Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:22])[C:2]([S:7]([N:10]([CH2:18][C:19]([OH:21])=O)[C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)(=[O:9])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[CH2:23]([NH:25][CH2:26][C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=1)[CH3:24]>>[CH2:23]([N:25]([CH2:26][C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=1)[C:19](=[O:21])[CH2:18][N:10]([S:7]([C:2]1[C:1]([CH3:22])=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:9])=[O:8])[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)[CH3:24]
Reactant: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccccc2C)cc1
Reactant: CCNCc1ccc2ccccc2n1
Product: CCN(Cc1ccc2ccccc2n1)C(=O)CN(c1ccc(C)cc1)S(=O)(=O)c1ccccc1C

Procedure:
prepared by reaction of [(toluene-2-sulfonyl)-p-tolyl-amino]-acetic acid with ethyl-quinolin-2-ylmethyl-amine
Reaction SMILES: C([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH:13]=[C:14]2[N:24]2[CH:28]=[CH:27][N:26]=[CH:25]2)[CH2:6]1)(=O)C>CO.[OH-].[K+]>[OH:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH:13]=[C:14]2[N:24]2[CH:28]=[CH:27][N:26]=[CH:25]2)[CH2:6]1
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(n4ccnc4)=CC[C@@H]32)C1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(n3ccnc3)=CC[C@@H]12
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.6 %

Procedure:
The method followed that described in Synthesis Example 4, but using 3,6-acetoxy-17-(1H-imidazol-1-yl) -androsta-5,16-diene (Compound 10) (2.72 g, 7.16 mmol) in methanol (30 ml), 10% methanolic KOH (17 ml), and the mixture was stirred at room temp under N2 for 2 h. Following the conventional workup gave rise to Compound 11 (2.34 g, 95%), mp 220-223° C. 1H NMR (300 MHz, CDCl3): δ 1.01 (3H, s, 18-Me), 1.06 (3H, s, 19-Me), 3.53 (1H, m, 3α-H), 5.39 (1H, d, J=5 Hz, 6-H), 5.69 (1H, s, 16-H), 7.08 (2H, br. s, 4′ and 5′-H), and 7.64 (1H, s, 2′-H). Analysis calculated for C22H30ON2: C, 78.05; H, 8.94; N, 8.28; Found: C, 78.02; H, 9.00; N, 8.22. HRMS calcd. for C22H30ON2 338.2358, found 338.2361.
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]2[NH:15][CH:16]=[N:17][C:12]2=[CH:11][CH:10]=1)C1C=CC=CC=1.[F:18][C:19]1[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][C:20]=1B(O)O>>[F:18][C:19]1[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][C:20]=1[N:15]1[C:13]2=[N:14][C:9]([OH:8])=[CH:10][CH:11]=[C:12]2[N:17]=[CH:16]1
Reactant: Cc1cccc(B(O)O)c1F
Reactant: c1ccc(COc2ccc3nc[nH]c3n2)cc1
Product: Cc1cccc(-n2cnc3ccc(O)nc32)c1F

Procedure:
From 5-(benzyloxy)-3H-imidazo[4,5-b]pyridine and 2-fluoro-3-methylphenylboronic acid, prepared in a similar manner as the one described in Example 1.26, the title compound was obtained. LCMS m/z=244.2 [M+H]+.
Reaction SMILES: [CH:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CS(O[CH2:18][CH2:19][C@@:20]1([C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[C:40]([Cl:45])[CH:39]=2)[CH2:24][CH2:23][N:22]([C:25](=[O:37])[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH:34]([CH3:36])[CH3:35])[CH:28]=2)[CH2:21]1)(=O)=O.C(#N)C>>[Cl:45][C:40]1[CH:39]=[C:38]([C@@:20]2([CH2:19][CH2:18][N:10]3[CH2:11][CH2:12][N:7]([CH:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)[CH2:8][CH2:9]3)[CH2:24][CH2:23][N:22]([C:25](=[O:37])[CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH:34]([CH3:35])[CH3:36])[CH:28]=3)[CH2:21]2)[CH:43]=[CH:42][C:41]=1[Cl:44]
Reactant: CC(C)Oc1cccc(CC(=O)N2CC[C@@](CCOS(C)(=O)=O)(c3ccc(Cl)c(Cl)c3)C2)c1
Reactant: C1CCC(N2CCNCC2)CC1
Solvent: CC#N
Product: CC(C)Oc1cccc(CC(=O)N2CC[C@](CCN3CCN(C4CCCCC4)CC3)(c3ccc(Cl)c(Cl)c3)C2)c1

