Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:12])([CH3:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[N+:13]([O-])([OH:15])=[O:14]>S(=O)(=O)(O)O>[N+:13]([C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([CH3:1])[C:10]2([CH3:12])[CH3:11])([O-:15])=[O:14]
Reactant: CC1=Nc2ccccc2C1(C)C
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CC1=Nc2ccc([N+](=O)[O-])cc2C1(C)C
Yield: 74 %

Procedure:
5-nitro-2,3,3-trimethylindole (1) was synthesized according to a modified literature procedure (see, Noland, W. E., et al., J. Org. Chem. 3457-3469, 1965). To a solution of 2,3,3-trimethylindole (10.6 g) in concentrated sulfuric acid cooled to 0° C. using an ice/brine bath was added dropwise fuming nitric acid (5.6 mL). The resultant solution was stirred at 0° C. for 1.5 hours; then poured into crushed ice; filtered; and washed with water. The combined filtrate was neutralized to a pH greater than 7. The product precipitated from the neutralized solution and was collected by filtration, washed with water, and dried to provide the desired product 1 (10.1 g, 74% yield): ESI-MS, calculated [M+H]+ 205.1, found 205.0.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[C:11]([Cl:17])[C:10]=2[O:18][CH3:19])=[O:5])[CH3:2].[F:20][CH2:21][CH2:22][CH2:23][CH2:24][NH2:25]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:25][CH2:24][CH2:23][CH2:22][CH2:21][F:20])=[CH:13][CH:12]=[C:11]([Cl:17])[C:10]=2[O:18][CH3:19])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c(OC)c(Cl)ccc2c1Cl
Reactant: NCCCCF
Product: CCOC(=O)c1cnc2c(OC)c(Cl)ccc2c1NCCCCF

Procedure:
4,7-Dichloro-8-methoxy-quinoline-3-carboxylic acid ethyl ester (250 mg, 84 mmol) was treated with 4-fluoro-butylamine following general procedure B to afford 7-chloro-4-(4-fluoro-butylamino)-8-methoxy-quinoline-3-carboxylic acid ethyl ester (240 mg). Thus obtained amino-ester was hydrolyzed to the corresponding acid using general procedure D and then transformed into the corresponding ethylamide (175 mg) following general procedure E. The above ethylamide (0.52 mmol) was subjected to reaction with methyl chloroformate according to general procedure F to furnish 8-chloro-3-ethyl-1-(4-fluoro-butyl)-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (117 mg). LCMS: m/z 380 [M+1]+.
Reaction SMILES: [CH2:1]([NH2:4])[C:2]#[CH:3].C(N(CC)CC)C.[C:12](Cl)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>ClCCl>[CH2:1]([NH:4][C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]#[CH:3]
Reactant: C#CCN
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CCNC(=O)c1ccccc1
Reaction time: 0.5 h

Procedure:
To a solution of propargylamine (6 g, 109 mmol) and triethylamine (15 mL, 109 mmol) in dichloromethane (125 mL) was added dropwise benzoyl chloride (10.5 mL, 90 mmol) at about 0° C. The ice-bath was removed and stirring was continued for about 30 min. Then the reaction mixture was concentrated under vacuum, the residue was diluted with water and was extracted with ethyl acetate. The combined organic extracts were dried (MgSO4), filtered and concentrated under vacuum to provide Example 643. MS (APCI): m/z 160 (M+H)+.
Reaction SMILES: C1(C[O:8][C:9](=[O:45])[CH2:10][O:11][C:12]([O:14][CH2:15][O:16][C:17]2[C:18](=[O:44])[C:19]([C:32]([NH:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=3[F:43])=[O:33])=[CH:20][N:21]3[C:26]=2[C:25](=[O:27])[N:24]2[C@@H:28]([CH3:31])[CH2:29][O:30][C@@H:23]2[CH2:22]3)=[O:13])C=CC=CC=1.[H][H]>[Pd].C(OCC)(=O)C.CO>[F:43][C:37]1[CH:38]=[C:39]([F:42])[CH:40]=[CH:41][C:36]=1[CH2:35][NH:34][C:32]([C:19]1[C:18](=[O:44])[C:17]([O:16][CH2:15][O:14][C:12]([O:11][CH2:10][C:9]([OH:45])=[O:8])=[O:13])=[C:26]2[C:25](=[O:27])[N:24]3[C@@H:28]([CH3:31])[CH2:29][O:30][C@@H:23]3[CH2:22][N:21]2[CH:20]=1)=[O:33]
Reactant: C[C@H]1CO[C@@H]2Cn3cc(C(=O)NCc4ccc(F)cc4F)c(=O)c(OCOC(=O)OCC(=O)OCc4ccccc4)c3C(=O)N12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: C[C@H]1CO[C@@H]2Cn3cc(C(=O)NCc4ccc(F)cc4F)c(=O)c(OCOC(=O)OCC(=O)O)c3C(=O)N12

