Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]([F:21])([F:20])[C:4]1[N:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH:14]([C:16]([O:18][CH3:19])=[O:17])[CH2:13][CH2:12][NH:11]2)=[CH:6][CH:5]=1.CCN(C(C)C)C(C)C.[C:31](Cl)(=[O:34])[O:32][CH3:33]>C(Cl)Cl>[F:21][C:3]([F:2])([F:20])[C:4]1[N:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH:14]([C:16]([O:18][CH3:19])=[O:17])[CH2:13][CH2:12][N:11]2[C:31]([O:32][CH3:33])=[O:34])=[CH:6][CH:5]=1
Reactant: COC(=O)C1CCNC(c2ccc(C(F)(F)F)nc2)C1
Reactant: COC(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1CCN(C(=O)OC)C(c2ccc(C(F)(F)F)nc2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 93.8 %

Procedure:
Methyl 2-(6-(trifluoromethyl)pyridin-3-yl)piperidine-4-carboxylate hydrochloride (3 g, 9.24 mmol) was dissolved in DCM (50 mL) and DIPEA (4.03 mL, 23.10 mmol). Methyl carbonochloridate (1.019 mL, 12.93 mmol) was added dropwise to the solution. The mixture was stirred at room temperature for 10 minutes. The mixture was washed with 0.1 M HCl (2×100 mL) and satd NaHCO3 (100 mL), then dried through a phase-separator and evaporated yielding crude dimethyl 2-(6-(trifluoromethyl)pyridin-3-yl)piperidine-1,4-dicarboxylate (3 g, 94%) as a dark brown oil. MS m/z 347 (M+H)+
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.Cl.[CH3:16][NH:17][O:18][CH3:19].O.ON1C2C=CC=C[C:25]=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C.CN(C1C=CN=CC=1)C.O.C(N(CC)CC)C>[CH3:19][O:18][N:17]([CH3:16])[O:8][C:6]([C:5]1[CH:9]=[CH:10][C:2]([CH3:25])=[CH:3][C:4]=1[C:11]([F:14])([F:13])[F:12])=[O:7]
Reactant: O=C(O)c1ccc(F)cc1C(F)(F)F
Reactant: CNOC
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CON(C)OC(=O)c1ccc(C)cc1C(F)(F)F
Reaction time: 24 h
Yield: 91.2 %

Procedure:
To a solution of 4-fluoro-2-trifluoromethylbenzoic acid (7.00 g), N,O-dimethylhydroxylamine hydrochloride (4.26 g) and 1-hydroxybenzotriazole monohydrate (6.69 g) in DMF (100 ml) was added triethylamine (4.42 g). Then, catalytic amount of 4-(N,N-dimethylamino)pyridine was added to the mixture, 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (8.38 g) was added to the mixture and the mixture was stirred for 1 day under nitrogen atmosphere. Water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1), to give 1-[[[methoxy(methyl)amino]oxy]carbonyl]-4-methyl-2-(trifluoromethyl)benzene (8.07 g) as colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([CH3:46])=[C:14]([C:18]2[C:30]3[C:29]4[C:24](=[CH:25][C:26]([NH:31][C:32]([O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])=[O:33])=[CH:27][CH:28]=4)[NH:23][C:22]=3[C:21]([C:41]([O:43]CC)=[O:42])=[N:20][CH:19]=2)[CH:15]=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+]>O1CCCC1.CO.O>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([CH3:46])=[C:14]([C:18]2[C:30]3[C:29]4[C:24](=[CH:25][C:26]([NH:31][C:32]([O:34][CH2:35][CH2:36][Si:37]([CH3:38])([CH3:39])[CH3:40])=[O:33])=[CH:27][CH:28]=4)[NH:23][C:22]=3[C:21]([C:41]([OH:43])=[O:42])=[N:20][CH:19]=2)[CH:15]=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ncc(-c2cccc(NC(=O)OCc3ccccc3)c2C)c2c1[nH]c1cc(NC(=O)OCC[Si](C)(C)C)ccc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(NC(=O)OCc2ccccc2)cccc1-c1cnc(C(=O)O)c2[nH]c3cc(NC(=O)OCC[Si](C)(C)C)ccc3c12
Reaction time: 1 h
Yield: 77.6 %

