate and icy water. The organic layer washed with water, brine, dried (Na2SO4), filtered and the solvent evaporated in vacuo to yield a crude solid. The crude solid was purified via flash chromatography (100% dichloromethane) to yield 1-(3-fluoro-benzyl)-5-nitro-1H-indazole Compound 4c (4.02 g, 46%) as a solid. 1H NMR (400 MHz, CDCl3) δ 8.76-8.75 (1H, m), 8.27-8.23 (2H, m), 7.40-7.38 (1H, m), 7.33-2.27 (1H, m), 7.01-6.97 (2H, m), 6.89-6.86 (1H, m), 5.64 (2H, s); MS (ES+) m/z 272.1 (MH+).
Reaction SMILES: [N:1]1([C:6]2[S:7][C:8]([C:12](=[S:14])[NH2:13])=[C:9]([NH2:11])[N:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.OO>C(O)(=O)C>[NH2:13][C:12]1[S:14][N:11]=[C:9]2[N:10]=[C:6]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[S:7][C:8]=12
Reactant: NC(=S)c1sc(N2CCCC2)nc1N
Agent: OO
Solvent: CC(=O)O
Product: Nc1snc2nc(N3CCCC3)sc12
Temperature: 22 °C
Reaction time: 1 h

Procedure:
5 parts of 2-pyrrolidino-4-amino-5-thiocarbamoylthiazole prepared as described in Example 3(a) and 3(b) are suspended in 50 parts of glacial acetic acid and 1 part of 50 percent strength by weight hydrogen peroxide is added at 20° C. Thereupon, the temperature rises to 30° C. After stirring for one hour at 22° C., the end product is precipitated by means of 100 parts of water, and is filtered off. 4.1 parts (82% of theory) of melting point 262°-264° C. are obtained.
Reaction SMILES: C([O:5][C:6](=[O:17])[C@@H:7]1[CH2:11][CH:10]([O:12]C(C)(C)C)[CH2:9][NH:8]1)(C)(C)C.C(OC(=O)[C@@H]1CCCN1)(C)(C)C.[C:30]([S:33][CH2:34][CH2:35][C:36](Cl)=[O:37])(=[O:32])[CH3:31]>>[C:30]([S:33][CH2:34][CH2:35][C:36]([N:8]1[CH2:9][CH:10]([OH:12])[CH:11]=[C:7]1[C:6]([OH:5])=[O:17])=[O:37])(=[O:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)[C@@H]1CC(OC(C)(C)C)CN1
Reactant: CC(=O)SCCC(=O)Cl
Agent: CC(C)(C)OC(=O)[C@@H]1CCCN1
Product: CC(=O)SCCC(=O)N1CC(O)C=C1C(=O)O

Procedure:
By substituting 4-tert-butoxy-L-proline tert-butyl ester for the L-proline tert-butyl ester and 3-acetylthiopropanoyl chloride for the 3-acethylthio-2-methylpropanoyl chloride in the procedure of Example 1, 1-(3-acetylthio-1-oxopropyl)-4,5-dihydro-4-hydroxy-1H-pyrrole-2-carboxylic acid is obtained.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>COCCOC>[C:13]1([C:2]2[C:11]([CH3:12])=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1cc2ccccc2nc1Cl
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: Cc1cc2ccccc2nc1-c1ccccc1
Yield: 95.7 %

Procedure:
2-Chloro-3-methylquinoline (5.43 g, 30.6 mmol), phenylboronic acid (4.47 g, 36.7 mmol), Pd(II) acetate (0.17 g, 0.76 mmol), and triphenylphosphine (0.80 g, 3.06 mmol) were dissolved in 100 mL DME. To the stirred solution was added K2CO3 (11.4 g dissolved into 41 mL H2O). The entire mixture was allowed to stir at reflux for 18 hours under N2 atmosphere. The cooled mixture was then removed of water, enriched with 150 mL of ethyl acetate, extracted three times from brine, dried over anhydrous sodium sulfate, filtered and evaporated of solvent. The crude liquid was then purified on a silica gel column using 20% ethyl acetate/hexanes. The purest fractions were combined to give 2-phenyl-3-methylquinoline (6.42 g, 95.8% yield).
Reaction SMILES: NC1C=CC2C=CC3N=C(NC(=O)C(C)(C)C)NC(=O)C=3C=2C=1.ClS([C:28]1[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=1)(=O)=O>N1C=CC=CC=1.O>[C:32]([OH:34])(=[O:33])[C:31]1[CH:35]=[CH:36][CH:28]=[CH:29][CH:30]=1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Agent: CC(C)(C)C(=O)Nc1nc2ccc3ccc(N)cc3c2c(=O)[nH]1
Solvent: c1ccncc1
Solvent: O
Product: O=C(O)c1ccccc1
Reaction time: 72 h
Yield: 59.8 %

