Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:17][C:11]3([CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[C:10](=[O:18])[CH2:9][C:8]=2[CH:19]=1)([O-:3])=[O:2].[CH3:20][N:21]=[C:22]=[S:23].CC(C)([O-])C.[K+]>CN(C)C=O>[OH:18][C:10]1[C:11]2([CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)[O:17][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:19][C:8]=2[C:9]=1[C:22](=[S:23])[NH:21][CH3:20]
Reactant: O=C1Cc2cc([N+](=O)[O-])ccc2OC12CCOCC2
Reactant: CN=C=S
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CNC(=S)C1=C(O)C2(CCOCC2)Oc2ccc([N+](=O)[O-])cc21
Temperature: 0 °C
Yield: 62 %

Procedure:
To a mixture of 4.8 g of 3,4-dihydro-6-nitrospiro[2H-1-benzopyran-2,4'-tetrahydropyran]-3-one and 60 ml of dried N,N-dimethylformamide was added 1.65 g of methyl isothiocyanate under nitrogen stream. Then, 2.39 g of potassium tertiary butoxide was added therein with stirring under ice-cooling and the mixture was stirred for 1 hour and then stirred at 5° C. for 17 hours. Ice water was added to the reaction solution and it was washed with ether. A water layer was acidified to be hydrochloric acid and extracted with ether. An organic layer was washed with water and dried, and the solvent was distilled. The obtained residue was recrystallized by a mixed solvent of ethyl acetate and hexane to obtain 3.8 g of 3-hydroxy-N-methyl-6-nitrospiro-[2H-1-benzopyran-2,4'-tetrahydropyran]-4-carbothioamide with a melting point of 217°-218° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:10])[CH:9]=1)[CH2:5][OH:6].[C:11](Cl)([Cl:13])=[O:12]>C(Cl)Cl>[Cl:13][C:11]([O:6][CH2:5][C:4]1[CH:3]=[C:2]([Cl:1])[CH:9]=[C:8]([Cl:10])[CH:7]=1)=[O:12]
Reactant: OCc1cc(Cl)cc(Cl)c1
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Product: O=C(Cl)OCc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 3,5-dichlorobenzyl alcohol (0.201 g, 1.06 mmol) in CH2Cl2 (0.5 mL) was added phosgene (20% in toluene; 0.42 mL, 0.79 mmol), and the mixture was stirred at room temperature for 30 minutes to give the title compound, which was used directly in the next step.
Reaction SMILES: ClC1C=C(C(Cl)=O)C=C(Cl)C=1.[Cl:12][C:13]1[CH:14]=[C:15]([C:20]([N:22]=[C:23]=[S:24])=[O:21])[CH:16]=[C:17]([Cl:19])[CH:18]=1.[CH3:25][O:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][C:36]=1[O:37][CH3:38])[N:33]=[CH:32][CH:31]=[C:30]2[O:39][C:40]1[CH:46]=[CH:45][C:43]([NH2:44])=[CH:42][C:41]=1[F:47].C1(C)C=CC=CC=1>C(O)C>[Cl:12][C:13]1[CH:14]=[C:15]([C:20]([N:22]=[C:23]=[S:24])=[O:21])[CH:16]=[C:17]([Cl:19])[CH:18]=1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:16]=[C:17]([Cl:19])[CH:18]=1)[C:20]([NH:22][C:23]([NH:44][C:43]1[CH:45]=[CH:46][C:40]([O:39][C:30]2[C:29]3[C:34](=[CH:35][C:36]([O:37][CH3:38])=[C:27]([O:26][CH3:25])[CH:28]=3)[N:33]=[CH:32][CH:31]=2)=[C:41]([F:47])[CH:42]=1)=[S:24])=[O:21]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Agent: O=C(Cl)c1cc(Cl)cc(Cl)c1
Agent: O=C(N=C=S)c1cc(Cl)cc(Cl)c1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4cc(Cl)cc(Cl)c4)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
3,5-Dichloro-1-benzenecarbonyl isothiocyanate was prepared using commercially available 3,5-dichloro-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 3,5-Dichloro-1-benzenecarbonyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (73 mg, yield 84%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[C:18]([NH:23][C@H:24]1[C@@H:29]([NH:30]C(=O)OCC[Si](C)(C)C)[CH2:28][C@H:27]3[C@@H:25]1[CH2:26]3)[N:17]=[CH:16]2.Cl>O1CCOCC1>[Cl:12][C:4]1[C:5]([O:10][CH3:11])=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Cl:1])[C:3]=1[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[C:18]([NH:23][C@H:24]1[C@@H:29]([NH2:30])[CH2:28][C@H:27]3[C@@H:25]1[CH2:26]3)[N:17]=[CH:16]2
Reactant: COc1cc(OC)c(Cl)c(-c2ccc3nc(N[C@@H]4[C@H]5C[C@H]5C[C@@H]4NC(=O)OCC[Si](C)(C)C)ncc3c2)c1Cl
Agent: Cl
Solvent: C1COCCO1
Product: COc1cc(OC)c(Cl)c(-c2ccc3nc(N[C@@H]4[C@H]5C[C@H]5C[C@@H]4N)ncc3c2)c1Cl
Reaction time: 8 h
Yield: 0 %

