Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([Cl:13])=[CH:8][N:7]=1.CS[C:16]1[NH:21][C:20](=[O:22])[C:19]([CH2:23][C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)=[CH:18][N:17]=1>N1C=CC=CC=1>[Cl:13][C:9]1[CH:10]=[C:11]([CH3:12])[C:6]([NH:5][CH2:4][CH2:3][CH2:2][NH:1][C:16]2[NH:21][C:20](=[O:22])[C:19]([CH2:23][C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)=[CH:18][N:17]=2)=[N:7][CH:8]=1
Reactant: CSc1ncc(Cc2ccncc2)c(=O)[nH]1
Reactant: Cc1cc(Cl)cnc1NCCCN
Solvent: c1ccncc1
Product: Cc1cc(Cl)cnc1NCCCNc1ncc(Cc2ccncc2)c(=O)[nH]1
Yield: 64 %

Procedure:
2-(3-Aminopropylamino)-5-chloro-3-methylpyridine (0.92 g) and 2-methylthio-5-(4-pyridylmethyl)-4-pyrimidone (0.90 g) were heated together under reflux in pyridine (5 ml) for 46 hr. After stripping to dryness the residue was triturated with wet ether to give a white solid. Repeated recrystallisation from isopropanol/water gave 2-[3-(5-chloro-3-methylpyrid-2-ylamino)propylamino]-5-(4-pyridylmethyl)-4-pyrimidone (0.95 g; 64%) m.p. 90°-92° C.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]#[N:8])=[CH:5][N:4]([CH3:9])[N:3]=1.[H-].[Na+].Cl[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[N+:20]([O-:22])=[O:21].O>O1CCCC1>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([NH:1][C:2]2[C:6]([C:7]#[N:8])=[CH:5][N:4]([CH3:9])[N:3]=2)=[C:14]([N+:20]([O-:22])=[O:21])[CH:15]=1
Reactant: Cn1cc(C#N)c(N)n1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cn1cc(C#N)c(Nc2ccc(Cl)cc2[N+](=O)[O-])n1
Reaction time: 0.17 h

Procedure:
3-Amino-1-methylpyrazole-4-carbonitrile (Helv. Chim. Acta (1959) 42 763) (3.66 g) was stirred in dry tetrahydrofuran (40 ml). Sodium hydride (50% oil dispersion, 2.28 g) was added and the mixture was stirred for 10 minutes. 2,5-Dichloronitrobenzene (5.76 g) was added and the solution stirred under nitrogen for 20 hours. Water was added dropwise to destroy any excess sodium hydride, then the solution was poured on to a mixture of ice and dilute hydrochloric acid. After standing for 1 hour the brick-red precipitate was filtered, washed with water and dried. Crystallization from ethanol-ethyl acetate afforded the product m.p. 205° C.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH2:8][CH:7]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[C:6]=2[C:5]([CH3:20])=[C:4]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:3]=1[CH3:29].[N:30]1[CH:35]=[CH:34][CH:33]=[C:32](B(O)O)[CH:31]=1>>[CH:17]([C:14]1[CH:13]=[CH:12][C:11]([CH:7]2[C:6]3[C:5]([CH3:20])=[C:4]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:3]([CH3:29])=[C:2]([C:32]4[CH:31]=[N:30][CH:35]=[CH:34][CH:33]=4)[C:10]=3[O:9][CH2:8]2)=[CH:16][CH:15]=1)([CH3:19])[CH3:18]
Reactant: OB(O)c1cccnc1
Reactant: Cc1c(Br)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)CO2
Product: Cc1c(NC(=O)CC(C)(C)C)c(C)c2c(c1-c1cccnc1)OCC2c1ccc(C(C)C)cc1
Yield: 32 %

Procedure:
Using N-(7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 35 and pyridin-3-ylboronic acid, the title compound was obtained in the same manner as in Example 107. Yield: 32%. Melting point: 142-144° C. (ethyl acetate-hexane).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[OH:11].[CH3:12][CH2:13]O.CS(O)(=O)=O>C1C=CC=CC=1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:12][CH3:13])=[O:7])=[CH:4][C:3]=1[OH:11]
Reactant: O=C(O)c1ccc(Br)c(O)c1
Reactant: CCO
Agent: CS(=O)(=O)O
Solvent: c1ccccc1
Product: CCOC(=O)c1ccc(Br)c(O)c1
Yield: 90 %