Procedure:
Phenylmethyl({[({[(3S,11aR)-8-({[(2,4-difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl)oxy]carbonyl}oxy)acetate (prepared as described in example 17) (247 mg, 0.394 mmol) 10 w.t. % palladium on carbon (190 mg) were stirred in an ethyl acetate/methanol mixture under 1 atm hydrogen atmosphere for 30 minutes. The reaction was filtered through celite and concentrated under reduced pressure to yield a white solid. 1H NMR (CDCl3) δ 10.28 (m, 1H), 8.32 (s, 1H), 7.28 (m, 1H), 6.76 (m, 2H), 5.92 (d, J=6.4 Hz, 1H), 5.86 (d, J=6.4 Hz, 1H), 5.28 (dd, J=10, 3.2 Hz, 1H), 4.55 (br s, 4H), 4.37-4.28 (m, 3H), 3.91 (m, 1H), 3.63 (m, 1H), 3.35 (m, 1H), 1.34 (d, J=6 Hz, 3H). ES+ MS: 538 (M+1).
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:30].[CH3:31][N:32]([CH3:44])[CH2:33][CH:34]([NH:36][C:37]1[CH:42]=[CH:41][C:40]([NH2:43])=[CH:39][CH:38]=1)[CH3:35]>C1COCC1>[CH3:44][N:32]([CH3:31])[CH2:33][CH:34]([NH:36][C:37]1[CH:38]=[CH:39][C:40]([NH:43][CH:2]=[C:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]([C:14]4[CH:15]=[C:16]([NH:20][C:21]([C:23]5[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=5)=[O:22])[CH:17]=[CH:18][CH:19]=4)=[O:13])=[CH:9][CH:10]=3)[NH:5][C:4]2=[O:30])=[CH:41][CH:42]=1)[CH3:35]
Reactant: CC(CN(C)C)Nc1ccc(N)cc1
Reactant: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)n(C)n1
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(NC(C)CN(C)C)cc3)c2)n(C)n1
Temperature: 65 °C
Reaction time: 24 h
Yield: 40.3 %