Procedure:
To a solution of 2-(trimethylsilyl)ethyl (1S,2R,3S,5S)-2-(6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-ylamino)bicyclo[3.1.0]hexan-3-ylcarbamate (200 mg, 340 mmol) in dioxane (10 mL) was added 12 M conc. HCl (1 mL) at room temperature. The resulting mixture was stirred overnight, then quenched with water (50 mL), and the pH of the solution was brought to pH=8-9 with saturated solution of sodium carbonate. The solution mixture was extracted with ethyl acetate (3×50 mL), and the combined layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by thin layer chromatography (Prep-TLC) (dichloromethane:methanol=15:1), and then further purified by silica gel column chromatography (dichloromethane:methanol=20:1) to afford the title compound (70 mg, 46%) as a white solid. MS (ES+) C22H22Cl2N4O2 requires: 444, 446, found: 445, 447 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:6]3[C:11]([C:12]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1.C([Li])CCC.[B:33](OCC)([O:37]CC)[O:34]CC.Cl>C1COCC1.CCCCCC>[C:16]1([C:12]2[C:11]3[C:6]([C:5]([C:4]4[CH:13]=[CH:14][CH:15]=[CH:2][CH:3]=4)=[C:22]4[C:23]=2[CH:24]=[C:25]([B:33]([OH:37])[OH:34])[CH:26]=[CH:27]4)=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Brc1ccc2c(-c3ccccc3)c3ccccc3c(-c3ccccc3)c2c1
Reactant: CCOB(OCC)OCC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OB(O)c1ccc2c(-c3ccccc3)c3ccccc3c(-c3ccccc3)c2c1
Temperature: -80 °C
Reaction time: 12 h
Yield: 71.9 %

Procedure:
An amount of 4.68 g (11.4 mmol) of 2-bromo-9,10-diphenylanthracene was dissolved in dehydrated THF and cooled to −80° C. An amount of 7.9 ml (12 mmol) of a solution of n butyllithium in n hexane was added dropwise and, 40 minutes later, 3.33 g (22.8 mmol) of triethyl borate was further added. After two-hour reaction, a dilute hydrochloric acid solution was added and the mixture was allowed to stand for 12 hours. Then, the separated organic layer was recrystallized to obtain 3.07 g (8.2 mmol) of 9,10-diphenylanthracene-2-boronic acid. The yield was 72%.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]([CH2:15][CH2:16][CH3:17])[C:12]([OH:14])=[O:13])=[CH:3]1.S(=O)(=O)(O)O.[CH3:23]O>>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]([CH2:15][CH2:16][CH3:17])[C:12]([O:14][CH3:23])=[O:13])=[CH:3]1
Reactant: CCCC(C(=O)O)c1cn(C)c2ccccc12
Reactant: CO
Agent: O=S(=O)(O)O
Product: CCCC(C(=O)OC)c1cn(C)c2ccccc12
Yield: 70 %