Procedure:
In 30 ml of acetonitrile (R)-3-(2-methanesulfonyloxyethyl)-3-(3,4-dichlorophenyl)-1-[(3-isopropoxyphenyl)acetyl)pyrrolidine (3.17 g), prepared as described, suora, is mixed with an equimolar amount of 1-cyclohexylpiperazine. The reaction mixture is then heated to reflux and refluxed for about ten hours. The mixture is then concentrated under vacuum and the residue is taken up in methylene chloride and washed with a 3N solution of hydrochloric acid, followed by a wash with brine. The organic fraction is dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue precipitates from an acetone/diethyl ether mixture to give the desired title product.
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:3]=1[O:4][CH:5]([CH3:9])[C:6]([OH:8])=[O:7].[Si:15]([O:22][C@H:23]1[CH2:32][C@H:31](O)[C@H:30]2[C:25]([CH:26]=[CH:27][C@H:28]([CH3:51])[C@@H:29]2[CH2:34][CH2:35][C@H:36]2[O:41][C:40](=[O:42])[CH2:39][C@H:38]([O:43][Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45])[CH2:37]2)=[CH:24]1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>>[Si:15]([O:22][C@H:23]1[CH2:32][C@H:31]([O:7][C:6](=[O:8])[CH:5]([O:4][C:3]2[C:10]([CH3:14])=[CH:11][CH:12]=[CH:13][C:2]=2[CH3:1])[CH3:9])[C@H:30]2[C:25]([CH:26]=[CH:27][C@H:28]([CH3:51])[C@@H:29]2[CH2:34][CH2:35][C@H:36]2[O:41][C:40](=[O:42])[CH2:39][C@H:38]([O:43][Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:45])[CH3:46])[CH2:37]2)=[CH:24]1)([C:18]([CH3:19])([CH3:20])[CH3:21])([CH3:17])[CH3:16]
Reactant: Cc1cccc(C)c1OC(C)C(=O)O
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Product: Cc1cccc(C)c1OC(C)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Yield: 94.7 %

Procedure:
A procedure similar to that described in Example 10, above, was followed, but using 0.81 g of (2RS)-2-(2,6-dimethylphenoxy)propionic acid and 1.0 g of (4R,6R)-6-{(1S,2S,6S,8S,8aR)-2-[1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above], to give 1.25 g of the title compound as a colorless foam.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][C@@H:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][C@@H:20]1[OH:28]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([C@@:19]2([NH2:18])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21][C@@H:20]2[OH:28])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: N[C@@H]1c2ccccc2C[C@@H]1O
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)[C@@]1(N)c2ccccc2C[C@@H]1O

Procedure:
Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (Example B) and 1-(R)-amino-2-(S)-indanol, the title compound was prepared.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7](Cl)(=[O:9])=[O:8])[CH:2]=1.[C:11]([O:15][C:16](=[O:34])[CH2:17][N:18]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][NH2:33])[N:27]=1)[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C.S([O-])(O)(=O)=O.[K+]>C(Cl)Cl>[C:11]([O:15][C:16](=[O:34])[CH2:17][N:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][NH:33][S:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)(=[O:9])=[O:8])[N:27]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: CC(C)(C)OC(=O)CN(C(=O)OC(C)(C)C)c1cccc(CN)n1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CN(C(=O)OC(C)(C)C)c1cccc(CNS(=O)(=O)c2cccnc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.1 %