Procedure:
To a mixture containing 4-bromo-3-hydroxybenzoic acid (5.0 g, 0.023 mol) and 5 ml of EtOH in 150 ml of benzene was added 1 ml of MeSO3H. The mixture was heated at reflux for 10 h using a Dean-Stark trap to collect water, then concentrated. The residue was dissolved in CH2Cl2, washed (water, 5% NaHCO3, and brine), dried (Na2SO4), and concentrated. The crude product was chromatographed (EtOAc/hexane) to gave a white solid (5.1 g, 90%): 1H NMR (300 MHz, CDCl3) δ 1.39 (t, J=7.2 Hz, 3 H), 4.37 (q, J=7.2 Hz, 2 H), 5.75 (s, 1 H), 7.48 (d, J=8.1 Hz, 1 H), 7.55 (d, J=8.1 Hz, 1 H), 7.68 ppm (s, 1 H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10](=[O:11])[CH2:9][C:8]([CH3:13])([CH3:12])[CH2:7][C:5]=2[N:6]=1.[Br:14][C:15]1[CH:19]=[C:18]([Cl:20])[S:17][C:16]=1[S:21](Cl)(=[O:23])=[O:22]>>[Br:14][C:15]1[CH:19]=[C:18]([Cl:20])[S:17][C:16]=1[S:21]([NH:1][C:2]1[S:3][C:4]2[C:10](=[O:11])[CH2:9][C:8]([CH3:13])([CH3:12])[CH2:7][C:5]=2[N:6]=1)(=[O:23])=[O:22]
Reactant: CC1(C)CC(=O)c2sc(N)nc2C1
Reactant: O=S(=O)(Cl)c1sc(Cl)cc1Br
Product: CC1(C)CC(=O)c2sc(NS(=O)(=O)c3sc(Cl)cc3Br)nc2C1

Procedure:
The title compound was prepared from 2-amino-5,5-dimethyl-5,6-dihydro-1,3-benzothiazol-7(4H)-one (53 mg) and 3-bromo-5-chlorothiophene-2-sulfonyl chloride (80 mg) as described in the synthetic method to give a white solid (62.2 mg) with purity >90%: MS (pos) m/z 455.2, 457.2.
Reaction SMILES: [S:1]1(=[O:7])(=[O:6])[CH:5]=[CH:4][CH2:3][NH:2]1.[CH3:8][O-:9].[Na+]>CO>[CH3:8][O:9][CH:4]1[CH2:5][S:1](=[O:7])(=[O:6])[NH:2][CH2:3]1
Reactant: C[O-]
Reactant: O=S1(=O)C=CCN1
Agent: [Na+]
Solvent: CO
Product: COC1CNS(=O)(=O)C1
Temperature: 70 °C
Reaction time: 3 h
Yield: 13 %

Procedure:
To a solution of 2,3-dihydroisothiazole-1,1-dioxide (0.100 g, 0.8 mmol) in methanol (1 mL) was added 25% sodium methoxide in methanol (0.181 g, 0.8 mmol) and the solution stirred at 60° C. for 2 hrs and at 70° C. for 3 hrs. The mixture was concentrated and suspended in 1 N aqueous hydrochloric acid. The aqueous mixture was extracted with ethyl acetate (3×), and the organic layers dried (anhydrous sodium sulfate), filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography (0-6% methanol/methylene chloride) to give the product (0.011 g, 13%). 1H NMR (300 MHz, CDCl3) δ 4.53 (br s, 1H), 4.33-4.29 (m, 1H), 3.48-3.30 (m, 3H), 3.37 (s, 3H), 3.19-3.13 (m, 1H). 13C NMR (100 MHz, CDCl3) δ 80.8, 57.1, 53.3, 48.7.
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:9])=[CH:6][CH:5]=[CH:4][NH:3]1.[CH2:17]([NH:24][C:25]([C:27]1[S:31][C:30](Br)=[N:29][C:28]=1[CH3:33])=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([NH:24][C:25]([C:27]1[S:31][C:30]([N:3]2[CH:4]=[CH:5][CH:6]=[C:7]([C:8](=[O:9])[NH:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:2]2=[O:1])=[N:29][C:28]=1[CH3:33])=[O:26])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(Nc1ccccc1)c1ccc[nH]c1=O
Reactant: Cc1nc(Br)sc1C(=O)NCc1ccccc1
Product: Cc1nc(-n2cccc(C(=O)Nc3ccccc3)c2=O)sc1C(=O)NCc1ccccc1
Yield: 15 %