Procedure:
To a solution of N-(9-Amino-1,2-dihydro-1-oxobenzo[f]quinazolin-3-yl)pivalamide (1.38 g, 4.5 mmoles) in dry pyridine (10 ml) was added 4-(chlorosulfonyl)benzoic acid (5.0 g, 22.6 mmoles) at room temperature under a nitrogen atmosphere. After stirring for 3 days, the pyridine was removed under reduced pressure to leave a gummy brown residue which was suspended in water (30 ml), filtered, washed with water and dried to give 4-((N-(1,2-dihydro-1-oxobenzo[f]quinazolin-3-yl)pivalamide)-9-yl)amino)sulfonyl)benzoic acid (1.65 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:6]=[CH:7][CH:8]=1)#[CH:2].I[C:18]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[CH:20][C:19]=1[NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31].C(N(CC)C(C)C)(C)C>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:30]([O:29][C:28]([NH:27][C:19]1[CH:20]=[CH:21][C:22]([N+:24]([O-:26])=[O:25])=[CH:23][C:18]=1[C:2]#[C:1][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])[CH:6]=[CH:7][CH:8]=1)=[O:34])([CH3:33])([CH3:31])[CH3:32]
Reactant: C#Cc1cccc(NC(=O)OC(C)(C)C)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc([N+](=O)[O-])cc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)Nc1cccc(C#Cc2cc([N+](=O)[O-])ccc2NC(=O)OC(C)(C)C)c1
Temperature: 20 °C
Reaction time: 8 h
Yield: 84.8 %

Procedure:
A solution of tert-butyl (3-ethynylphenyl)carbamate (12.7 g, 58.5 mmol), tert-butyl (2-iodo-4-nitrophenyl)carbamate (14.2 g, 39.0 mmol), bis(triphenylphosphine)palladium(II) chloride (1.37 g, 1.95 mmol), and copper(I) iodide (371 mg, 1.95 mmol) in THF (200 mL) was treated with N,N-diisopropylethylamine (7.47 mL, 42.9 mmol) dropwise and stirred at 20° C. overnight. The reaction mixture was concentrated and diluted with water (200 mL) and ethyl acetate (200 mL). The organic layer was separated, washed with brine, dried with sodium sulfate, filtered, and concentrated to give a yellow/brown solid which was washed with ethyl acetate to give the desired product as light yellow solid (15 g, 85%). LCMS calculated for C24H27N3O6Na (M+Na)+: m/z=476.2.
Reaction SMILES: [CH2:1]([O:8][N:9]([C:20](=[O:40])[CH2:21][CH2:22][C:23](=[O:39])[NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][NH:30][O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:41]1(=[O:47])[O:46][C:44](=[O:45])[CH2:43][CH2:42]1>N1C=CC=CC=1>[CH2:32]([O:31][N:30]([CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][NH:24][C:23](=[O:39])[CH2:22][CH2:21][C:20](=[O:40])[N:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH3:19])[C:41](=[O:47])[CH2:42][CH2:43][C:44]([OH:46])=[O:45])[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: COCCOCCOCCN(OCc1ccccc1)C(=O)CCC(=O)NCCCCCNOCc1ccccc1
Reactant: O=C1CCC(=O)O1
Solvent: c1ccncc1
Product: COCCOCCOCCN(OCc1ccccc1)C(=O)CCC(=O)NCCCCCN(OCc1ccccc1)C(=O)CCC(=O)O
Yield: 95 %

