Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[N:7][C:6]=12.[NH:17](C(OC(C)(C)C)=O)[C@H:18]([C:23](O)=[O:24])[CH2:19][CH:20]([CH3:22])[CH3:21].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.C(Cl)Cl>[NH2:17][C@@H:18]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:23]([N:14]1[CH2:15][CH2:16][N:11]([C:8]2[CH:9]=[CH:10][N:5]3[N:4]=[CH:3][C:2]([Br:1])=[C:6]3[N:7]=2)[CH2:12][CH2:13]1)=[O:24]
Reactant: Brc1cnn2ccc(N3CCNCC3)nc12
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)C[C@H](N)C(=O)N1CCN(c2ccn3ncc(Br)c3n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 213.8 %

Procedure:
3-bromo-5-(piperazin-1-yl)pyrazolo[1,5-a]pyrimidine (200 mg, 0.71 mmol), Boc-L-Leu (196 mg, 0.85 mmol), HATU (245 mg, 1.06 mmol), and triethylamine (394 uL, 2.83 mmol) taken up in DMF and stirred at room temperature overnight. Reaction was diluted with DCM and washed with water. The organic layer was dried over magnesium sulfate, filtered and reduced in vacuo. The residue was taken up in 20 mL of a 40% TFA in DCM solution and stirred at 35° C. overnight. The mixture was concentrated in vacuo and passed through a silica plug with 10% MeOH in DCM. Solvent was removed and the residue was dried to give 600 mg crude product as TFA salt for further reactions.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[F:13])[CH:5]=[CH:6][C:7](O)=[O:8].S(Cl)([Cl:16])=O>ClC(Cl)C.CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([CH2:5][CH2:6][C:7]([Cl:16])=[O:8])[CH:10]=[CH:11][C:12]=1[F:13]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C=Cc1ccc(F)c(F)c1
Solvent: CC(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)CCc1ccc(F)c(F)c1

Procedure:
To 0.27 mol of 3,4-difluorocinnamic acid dissolved in dichloroethane there are added 20 drops of dimethylformamide and 100 ml of thionyl chloride.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[N:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[F:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][S:19]([CH2:22][CH2:23][CH3:24])(=[O:21])=[O:20])=[CH:14][C:13]=1[CH:25]=[O:26].[OH-].[K+].Cl>CO.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([CH:25]([OH:26])[C:13]3[CH:14]=[C:15]([NH:18][S:19]([CH2:22][CH2:23][CH3:24])(=[O:21])=[O:20])[CH:16]=[CH:17][C:12]=3[F:11])=[CH:6][NH:7][C:8]2=[N:9][CH:10]=1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C=O)c1
Reactant: Brc1cnc2[nH]ccc2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(O)c2c[nH]c3ncc(Br)cc23)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 5-bromo-7-azaindole (67, 170.0 mg, 0.86 mmol) in methanol (7.0 mL) were added propane-1-sulfonic acid (4-fluoro-3-formyl-phenyl)-amide (672, 220.0 mg, 0.90 mmol) and potassium hydroxide (0.50 g, 0.0089 mol) under an atmosphere of nitrogen. The reaction was stirred at room temperature overnight. The reaction was poured into water, acidified with 1N HCl to pH=5, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 10% methanol in methylene chloride to give the compound (673, 55.0 mg, 14.0%). MS (ESI) [M+H+]+=442.1, 444.1.
Reaction SMILES: Cl.C([N:5]([CH2:9][CH3:10])[CH:6]([CH3:8])[CH3:7])(C)C.Cl[C:12]1[CH:16]=CS[C:13]=1C(OCC1C=CC=CC=1)=O>O1CCOCC1>[NH:5]1[C:6]2[C:7](=[CH:13][CH:12]=[CH:16][CH:8]=2)[CH2:10][CH2:9]1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(OCc1ccccc1)c1sccc1Cl
Agent: Cl
Solvent: C1COCCO1
Product: c1ccc2c(c1)CCN2
Temperature: 23 °C
Reaction time: 2.5 h