Procedure:
Following the procedure as described in Example 3, making variations only as required to use 2-oxo-N-phenyl-1,2-dihydropyridine-3-carboxamide in place of 4-aminopyridin-2(1H)-one to react with N-benzyl-2-bromo-4-methylthiazole-5-carboxamide, the title compound was obtained as a colorless solid in 15% yield: mp 225-227° C. (hexane/ethyl acetate); 1H NMR (300 MHz, DMSO-d6) δ 13.14 (s, 1H), 8.64-8.55 (m, 2H), 8.18 (dd, J=6.6, 2.1 Hz, 1H), 7.58-7.47 (m, 5H), 7.32-7.26 (m, 4H), 7.24-7.17 (m, 1H), 6.75-6.70 (m, 1H), 4.37 (d, J=5.9 Hz, 2H), 2.44 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 162.0, 161.8, 156.0, 151.4, 146.0, 145.7, 140.2, 140.0, 129.7, 129.5, 128.7, 127.6, 127.2, 127.2, 120.1, 118.4, 107.8, 43.1, 17.4; (ES+) m/z 445.1 (M+1).
Reaction SMILES: [N-:1]([C:4]#[N:5])[C:2]#[N:3].[Na+].[C:7](#[N:11])[CH2:8][C:9]#[N:10].CC(O)CC>CN(C)C(=O)C>[NH2:3][C:2]([NH:1][C:4]#[N:5])=[C:8]([C:7]#[N:11])[C:9]#[N:10]
Reactant: N#CCC#N
Reactant: N#C[N-]C#N
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCC(C)O
Product: N#CNC(N)=C(C#N)C#N
Temperature: 147 °C
Reaction time: 0.25 h
Yield: 108.9 %

Procedure:
To a 1 liter flask is charged 89 gm(1.0 mole) of sodium dicyanamide and 282 ml of N,N-dimethylacetamide. The stirred mixture is heated to 147° C. and 72.6 gm (1.1 mole) of malononitrile in 72.6 gm of N,N-dimethylacetamide is added dropwise over 2 hours and 25 minutes. The mixture is stirred at 147° C. for an additional 3 hours and 15 minutes; then cooled to 60° C. Next the reaction mixture is charged to a 2 liter flask containing 1276 gm of 2-butanol and stirred overnight at room temperature. The slurry is then filtered, and the wet cake slurried in 319 gm 2-butanol and again filtered. The solids are dried overnight at 70° C. in a vacuum oven. There is obtained 144.9 gm of 1-amino-1-cyanamido-2,2-dicyanoethylene, sodium salt, 84.5% pure, or a 78.9% yield.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:12]=[C:11]([NH:19][C:20]3[CH:34]=[CH:33][C:23]([CH2:24][P:25](=[O:32])([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28])=[CH:22][CH:21]=3)[N:10]=2)=[C:4]([C:35](=[O:38])[NH:36][CH3:37])[CH:3]=1.[CH2:39]([N:43]1[CH:47]=[C:46](B2OC(C)(C)C(C)(C)O2)[CH:45]=[N:44]1)[CH:40]([CH3:42])[CH3:41]>>[CH3:37][NH:36][C:35]([C:4]1[CH:3]=[C:2]([C:46]2[CH:45]=[N:44][N:43]([CH2:39][CH:40]([CH3:42])[CH3:41])[CH:47]=2)[CH:7]=[CH:6][C:5]=1[NH:8][C:9]1[C:14]([C:15]([F:16])([F:18])[F:17])=[CH:13][N:12]=[C:11]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([CH2:24][P:25](=[O:32])([O:26][CH2:27][CH3:28])[O:29][CH2:30][CH3:31])=[CH:33][CH:34]=2)[N:10]=1)=[O:38]
Reactant: CC(C)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)cc3C(=O)NC)n2)cc1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CC(C)C)c4)cc3C(=O)NC)n2)cc1)OCC