Procedure:
A small screw cap test tube was charged with 2,5-Dimethyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 60, 116 mg, 0.288 mmol) and THF (2 mL). To the resulting solution was added N-(2-Dimethylamino-1-methyl-ethyl)-benzene-1,4-diamine (prepared below, 61.4 mg, 0.314 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature. Hexanes were added to the reaction mixture and the reaction mixture was vacuum filtered. The black solid collected was set aside. The filtrate was then concentrated in vacuo and then redissolved into EtOAc and then Hexanes were added causing a precipitate to form. The precipitate was then filtered and washed with ˜1 mL of i-prOH yielding 40% (0.067 g, 0.116 mmol) of the title compound.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:9]2[N:10]=[C:11]([C:13]3[NH:22][C:16]4[CH2:17][CH2:18][NH:19][CH2:20][CH2:21][C:15]=4[N:14]=3)[S:12][C:8]=2[C:7]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:6][CH:5]=1.C(N(C(C)C)C(C)C)C.Cl.[Cl:39][CH2:40][C:41]1[CH:42]=[C:43]([CH:47]=[CH:48][N:49]=1)[C:44](Cl)=[O:45]>O1CCCC1>[Cl:39][CH2:40][C:41]1[CH:42]=[C:43]([C:44]([N:19]2[CH2:20][CH2:21][C:15]3[N:14]=[C:13]([C:11]4[S:12][C:8]5[C:7]([N:23]6[CH2:24][CH2:25][O:26][CH2:27][CH2:28]6)=[CH:6][CH:5]=[C:4]([O:3][CH3:2])[C:9]=5[N:10]=4)[NH:22][C:16]=3[CH2:17][CH2:18]2)=[O:45])[CH:47]=[CH:48][N:49]=1
Reactant: O=C(Cl)c1ccnc(CCl)c1
Reactant: COc1ccc(N2CCOCC2)c2sc(-c3nc4c([nH]3)CCNCC4)nc12
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(N2CCOCC2)c2sc(-c3nc4c([nH]3)CCN(C(=O)c3ccnc(CCl)c3)CC4)nc12
Yield: 91.4 %

Procedure:
To a suspension of 0.04 g 2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-1,4,5,6,7,8-hexahydro-imidazo[4,5-d]azepine hydrochloride in 3.4 ml tetrahydrofurane were added at 0–4° C. 0.09 ml N-ethyldiisopropylamine and 0.017 g 2-chloromethyl-isonicotinoyl chloride hydrochloride. The mixture was refluxed for 17 hours, silicagel was added and the solvent was distilled off. The residue was transferred to a column prefilled with silicagel and was chromatographed with dichloromethane/methanol 96:4 to yield 0.037 g (68%) (2-chloromethyl-pyridin-4-yl)-[2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-4,5,7,8-tetrahydro-1H-imidazo[4,5-d]azepin-6-yl]-methanone as yellow solid; MS (ISP): m/e=540 (M+H+).
Reaction SMILES: [O:1]1CCOCC1.[CH2:7]([C:10]([CH2:17][CH2:18][CH3:19])([CH2:14][CH2:15][CH3:16])[C:11](N)=[O:12])[CH2:8][CH3:9].Cl>[OH-].[K+]>[CH2:7]([C:10]([CH2:17][CH2:18][CH3:19])([CH2:14][CH2:15][CH3:16])[C:11]([OH:1])=[O:12])[CH2:8][CH3:9]
Reactant: CCCC(CCC)(CCC)C(N)=O
Reactant: C1COCCO1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: CCCC(CCC)(CCC)C(=O)O
Yield: 75.8 %

Procedure:
In a flask equipped with a dropping-funnel were placed 480 g of distilled dioxan followed by 80 g (0.432 mol) of tri-n-propylacetamide which was dissolved by stirring. For a period of 20 minutes a current of dry hydrochloric acid gas was passed through the dioxan solution at room-temperature, which represented a total of 100 g of hydrochloric acid gas. At the end of this operation, 88 g (0.86 mol) of freshly distilled butyl nitrile was slowly added over a period of 2 hours through the dropping-funnel. The temperature of the reaction medium rose from 31 to 43° C which necessitated cooling in a water-bath. The solution was then maintained for 2 hours at 85°-90° C. The dioxan was distilled off under a reduced pressure of 20 mm. Hg and a pasty residue obtained at room-temperature. This residue was dissolved in 290 g of a 10% aqueous solution of potassium hydroxide. The aqueous layer was decanted out and extracted twice with 75 g of ethyl ether. The potassium solution was acidified with 118 g of a 36% solution of hydrochloric acid (at 10/20° C) after which the oily phase was decanted out. The aqueous phase was extracted twice with 75 g of ethyl ether after which the oily phase and the ethereal extracts were placed together. The ethereal solution was washed twice with 100 g of water and dried for 24 hours over 100 g of anhydrous sodium sulphate. The sodium sulphate was then centrifuged out. The ethyl ether was distilled off under atmospheric pressure and the residue recuperated under 7 mm Hg. The fraction obtained boiled at 126° to 128° C and crystallized rapidly. In this way, 61 g of crude tri-n-propylacetic acid were obtained, which represents a yield of 76%. The crude product was then dissolved by heating in 75 g of ethyl ether. The ethereal solution was filtered while hot and the filtrate left at a temperature of -30° C for 4 hours. The precipitate which formed was centrifuged out and dried in a desiccator under a reduced pressure of 20 mm Hg for 6 hours. By this means, 46 g of pure tri-n-propylacetic acid were obtained which represents a yield in pure product of 75.4% and a total yield of 57.3%. M.P. 67° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[N+:7]([C:10]1[CH:11]=[C:12]([S:16](Cl)(=[O:18])=[O:17])[CH:13]=[CH:14][CH:15]=1)([O-:9])=[O:8].[OH-].[Na+].O>N1C=CC=CC=1>[S:3]1[CH:4]=[CH:5][N:6]=[C:2]1[NH:1][S:16]([C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([N+:7]([O-:9])=[O:8])[CH:11]=1)(=[O:17])=[O:18]
Reactant: Nc1nccs1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Product: O=[N+]([O-])c1cccc(S(=O)(=O)Nc2nccs2)c1
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 82.8 %