Procedure:
To a homogeneous, burgundy solution of ethyl 4-(3-(benzyloxycarbonylamino)-2-methylphenyl)-7-((2-(trimethylsilyl)ethoxy)carbonylamino)-9H-pyrido[3,4-b]indole-1-carboxylate (0.565 g, 0.884 mmol) in tetrahydrofuran (30.2 mL) and methanol (10.05 mL) was added a solution of lithium hydroxide hydrate (0.148 g, 3.54 mmol) in water (4 mL). After 1 hr, the reaction was concentrated in vacuo, acidified with 1 N aqueous HCl to pH ˜5 by litmus paper. The precipitate was filtered, dried over Drierite to give the desired product (0.419 g, 0.686 mmol, 78% yield) as a light brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH:20]=[CH:19][C:8]2[N:9]([CH3:18])[C:10](=[O:17])[C:11]([CH3:16])(C(O)=O)[O:12][C:7]=2[CH:6]=1.[NH3:29].[O:30]1CC[CH2:32][CH2:31]1>>[Cl:1][C:2]1[CH:24]=[C:23]([C:25]([F:28])([F:26])[F:27])[CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH:20]=[CH:19][C:8]2[N:9]([CH3:18])[C:10](=[O:17])[C:11]([CH3:16])([CH2:32][C:31]([NH2:29])=[O:30])[O:12][C:7]=2[CH:6]=1
Reactant: C1CCOC1
Reactant: CN1C(=O)C(C)(C(=O)O)Oc2cc(Oc3ccc(C(F)(F)F)cc3Cl)ccc21
Reactant: N
Product: CN1C(=O)C(C)(CC(N)=O)Oc2cc(Oc3ccc(C(F)(F)F)cc3Cl)ccc21
Reaction time: 1 h

Procedure:
An acid chloride (0.4 g) prepared in the same manner as in Example 6 from 7-(2-chloro-4-trifluoromethylphenoxy)-2,4-dimethyl-3,4-dihydro-3-oxo-2H-1,4-benzoxazine-2-carboxylic acid (Compound 23) was dissolved in tetrahydrofuran (hereinafter abbreviated as THF) (5 ml), and the solution was stirred while blowing ammonia gas therein for one hour. Then, after an evaporation of the solvent, the residue was purified by silica gel chromatography (eluant: n-hexane/ethyl acetate=1/1) to give 0.3 g of the title compound (colorless crystals).
Reaction SMILES: NC1C=CC(C)=C([NH:8][C:9]2[CH:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[C:18]([Cl:23])[CH:17]=3)[N:12]=[CH:11][N:10]=2)C=1.ClC1C=C(C2(N)C=C(Cl)N=CN2)C=CC=1F.[CH3:41][C:42]1[CH:48]=[CH:47][C:46]([N+:49]([O-:51])=[O:50])=[CH:45][C:43]=1N.Cl>C(O)CCC.CCOC(C)=O>[Cl:23][C:18]1[CH:17]=[C:16]([N:15]([C:48]2[CH:47]=[C:46]([N+:49]([O-:51])=[O:50])[CH:45]=[CH:43][C:42]=2[CH3:41])[C:13]2[CH:14]=[C:9]([NH2:8])[N:10]=[CH:11][N:12]=2)[CH:21]=[CH:20][C:19]=1[F:22]
Reactant: Cc1ccc(N)cc1Nc1cc(Nc2ccc(F)c(Cl)c2)ncn1
Reactant: Cc1ccc([N+](=O)[O-])cc1N
Agent: Cl
Agent: NC1(c2ccc(F)c(Cl)c2)C=C(Cl)N=CN1
Solvent: CCCCO
Solvent: CCOC(C)=O
Product: Cc1ccc([N+](=O)[O-])cc1N(c1ccc(F)c(Cl)c1)c1cc(N)ncn1
Temperature: 120 °C