Procedure:
The title compound was prepared using the procedure from Example 97 with Diethyl (4-{[4-{[4-bromo-2-(methylcarbamoyl)phenyl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate (Example 106) and the commercially available 1-isobutyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. MS (ES+): m/z 666.20 (100) [MH+]; HPLC: tR=3.60 min (ZQ3, polar—5 min).
Reaction SMILES: [SH:1][C:2]([CH3:8])([CH3:7])[CH2:3][C:4]([OH:6])=[O:5].FC(F)(F)C(O)=O.[CH3:16][O:17][C:18]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([O:28][CH3:29])[C:19]=1[CH2:20]O>C(Cl)Cl>[CH3:7][C:2]([S:1][CH2:20][C:19]1[C:22]([O:28][CH3:29])=[CH:23][C:24]([O:26][CH3:27])=[CH:25][C:18]=1[O:17][CH3:16])([CH3:8])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: COc1cc(OC)c(CO)c(OC)c1
Reactant: CC(C)(S)CC(=O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(OC)c(CSC(C)(C)CC(=O)O)c(OC)c1
Reaction time: 0.08 h
Yield: 70 %

Procedure:
To a solution of 3-mercapto-3-methylbutyric acid (B. J. Sweetman et al. J. Med Chem., 14, 868 (1971)) (4.6 g, 34 mmol) in methylene chloride (250 mL) under nitrogen and cooled over ice/salt to 5 ûC (internal temperature) was added trifluoroacetic acid (82 g, 0.72 mol). No significant temperature rise was noted during the addition. To this was then added dropwise a solution of 2,4,6-trimethoxybenzyl alcohol (M. C. Munson et al., J. Org. Chem., 57, 3013 (1992)) (6.45 g, 32 mmol) in methylene chloride (150 mL) such that the reaction temperature does not rise above 5 ûC. After the addition was complete, the mixture was stirred for an additional 5 min at 5 ûC and the volatiles were removed in vacuo (toluene or ethyl acetate can be used to assist in the removal of volatile material). The residue was partitioned between diethyl ether and water and the organic phase dried over anhydrous sodium sulfate, filtered and the volatile material removed in vacuo. The residue was treated with activated charcoal and recrystalised from diethyl ether/hexane. The product was isolated as an white solid in 70% yield (7 g) mp 103-105° C. 1H NMR (CDCl3) δ6.12 (s, 2H), 3.80-3.85 (m, 11 H), 2.74 (s, 2H), 1.47 (s, 6H). 13C NMR (CDCl3) δ173.9, 160.6, 158.6, 105.6, 90.5, 55.7, 55.3, 45.9, 43.6, 28.4, 21.0.
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:18]2[C:17](=[O:19])[C:16]3[C:11](=[C:12]([OH:20])[CH:13]=[CH:14][CH:15]=3)[C:10](=[O:21])[C:9]=2[C:8](Br)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[CH2:23]([NH2:27])[CH:24]([CH3:26])[CH3:25]>CO.[Cu]Cl.S([O-])([O-])(=O)=O.[Cu+2]>[CH:1]([NH:4][C:5]1[C:18]2[C:17](=[O:19])[C:16]3[C:11](=[C:12]([OH:20])[CH:13]=[CH:14][CH:15]=3)[C:10](=[O:21])[C:9]=2[C:8]([NH:27][CH2:23][CH:24]([CH3:26])[CH3:25])=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)CN
Reactant: CC(C)Nc1ccc(Br)c2c1C(=O)c1cccc(O)c1C2=O
Agent: Cl[Cu]
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CO
Product: CC(C)CNc1ccc(NC(C)C)c2c1C(=O)c1c(O)cccc1C2=O

Procedure:
10 Parts 1-isopropylamino-4-bromo-5-hydroxy-anthraquinone, 50 parts isobutylamine, 0.1 part each of copper(I) chloride and basic copper sulphate are boiled under reflux (appr. 70°) until only small amounts of starting material can be detected (appr. 2 hours are required). The mixture is diluted with 50 parts methanol, the precipitated needles are filtered off with suction in the cold, washed with methanol and hot water. It is also possible to filter off with suction without previous dilution with methanol. The 1-isopropylamino-5-hydroxy-4-isobutylamino-anthraquinone so obtained is sulphonated as follows:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:12]([NH:13][C:14]2[C:15]3[CH:23]=[C:22](Cl)[N:21]=[CH:20][C:16]=3[N:17]=[CH:18][N:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:12]([NH:13][C:14]2[C:15]3[CH:23]=[C:22]([N:31]4[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]4)[N:21]=[CH:20][C:16]=3[N:17]=[CH:18][N:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cc2c(Nc3ccc(OCc4ccccc4)cc3)ncnc2cn1
Reactant: CN1CCNCC1
Product: CN1CCN(c2cc3c(Nc4ccc(OCc5ccccc5)cc4)ncnc3cn2)CC1