Procedure:
To a solution of 2-aminothiazole (1 g, 10.5 mmol) in dry pyridine (3 ml) was added, portionwise, 3-nitrobenzenesulphonyl chloride (2.32 g, 10.5 mmol), maintaining the internal temperature below 55° C. After addition was complete, the mixture was heated at 100° C. for 75 min. 4M Sodium hydroxide solution (2.75 ml, 11 mmol) was then added dropwise and heating was continued for a further 5 min. After cooling, water (25 ml) was added and the precipitate was collected by filtration to afford the product (2.48 g, 87%) as a brown solid. mp 195° C. (dec.). 1H NMR (360 MHz, D6 -DMSO) δ 6.91 (1H, d, J=4.6 Hz), 7.31 (1H, d, J=4.5 Hz), 7.86 (1H, dd, J=8.0 and 8.1 Hz), 8.20-8.26 (1H, m), 8.40-8.45 ( 1H, m), 8.46-8.49 (1H, m), 13.00 (1H, brs).
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:9](O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:42][C@@H:43]1[C:50](=[O:51])[N:49]2[CH2:52][CH2:53][CH2:54][CH2:55][C@@H:48]2[CH:47]=[CH:46][CH2:45][CH2:44]1>>[CH2:34]([C@@H:14]([CH2:13][CH2:12][C@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9](=[O:10])[NH:42][C@@H:43]1[C:50](=[O:51])[N:49]2[CH2:52][CH2:53][CH2:54][CH2:55][C@@H:48]2[CH:47]=[CH:46][CH2:45][CH2:44]1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)O)Cc3ccccc3)C(=O)N21
Reactant: N[C@H]1CCC=C[C@H]2CCCCN2C1=O
Agent: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)N[C@H]3CC/C=C\[C@H]4CCCCN4C3=O)Cc3ccccc3)C(=O)N21
Agent: Cl
Agent: N[C@H]1CC/C=C\[C@H]2CCCCN2C1=O
Product: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)N[C@H]3CCC=C[C@H]4CCCCN4C3=O)Cc3ccccc3)C(=O)N21