Procedure:
Synthesis of N-(5-Amino-2-methylphenyl)-N′-(3-chloro-4-fluorophenyl)-pyrimidine-4,6-diamine (Int-F) A mixture of 4-(3-chloro-4-fluorophenyl)-6-chloropyrimidin-4-ylamine (IR-4) (1.2 g, 4.6 mmol), 2-methyl-5-nitroaniline (0.85 g, 5.5 mmol) and 1 mL of concentrated HCl in 10 mL of n-butanol was heated at 120° C. for 16 h. With stirring, 5 mL of EtOAc was added to the reaction mixture. The light yellow colored product that precipitated was filtered and dried under vacuum to give N-(3-chloro-4-fluorophenyl)-N-(2-methyl-5-nitrophenyl)pyrimidine-4,6-diamine. MS (APCI) (m/z): 374/376 (M+1). A mixture of N-(3-chloro-4-fluorophenyl)-N-(2-methyl-5-nitrophenyl)pyrimidine-4,6-diamine (0.55 g, 1.5 mmol) and iron powder (35 mesh, 0.5 g, 5 eq) in 5 mL of HOAc and 2 mL of MeOH was heated at reflux for 2 h. The solvent was removed in vacuo and the dark colored residue was mixed with 150 mL of CH2Cl2 and 15 mL of sat. K2CO3 solution and was stirred at room temperature for 30 min. The organic layer was dried (MgSO4), was concentrated, and was then purified by flash chromatography (silica gel, MeOH/NH4OH/CH2Cl2) to afford 0.115 g of N-(5-amino-2-methylphenyl)-N′-(3-chloro-4-fluorophenyl)pyrimidine-4,6-diamine as a light colored solid. (Int-F) MS (m/z): 344/346 (M+1).
Reaction SMILES: [NH2:1][C@@H:2]([CH:27]([CH3:29])[CH3:28])[C:3]([NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[C:10]([O:25][CH3:26])[CH:9]=1)=[O:4].C(N(CC)CC)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39].O>O1CCOCC1>[CH3:37][S:38]([C@@:2]([NH2:1])([CH:27]([CH3:29])[CH3:28])[C:3]([NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)=[C:10]([O:25][CH3:26])[CH:9]=1)=[O:4])(=[O:40])=[O:39]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(CCNC(=O)[C@@H](N)C(C)C)ccc1OCCCc1ccc(Cl)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COc1cc(CCNC(=O)[C@](N)(C(C)C)S(C)(=O)=O)ccc1OCCCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (S)-2-amino-N-(2-{4-[3-(4-chloro-phenyl)-propoxy]-3-methoxy-phenyl}-ethyl)-3-methyl-butyramide (2 g) and triethylamine (0.9 ml) in dioxane (30 ml) is added methanesulfonyl chloride (0.4 ml). The reaction mixture is stirred overnight at room temperature. Water (200 ml) is then added. It is extracted with ethyl acetate (2×200 ml). The organic layers are washed with brine (2×200 ml), dried (MgSO4) and evaporated. (S)-2-Methanesulfonyl-aminoN-(2-{3-methoxy-4-[3-(4-chloro-phenyl)-propoxy]-phenyl}-ethyl)-3-methyl-butyramide is obtained.
Reaction SMILES: F[C:2](F)(F)[C:3](O)=[O:4].[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[CH:19]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]3[CH2:27][CH2:28][NH:29][CH2:30][CH:31]=3)[CH:21]=2)[CH2:18][C:17]([C:32]([C:38]([F:41])([F:40])[F:39])([C:34]([F:37])([F:36])[F:35])[OH:33])=[N:16]1.C(Cl)(=O)C.C(N(CC)CC)C>ClCCl>[C:3]([N:29]1[CH2:28][CH:27]=[C:26]([C:22]2[CH:21]=[C:20]([CH:19]3[N:15]([C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[Cl:8])[N:16]=[C:17]([C:32]([C:38]([F:41])([F:39])[F:40])([C:34]([F:35])([F:36])[F:37])[OH:33])[CH2:18]3)[CH:25]=[CH:24][CH:23]=2)[CH2:31][CH2:30]1)(=[O:4])[CH3:2]
Reactant: O=C(O)C(F)(F)F
Reactant: OC(C1=NN(c2ccccc2Cl)C(c2cccc(C3=CCNCC3)c2)C1)(C(F)(F)F)C(F)(F)F
Solvent: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CC=C(c2cccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccccc3Cl)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.5 %