Procedure:
To a solution of 3-pyridylsulfonyl chloride (640 mg, 3.60 mmol) in methylene chloride (14 ml) were added tert-butyl[(6-aminomethylpyridin-2-yl)tert-butoxycarbonylamino]acetate (1.20 g, 3.56 mmol) obtained in Reference Example 12-(c) and triethylamine (2.24 ml, 16.2 mmol), followed by stirring at room temperature for 1 hour. After completion of the reaction, a 5% aqueous potassium hydrogensulfate solution was added to the reaction solution, followed by extraction with chloroform. The separated organic layer was washed sequentially with a saturated aqueous sodium hydrogencarbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluent; hexane:ethyl acetate=1:1→1:2 (V/V)), and fractions containing the desired compound were concentrated under reduced pressure to afford the title compound (1.45 g) as a colorless oil. (Yield: 85%)
Reaction SMILES: [H-].[Na+].[O:3]1[C:7]2([CH2:11][CH2:10][N:9]([C@H:12]3[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]3[OH:18])[CH2:8]2)[O:6][CH2:5][CH2:4]1.[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:21]=1[CH2:22]Br>COCCOC>[O:6]1[C:7]2([CH2:11][CH2:10][N:9]([C@H:12]3[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]3[O:18][CH2:22][C:21]3[C:20]([Cl:19])=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:28])[CH2:8]2)[O:3][CH2:4][CH2:5]1
Reactant: O[C@H]1CCCC[C@@H]1N1CCC2(C1)OCCO2
Reactant: Clc1cccc(Cl)c1CBr
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: Clc1cccc(Cl)c1CO[C@H]1CCCC[C@@H]1N1CCC2(C1)OCCO2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of sodium hydride, 80% oil dispersion (222 mg, 7.25 mmol) in ethyleneglycol dimethyl ether (20 mL) was added a solution of (1R,2R)/(1S,2S)-2-(1,4-dioxa-7-azaspiro[4.4]non-7-yl)cyclohexanol (1.5 g, 6.60 mmol, step (v) of Example 15) in ethylene glycol dimethyl ether (10 mL). The resulting mixture was stirred at room temperature for 2 hours and then a solution of 2,6-dichlorobenzyl bromide (1.9 g, 7.9 mmol) in ethylene glycol dimethyl ether (10 mL) was added. The reaction mixture was refluxed for 16 hours under argon atmosphere, the solvent was evaporated in vacuo and the residue was taken up with water (70 mL). The aqueous solution was acidified to pH 0.5 with 6M HCl aqueous solution and then extracted with diethyl ether (2×40 mL). Basification of the aqueous solution to pH 4.5-5.5, followed by extraction with diethyl ether (4×40 mL), drying of the combined organic extracts over sodium sulfate and evaporation of the solvent in vacuo provided the intermediate title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:13]=[C:14]=[O:15])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[Cl:16][C:17]1[CH:18]=[C:19]([CH:33]=[CH:34][C:35]=1[Cl:36])[CH2:20][CH:21]1[CH2:26][CH2:25][N:24]([CH2:27][C@H:28]([NH2:32])[CH:29]([CH3:31])[CH3:30])[CH2:23][CH2:22]1>C(Cl)Cl>[Cl:16][C:17]1[CH:18]=[C:19]([CH:33]=[CH:34][C:35]=1[Cl:36])[CH2:20][CH:21]1[CH2:22][CH2:23][N:24]([CH2:27][C@H:28]([NH:32][C:14]([NH:13][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=2)=[O:15])[CH:29]([CH3:31])[CH3:30])[CH2:25][CH2:26]1
Reactant: COc1cc(N=C=O)cc(OC)c1OC
Reactant: CC(C)[C@@H](N)CN1CCC(Cc2ccc(Cl)c(Cl)c2)CC1
Solvent: ClCCl
Product: COc1cc(NC(=O)N[C@@H](CN2CCC(Cc3ccc(Cl)c(Cl)c3)CC2)C(C)C)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 90.5 %

Procedure:
3,4,5-Trimethoxyphenyl isocyanate (1.9 g, 9.11 mmol) was added to a solution of 1-(R)-[4-(3,4-dichlorobenzyl)piperidin-1-ylmethyl]-2-methylpropylamine (2.5 g, 7.59 mmol) in methylene chloride (25 ml) under argon atmosphere. The solution was stirred for 45 min., at room temperature, followed by 30 min., at 38° C. The reaction mixture was concentrated in vacuo. The crude product was chromatographed on a silica gel column, eluting with 1.5-2.5% MeOH/CH2Cl2 containing 1% NH4OH to give 1-{1-(R)-[4-(3,4-dichlorobenzyl)piperidin-1-ylmethyl]-2-methylpropyl}-3-(3,4,5-trimethoxyphenyl)urea (3.7 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=1)(=[O:13])=[O:12].[H][H]>C(O)C.[Pd]>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1)(=[O:12])=[O:13]
Reactant: [H][H]
Reactant: COC(=O)c1ccccc1NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1ccccc1NS(=O)(=O)c1ccc(N)cc1