Procedure:
HCl (6 mL of a 4.0 M solution in 1,4-dioxane) was added to a solution of (2,3-dihydroindole)-3-[BOC-L-LeuΨ[COCH2]-L-Phe-L-(Tr-Gln)]-E-propenamide (0.204 g, 0.233 mmol, 1 equiv) in 1,4-dioxane (8 mL). The reaction mixture was stirred at 23° C. for 2.5 hours and then concentrated. The resulting oil was dissolved in CH2Cl2 (8 mL), and N,N-diisopropylethylamine (0.081 mL, 0.465 mmol, 2.0 equiv) and benzyl chlorothiolformate (0.042 mL, 0.279 mmol, 1.2 equiv) were added sequentially. The reaction mixture was stirred for 2 hours at 23° C. and then partitioned between water (100 mL) and a 1:1 mixture of EtOAc and hexanes (2×100 mL). The combined organic layers were dried over Na2SO4 and concentrated to provide crude (2,3-dihydroindole)-3-[BnSCO-L-LeuΨ[COCH2-L-Phe-L-(Tr-Gln)]-E-propenamide as an off-white foam. This material was dissolved in CH2Cl2 (5 mL), and triisopropylsilane (0.075 mL), and trifluoroacetic acid (5 mL) were added sequentially producing a bright yellow solution. The reaction mixture was stirred for 30 minutes at 23° C., then carbon tetrachloride (4 mL) was added, and the mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (5% CH3OH in CH2Cl2) to afford (2,3-dihydroindole)-3-(BnSCO-L-LeuΨ[COCH2]-L-Phe-L-Gln)-E-propenamide (0.016 g, 10%) as a white foam: Rf=0.51 (10% CH3OH in CH2Cl2); 1H NMR (CDCl3) δ 0.92 (d, 6H, J=6.2), 1.11-1.25 (m, 1H), 1.33-1.36 (m, 1H), 1.49-2.17 (m, 4H), 2.25 (s, br, 2H), 2.58 (d, 1H, J=17.1), 2.70-2.72 (m, 1H), 2.94-3.17 (m, 4H), 4.01-4.04 (m, 2H), 4.11 (s, 2H), 4.5-4.58 (m 2H), 5.47 (s, br, 1H), 6.13 (d, 1H, J=13.4), 6.29 (s, br, 1H), 6.41 (s, br, 1H 6.66)s, br, 1H), 7.00-7.05 (m, 1H), 7.17-7.29 (m, 13H), 8.25 (d, 1H, J=7.2).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([NH:12][C:13]2[CH:54]=[CH:53][C:16]([C:17]([N:19]([CH2:45][C:46]([O:48]C(C)(C)C)=[O:47])[CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]4[N:31]=[C:30]([C:32]5[CH:37]=[CH:36][C:35]([C:38]6[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=6)=[CH:34][CH:33]=5)[O:29][N:28]=4)=[CH:23][CH:22]=3)=[O:18])=[CH:15][CH:14]=2)=[O:11])=[C:5]([C:55]([F:58])([F:57])[F:56])[CH:4]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([C:17]([N:19]([CH2:45][C:46]([OH:48])=[O:47])[CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]4[N:31]=[C:30]([C:32]5[CH:37]=[CH:36][C:35]([C:38]6[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=6)=[CH:34][CH:33]=5)[O:29][N:28]=4)=[CH:23][CH:22]=3)=[O:18])=[CH:53][CH:54]=2)=[O:11])=[C:5]([C:55]([F:58])([F:57])[F:56])[CH:4]=1
Reactant: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)OC(C)(C)C)Cc3ccc(-c4noc(-c5ccc(-c6ccc(C)cc6)cc5)n4)cc3)cc2)c(C(F)(F)F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)O)Cc3ccc(-c4noc(-c5ccc(-c6ccc(C)cc6)cc5)n4)cc3)cc2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
Prepared using General Procedure 8: To a stirring solution of tert-butyl 2-(4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)-N-(4-(5-(4′-methyl-[1,1′-biphenyl]-4-yl)-1,2,4-oxadiazol-3-yl)benzyl)benzamido)acetate INT-34 (54.0 mg, 0.068 mmol) in DCM (2 mL) was added TFA (2 mL). After stirring at room temperature for 2 h, the solvent was concentrated and the reaction mixture was further concentrated from acetonitrile (2×3 mL). The solid was re-slurried from DCM (4 mL), washed with DCM (2 mL) and acetonitrile (2 mL) to afford 44 mg (87%) of 2-(4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)-N-(4-(5-(4′-methyl-[1,1′-biphenyl]-4-yl)-1,2,4-oxadiazol-3-yl)benzyl)benzamido)acetic acid 354. LCMS-ESI (m/z) calculated for C41H33F3N4O6: 734; found 735 [M+H]+, tR=9.40 min (Method 9). 1H NMR (400 MHz, DMSO) δ 12.80 (s, 1H), 10.34 (s, 1H), 8.33-8.22 (m, 2H), 8.15-8.06 (m, 2H), 8.02-7.91 (m, 2H), 7.76-7.69 (m, 2H), 7.69-7.56 (m, 3H), 7.53-7.33 (m, 6H), 7.26-7.14 (m, 2H), 4.77 (s, 1H), 4.69 (s, 1H), 4.04 (s, 1H), 3.98 (s, 1H), 3.90-3.77 (m, 5H), 2.39 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[C:5](=[O:11])[N:4]([CH2:12][CH2:13][CH3:14])[C:3]1=[O:15].Cl[CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:24])([CH3:23])[CH3:22].CN1C2N=CN(CCCCC(=O)C)C=2C(=O)N(CCC)C1=O.C[Mg]Br.[Cl-]>O1CCCC1>[OH:24][C:21]([CH3:23])([CH3:22])[CH2:20][CH2:19][CH2:18][CH2:17][N:7]1[C:6]2[C:5](=[O:11])[N:4]([CH2:12][CH2:13][CH3:14])[C:3](=[O:15])[N:2]([CH3:1])[C:10]=2[N:9]=[CH:8]1
Reactant: CCCn1c(=O)c2[nH]cnc2n(C)c1=O
Reactant: CC(C)(O)CCCCCl
Agent: CCCn1c(=O)c2c(ncn2CCCCC(C)=O)n(C)c1=O
Agent: C[Mg]Br
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCCn1c(=O)c2c(ncn2CCCCC(C)(C)O)n(C)c1=O