Procedure:
1-(2-Chloro-phenyl)-5-[3-(1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole trifluoroacetate (11.0 mg, 0.02 mmol) prepared in Example 230, acetyl chloride (1.5 uL, 0.02 mmol), and triethylamine (7.5 uL, 0.05 mmol) were added to dichloromethane (0.5 mL). The reaction mixture was stirred at room temperature for 1 hour, washed with distilled water and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/1) to give 3.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([OH:33])[C:5]2[CH2:16][S:15][CH2:14][C@@H:13]([C:17](OC)=[O:18])[NH:12][C:11](=[O:21])[C@@H:10]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:9][O:8][C:7](=[O:30])[C:6]=2[C:31]=1[CH3:32].O.[NH2:35][NH2:36]>CO.C(OCC)(=O)C>[C:17]([C@H:13]1[NH:12][C:11](=[O:21])[C@@H:10]([NH:22][C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:9][O:8][C:7](=[O:30])[C:6]2[C:31]([CH3:32])=[C:2]([OH:1])[CH:3]=[C:4]([OH:33])[C:5]=2[CH2:16][S:15][CH2:14]1)(=[O:18])[NH:35][NH2:36]
Reactant: COC(=O)[C@@H]1CSCc2c(O)cc(O)c(C)c2C(=O)OC[C@H](NC(=O)OC(C)(C)C)C(=O)N1
Reactant: NN
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1c(O)cc(O)c2c1C(=O)OC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)NN)CSC2

Procedure:
A solution of 97 mg of the product of Example 2 and 0.2 ml of hydrazine hydrate in 1 ml of methanol was stirred at 20° C. for 45 minutes. The solution was diluted with ethyl acetate, and washed with 0.5M sodium dihydrogenphosphate solution and with water. The organic layer was dried over sodium sulfate and evaporated in vacuo, and the residue was crystallized from methanol/ethyl acetate/hexane to give 85 mg of tert-butyl (4R, 7S)-4-carbazoyl-1,3,4,5,6,7,8,10-octahydro-12,14-dihydroxy-11-methyl-6,10-dioxo-9,2,5-benzoxathiaazacyclododecine-7-carbamate as a white solid. as a white solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([NH:10][CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[N:5][C:6]([Cl:9])=[N:7][CH:8]=1.CCN(C(C)C)C(C)C.CN(C=O)C.[CH3:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][C:39](O)=[O:40])=[CH:34][CH:33]=1>C(OCC)(=O)C>[Cl:9][C:6]1[N:5]=[C:4]([NH:10][CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[C:3]([CH2:2][NH:1][C:39](=[O:40])[CH2:38][C:35]2[CH:36]=[CH:37][C:32]([O:31][CH3:30])=[CH:33][CH:34]=2)=[CH:8][N:7]=1
Reactant: CC(C)(C)CNc1nc(Cl)ncc1CN
Reactant: COc1ccc(CC(=O)O)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(CC(=O)NCc2cnc(Cl)nc2NCC(C)(C)C)cc1
Reaction time: 16 h