Procedure:
Prepared according to Procedure C from 4-(4-benzyloxyanilino)-6-chloropyrido[3,4-d]pyrimidine and 1-methylpiperazine; δH (CDCl3) 9.00 (1H,s), 8.58 (1H,s), 7.59 (2H, d), 7.28-7.40 (5H,m), 7.02 (2H,d), 6.59 (1H,s), 5.08 (2H,s), 3.60-3.74 (4H,m), 2.52-2.64 (4H,m), 2.40 (3H,s); m/z (M+1)+427.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[CH2:8][N:7]3[CH:15]=[CH:16][CH:17]=[C:6]3[C:5]=12.P(Cl)(Cl)(Cl)=O.CN(C)[CH:25]=[O:26]>>[N:1]1[CH:2]=[CH:3][N:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[CH2:8][N:7]3[CH:15]=[C:16]([CH:25]=[O:26])[CH:17]=[C:6]3[C:5]=12
Reactant: CN(C)C=O
Reactant: c1ccc2c(c1)Cn1cccc1-c1nccn1-2
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1cc2n(c1)Cc1ccccc1-n1ccnc1-2
Reaction time: 2 h

Procedure:
9H-Imidazo[1,2-a]pyrrolo[2,1-c][1,4]benzodiazepine (8.00 g, 36.1 mmoles) was heated in dry dimethylformamide (120 mL) at 120° C. in the presence of phosphoryl chloride (10.4 g, 6.32 mL). After 2 hours, the reaction mixture was poured onto ice-water and then extracted several times with chloroform. The combined extracts were washed with water, brine, dried and evaporation of solvent gave a tan residual solid. Crystallization of the solid form toluene-hexane gave 9H-imidazo[1,2-a]pyrrolo[2,1-c][1,4]benzodiazepine-12-carboxaldehyde (3.57 g): mp 203°-205° C.; Anal. Calcd for C15H11N3O: C, 72.27% H, 4.45% N, 16.86%, Found: C, 72.08% H, 4.51% N, 16.77%.
Reaction SMILES: [N+:1]([C:4]1C=C(N)C=[CH:8][C:9]=1NCC=C)([O-])=O.F[C:16]1[CH:21]=[CH:20][C:19]([N:22]([CH2:28][CH:29]([OH:32])[CH2:30][OH:31])[CH2:23][CH:24]([OH:27])[CH2:25][OH:26])=[CH:18][C:17]=1[N+:33]([O-:35])=[O:34]>>[N+:33]([C:17]1[CH:18]=[C:19]([N:22]([CH2:28][CH:29]([OH:32])[CH2:30][OH:31])[CH2:23][CH:24]([OH:27])[CH2:25][OH:26])[CH:20]=[CH:21][C:16]=1[NH:1][CH2:4][CH:9]=[CH2:8])([O-:35])=[O:34]
Reactant: O=[N+]([O-])c1cc(N(CC(O)CO)CC(O)CO)ccc1F
Reactant: C=CCNc1ccc(N)cc1[N+](=O)[O-]
Product: C=CCNc1ccc(N(CC(O)CO)CC(O)CO)cc1[N+](=O)[O-]

Procedure:
Synthesis as for compound 1, but with 4-fluoro-3-nitro-N,N-bis-(2,3-dihydroxypropyl)-aminobenzene instead of 4-fluoro-3-nitroaminobenzene. Working up: the reaction mixture was concentrated and the dark oil was dissolved in ethanol. Compound (3) was then precipitated with HCl gas in the form of the hydrochloride. Yellow crystals, melting point 154°-158° C.
Reaction SMILES: C([O:5][C:6](=[O:21])[CH2:7][O:8][C:9]1[CH:14]=[C:13]([F:15])[C:12]([C:16]([CH3:19])([CH3:18])[CH3:17])=[C:11]([F:20])[CH:10]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:16]([C:12]1[C:11]([F:20])=[CH:10][C:9]([O:8][CH2:7][C:6]([OH:21])=[O:5])=[CH:14][C:13]=1[F:15])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)COc1cc(F)c(C(C)(C)C)c(F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1c(F)cc(OCC(=O)O)cc1F
Yield: 77.3 %