Procedure:
(4S,7S,10aS)-Methyl 4-((2R,5R)-2,5-dibenzyl-6-oxo-6-((7S,11aR,Z)-6-oxo-2,3,4,6,7,8,9,11a-octahydro-1H-pyrido[1,2-a]azocin-7-ylamino)hexanamido)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate was synthesized as described in General Procedure H using Intermediate 23 (11 mg, 0.019 mmol) and Intermediate 55 (4.9 mg, 0.021 mmol) to give a white solid (10 mg, 74% yield). Anal. Calcd. for C42H54N4O6S m/z 742.4. found: 743.3 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.28-7.08 (12H, m), 5.94 (1H, t, J=9.3 Hz), 5.81-5.71 (1H, m), 5.33 (1H, t, J=4.7 Hz), 5.15-5.10 (1H, m), 5.04-4.95 (1H, m), 4.92-4.84 (1H, m), 4.73-4.65 (1H, m), 4.21 (1H, d, J=13.2 Hz), 3.68 (3H, s), 3.16 (1H, ddd, J=14.2, 11.1, 2.7 Hz), 2.87-2.65 (6H, m), 2.48-2.30 (4H, m), 2.18-2.07 (1H, m), 2.07-2.00 (2H, m), 1.91-1.42 (16H, m), 1.11-0.98 (1H, m).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[CH:7][N:6]=1)=[O:4].[Li+].[OH-]>CO.O>[F:16][C:13]([F:14])([F:15])[CH2:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[N:6][CH:7]=1
Reactant: COC(=O)c1ccc(OCC(F)(F)F)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(OCC(F)(F)F)cn1
Reaction time: 2 h
Yield: 61.5 %

Procedure:
A solution of 5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid methyl ester (216 mg) in MeOH (1 ml) was treated with a solution of LiOH (78 mg) in water (0.1 ml) and stirring was continued at 22° C. for 2 h. The solution was evaporated and the residue triturated with 1N aqueous HCl. The suspension was filtered, the residue washed with water and dried to give 5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (125 mg) as a white solid. MS (ESI): m/z=220.1 [M−H]−.
Reaction SMILES: [C:1]1([NH2:11])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>CCO>[C:1]1([NH:11][C:12](=[O:14])[CH3:13])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cccc2c1CCCC2
Solvent: CCO
Product: CC(=O)Nc1cccc2c1CCCC2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 97.1 %

Procedure:
To a solution of commercially available 5,6,7,8-tetrahydronaphthylamine (2 g, 14 mmol) in EtOH (5 mL) at rt was slowly added acetic anhydride (1.28 mL, 13.6 mmol). After addition, the reaction mixture was stirred at rt for 5 min. The resulting suspension was filtered, the collected solid washed with hexane (5×) and dried under vacuum to furnish the title compound (2.5 g) as an off-white solid.
Reaction SMILES: Cl.Cl.C[O:4][C:5]1[CH:24]=[CH:23][C:22]([N:25]2[C:29]([C:30]([F:33])([F:32])[F:31])=[N:28][N:27]=[N:26]2)=[CH:21][C:6]=1[CH2:7][NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][NH:11][C@H:10]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C.B(Br)(Br)Br.CSC>C(Cl)(Cl)Cl.CO>[OH:4][C:5]1[CH:24]=[CH:23][C:22]([N:25]2[C:29]([C:30]([F:33])([F:32])[F:31])=[N:28][N:27]=[N:26]2)=[CH:21][C:6]=1[CH2:7][NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][NH:11][C@H:10]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COc1ccc(-n2nnnc2C(F)(F)F)cc1CN[C@H]1CCCN[C@H]1c1ccccc1
Agent: BrB(Br)Br
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CSC
Product: Oc1ccc(-n2nnnc2C(F)(F)F)cc1CN[C@H]1CCCN[C@H]1c1ccccc1
Temperature: 25 °C
Yield: 80.3 %