Procedure:
A solution of the title A compound, 2-(4-nitro-benzenesulfonylamino)-benzoic acid methyl ester (1 g, 2.98 mmol) in 40 mL of ethanol containing 0.32 g of 10% palladium on carbon is shaken under 40 psi of hydrogen pressure at RT for 2.5 h. The mixture is filtered and concentrated under vacuum to give 2-(4-amino-benzenesulfonyl-amino)-benzoic acid methyl ester.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C@@H:7]([CH3:12])[CH2:6][C@H:5]2[NH:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1.C(N(CC)CC)C.[CH:28]1([C:34](Cl)=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.[Cl-].[NH4+]>ClCCl>[CH:28]1([C:34]([N:8]2[C:9]3[C:4](=[CH:3][C:2]([F:1])=[CH:11][CH:10]=3)[C@H:5]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH2:6][C@@H:7]2[CH3:12])=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: C[C@H]1C[C@@H](Nc2ccc(F)cc2)c2cc(F)ccc2N1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H]1C[C@@H](Nc2ccc(F)cc2)c2cc(F)ccc2N1C(=O)C1CCCCC1
Reaction time: 16 h
Yield: 17 %

Procedure:
88 mg of cis-6-fluoro-4-[(4-fluorophenyl)amino]-2-methyl-1,2,3,4-tetrahydroquinoline was dissolved in 3 mL of dichloromethane, and 117 mg of triethylamine and 168 mg of cyclohexanecarbonyl chloride were added to the solution under ice cooling. The mixture was stirred for 16 hours under ice cooling. After completion of the reaction, a saturated aqueous solution of ammonium chloride was added to the reaction liquid, and the mixture was extracted with dichloromethane. Subsequently, the extraction product was dehydrated over anhydrous magnesium sulfate, and then was concentrated under reduced pressure. The resulting residue was subjected to recrystallization using chloroform, and thus 21 mg (17%) of the title compound was obtained as a colorless flake-shaped crystal.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]2[NH:12][C:11]3[CH:13]=[CH:14][C:15]([C:17]([NH2:19])=[NH:18])=[CH:16][C:10]=3[N:9]=2)=[CH:6][C:5]([S:20](=[O:34])(=[O:33])[NH:21][C:22](=[O:32])[CH2:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:4][C:3]=1[C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([N+:41]([O-])=O)[CH:36]=1.[Cl-].[NH4+]>CO.[Fe]>[NH2:41][C:37]1[CH:36]=[C:35]([C:3]2[CH:4]=[C:5]([S:20](=[O:34])(=[O:33])[NH:21][C:22](=[O:32])[CH2:23][CH2:24][CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:6]=[C:7]([C:8]3[NH:12][C:11]4[CH:13]=[CH:14][C:15]([C:17]([NH2:19])=[NH:18])=[CH:16][C:10]=4[N:9]=3)[C:2]=2[OH:1])[CH:40]=[CH:39][CH:38]=1
Reactant: N=C(N)c1ccc2[nH]c(-c3cc(S(=O)(=O)NC(=O)CCCc4ccccc4)cc(-c4cccc([N+](=O)[O-])c4)c3O)nc2c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: N=C(N)c1ccc2[nH]c(-c3cc(S(=O)(=O)NC(=O)CCCc4ccccc4)cc(-c4cccc(N)c4)c3O)nc2c1
Yield: 29.9 %