Procedure:
A mixture of 2-(1-methyl-1H-indol-3-yl)pentanoic acid (12a) (1.22 g, 5.28 mmol) and concentrated sulfuric acid (1 mL) in methanol (40 mL) was refluxed for 3 hours. After concentration, the mixture was quenched with a saturated aqueous solution of sodium carbonate and the aqueous layer was extracted with dichloromethane (2×20 mL). The organic layer was dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 93/7) to afford the desired ester (12b) as a white solid (910 mg, 3.71 mmol, 70%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](O)=[O:5].[C:12](N1C=CN=C1)([N:14]1C=CN=C1)=O.Cl.CN.C(N(C(C)C)CC)(C)C>>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([NH:14][CH3:12])=[O:5]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1c(F)cccc1F
Agent: CN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1c(F)cccc1F

Procedure:
The title compound was prepared from 2,6-difluorobenzoic acid (10 g, 63.2 mmol), carbonyldiimidazole (10.26 g, 63.5 mmol), methylamine hydrochloride (4.27 g, 63.25 mmol) and diisopropylethyl amine according to the procedure used for example 84 (Step A) to give near quantitative yield of the title compound.
Reaction SMILES: C(OC([NH:11][C@H:12]1[CH2:17][CH2:16][CH2:15][N:14]([P:18]([NH:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:19])[C:13]1=[O:34])=O)C1C=CC=CC=1>CO.[Pd]>[NH2:11][C@H:12]1[CH2:17][CH2:16][CH2:15][N:14]([P:18]([NH:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:19])[C:13]1=[O:34]
Reactant: CCCCCCNP(=O)(NCCCCCC)N1CCC[C@H](NC(=O)OCc2ccccc2)C1=O
Agent: [Pd]
Solvent: CO
Product: CCCCCCNP(=O)(NCCCCCC)N1CCC[C@H](N)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Palladium black (31 mg) was added to a solution of (3S)-3-benzyloxycarbonylamino-1-bis(n-hexylamino)phosphinyl-2-piperidone (310.9 mg, 0.6286 mmol) in methanol (3 mL), and the resulting mixture was stirred at room temperature for 1 hour under a hydrogen atmosphere.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([Cl:19])[CH:17]=3)[N:12]([S:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)(=[O:22])=[O:21])[CH:11]=2)O)=[CH:4][CH:3]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[C:23]1([S:20]([N:12]2[C:13]3=[N:14][CH:15]=[C:16]([Cl:19])[CH:17]=[C:18]3[C:10]([CH2:8][C:5]3[CH:4]=[CH:3][C:2]([NH2:1])=[N:7][CH:6]=3)=[CH:11]2)(=[O:22])=[O:21])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Nc1ccc(C(O)c2cn(S(=O)(=O)c3ccccc3)c3ncc(Cl)cc23)cn1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccc(Cc2cn(S(=O)(=O)c3ccccc3)c3ncc(Cl)cc23)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.8 %

Procedure:
To (6-amino-pyridin-3-yl)-(1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol (598, 1.00 g, 0.00241 mol) in dichloromethane (25.0 mL) were added triethylsilane (3.00 mL, 0.0188 mol) and trifluoroacetic acid (1.50 mL, 0.0195 mol). The reaction was stirred at room temperature overnight, then concentrated, poured into aqueous potassium carbonate, 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 20% to 100% ethyl acetate in hexane to give the desired compound (599, 0.70 g, 73%).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[N:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([N:25]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:22]=[CH:21][N:20]=1)=[O:18].[C:40](Cl)(=[O:43])[CH2:41][CH3:42]>>[C:29]([O:28][C:26]([N:25]([C:23]1[CH:22]=[CH:21][N:20]=[C:19]([C:17]([C:3]2[N:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:5]3[C:10]([C:2]=2[NH:1][C:40](=[O:43])[CH2:41][CH3:42])=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=3)=[O:18])[CH:24]=1)[C:33]([O:35][C:36]([CH3:38])([CH3:37])[CH3:39])=[O:34])=[O:27])([CH3:30])([CH3:31])[CH3:32]
Reactant: CCC(=O)Cl
Reactant: CCOC(=O)n1c(C(=O)c2cc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccn2)c(N)c2ccc(Cl)cc21
Product: CCOC(=O)n1c(C(=O)c2cc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccn2)c(NC(=O)CC)c2ccc(Cl)cc21