Procedure:
A suspension of [2-methoxy-5-(5-trifluoromethyl-tetrazol-1-yl)-benzyl]-([2S,3S]-2-phenylpiperidin-3yi)amine dihydrochloride (1.01 g, 2 mmol) in chloroform (20ml) was stirred at room temperature and treated with triethylamine, (0.58 ml, 406 mg, 4 mmol) to give a clear solution. This was then treated slowly with a solution of boron tribromide: dimethylsulfide complex (20 ml of 1M solution in dichloromethane; 20 mmol) and the reaction mixture was refluxed under nitrogen for 3 days. Further reagent (10 ml, 10 mmol) was then added and after a further 3 days the mixture was cooled in an ice-bath, stirred and treated with methanol (40 ml ). The mixture was evaporated to dryness. This treatment was repeated twice further. The resulting oil was partitioned between ethyl acetate (100 ml) and saturated aqueous sodium bicarbonate (100 ml). The aqueous phase was extracted with further ethyl acetate (50 ml) after pH adjustment (to pH ca 8). Combined extracts were washed with brine (100 ml) dried (MgSO4) and evaporated to a brown foam, which was chromatographed on silica (Merck 9385) eluting with 2% then 5% methanol in dichloromethane. The required fractions were combined and evaporated to give the title compound as a light brown foam (672 mg), mass spectrum (thermospray +ve) m/e 419 (MH+).
Reaction SMILES: CN(C)C([S:5][C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([S:14]C(=O)N(C)C)[CH:13]=1)[CH2:9][OH:10])=O.[OH-].[Na+]>>[SH:5][C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([SH:14])[CH:13]=1)[CH2:9][OH:10]
Reactant: CN(C)C(=O)Sc1cc(CO)cc(SC(=O)N(C)C)c1
Agent: [Na+]
Agent: [OH-]
Product: OCc1cc(S)cc(S)c1

Procedure:
3,5-Bis(dimethylcarbamoylthio)benzyl alcohol was treated with sodium hydroxide according to the ordinary method to give 3,5-dimercaptobenzyl alcohol. This alcohol was then brominated in a manner similar to that in EXAMPLE 17, giving 3,5-dimercaptobenzyl bromide, followed by the reaction with urea according to the ordinary method giving 3,5-dimercaptobenzyl mercaptan.
Reaction SMILES: [NH2:1][C@H:2]([C:18]([NH:20][C@H:21]([C:32]([NH:34][C@H:35]([C:51]([NH:53][CH2:54][C:55]([NH:57][C@H:58]([C:68]([NH:70][CH2:71][C:72]([NH:74][C@H:75]([C:83]([NH:85][C@H:86]([C:94]([O:96][CH3:97])=[O:95])[CH2:87][C:88]1[CH:93]=[CH:92][CH:91]=[CH:90][CH:89]=1)=[O:84])[CH2:76][C:77]1[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=1)=[O:73])=[O:69])[CH2:59][O:60]CC1C=CC=CC=1)=[O:56])=[O:52])[CH2:36][CH2:37][CH2:38][CH2:39][NH:40]C(OCC1C=CC=CC=1)=O)=[O:33])[C@@H:22]([CH3:31])[O:23]CC1C=CC=CC=1)=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7]C(OCC1C=CC=CC=1)=O.Cl.[H][H]>CC(O)=O.[Pd]>[NH2:1][C@H:2]([C:18]([NH:20][C@H:21]([C:32]([NH:34][C@H:35]([C:51]([NH:53][CH2:54][C:55]([NH:57][C@H:58]([C:68]([NH:70][CH2:71][C:72]([NH:74][C@H:75]([C:83]([NH:85][C@H:86]([C:94]([O:96][CH3:97])=[O:95])[CH2:87][C:88]1[CH:93]=[CH:92][CH:91]=[CH:90][CH:89]=1)=[O:84])[CH2:76][C:77]1[CH:78]=[CH:79][CH:80]=[CH:81][CH:82]=1)=[O:73])=[O:69])[CH2:59][OH:60])=[O:56])=[O:52])[CH2:36][CH2:37][CH2:38][CH2:39][NH2:40])=[O:33])[C@@H:22]([CH3:31])[OH:23])=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)[C@H](COCc1ccccc1)NC(=O)CNC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)[C@@H](NC(=O)[C@@H](N)CCCCNC(=O)OCc1ccccc1)[C@@H](C)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CCCCN)NC(=O)[C@@H](NC(=O)[C@@H](N)CCCCN)[C@@H](C)O
Yield: 46.4 %