Procedure:
2-[2-Hydroxy-3′-nitro-5-(4-phenyl-butyrylsulfamoyl)-biphenyl-3-yl]-1H-benzoimidazole-5-carboxamidine (0.063 g, 0.1 mmol), prepared as in Example 10 was dissolved in methanol (3 mL) and saturated aqueous ammonium chloride (1 mL) was added to the solution. The mixture was heated with iron powder (1 g) for 5-10 minutes, filtered through celite and concentrated under reduced pressure. Product was purified from the residue by reverse phase HPLC (acetonitrile gradient) to give 2-[3′-amino-2-hydroxy-5-(4-phenyl-butyrylsulfamoyl)-biphenyl-3-yl]-1H-benzoimidazole-5-carboxamidine (0.017 g). MS. found (M+H+) 569.3, (M−H+) 567.4, calc. 568.19.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:20])[C:13]3[CH:18]=[CH:17][C:16]([NH2:19])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][C:7](=[O:21])[C:6]=2[CH:22]=1.[CH3:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27].O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:20])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:26](=[O:27])[C:25]4[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=4[CH3:23])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][C:7](=[O:21])[C:6]=2[CH:22]=1
Reactant: Cc1ccccc1C(=O)Cl
Reactant: Nc1ccc(C(=O)N2CCCC(=O)c3cc(Cl)ccc32)cn1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(=O)c3cc(Cl)ccc32)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.3 %

Procedure:
To a solution of 7-chloro-5-oxo-1-(6-aminonicotinoyl)-2,3,4,5-tetrahydro-1H-benzazepine (0.25 g) in pyridine (2 ml) is added with stirring 2-methylbenzoyl chloride (0.18 g) under ice-cooling, and the mixture is stirred at room temperature for one hour. To the reaction solution is added water, and the mixture is extracted with ethyl acetate. The extract is washed successively with 0.1N aqueous hydrochloric acid solution and water, and dried over magnesium sulfate. The resultant is evaporated under reduced pressure to remove the solvent, and the residue is purified by silica gel column chromatography to give 7-chloro-5-oxo-1-[6-(2-methylbenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.3 g) as colorless amorphous.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:13]3[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=3)[CH:9]=[C:10]([CH2:11][OH:12])[N:6]2[N:5]=[CH:4][N:3]=1.C1([O:26][C:27](=O)[NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[N:30]=2)C=CC=CC=1.C(N(CC)CC)C>CN(C=O)C>[NH2:1][C:2]1[C:7]2=[C:8]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:27]([NH:28][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:37])([F:36])[F:38])[N:30]=4)=[O:26])=[CH:15][CH:14]=3)[CH:9]=[C:10]([CH2:11][OH:12])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: Nc1ccc(-c2cc(CO)n3ncnc(N)c23)cc1
Reactant: O=C(Nc1cccc(C(F)(F)F)n1)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1ncnn2c(CO)cc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)n4)cc3)c12
Yield: 7.1 %