Procedure:
5,16-Bis (benzyloxy)-4,12,15-trioxo-5,11,16-triaza-19,22,25-trioxahexacosanoic acid (19) was synthesized by reacting compound (18) (3.40 g, 6.07 mmol) with succinic anhydride in pyridine following the procedure of (16) to produce 3.81 g (95%) of (19) as an oil: NMR δ 1.2-1.8 (m, 6 H) t 2.38-2.91 (m, 8 H) t 3.07-3.83 (m, 19 H) t 4.79 (s, 2 H), 4.88 (s, 2 H), 5.7 (br s, 1 H), 6.62 (br s, 1 H), 7.33 (s, 10 H). Analysis: (C34H49N3O10) C, H, N.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([N:5]=C=O)=[O:4].[O:10]1[CH:14]=[CH:13][CH:12]=[C:11]1/[C:15](=[N:33]/[O:34][CH3:35])/[C:16]([NH:18][C@@H:19]1[C:31](=[O:32])[N:21]2[C:22]([C:28]([OH:30])=[O:29])=[C:23]([CH2:26][OH:27])[CH2:24][S:25][C@H:20]12)=[O:17].C(C(CCCC)C([O-])=O)C.[Na+:46]>CO.C1COCC1.ClCCl>[CH3:35][O:34]/[N:33]=[C:15](\[C:16]([NH:18][C@@H:19]1[C:31](=[O:32])[N:21]2[C:22]([C:28]([O-:30])=[O:29])=[C:23]([CH2:26][O:27][C:3]([NH2:5])=[O:4])[CH2:24][S:25][C@H:20]12)=[O:17])/[C:11]1[O:10][CH:14]=[CH:13][CH:12]=1.[Na+:46]
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CO)CS[C@H]12)c1ccco1
Agent: CCCCC(CC)C(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(COC(N)=O)CS[C@H]12)c1ccco1
Reaction time: 0.17 h

Procedure:
A mixture of THF (130 ml), dichloromethane (45 ml), and trichloroacetyl isocyanate (9.3 ml) was protected from moisture and cooled to -10°.To the stirred mixture was added (6R,7R)-7-[Z-2-(fur-2-yl)-2-methoxyiminoacetamido]-3-hydroxymethylceph-3-em-4-carboxylic acid (20 g) in one charge followed by THF (40 ml). The mixture was stirred for 10 minutes at 0° to +5° and then warmed to 22° , There was then added, in one charge, a solution of sodium 2-ethylhexanoate (20 g) in methanol (40 ml) and, after stirring for1 minute, the mixture was left undisturbed at 25° for 2 hours to crystallise. The crystalline material was collected by filtration, washed with ethanol (2×100 ml), and dried in vacuo at 35° to give sodium cefuroxime (24.1 g). The isolated product was shown by G.L.C. to contain 5.3% w/w of ethanol, 0.6% w/w of THF, and 0.04% w/w of methanol.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]2[N:10]([C:12]([CH:15]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[N:22]([CH3:26])[N:21]=[CH:20]4)[CH3:16])=[CH:13][N:14]=2)[N:11]=1)=[CH2:5])C.Cl.CN1C2C(=CC(CC3N4N=C(C(=O)C)C=CC4=NC=3)=CC=2)C=N1>>[CH3:26][N:22]1[C:23]2[C:19](=[CH:18][C:17]([CH:15]([C:12]3[N:10]4[N:11]=[C:6]([C:4](=[O:3])[CH3:5])[CH:7]=[CH:8][C:9]4=[N:14][CH:13]=3)[CH3:16])=[CH:25][CH:24]=2)[CH:20]=[N:21]1
Reactant: C=C(OCC)c1ccc2ncc(C(C)c3ccc4c(cnn4C)c3)n2n1
Agent: CC(=O)c1ccc2ncc(Cc3ccc4c(cnn4C)c3)n2n1
Agent: Cl
Product: CC(=O)c1ccc2ncc(C(C)c3ccc4c(cnn4C)c3)n2n1
Yield: 84.8 %

Procedure:
The title compound (325.0 mg, 75%, 88% purity) was synthesized from 6-(1-ethoxy-vinyl)-3-[1-(1-methyl-1H-indazol-5-yl)-ethyl]-imidazo[1,2-b]pyridazine (415.0 mg, 1.20 mmol) and HCl (1.20 mL, 1.20 mmol) using the same procedure as described in the synthesis of compound 13.4. LCMS (method A): [MH]+=320, tR=5.21 min.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[Br:12]Br>ClCCl.C(O)(=O)C>[Br:12][C:7]1[CH:8]=[C:2]([F:1])[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]=1[NH2:6]
Reactant: BrBr
Reactant: Nc1ccc(F)cc1[N+](=O)[O-]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Nc1c(Br)cc(F)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To a solution of 4-fluoro-2-nitroaniline (20 g) in a mixture of dichloromethane (600 mL) and acetic acid (200 mL) was slowly added bromine (13 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1 hour and at ambient temperature for 16 hours. The reaction mixture was concentrated and the concentrate partitioned between ethyl acetate (500 mL) and sodium bicarbonate solution (500 mL). The organic phase was washed with sodium bisulphite solution (400 mL) and concentrated. The concentrate was recrystallized from hexanes containing some dichloromethane.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[CH3:10][C@H:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:12][NH2:13].[OH-].[Na+]>CC#N.O>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([NH:13][CH2:12][C@@H:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:10])[N:7]=1
Reactant: C[C@@H](CN)c1ccccc1
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: C[C@@H](CNc1nc(Cl)nc(Cl)n1)c1ccccc1