Procedure:
Partially protected octapeptide (IV) (0.10 g) was hydrogenated in 85% AcOH (70 ml) with 10% Pd/C catalyst (0.20 g) over a steady stream of hydrogen for 20 hours. The mixture was filtered, evaporated in vacuo and residue filtered on Sephadex LH20 eluting with water to give the desired octapeptide methyl ester (V) (0.03 g, 46% yield). TLC examination showed 1 spot at Rf 0.2 in 5:2:2 BAW (t-BuOCl/KI-starch stain) and Rf 0.5 in 5:2:3 BAW (Ninhydrin stain). Amino acid analysis:
Reaction SMILES: [N:1]1([NH:6][S:7]([CH:10]2[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH2:13][CH2:12][CH2:11]2)(=[O:9])=[O:8])[CH:5]=[CH:4][CH:3]=[CH:2]1.[Cl:21]N1C(=O)CCC1=O.O>O1CCCC1>[Cl:21][C:5]1[N:1]([NH:6][S:7]([CH:10]2[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH2:13][CH2:12][CH2:11]2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)C1=CCCCC1S(=O)(=O)Nn1cccc1
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C1=CCCCC1S(=O)(=O)Nn1cccc1Cl
Yield: 29.9 %

Procedure:
150 mg (0.503 mmol) of ethyl 6-[N-(1H-pyrrol-1-yl)sulfamoyl]-1-cyclohexene-1-carboxylate obtained in Example 31 was dissolved in 3 ml of tetrahydrofuran, and 70 mg (0.528 mmol) of N-chlorosuccinimide was added thereto with stirring under ice-cooling, followed by stirring overnight at room temperature. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel thin layer chromatography (solvent; hexane:ethyl acetate=2:1) and the resulting solid was further washed with isopropyl ether to give 50 mg of the title compound as a white powder (yield: 30%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[O:15][C:16]4[C:21]([C:22](=[O:31])[C:23]=3[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=3)=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH3:13])[N:9]=[C:10](I)[C:3]=12.[NH:32]1[C:40]2[C:35](=[CH:36][CH:37]=[C:38](B3OC(C)(C)C(C)(C)O3)[CH:39]=2)[CH:34]=[CH:33]1.C(=O)([O-])[O-].[Na+].[Na+].ClCCl>CN(C=O)C.C(O)C.O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[O:15][C:16]4[C:21]([C:22](=[O:31])[C:23]=3[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=3)=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH3:13])[N:9]=[C:10]([C:38]3[CH:39]=[C:40]4[C:35]([CH:34]=[CH:33][NH:32]4)=[CH:36][CH:37]=3)[C:3]=12
Reactant: CC(c1oc2ccccc2c(=O)c1-c1cccc(F)c1)n1nc(I)c2c(N)ncnc21
Reactant: CC1(C)OB(c2ccc3cc[nH]c3c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCO
Product: CC(c1oc2ccccc2c(=O)c1-c1cccc(F)c1)n1nc(-c2ccc3cc[nH]c3c2)c2c(N)ncnc21
Temperature: 80 °C
Reaction time: 12 h
Yield: 14.6 %

Procedure:
To a solution of Example 57c (0.350 g, 0.663 mmoles) in DMF (4 ml), ethanol (2 ml) and water (2 ml), 6-indoleboronic acid pinacol ester (0.213 g, 1.327 mmoles) and sodium carbonate (0.351 g, 3.318 mmoles) were added and the system is degassed for 30 min Tetrakistriphenylphosphine Palladium (0.151 g, 0.130 mmoles) was added under nitrogen atmosphere and heated to 80° C. After 12 h, the reaction mixture was celite filtered, concentrated and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol: dichloromethane to afford the title compound as brown solid (0.050 g, 15% yield). MP: 222-225° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 11.27(s,1H), 8.06(s,1H), 8.05(dd, J=8.0,1.6Hz, 1H), 7.86(m,1H), 7.69(d, J=7.2Hz, 2H), 7.62(s,1H), 7.53(t, J=8.1Hz, 1H), 7.45(t, J=2.8Hz, 1H), 7.28(m, 2H), 7.06-6.89(m, 3H), 6.50(s,1H), 6.04(q, J=7.1Hz, 1H),1.91(d, J=7.1Hz, 3H). Mass: 516.84(M+).