Procedure:
A solution of [4-amino-5-(4-aminophenyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]methanol (170.0 mg, 0.67 mmol), phenyl[6-(trifluoromethyl)pyridin-2-yl]carbamate (281.9 mg, 1.00 mmol), and triethylamine (0.46 mL, 1.33 mmol) in DMF (5 mL) was stirred at rt for 3 d. The crude reaction mixture was purified directly by HPLC using a gradient of 20-90% MeCN in water to yield 21.1 mg (7%) of the title compound. 1H-NMR (DMSO-d6) 9.89 (bs, 1 H), 9.72 (bs, 1 H), 8.05-7.98 (m, 2 H), 7.89 (s, 1 H), 7.57 (d, J=8.6 Hz, 2 H), 7.51-7.49 (m, 1 H), 7.40 (d, J=8.6 Hz, 1 H), 6.64 (s, 1 H), 5.19 (t, J=5.7 Hz, 1 H), 4.74 (d, J=5.6 Hz, 3 H); MS [M+H]+=444.1; LCMS RT=2.63 min.
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:12])[CH:8]=2)[N:3]=1.[C:13]1([CH2:19][NH2:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>CS(C)=O>[CH2:19]([NH:20][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:12])[CH:8]=2)[N:3]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Clc1ccc2nc(Cl)cnc2c1
Reactant: NCc1ccccc1
Solvent: O
Solvent: CS(C)=O
Product: Clc1ccc2nc(NCc3ccccc3)cnc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2,6-Dichloroquinoxaline (0.500 g, 2.5 mmol) was dissolved in DMSO (10 mL) at RT and phenylmethanamine (1.3 g, 12.56 mmol) was added. The reaction mixture was stirred at RT for 16 h. After completion of reaction (confirmed by TLC), water (100 mL) was added to the reaction mixture and this layer was extracted with ethyl acetate (50 mL×3). The organic layer was washed with water (15 mL), brine (15 mL) and dried over Na2SO4. The organic layer was concentrated under vacuum to give crude product.
Reaction SMILES: [Pt:1].[C:2]([O:19]C(=O)CCCCCCCCCCCCCCC)(=O)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>C(=O)(O)[O-].C([NH+](CC)CC)C.C(O)(C)C.O.[Pd]>[C:2]([Pt:1])(=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: [Pt]
Reactant: CCCCCCCCCCCCCCCC(=O)OC(=O)CCCCCCCCCCCCCCC
Agent: [Pd]
Agent: CC[NH+](CC)CC
Agent: O=C([O-])O
Solvent: O
Solvent: CC(C)O
Product: CCCCCCCCCCCCCCCC(=O)[Pt]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Preparation used the same procedure as the platinum cluster conjugate: an estimated 30 nmol of amino-derivatized 2-3 nm palladium cluster, dissolved in 0.6 M triethylammonium bicarbonate in 20% isopropanol/water, was evaporated to dryness five times from methanol, dissolved in 3 mL of dichloromethane, then treated with 200 nmol of palmitic anhydride. The mixture was stirred for one hour at room temperature, washed three times with 0.1 M sodium phosphate buffer at pH 6.5, evaporated to dryness, redissolved in 2:1 methanol/chloroform and separated by gel filtration (GH25, Amicon, eluted with 2:1 methanol:chloroform). After evaporation to dryness, lipid conjugation was demonstrated by extraction of the cluster label into the chloroform layer when the palmitoyl palladium cluster conjugate was shaken in a chloroform/water mixture with a small amount of methanol as a phase transfer agent.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@H:14]([CH3:15])[CH2:13][N:12]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][C:17]=2[N+:22]([O-])=O)[CH2:11][C@H:10]1[NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CC(O)=O>CCOC(C)=O.[Fe]>[NH2:22][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:16]=1[N:12]1[CH2:13][C@H:14]([CH3:15])[C@@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[C@H:10]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:11]1
Reactant: C[C@H]1CN(c2ccncc2[N+](=O)[O-])C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: C[C@H]1CN(c2ccncc2N)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 510.6 %

Procedure:
A mixture of tert-butyl [(3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methyl-1-(3-nitropyridin-4-yl)piperidin-3-yl]carbamate (130 mg, 0.279 mmol), AcOH (10.0 mL, 176 mmol) and iron powder (558 mg, 1.00 mmol) was stirred at room temperature for 2 h. The mixture was diluted with 30 mL of EtOAc and filtered through a pad of diatomaceous earth and the filtrate was then concentrated under reduced pressure. The resulting residue was diluted with EtOAc and then washed with aq. Na2CO3 solution and 0.2 M NaOH. The organic extract was concentrated under reduced pressure to give 0.622 g of the sub-title compound as a brown solid. LCMS calc. for C22H41N4O3Si (M+H)+: m/z=437.3. found: 437.1.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[NH:4][N:3]=1.Br[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[OH-].[Na+]>CN(C)C=O.O>[CH2:9]([N:3]1[C:2]([CH3:1])=[N:6][C:5]([CH3:7])=[N:4]1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCBr
Reactant: Cc1n[nH]c(C)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCn1nc(C)nc1C
Temperature: 120 °C

Procedure:
A mixture of 3,5-dimethyl-1,2,4-triazole (6.0 parts; 0.062 mol ex (b) above) and 1-bromodecane (14.4 parts; 0.065 mol) in dimethylformamide (16 ml) was heated together at 120° C. for 23 hours. The cooled reaction mixture was diluted with water (100 ml), a solution of sodium hydroxide (2.62 parts; 0.065 mol) in water (100 ml) added, and the product extracted into ether (3×50 ml). After drying over magnesium sulphate the solution was evaporated to yield a pale yellow oil (3.3 parts; 22% theory).