Procedure:
Both alkylation of 3-methyl-1-propylxanthine with 1-chloro-5-hydroxy-5-methylhexane analogously to the following example 4 and Grignard synthesis with 3-methyl-7-(5-oxohexyl)-1-propylxanthine and methylmagnesium bromide or chloride in anhydrous tetrahydrofuran led to the same compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[Li].C[Si](Cl)(C)C.[CH:15]([N:18]([CH:28]([CH3:30])[CH3:29])[C:19](=[O:27])[CH:20]=[CH:21][C:22]1[S:23][CH:24]=[CH:25][CH:26]=1)([CH3:17])[CH3:16]>CSC.C(OCC)C>[CH:28]([N:18]([CH:15]([CH3:17])[CH3:16])[C:19](=[O:27])[CH2:20][CH:21]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[C:22]1[S:23][CH:24]=[CH:25][CH:26]=1)([CH3:30])[CH3:29]
Reactant: CC(C)N(C(=O)C=Cc1cccs1)C(C)C
Reactant: [Li]c1ccccc1OC
Agent: C[Si](C)(C)Cl
Solvent: CSC
Solvent: CCOCC
Product: COc1ccccc1C(CC(=O)N(C(C)C)C(C)C)c1cccs1
Reaction time: 0.17 h

Procedure:
Copper(I)bromide dimethyl sulfide complex (4.63 g 22.5 mmol) was dissolved in dimethyl sulfide (18 mL), and diethyl ether (15 mL). The solution was cooled to 0° C., whereafter 2-methoxyphenyllithium (41.2) (45 mmol) was added. After 10 min., the temperature was lowered to −78° C. Trimethylsilylchloride (4.89 g, 45.0 mmol) was added, followed by N,N-diisopropyl-3-(2-thienyl)propenamide (41.1) (3.56 g, 15 mmol) in diethyl ether (20 mL). The temperature was allowed to slowly rise to room temperature overnight. The reaction was quenched with saturated NH4Cl (10 mL) and conc. ammonia (10 mL). Diethyl ether (80 mL) was added and the mixture was filtered through Celite. The aqueous phase was extracted twice with diethyl ether. The combined organic phases were washed once with brine and dried (MgSO4). The solvent was evaporated and the crude product was chromatographed on silica (petroleum ether-ethyl acetate 3:1), affording a yellow oil, 3.75 g (73%): 1H NMR (CDCl3) d 1.12 (t, 6H), 1.29 (t, 6H), 3.02 (m, 2H), 3.4 (br, 1H), 3.80 (s, 3H), 4.03 (m, 1H), 5.26 (t, 1H), 6.8-7.3 (m, 7H).
Reaction SMILES: N[C:2]1[C:3]2[C:11](=O)[CH:10]=[CH:9][N:8]([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)[C:4]=2[N:5]=[CH:6][N:7]=1.Cl[Si](C(C)C)(C(C)C)O[Si](Cl)(C(C)C)C(C)C.O>N1C=CC=CC=1>[N:5]1[C:4]2[N:8]=[CH:9][CH:10]=[CH:11][C:3]=2[CH:2]=[N:7][CH:6]=1
Reactant: Nc1ncnc2c1c(=O)ccn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: CC(C)[Si](Cl)(O[Si](Cl)(C(C)C)C(C)C)C(C)C
Solvent: O
Solvent: c1ccncc1