Procedure:
To a solution of 0.089 g (0.38 mmol) of (5-aminomethyl-2-chloro-pyrimidin-4-yl](2,2-dimethyl-propyl)-amine and 0.27 ml (1.6 mmol) DIEA in 2.5 ml of DMF 0.063 g (0.38 mmol) of (4-methoxy-phenyl)-acetic acid is added and the reaction mixture is stirred at r.t for 16 h. The reaction mixture is then diluted with ethyl acetate and twice washed with H2O, the organic layer is separated and dried over Na2SO4 and then concentrated under reduced pressure. Flash chromatography (ethyl acetate/hexanes 1:1) of the residue provided N-[2-chloro-4-(2,2-dimethyl-propylamino)-pyrimidin-5-ylmethyl]-2-(4-methoxy-phenyl)acetamide as white crystalls.
Reaction SMILES: [P:1]([OH:6])([O:4][CH3:5])[O:2][CH3:3].C(O[O:12][C:13](C)(C)C)(C)(C)C.[CH3:17][C:18]1[CH:23]2[C:24]([CH3:26])([CH3:25])[CH:21]([CH2:22]2)[CH2:20][CH:19]=1>>[CH:18]1([CH3:17])[CH:19]([P:1](=[O:6])([O:4][CH3:5])[O:2][CH3:3])[CH2:20][CH:21]([CH:24]([CH3:26])[CH3:25])[CH2:22][CH:23]1[P:1](=[O:4])([O:12][CH3:13])[O:2][CH3:3]
Reactant: COP(O)OC
Reactant: CC(C)(C)OOC(C)(C)C
Reactant: CC1=CCC2CC1C2(C)C
Product: COP(=O)(OC)C1CC(C(C)C)CC(P(=O)(OC)OC)C1C

Procedure:
In a manner similar to the previous examples, 233 ml of dimethyl hydrogen phosphite was stirred with 4.6 ml of di-tertiary-butyl peroxide at 140°-150° while α-pinene (81 ml) was added over a period of 15 minutes. After maintaining the reaction mixture at 140° for 18 hours, an additional 4.6 ml of di-tertiary-butyl peroxide was added. After heating an additional 30 minutes, the reaction mixture was subjected to distillation which provided the di-adduct. The NMR spectrum showed the methyl ester groups as a multiplet consisting mainly of 2 spikes at 3.70δ and 3.88δ along with the remainder of the protons between 0.7δ and 3.5δ.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([NH:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[O:11])=[N:6][C:5]=1[C:18]1[O:19][CH:20]=[CH:21][CH:22]=1)([OH:3])=O.[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.CCN=C=NCCCN(C)C.Cl.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C.O>[O:19]1[CH:20]=[CH:21][CH:22]=[C:18]1[C:5]1[N:6]=[C:7]([NH:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[O:11])[S:8][C:4]=1[C:1]([N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)=[O:3]
Reactant: O=C(Nc1nc(-c2ccco2)c(C(=O)O)s1)c1ccncc1
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(Nc1nc(-c2ccco2)c(C(=O)N2CCOCC2)s1)c1ccncc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 31.8 %