Procedure:
To a suspension of sodium hydride (75 mg, 1.9 mmol) in THF (5 ml) was added 4-tert-butyl-3,5-difluorophenol (290 mg, 1.6 mmol) at 0° C., followed by stirring for 30 minutes. Then, tert-butyl bromoacetate (370 mg, 1.9 mmol) was added and the mixture was refluxed at 90° C. for 1 hour. The reaction was quenched with saturated ammonium chloride aqueous solution and the product was extracted with EtOAc, washed with brine, dried over magnesium sulfate. Then, filtration, evaporation, and purification through silica gel column chromatography eluting with hexane/EtOAc (20:1 to 4:1) gave the tert-butyl(4-tert-butyl-3,5-difluorophenoxy)acetate (403 mg, 86%). The DCM (2.0 ml) solution of tert-butyl(4-tert-butyl-3,5-difluorophenoxy)acetate (400 mg, 1.34 mmol) and TFA (2.0 ml), was stirred for 1 hour at room temperature. Evaporation gave the residue which was triturated with Hexane to furnish the title compound as a white solid (253 mg, 77%). 1H NMR (300 MHz, CDCl3): δ 1.42 (9H, t, J=2.2 Hz), 4.63 (2H, s), 6.39 (2H, d, J=12.1 Hz). MS (ESI) m/z 243 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:16]([OH:18])[CH3:17])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[CH3:50][O:51][C:52](=[O:77])[C@@H:53]([NH:62][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][C:64]=1[C:69](=[O:76])[C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=1)[CH2:54][C:55]1[CH:60]=[CH:59][C:58](O)=[CH:57][CH:56]=1>C1COCC1>[CH3:50][O:51][C:52](=[O:77])[C@@H:53]([NH:62][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][C:64]=1[C:69](=[O:76])[C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=1)[CH2:54][C:55]1[CH:56]=[CH:57][C:58]([O:18][CH:16]([C:3]2[C:2]([CH3:1])=[CH:11][C:10]3[C:9]([CH3:13])([CH3:12])[CH2:8][CH2:7][C:6]([CH3:15])([CH3:14])[C:5]=3[CH:4]=2)[CH3:17])=[CH:59][CH:60]=1
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)Nc1ccccc1C(=O)c1ccccc1
Reactant: Cc1cc2c(cc1C(C)O)C(C)(C)CCC2(C)C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@H](Cc1ccc(OC(C)c2cc3c(cc2C)C(C)(C)CCC3(C)C)cc1)Nc1ccccc1C(=O)c1ccccc1

Procedure:
A solution of 1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-ethanol (184 mg; 0.75 mmol), triphenylphosphine (268 mg; 1.0 mmol), diethyl azodicarboxylate (0.161 ml; 1.0 mmol) and (2S)-2-((2-benzoylphenyl)amino)-3-(4-hydroxyphenyl)-propionic acid methyl ester (190 mg; 0.5 mmol) in THF (10 ml) was stirred at 0° C. for 1.5 hours and for 16 hours at room temperature. The reaction mixture was evaporated and the residue was purified on column chromatography using methylene chloride as eluent. Yield 118 mg.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([N+:9]([O-])=O)=[CH:7][CH:6]=[CH:5][N:4]=1.[H][H]>CO.[Pd]>[CH3:1][O:2][C:3]1[C:8]([NH2:9])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: COc1ncccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COc1ncccc1N
Yield: 91.5 %