Product: c1cnc2ncncc2c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A reaction mixture of 4-amino-5-oxo-8-(β-D-ribofuranosyl)pyrido[2,3-d]pyrimidine (1.8 g, 6.20 mmol) and 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane (2.15 mL, 6.73 mmol) in anhydrous pyridine (25 mL) was stirred at room temperature for 20 h and cooled with ice. Water (0.5 mL) was added, and the mixture stirred at ambient temperature for 30 min and concentrated. The residue was dissolved in ethyl acetate, washed with diluted sodium bicarbonate, dried over Na2SO4, and concentrated. Chromatography on silica (EtOAc-hexanes 3:2) gave 2.0 g of 4-amino-5-oxo-8-[3,5-O-(1,1,3,3-tetraisopropyldisiloxy)-β-D-ribofuranosyl)]pyrido[2,3-d]pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[C:6]([C:7](Cl)=[O:8])=[C:5]([Cl:10])[N:4]([CH3:11])[N:3]=1.[CH3:12][C:13]1([C:19]2[S:20][CH:21]=[C:22]([CH2:24][P:25](=[O:32])([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28])[N:23]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.CC(C)([O-])C.[K+].O>O1CCCC1>[Cl:1][C:2]1[C:6]([C:7](=[O:8])[CH:24]([C:22]2[N:23]=[C:19]([C:13]3([CH3:12])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[S:20][CH:21]=2)[P:25]([O:29][CH2:30][CH3:31])([O:26][CH2:27][CH3:28])=[O:32])=[C:5]([Cl:10])[N:4]([CH3:11])[N:3]=1
Reactant: Cn1nc(Cl)c(C(=O)Cl)c1Cl
Reactant: CCOP(=O)(Cc1csc(C2(C)CCCCC2)n1)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)C(C(=O)c1c(Cl)nn(C)c1Cl)c1csc(C2(C)CCCCC2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.7 %

Procedure:
0.85 g (4 mmols) of 3,5-dichloro-1-methylpyrazole-4-carboxylic acid chloride and 1.32 g (4 mmols) of diethyl {2-(1-methylcyclohexan-1-yl)-thiazol-4-yl}methylphosphonate were dissolved in 15 ml of dry tetrahydrofuran, and 1.12 g (10 mmols) of potassium t-butoxide was added thereto at room temperature. The reaction mixture was stirred for 1 hour at room temperature, and 20 ml of water was added thereto, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified through silica gel column chromatography to obtain 0.4 g of the intended 1-(3,5-dichloro-1-methylpyrazol-4-yl)-2-{2-(1-methylcyclohexan-1-yl)-thiazol-4-yl}-2-diethylphosphonoethanone.
Reaction SMILES: [Br:1][C:2]([F:17])([F:16])[C:3]([F:15])([F:14])[O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1.[OH-].[NH4+:19]>>[Br:1][C:2]([F:17])([F:16])[C:3]([F:15])([F:14])[O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH2:19])=[O:10])=[CH:7][CH:6]=1
Reactant: O=C(Cl)c1ccc(OC(F)(F)C(F)(F)Br)cc1
Reactant: [NH4+]
Agent: [OH-]
Product: NC(=O)c1ccc(OC(F)(F)C(F)(F)Br)cc1
Yield: 99 %