Procedure:
Compound 95 (410 mg, 1.30 mmol), morpholine (0.141 mL, 1.60 mmol), EDC hydrochloride (500 mg, 2.60 mmol), 1-hydroxybenzotriazole monohydrate (400 mg, 2.60 mmol) and triethylamine (0.36 mL, 2.60 mmol) were dissolved in DMF (5 mL), followed by stirring at room temperature for 3 hours. Water was added to the reaction mixture, followed by extraction with chloroform. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was recrystallized from ethanol to afford the entitled Compound 96 (159 mg, 34%) as colorless crystals.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH2:9])[CH:3]=1.[C:10]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:15]=[CH:14][C:13]([CH:16]2[CH2:22][C:21](=O)[O:20][C:18](=[O:19])[CH2:17]2)=[CH:12][CH:11]=1.[ClH:30]>ClCCl.O1CCOCC1>[ClH:30].[C:10]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:15]=[CH:14][C:13]([CH:16]([CH2:22][C:21]2[NH:9][C:4]3[CH:3]=[C:2]([I:1])[CH:7]=[CH:6][C:5]=3[N:8]=2)[CH2:17][C:18]([OH:20])=[O:19])=[CH:12][CH:11]=1
Reactant: Nc1ccc(I)cc1N
Reactant: O=C1CC(c2ccc(-c3ccccc3)cc2)CC(=O)O1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(O)CC(Cc1nc2ccc(I)cc2[nH]1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Iodo-1,2-phenylenediamine (0.47 g) and 3-(biphenyl-4-yl)glutaric anhydride (0.53 g) were dissolved in dichloromethane (5 ml) with heating. The dark solution was stirred at rt for 1 h. The precipitate formed was collected by suction filtration, washed with dichloromethane, and dried in vacuo to give a mixture of regioisomeric amides (0.74 g) as light brown solid. This solid was dissolved in 1,4-dioxane (1 ml) with heating. 4M HCl in 1,4-dioxane (3 ml) was added and the solution was heated to reflux for 1 h. All volatiles were removed at the water aspirator and the amorphous residue is fractionally crystallised to provide 3-(biphenyl-4-yl)-4-(5-iodo-2-benzimidazolyl)butanoic acid HCl (0.43 g) as off-white solid.
Reaction SMILES: [NH2:1][C@H:2]([C:11]([O:13][CH3:14])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Cl>C(OC(C)(C)C)(=O)C>[NH2:1][C@H:2]([C:11]([O:13][CH3:14])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[C:8]([C:4]([CH3:9])([CH3:5])[CH3:3])[CH:9]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Agent: Cl
Solvent: CC(=O)OC(C)(C)C
Product: COC(=O)[C@@H](N)Cc1ccc(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a solution of 25.0 g (0.108 mol) of Tyr-OMe.HCl in 500 ml of tert-butyl acetate, 18 ml (0.204 mol) of 70% HClO4 was added and the mixture was stirred at room temperature for 4 days. The reaction mixture was concentrated under reduced pressure and the resulting residue was dissolved in 400 ml of ethyl acetate; thereafter, the solution was poured into 800 ml of a saturated aqueous solution of NaHCO3 and the mixture was stirred. The organic layer was taken out and washed first with a saturated aqueous solution of NaHCO3, then with saturated brine, dried with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. To the resulting residue, 500 ml of ether was added and the mixture was stirred overnight at room temperature. The precipitating crystals were recovered by filtration to give Tyr(3-tBu)-OMe in the amount of 10.9 g (40%).
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li])CCC.CCCCCC.[C:25]([C:29]1[CH:30]=[C:31]([CH3:55])[C:32](=[C:34]([C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([C:51]([F:54])([F:53])[F:52])[CH:46]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:44])([F:43])[F:42])[CH:36]=2)[CH:33]=1)([CH3:28])([CH3:27])[CH3:26].Cl>C(OCC)C>[C:25]([C:29]1[CH:30]=[C:31]([CH3:55])[CH:32]([C:34]([C:1]2[C:13]3[CH2:12][C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:5]=3[CH:4]=[CH:3][CH:2]=2)([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:42])([F:43])[F:44])[CH:36]=2)[C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([C:51]([F:54])([F:53])[F:52])[CH:46]=2)[CH:33]=1)([CH3:26])([CH3:27])[CH3:28]
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Reactant: CC1=CC(C(C)(C)C)=CC1=C(c1cccc(C(F)(F)F)c1)c1cccc(C(F)(F)F)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CC1=CC(C(C)(C)C)=CC1C(c1cccc(C(F)(F)F)c1)(c1cccc(C(F)(F)F)c1)c1cccc2c1Cc1ccccc1-2
Temperature: 25 °C