Procedure:
The title compound was prepared according ot the procedure described in step 1 of Example 2 (Method A) employing 3-amino-2-[4-[N,N-bis(tert-butoxycarbonyl)amino]pyridine-2-carbonyl]-6-chloro-1-(ethoxycarbonyl)indole (step 2) and propionyl chloride. 1H-NMR (CDCl3) δ: 9.52 (1 H, br s), 8.61 (1 H, d, J=5.1 Hz), 8.21 (1 H, d, J=1.8 Hz), 8.05 (1 H, d, J=8.7 Hz), 7.95 (1 H, d, J=2.1 Hz), 7.28-7.23 (2 H, m), 3.93 (2 H, q, J=7.1 Hz), 2.51 (2 H, q, J=7.4 Hz), 1.50 (18 H, s), 1.26 (3 H, t, J=7.4 Hz), 1.02 (3 H, t, J=7.1 Hz).
Reaction SMILES: [CH2:1]([NH2:5])[CH:2]([CH3:4])[CH3:3].Cl[C:7]1[C:12]([Cl:13])=[C:11]([Cl:14])[CH:10]=[CH:9][C:8]=1[N+:15]([O-:17])=[O:16].O>C1(C)C=CC=CC=1>[Cl:13][C:12]1[C:11]([Cl:14])=[CH:10][CH:9]=[C:8]([N+:15]([O-:17])=[O:16])[C:7]=1[NH:5][CH2:1][CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CN
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1Cl
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)CNc1c([N+](=O)[O-])ccc(Cl)c1Cl
Temperature: 60 °C
Reaction time: 72 h
Yield: 98 %

Procedure:
Forty-eight grams of isobutylamine and 75.5 gm of 2,3,4-trichloronitrobenzene were dissolved in 200 ml of toluene and kept at room temperature for 3 days. The mixture was then treated with a further 5 gm of isobutylamine and heated to 60° C. for 4 hours. The toluene solution was shaken with water, dried, and evaporated. The yield was 86 gm of 2,3-dichloro-6-nitro-N-isobutylaniline (98% of theory), which was obtained as a brownish oil.
Reaction SMILES: [NH2:1][C:2]([O:4][CH2:5][C@@H:6]1[CH2:11][C:10]([C:12]2[N:13]=[C:14]([S:17]CC3C=CC(OC)=CC=3)[S:15][CH:16]=2)=[CH:9][CH2:8][N:7]1[C:27]([O:29][CH2:30][CH:31]=[CH2:32])=[O:28])=[O:3].C1(OC)C=CC=CC=1.C(N)(=S)C1C=CN=CC=1>FC(F)(F)C(O)=O>[NH2:1][C:2]([O:4][CH2:5][C@@H:6]1[CH2:11][C:10]([C:12]2[N:13]=[C:14]([SH:17])[S:15][CH:16]=2)=[CH:9][CH2:8][N:7]1[C:27]([O:29][CH2:30][CH:31]=[CH2:32])=[O:28])=[O:3]
Reactant: C=CCOC(=O)N1CC=C(c2csc(SCc3ccc(OC)cc3)n2)C[C@H]1COC(N)=O
Agent: NC(=S)c1ccncc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: C=CCOC(=O)N1CC=C(c2csc(S)n2)C[C@H]1COC(N)=O
Yield: 65.6 %