Procedure:
A mixture of cyanuric chloride (75 mg, 0.407 mmol, 1 equivalent) in CH3CN/H2O (1/1, 5 ml) was cooled to 0° C. (R)-(+)-beta-methylphenethylamine (55 mg, 0.407 mmol, 1 equivalent) was added, followed by 1N NaOH (0.366 ml). LCMS analysis showed the complete consumption of the 2,4,6-trichloro-1,3,5-triazine. The crude product was used in the next step. MS (ES+): m/e 283.06 [M+H]+.
Reaction SMILES: NC(CCCCCCCCC(N)C(C)C)C(C)C.C(C1CC=CCCC=CCC(C(C)C)N=N1)(C)C.[CH:37]1([CH:43]2[CH2:54][CH:53]=[CH:52][CH2:51][CH2:50][CH:49]=[CH:48][CH2:47][CH:46]([CH:55]3[CH2:60][CH2:59][CH2:58][CH2:57][CH2:56]3)[N:45]=[N:44]2)[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>>[NH2:44][CH:43]([CH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1)[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][CH:46]([NH2:45])[CH:55]1[CH2:60][CH2:59][CH2:58][CH2:57][CH2:56]1
Reactant: C1=CCC(C2CCCCC2)N=NC(C2CCCCC2)CC=CCC1
Agent: CC(C)C(N)CCCCCCCCC(N)C(C)C
Agent: CC(C)C1CC=CCCC=CCC(C(C)C)N=N1
Product: NC(CCCCCCCCC(N)C1CCCCC1)C1CCCCC1
Yield: 90.3 %

Procedure:
If there are used in the manner described under (a), instead of 250 g (1 mol) of 3,12-diisopropyl-1,2-diaza- 1,5,9-cyclododecatriene, 328.5 g (1 mol) of 3,12-dicyclohexyl-1,2-diaza-1,5,9-cyclododecatriene (diastereoisomeric mixture) and correspondingly reduced amounts of catalyst and solvent, with otherwise the same procedure, there is obtained, as the main fraction, 304 g (90% of theory) of 1,10-diamino-1,10-dicyclohexyldecane in the form of colourless oil [b.p. 190°-193° C./0.05 Torr; nD20 =1.4944; IR (liquid) inter alia bands at 3355, 3278 and 1613 cm-1 ].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[C:4]([C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]2[CH:28]=[CH:27][C:26]([CH:29]=[C:30]3[S:34][C:33](=[O:35])[NH:32][C:31]3=[O:36])=[CH:25][CH:24]=2)=[CH:18][CH:17]=1)=[CH:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]([O:14][CH3:15])[CH:7]=1.C([O-])=O.[NH4+]>[Pt].C(O)(=O)C>[CH3:1][O:2][C:3](=[O:37])[C:4]([C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][CH:30]3[S:34][C:33](=[O:35])[NH:32][C:31]3=[O:36])=[CH:25][CH:24]=2)=[CH:18][CH:17]=1)=[CH:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]([O:14][CH3:15])[CH:7]=1
Reactant: COC(=O)C(=Cc1cc(OC)cc(OC)c1)c1ccc(Oc2ccc(C=C3SC(=O)NC3=O)cc2)cc1
Agent: [Pt]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: COC(=O)C(=Cc1cc(OC)cc(OC)c1)c1ccc(Oc2ccc(CC3SC(=O)NC3=O)cc2)cc1
Temperature: 124 °C
Reaction time: 15 h
Yield: 64.1 %