Procedure:
In a 200 ml three-necked flask equipped with a magnetic stirrer chip and three-way cock thoroughly purged with nitrogen, 1.44 g of fluorene (8.69 mmol) was dissolved in 60 ml of dehydrated diethylether in a nitrogen atmosphere. To the solution, 5.8 ml of n-butyl lithium/hexane solution (1.58M: 9.16 mmol) was gradually added dropwise in an ice bath and stirred at room temperature over night. To the reaction solution, 4.15 g of 3-tert-butyl-1-methyl-6,6-di(3-trifluoromethyl-phenyl)fulvene (9.50 mmol) was added and stirred under reflux for several days. The reaction mixture was gradually added dropwise to 30 ml of a hydrochloric acid aqueous solution set (IN) in an ice bath, and stirred at room temperature briefly. Therein, diethyl ether was added to separate an organic phase. The organic phase was washed with distilled water and saturated brine. The organic phase was dried with anhydrous magnesium sulfate, thereafter the drying agent was filtered off and the solvent was distilled off from the filtrate under reduced pressure to give a dark red solid. The solid was purified with a column chromatography using 220 g of silica gel (developing solvent: n-hexane) and the developing solvent was distilled off under reduced pressure. Thereafter, the remaining product was re-crystallized using hexane and dried under reduced pressure, and thereby the aimed compound was obtained in an amount of 1.69 g (2.72 mmol) as a white solid (yield: 31%).
Reaction SMILES: [NH2:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3]O.[C:8]1(S)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl.C1(S[CH2:23][C@@H:24](C(O)=O)[NH2:25])C=CC=CC=1>>[NH2:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][C:23]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:25][CH:24]=1
Reactant: N[C@@H](CSc1ccccc1)C(=O)O
Reactant: N[C@@H](CO)C(=O)O
Reactant: Sc1ccccc1
Agent: Cl
Product: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Reaction time: 0.08 h

Procedure:
Placed in a 100-ml Erlenmeyer flask were 19 ml of one of the L-serine solutions and 0.2 ml of one of the PLP solution. Thiophenol (0.5 ml) was added, followed by incubation at 35° C. for 5 minutes. The cell suspension (0.5 ml) was added, followed by incubation for 60 minutes under shaking. Sixty minutes later, 1 ml of 35% hydrochloric acid was added to terminate the reaction, and the concentration of S-phenyl-L-cysteine in the solution was quantitated by HPLC. The amount (g) of S-phenyl-L-cysteine formed in an hour per gram of the dried cells was defined as S-phenyl-L-cysteine forming activity.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]2[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][C:8]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)=[CH:7][C:6]=12.[C:25]([C:27]1[CH:28]=[CH:29][C:30]([NH2:33])=[N:31][CH:32]=1)#[CH:26]>>[F:14][C:11]([F:12])([F:13])[C:10]1[N:5]2[N:4]=[CH:3][C:2]([C:26]#[C:25][C:27]3[CH:28]=[CH:29][C:30]([NH2:33])=[N:31][CH:32]=3)=[C:6]2[CH:7]=[C:8]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:19][CH:20]=2)[CH:9]=1
Reactant: C#Cc1ccc(N)nc1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)n3ncc(I)c3c2)cc1
Product: Nc1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)cc23)cn1

Procedure:
The title compound was prepared from 3-iodo-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyridine (example C.22 step 9) (300 mg, 0.7 mmol) and 5-ethynyl-pyridin-2-ylamine (example D.1) (93 mg, 0.8 mmol) according to general procedure II. Obtained as a yellow solid (230 mg, 78%). MS (ISP) 447.2 [(M+H)+]; mp 243–245° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[C:9]([C:12]#[N:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[N+:19]([C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)([O-:21])=[O:20].N1C(C)=CC=CC=1C>C(OCC)(=O)C>[C:12]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][O:17][CH3:18])[N:5]=[CH:4][CH:3]=[C:2]2[O:28][C:25]1[CH:26]=[CH:27][C:22]([N+:19]([O-:21])=[O:20])=[CH:23][CH:24]=1)#[N:13]
Reactant: COCCOc1cc2nccc(Cl)c2cc1C#N
Reactant: O=[N+]([O-])c1ccc(O)cc1
Solvent: Cc1cccc(C)n1
Solvent: CCOC(C)=O
Product: COCCOc1cc2nccc(Oc3ccc([N+](=O)[O-])cc3)c2cc1C#N
Temperature: 155 °C
Reaction time: 1.5 h
Yield: 43.1 %

Procedure:
A mixture of 4-chloro-6-cyano-7-(2-methoxyethoxy)quinoline (3 g), 4-nitrophenol (3.17 g) and 2,6-lutidine (2.7 ml) was heated and stirred in an oil bath at 155° C. for 1.5 hours. After completion of the reaction, ethyl acetate was added, and the precipitated solid was filtered out. The solid was washed with 1N sodium hydroxide water and then with water and dried to obtain 1.8 g of the title compound.