Procedure:
4-(2-Bromotetrafluoroethoxy)benzoic acid prepared as in Example 18 (26.6 g, 0.083 mol) is transferred to a 250 mL round-bottomed flask along with 150 mL of methylene chloride oxalyl chloride (11.64 g, 0.92 mol) is added and the mixture is stirred under nitrogen overnight to form a turbid solution which is concentrated by rotary evaporation and distilled at 80°-90° C./0.1 mmHg to yield 20.88 g of 4(2-bromo-tetrafluoroethoxy)benzoyl chloride as a colorless liquid, leaving 6.16 g of unreacted acid (76.8% conversion, 96.5% yield). The benzoyl chloride is added slowly with stirring to 8 mL of cold ammonium hydroxide (0.12 mol). The product amide precipitates as fine white needles which are filtered and dried under vacuum to yield 14.74 g of 4-(2-bromotetrafluoroethoxy)benzamide (75% conversion, 99% yield, m.p. 150.5°-151.5° C.), along with 4.8 g of 4-(2-bromotetrafluoroethoxy)benzoic acid which is recovered from the mother liquor (24.3% recovery).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]=O)[CH:9]=2)[NH:4][N:3]=1.[NH2:13][C:14]([C:18]([F:21])([F:20])[F:19])=[CH:15][C:16]#[N:17]>C(O)(=O)C.CO.ClCCl>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]3[C:15]([C:16]#[N:17])=[C:14]([C:18]([F:21])([F:20])[F:19])[NH:13][C:14]([C:18]([F:21])([F:20])[F:19])=[C:15]3[C:16]#[N:17])[CH:9]=2)[NH:4][N:3]=1
Reactant: N#CC=C(N)C(F)(F)F
Reactant: Cc1n[nH]c2ccc(C=O)cc12
Solvent: CO
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1n[nH]c2ccc(C3C(C#N)=C(C(F)(F)F)NC(C(F)(F)F)=C3C#N)cc12

Procedure:
A mixture of 50 mg (0.31 mmol) 3-methyl-1H-indazole-5-carbaldehyde (Example 1A), 106 mg (0.78 mmol) 3-amino-4,4,4-trifluorobut-2-enenitrile [preparation: A. W. Lutz, U.S. Pat. No. 3,635,977; C. G. Krespan, J. Org. Chem. 34, 42 (1969)] and a trace amount of powdered 4 Å molecular sieve in acetic acid (0.30 ml) was heated to reflux temperature for 2 h. After cooling, the reaction mixture was diluted with methanol/dichloromethane and filtered. The filtrate was evaporated, and the residue was purified by preparative RP-HPLC (acetonitrile/water+0.1% TFA gradient) to give 19 mg (15% of th.) of the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[F:25][C:26]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:27]=1[CH2:28]Br.C(OC(N1CCC2C(=C(C3C=CC(Cl)=CC=3)N(CC3C=CC(F)=CC=3F)N=2)CC1)=O)(C)(C)C>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:28][C:27]3[CH:30]=[CH:31][C:32]([F:34])=[CH:33][C:26]=3[F:25])[N:13]=2)=[CH:23][CH:22]=1
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Agent: CC(C)(C)OC(=O)N1CCc2nn(Cc3ccc(F)cc3F)c(-c3ccc(Cl)cc3)c2CC1
Product: Fc1ccc(Cn2nc(-c3ccc(Cl)cc3)c3c2CCNCC3)c(F)c1
Yield: 40.1 %