Procedure:
Allyl (2S)-2-{[(aminocarbonyl)oxy]methyl}-4-{2-[(4-methoxybenzyl)sulfanyl]-1,3-thiazol-4-yl}-3,6-dihydro-1(2 H)-pyridinecarboxylate (74.5 mg, 0.16 mmol) and anisole (35 ml, 0.32 mmol) were dissolved in trifluoroacetic acid (6 ml). And then thioisonicotinamide (3 mg) was added to the solution and the mixture was refluxed at 80–90° C. Four hours later the solvent was removed in vacuo. To the residue was added an aqueous 1N NaOH solution to make the solution alkaline. To the solution were added ethyl acetate and hexane, and the solution was separated with a separating funnel. To the aqueous layer was added 6N hydrochloric acid and the solution was separated with a separating funnel by addition of ethyl acetate. The aqueous layer was extracted with ethyl acetate and the organic layer was washed twice with a saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed in vacuo to give allyl (2S)-2-{[(aminocarbonyl)oxy]methyl}-4-(2-mercapto-1,3-thiazol-4-yl)-3,6-dihydro-1(2 H)-pyridinecarboxylate (37.3 mg, 67%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[N:6][C:5]([C:8]([OH:10])=O)=[CH:4][CH:3]=1.[C:11]([O:15][C:16]([N:18]1[CH:23]2[CH2:24][CH2:25][CH:19]1[CH2:20][NH:21][CH2:22]2)=[O:17])([CH3:14])([CH3:13])[CH3:12].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.CCOC(C)=O>[C:11]([O:15][C:16]([N:18]1[CH:19]2[CH2:25][CH2:24][CH:23]1[CH2:22][N:21]([C:8]([C:5]1[N:6]=[N:7][C:2]([NH2:1])=[CH:3][CH:4]=1)=[O:10])[CH2:20]2)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1C2CCC1CNC2
Reactant: Nc1ccc(C(=O)O)nn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1C2CCC1CN(C(=O)c1ccc(N)nn1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
To a solution of 6-amino-pyridazine-3-carboxylic acid (212 mg, 1.0 mmol) in DMF (5 mL) was added 3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (139 mg, 1.0 mmol), HATU (456 mg, 1.2 mmol) and N,N-diisopropylethylamine (0.52 mL, 3.0 mmol). The mixture was stirred at room temperature overnight after which it was diluted with EtOAc, washed with brine, dried over Na2SO4, concentrated and purified over normal silica with 0-20% MeOH/DCM which gave a white solid (169 mg, 0.51 mmol). MS m/z 334.4 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH:11][C:12]2[CH:20]=[C:19]3[C:15]([CH2:16][C:17](=[O:21])[NH:18]3)=[CH:14][CH:13]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH3:22][C:23]1[N:24]=[CH:25][N:26]([C:28]2[CH:29]=[C:30]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=2)[C:31](O)=[O:32])[CH:27]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:22][C:23]1[N:24]=[CH:25][N:26]([C:28]2[CH:29]=[C:30]([CH:34]=[C:35]([C:37]([F:40])([F:38])[F:39])[CH:36]=2)[C:31]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][C:9]([NH:11][C:12]3[CH:20]=[C:19]4[C:15]([CH2:16][C:17](=[O:21])[NH:18]4)=[CH:14][CH:13]=3)=[O:10])[CH:3]=2)=[O:32])[CH:27]=1
Reactant: Nc1cccc(NC(=O)Nc2ccc3c(c2)NC(=O)C3)c1
Reactant: Cc1cn(-c2cc(C(=O)O)cc(C(F)(F)F)c2)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cn(-c2cc(C(=O)Nc3cccc(NC(=O)Nc4ccc5c(c4)NC(=O)C5)c3)cc(C(F)(F)F)c2)cn1
Reaction time: 24 h