Procedure:
Compound 10 (20 g, 38.6 mmol), ammonium formate (150 g, 2.38 mol), 10% Pt/C (dry, 4 g) and acetic acid (660 mL) were combined into a round bottom flask equipped with reflux condenser, thermometer and mechanical stirrer. The reactor was evacuated and purged three times with nitrogen then, heated to a steady reflux (ca. 124° C.). Reaction was completed within 15 h and allowed to cool with stirring to ambient room temperature. After cooling, the mixture was filtered though a pad of Celite® (5 g) and the filter pad washed with fresh acetic acid (2×100 mL). The mother liquor and washes were combined and concentrated. The residue was then diluted with dichloromethane (400 mL), and the combined organics were extracted twice with water (400 mL) and 5% bicarbonate (400 mL). The organic portion was then dried and poured through silica gel (30 g) and washed with dichloromethane (2×100 mL). The washes were combined and concentrated. The residue was diluted with ethanol, allowed to cool to 60° C. and seed crystals were added. This slurry was stirred at 50° C. for about 30 min then allowed to cool to ambient room temperature to yield compound 11 (12.85 g, 64%) with an HPLC assay of 98.1%.
Reaction SMILES: [NH:1]([C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])[C@H:2]([C:4]([NH:6][CH2:7][C:8]([NH:10][C@H:11]([C:15]([N:17]1[CH2:61][CH2:60][CH2:59][C@H:18]1[C:19]([NH:21][CH2:22][C:23]([NH:25][C@H:26]([C:34]([NH:36][CH2:37][C:38]([NH:40][C@H:41]([C:45]([NH:47][CH2:48][C:49]([O:51]CC1C=CC=CC=1)=[O:50])=[O:46])[CH:42]([CH3:44])[CH3:43])=[O:39])=[O:35])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:24])=[O:20])=[O:16])[CH:12]([CH3:14])[CH3:13])=[O:9])=[O:5])[CH3:3].N(C(OC(C)(C)C)=O)[C@H](C(NCC(O)=O)=O)C>O>[NH:1]([C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])[C@H:2]([C:4]([NH:6][CH2:7][C:8]([NH:10][C@H:11]([C:15]([N:17]1[CH2:61][CH2:60][CH2:59][C@H:18]1[C:19]([NH:21][CH2:22][C:23]([NH:25][C@H:26]([C:34]([NH:36][CH2:37][C:38]([NH:40][C@H:41]([C:45]([NH:47][CH2:48][C:49]([OH:51])=[O:50])=[O:46])[CH:42]([CH3:43])[CH3:44])=[O:39])=[O:35])[CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:24])=[O:20])=[O:16])[CH:12]([CH3:13])[CH3:14])=[O:9])=[O:5])[CH3:3]
Reactant: CC(C)[C@H](NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)CNC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(C)C)C(=O)NCC(=O)OCc1ccccc1
Agent: C[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)O
Solvent: O
Product: CC(C)[C@H](NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)CNC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(C)C)C(=O)NCC(=O)O

Procedure:
The nonapeptide benzylester (IX) was hydrogenated as described under VIII to obtain the acid in quantitative yield. Rf3 0 24. Anal. calcd. for C40H61N9O12 .H2O: C 55.09, H 7.16, N 14.3%. Found: C 54.69, H 7.16, N 13.81%.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[C:12]([N+:14]([O-])=O)[CH3:13])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O>C1COCC1>[CH3:13][CH:12]([CH2:11][C:6]1[C:5]2[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=2)[NH:8][CH:7]=1)[NH2:14]
Reactant: CC(=Cc1c[nH]c2cc(F)ccc12)[N+](=O)[O-]
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(N)Cc1c[nH]c2cc(F)ccc12
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 92.2 %

Procedure:
α-Methyl-6-fluorotryptamine was prepared by the dropwise addition of an anhydrous THF solution of 6-fluoro-3-(2-nitropropenyl)-1H-indole (560 mg, 2.54 mmol) to a stirred mixture of LiAlH4 (480 mg, 12.7 mmol) in THF (40 mL) at 0° C. The reaction slurry was allowed to stir under N2 from 0° C. to ambient room temperature over 3.5 hours. The reaction solution was again cooled to 0° C. prior to the dropwise addition of H2O to quench excess LiAlH4. The reaction suspension was filtered through a pad of Celite to remove Al salts. The filtrate was concentrated under reduced pressure, diluted with EtOAc (200 mL), washed with NaCl (50 mL×2), dried over Na2SO4, filtered and concentrated under reduced pressure to provide 450 mg of α-methyl-6-fluorotryptamine as a viscous oil; 1H NMR (CDCl3) δ 8.30 (1H, br s), 7.52 (1H, m), 6.98-7.04 (2H, m), 6.87 (1H, t), 3.29 (1H, m), 2.87 (1H, dd), 2.64 (1H, q), 1.25 (3H, d); MS (ESI): 193 (MH+); TLC (SiO2 plate, 100% DCM) Rf=0.1.