Procedure:
The title compound (0.030 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 0.2 mmol) using 2,4-difluorobenzyl bromide (0.3 mmol) in place of 2-chloromethyl-thiophene. The reaction sequence also yielded 3-(4-chloro-phenyl)-2-(2,4-difluoro-benzyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester in the alkylation step. MS (ESI): exact mass calculated for C20H18ClF2N3, 373.12; found, m/z 374.1 [M+H]+. 1H NMR (400 MHz, CD3OD): 7.52-7.49 (br m, 4H), 7.27-7.24 (br m, 1H), 7.01-6.99 (br m, 2H), 5.52 (s, 2H), 3.51-3.49 (br m, 2H), 3.43-3.40 (br m, 2H), 3.34-3.31 (br m, 2H), 3.11-3.09 (br m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][C:11]([NH:14][CH2:15][C@H:16]([O:26][Si](C(C)(C)C)(C)C)[C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([CH2:24][OH:25])[CH:18]=2)([CH3:13])[CH3:12])[CH:5]=1.[F-].[NH4+]>CO.O>[NH3:14].[OH:26][C@H:16]([C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([CH2:24][OH:25])[CH:18]=1)[CH2:15][NH:14][C:11]([CH3:13])([CH3:12])[CH2:10][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[C:3]([O:2][CH3:1])=[O:34]
Reactant: COC(=O)c1cccc(CC(C)(C)NC[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(O)c(CO)c2)c1
Agent: [F-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: COC(=O)c1cccc(CC(C)(C)NC[C@H](O)c2ccc(O)c(CO)c2)c1
Product: N
Temperature: 40 °C

Procedure:
A mixture of 3-(2-[(2R)-2-(tert-butyldimethylsilanyloxy)-2-(4-hydroxy-3-hydroxymethyl-phenyl)ethylamino]-2-methylpropyl}benzoic acid methyl ester (preparation 36), (4.0 g, 8.21 mmol) and ammonium fluoride (3.04 g, 82.0 mmol) in methanol (20 mL) and water (5 mL) was heated at 40° C. for 18 hours. The reaction mixture was then concentrated in vacuo and the residue was purified by column chromatography on silica gel, eluting with dichloromethane:methanol: 0.88 ammonia, 100:0:0 to 90:10:0.1, to afford the title compound as a white foam in 81% yield, 2.42 g.
Reaction SMILES: [CH3:1][CH:2]([NH:5][S:6]([C:9]1[CH:20]=[C:13]2[C:14]([O:16]C(=O)[NH:18][C:12]2=[CH:11][CH:10]=1)=[O:15])(=[O:8])=[O:7])[CH2:3][CH3:4].[Cl:21]C1C=CC(S(Cl)(=O)=O)=CC=1C(O)=O>>[CH3:1][CH:2]([NH:5][S:6]([C:9]1[CH:10]=[CH:11][C:12]([Cl:21])=[C:13]([CH:20]=1)[C:14]([OH:16])=[O:15])(=[O:8])=[O:7])[CH2:3][CH3:4].[CH3:1][CH:2]([NH:5][S:6]([C:9]1[CH:20]=[C:13]([C:14]([OH:16])=[O:15])[C:12]([NH2:18])=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH2:3][CH3:4]
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)ccc1Cl
Reactant: CCC(C)NS(=O)(=O)c1ccc2[nH]c(=O)oc(=O)c2c1
Product: CCC(C)NS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Product: CCC(C)NS(=O)(=O)c1ccc(N)c(C(=O)O)c1

Procedure:
5-[N-(2-Butyl)-sulfamoyl]-isatoic anhydride, which is to be used as the starting material, can be obtained, for example, in a manner analogous to that described in Example 1, using 2-chloro-5-chlorosulfonylbenzoic acid as the starting material, the product being obtained via 5-[N-(2-butyl)-sulfamoyl]-2-chloro-benzoic acid with a melting point of 118°-123° and 5-[N-(2-butyl)-sulfamoyl]-anthranilic acid with a melting point of 187°-188°. It melts at 228°-229°.
Reaction SMILES: [O:1]1[CH2:16][CH:2]1[CH2:3][O:4][C:5]1[CH:13]=[C:12]([CH2:14][OH:15])[CH:11]=[C:10]2[C:6]=1[CH:7]=[CH:8][NH:9]2.[C:17](Cl)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19]>N1C=CC=CC=1>[O:1]1[CH2:16][CH:2]1[CH2:3][O:4][C:5]1[CH:13]=[C:12]([CH2:14][O:15][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[CH:11]=[C:10]2[C:6]=1[CH:7]=[CH:8][NH:9]2
Reactant: CC(C)(C)C(=O)Cl
Reactant: OCc1cc(OCC2CO2)c2cc[nH]c2c1
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)OCc1cc(OCC2CO2)c2cc[nH]c2c1
Temperature: 0 °C