Procedure:
1-(3-amino-phenyl)-3-(2-oxo-2,3-dihydro-1H-indol-6-yl)-urea (75 mg, 0.27 mmol) is dissolved in DMF (5 ml). To this solution is added 3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-benzoic acid (73 mg, 0.27 mmol), N,N-diisopropylethylamine (105 mg, 0.81 mmol) and HATU (0.10 g, 0.26 mmol). It is stirred for 24 hours and then concentrated. 3-(4-methyl-imidazol-1-yl)-N-{3-[3-(2-oxo-2,3-dihydro-1H-indol-6-yl)-ureido]-phenyl}-5-trifluoromethyl-benzamide is obtained after HPLC purification. LC-MS: 535.2 (MH+).
Reaction SMILES: [NH:1]([C:3]([C@@H:5]([C@@H:14]([C@@H:23]([CH2:25][O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)O)[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4])[NH2:2].[N+:34]([C:37]1[CH:44]=[CH:43][C:40]([CH:41]=O)=[CH:39][CH:38]=1)([O-:36])=[O:35]>CO>[CH2:7]([O:6][C@@H:5]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:23]([CH2:25][O:26][CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[O:4][CH:3]1[NH:1][N:2]=[CH:41][C:40]1[CH:43]=[CH:44][C:37]([N+:34]([O-:36])=[O:35])=[CH:38][CH:39]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NNC(=O)[C@H](OCc1ccccc1)[C@H](OCc1ccccc1)[C@H](O)COCc1ccccc1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Solvent: CO
Product: O=[N+]([O-])c1ccc(C=NNC2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1
Reaction time: 0.08 h

Procedure:
2.4 g (5.55 mmoles) of 1-hydrazino-2,3,5-tri-O-benzyl-D-ribose are dissolved in 10 ml of absolute methanol. 0.84 g (5.55 mmoles) of p-nitrobenzaldehyde (dissolved in 8 ml of absolute methanol) are added to the solution. Stirring is carried out at room temperature and after approximately 5 minutes a yellow flaky precipitate appears. After 24 hours the precipitate is drawn off by suction and dried. Yield: 2.4 g (76 %). Melting point: 93° C. (from methanol).
Reaction SMILES: C(Cl)(=O)C.[NH:5]1[CH2:10][CH2:9][CH:8]=[C:7]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)[CH2:6]1>[OH-].[OH-].[Pd+2].CO>[NH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)[CH2:6]1
Reactant: C1=C(c2c[nH]c3ncccc23)CNCC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)Cl
Product: c1cnc2[nH]cc(C3CCCNC3)c2c1
Reaction time: 0.25 h
Yield: 56 %

Procedure:
10 ml acetylchloride was slowly added to 200 ml of MeOH (−10° C.). After 15 minutes, this solution was added to compound 5 (1.43 g, 7.18 mmol) and 20% Pd(OH)2/C (130 mg). The mixture was hydrogenated at 50 psi for 1 hour. The mixture was filtered and concentrated. A subsequent filtration over SCX-2, followed by flash chromatography (MeOH/triethylamine (97/3) afforded compound 6 (0.81 g, 4.02 mmol, 55%) which was reacted with 1 equivalent of fumaric acid in EtOH and concentrated. Recrystallization from EtOH/ethylacetate afforded a solid (free base/fumaric acid (2:1)), mp>225° C. (decomposition). 1H-NMR (400 MHz, D2O): δ 8.04 (bd, J=5 Hz, 1H), 7.93 (bd, J=8 Hz, 1H), 7.13 (bs, 1H), 7.01 (dd, J=8 Hz, 5 Hz, 1H), 6.36 (s, 1H), 3.46-3.40 (m, 1H), 3.37-3.31 (m, 1H), 3.14-3.04 (m, 1H), 2.92-2.82 (m, 2H), 2.0-1.87 (m, 2H), 1.8-1.54 (m, 2H).
Reaction SMILES: Br[C:2]1[C:3]([O:14][CH3:15])=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[CH2:21]([O:28][C:29]1[C:34]([CH:35]=[O:36])=[CH:33][CH:32]=[CH:31][C:30]=1[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:21]([O:28][C:29]1[C:34]([CH:35]([C:2]2[C:3]([O:14][CH3:15])=[C:4]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:5]=[CH:6][CH:7]=2)[OH:36])=[CH:33][CH:32]=[CH:31][C:30]=1[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=Cc1cccc(-c2ccccc2)c1OCc1ccccc1
Reactant: COc1c(Br)cccc1-c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1c(-c2ccccc2)cccc1C(O)c1cccc(-c2ccccc2)c1OCc1ccccc1
Reaction time: 1 h