Procedure:
10% palladium-activated carbon (2.5 g) was added to a solution of commercially available 2-methoxy-3-nitropyridine (50.5 g) in methanol (500 mL), and the mixture was stirred for four hours in a hydrogen atmosphere. The reaction solution was filtered through celite, and then the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=8:1) to give 2-methoxypyridin-3-amine as a yellow powder (37.2 g, 92%).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[N:11]1[CH:15]=[C:14]([C:16]2[CH:17]=[N:18][C:19]([CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[CH:20][CH:21]=2)[N:13]=[N:12]1.[NH2:29][C:30]1[C:31]([O:45][CH3:46])=[C:32]([NH:40][S:41]([CH3:44])(=[O:43])=[O:42])[CH:33]=[C:34]([C:36]([CH3:39])([CH3:38])[CH3:37])[CH:35]=1>>[C:36]([C:34]1[CH:33]=[C:32]([NH:40][S:41]([CH3:44])(=[O:43])=[O:42])[C:31]([O:45][CH3:46])=[C:30]([NH:29][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([N:11]3[CH:15]=[C:14]([C:16]4[CH:17]=[N:18][C:19]([CH2:22][N:23]5[CH2:24][CH2:25][O:26][CH2:27][CH2:28]5)=[CH:20][CH:21]=4)[N:13]=[N:12]3)[CH:4]=2)[CH:35]=1)([CH3:39])([CH3:37])[CH3:38]
Reactant: COc1c(N)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reactant: Cc1ccc(C(=O)O)cc1-n1cc(-c2ccc(CN3CCOCC3)nc2)nn1
Product: COc1c(NC(=O)c2ccc(C)c(-n3cc(-c4ccc(CN5CCOCC5)nc4)nn3)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O

Procedure:
Example 13 was prepared by coupling 4-methyl-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-[1,2,3]triazol-1-yl]-benzoic acid (2:1 with 4-methyl-3-[5-(6-morpholin-4-ylmethyl-pyridin-3-yl)-1,2,3-triazol-1-yl]-benzoic acid) with N-(3-amino-5-tert-butyl-2-methoxy-phenyl)-methane-sulfonamide in the same manner as Example 1. Chromatography separated the triazole isomers. ESI MS m/z 635 [C32H39N7O5S+H]+.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C.[CH2:55]([O:57][C:58]([C:60]1[S:64][C:63]([NH2:65])=[N:62][CH:61]=1)=[O:59])[CH3:56]>C(Cl)Cl>[CH2:55]([O:57][C:58]([C:60]1[S:64][C:63]([NH:65][C:8](=[O:10])[CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[CH2:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[N:62][CH:61]=1)=[O:59])[CH3:56]
Reactant: CCOC(=O)c1cnc(N)s1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1cnc(NC(=O)C(CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)s1
Yield: 98 %

Procedure:
A solution of 3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionic acid (300 mg, 1.01 mmol), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (717 mg, 1.62 mmol), triethylamine (420 μL, 3.03 mmol), and 2-amino-thiazole-5-carboxylic acid ethyl ester: (279 mg, 1.62 mmol) in methylene chloride (10 mL) was stirred at 25° C. under nitrogen for 14 h. The reaction mixture was partitioned between water and methylene chloride. The organic layer was sequentially washed with a 1N aqueous hydrochloric acid solution (1×10 mL), water (1×10 mL), and a saturated aqueous sodium bicarbonate solution (1×10 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 10/11 hexanes/ethyl ether) afforded 2-[3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-thiazole-5-carboxylic acid ethyl ester (448 mg, 98%) as a white solid: mp 100-103° C.; EI-HRMS m/e calcd for C21H26N2O5S2(M+) 450.1283, found 450.1285.
Reaction SMILES: [C:1]1([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:15]Br>C(Cl)(Cl)(Cl)Cl>[Br:15][CH:8]=[C:7]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrBr
Reactant: C=C(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrC=C(c1ccccc1)c1ccccc1
Reaction time: 7 h
Yield: 81 %

Procedure:
Into a reactor were introduced 110 g (0.60 mol) of the 1,1-diphenylethylene and 1,098 g of carbon tetrachloride under a nitrogen atmosphere. A solution prepared by mixing 95.9 g (0.60 mol) of bromine with 288 g of carbon tetrachloride was added dropwise thereto over 1 hour with cooling with ice. After completion of the addition, the reaction mixture was stirred at that temperature for 7 hours and then concentrated. To the residue were added 119 g of pyridine and 500 mL of toluene. This mixture was refluxed for 3 hours. After being cooled, the reaction mixture was washed with 5% hydrochloric acid and water, subsequently dried with anhydrous sodium sulfate, and then concentrated under reduced pressure. The resultant concentrate was distilled and then recrystallized from methanol to obtain 126 g (81%) of the target compound as white crystals.