Procedure:
8.7 g. 4-(2,3-epoxypropoxy)-6-hydroxymethyl-indole (cf. the preparation of the starting material in Example 15) were dissolved in 50 ml. anhydrous pyridine. To this solution were added dropwise, while stirring and cooling to 5°-10° C., 5 ml. pivalic acid chloride, 1.5-2 hours after the ending of the addition, the reaction mixture was poured into ice water. The aqeuous phase was extracted 3 or 4 times with diethyl ether. The ethereal extract was successively washed with 1 N sulfuric acid, a saturated aqueous solution of sodium bicarbonate and water, then dried, treated with active charcoal and fullers' earth and subsequently evaporated. The crude 4-(2,3-epoxypropoxy)-6-pivaloyloxymethyl-indole thus obtained (12.5 g.; about 100% of theory) was further reacted without further purification.
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([C:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]([CH3:33])[CH:25]=2)=[O:23])[CH2:12][CH2:11]1)=[O:7])(C)(C)C.[ClH:34].O1[CH2:40][CH2:39][O:38][CH2:37]C1>>[NH2:26][C:27]1[C:28]([Cl:34])=[CH:29][C:40]([C:6]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([C:24]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]([CH3:33])[CH:25]=3)=[O:23])[CH2:14][CH2:15]2)=[O:7])=[C:39]([O:38][CH3:37])[CH:32]=1
Reactant: C1COCCO1
Reactant: Cn1cc(C(=O)NCCCCCN2CCC(CNC(=O)OC(C)(C)C)CC2)c2ccccc21
Reactant: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCNC(=O)c2cn(C)c3ccccc23)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
N-(5-(4-tert-Butoxycarbonylaminomethylpiperidin-1-yl)pentyl)-1-methyl-1 H-indole-3-carboxamide (1.12 g) was dissolved in 4N hydrochloric acid-dioxane solution (30 ml) and the mixture was stood at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure. Dimethylformamide (30 ml) was added to the residue and the mixture was neutralized with triethylamine (0.68 ml). 4-Amino-5-chloro-2-methoxybenzoic acid (0.49 g) and 1-hydroxybenzotriazole (0.36 g) were added thereto, and the mixture was stirred at 0° C. for 20 min. Then, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.52 g) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure. Aqueous potassium carbonate solution was added to the residue and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography to give 0.60 g of N-(5-(4 -(4-amino-5-chloro-2-methoxybenzoylaminomethyl)piperidin-1-yl)pentyl)-l-methyl-1 H-indole-3-carboxamide.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([C:17]1[N:18]=[CH:19][N:20](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:21]=1)([OH:16])[CH:13]([CH3:15])[CH3:14])[CH:6]=[CH:5]2.C([Li])CCC.CN(OC)[C:48](=[O:50])[CH3:49].O>C1COCC1.CCCCCC>[OH:16][C:12]([C:7]1[CH:8]=[C:3]2[C:4](=[CH:5][CH:6]=1)[CH:9]=[C:10]([C:48](=[O:50])[CH3:49])[CH:11]=[CH:2]2)([C:17]1[N:18]=[CH:19][NH:20][CH:21]=1)[CH:13]([CH3:14])[CH3:15]
Reactant: CC(C)C(O)(c1ccc2cc(Br)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CON(C)C(C)=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1ccc2cc(C(O)(c3c[nH]cn3)C(C)C)ccc2c1
Temperature: -70 °C
Reaction time: 0.33 h
Yield: 96.1 %

Procedure:
1-(6-Bromonaphthalen-2-yl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol (7.0 g) was dissolved in THF (150 ml). The solution was cooled to −70° C. To the mixture was slowly added a solution of n-butyl lithium in hexane (1.6 M; 16.4 ml), and the mixture was stirred at −70° C. for 20 min. To the mixture was added dropwise a solution of N-methyl-N-methoxyacetamide (2.45 g) in THF (10 ml), and the mixture was stirred at −70° C. for 20 min. To the mixture was added water, and the mixture was extracted with ethyl acetate, washed with saturated sodium chloride solution and dried. The solvent was distilled off and the residue was purified column chromatography (eluent, hexane:THF=6:1→3:1) to give the titled compound (3.53 g) as a colorless powder.