Procedure:
A solution of 2 (0.91 g, 3.46 mmol) in anhydrous tetrahydrofuran (15 mL) was stirred under nitrogen at −78° C. and 2.5M n-butyllithium in hexanes (1.38 mL, 3.46 mmol) was added at such a rate that the temperature did not exceed −70° C. Stirring was continued at −78° C. for 1 hr when a solution of 2-(benzyloxy)biphenyl-3-carbaldehyde (1.0 g, 3.46 mmol) in tetrahydrofuran (5 mL) was added at such a rate that the temperature did not exceed −65° C. Stirring was continued at −78° C. for 20 min, then for 2 hr at room temperature. The reaction mixture was poured on saturated ammonium chloride (150 mL) and extracted with ethyl acetate (150 mL). The organic extract was washed with water (2×100 mL), dried over sodium sulfate and stripped. The crude 3 was used as such in the next step.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][O:11][CH2:12][CH:13]([OH:18])[CH2:14][N:15]=[N+]=[N-])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][O:11][CH2:12][CH:13]([OH:18])[CH2:14][NH2:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [N-]=[N+]=NCC(O)COCCCCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCC(O)COCCCCc1ccccc1
Yield: 96.1 %

Procedure:
A procedure similar to that described in Preparation 13 was repeated, except that 4.30 g of 3-(4-phenylbutoxy)-2-hydroxypropylazide (prepared as described in Preparation 59), 1.31 g of lithium aluminum hydride and 120 ml of anhydrous tetrahydrofuran were used, to give 3.70 g of the title compound as a colorless oil having an Rf value of 0.08 (on silica gel thin layer chromatography, using a 10:1 by volume mixture of ethyl acetate and methanol as the developing solvent).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:12]2[NH:11][C:10]3[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17][C:9]=3[C:8]=2[C:7]([Cl:25])=[CH:6][CH:5]=1.Br[CH2:27][CH2:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C=O)C>[Cl:3][C:4]1[C:12]2[N:11]([CH2:27][CH2:28][O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:10]3[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:16][CH2:17][C:9]=3[C:8]=2[C:7]([Cl:25])=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3c(Cl)ccc(Cl)c3c2CC1
Reactant: BrCCOc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2c(n(CCOc3ccccc3)c3c(Cl)ccc(Cl)c23)CC1
Reaction time: 0.42 h
Yield: 79 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 51 mg, 1.3 mmol) was added to a solution of tert-butyl 7,10-dichloro-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.30 g, 0.84 mmol) in DMF (5 mL). After 25 min, β-bromophenetole was added (0.23 mL). The reaction was quenched with saturated aqueous NH4Cl after 18 h and extracted with EtOAc (3×20 mL). The combined organic extracts were washed with brine, dried over Na2SO4, decanted, and concentrated. The crude product was purified by column chromatography (Biotage, 40S) with heptane/EtOAc (9:1) to give 0.32 g (79%) of a white solid: mp 131.5-133.0° C.; 1H NMR (300 MHz, CDCl3) δ 6.96 (m, 3H), 6.81 (m, 2H), 4.92 (t, J=4.9 Hz, 2H), 4.27 (m, 2H), 3.80 (m, 2H), 3.67 (m, 2H), 3.52 (m, 2H), 3.18 (m, 2H), 1.49 (s, 9H); IR (diffuse reflectance) 1686, 1498, 1474, 1404, 1366, 1350, 1318, 1295, 1248, 1227, 1221, 1167, 1116, 788, 757 cm−1; MS (EI) m/z 474 (M+), 418, 376, 374, 339, 334, 332, 77, 57, 56, 55; Anal. Calcd for C25H28Cl2N2O3: C, 63.16; H5.94; N, 5.89; found: C, 63.13; H, 6.00; N, 5.89.