Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7]O)=[CH:3][CH:2]=1.C(C=P(CCCC)(CCCC)CCCC)#N.[CH3:25][Si:26]([CH3:42])([CH3:41])[C:27]1[CH:35]=[C:34]2[C:30]([CH:31]=[C:32]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[NH:33]2)=[CH:29][CH:28]=1>C1(C)C=CC=CC=1>[CH3:25][Si:26]([CH3:41])([CH3:42])[C:27]1[CH:35]=[C:34]2[C:30]([CH:31]=[C:32]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[N:33]2[CH2:7][C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)=[CH:29][CH:28]=1
Reactant: OCc1ccncc1
Reactant: CCOC(=O)c1cc2ccc([Si](C)(C)C)cc2[nH]1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc2ccc([Si](C)(C)C)cc2n1Cc1ccncc1
Temperature: 110 °C
Reaction time: 15 h
Yield: 95.7 %

Procedure:
0.42 g (3.82 mmol) of 4-pyridinylmethanol and 0.92 g (3.826 mmol) of (cyano-methylene)tributylphosphorane (CMBP) are added, at ambient temperature, to a solution of 0.5 g (1.91 mmol) of ethyl 6-trimethylsilyl-1H-indole-2-carboxylate, obtained according to the protocol described in stage 1.2, in 8 ml of dry toluene, maintained under an inert atmosphere. The reaction mixture is stirred at 110° C. for 15 hours and then concentrated to dryness. The reaction crude is subsequently purified by flash chromatography on a silica gel column, elution being carried out with a mixture of heptane and ethyl acetate, to give 0.644 g of the expected ethyl 6-trimethylsilyl-1-[(pyridin-4-yl)methyl]-1H-indole-2-carboxylate in the form of a yellow solid.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:22][N:23]([C:35]1[CH:40]=[CH:39][N:38]=[C:37]([NH:41][C:42]2[CH:47]=[CH:46][C:45]([CH2:48][S:49]([CH3:52])(=[O:51])=[O:50])=[CH:44][CH:43]=2)[N:36]=1)[C:24]1[CH:34]=[CH:33][C:27]2[N:28]([CH3:32])[C:29]([NH2:31])=[N:30][C:26]=2[CH:25]=1.C(N(CC)CC)C>CN(C)C=O>[CH3:32][N:28]1[C:27]2[CH:33]=[CH:34][C:24]([N:23]([CH3:22])[C:35]3[CH:40]=[CH:39][N:38]=[C:37]([NH:41][C:42]4[CH:43]=[CH:44][C:45]([CH2:48][S:49]([CH3:52])(=[O:50])=[O:51])=[CH:46][CH:47]=4)[N:36]=3)=[CH:25][C:26]=2[N:30]=[C:29]1[NH:31][C:1](=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(c1ccc2c(c1)nc(N)n2C)c1ccnc(Nc2ccc(CS(C)(=O)=O)cc2)n1
Reactant: O=C(O)c1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(c1ccc2c(c1)nc(NC(=O)c1ccccc1)n2C)c1ccnc(Nc2ccc(CS(C)(=O)=O)cc2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of benzoic acid (51 mg, 0.402 mmol) in N,N-dimethylformamide (2 ml) was added 1,1′-carbonyldiimidazole (65.2 mg, 0.400 mmol). The mixture was stirred for 30 minutes at room temperature and then a solution of N5,1-dimethyl-N5-[2-({4-[(methylsulfonyl)methyl]phenyl}amino)pyrimidin-4-yl]-1H-benzimidazole-2,5-diamine (88 mg, 0.201 mmol) and triethylamine (0.03 ml, 0.201 mmol) in N,N-dimethylformamide (2 ml) was added. The reaction mixture was stirred for 16 h, quenched with saturated sodium bicarbonate solution (30 ml) and the product then precipitated. The crude product was filtered, washed with water, diethyl ether and air dried to give the desired product without further purification. 1H NMR (400 MHz, d6-DMSO) δ 12.82 (s, 1H), 9.28 (s, 1H), 8.28 (d, J=7.3 Hz, 2H), 7.89 (d, J=6.1 Hz, 1H), 7.74 (d, J=8.2 Hz, 2H), 7.59 (d, J=8.4 Hz, 1H), 7.51-7.44 (m, 4H), 7.25-7.20 (m, 3H), 5.79 (d, J=5.9 Hz, 1H), 4.34 (s, 2H), 3.77 (s, 3H), 3.47 (s, 3H), 2.84 (s, 3H). MS (ESI) m/z=542 [M+H]+.
Reaction SMILES: [I:1][C:2]1[C:3]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[F:18][C:19]([F:28])([F:27])[C:20]1[N:24]=[C:23]([CH2:25][NH2:26])[O:22][N:21]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[OH-].[Na+]>CN(C=O)C>[I:1][C:2]1[C:3]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH:26][CH2:25][C:23]1[O:22][N:21]=[C:20]([C:19]([F:28])([F:27])[F:18])[N:24]=1)=[O:9]
Reactant: NCc1nc(C(F)(F)F)no1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(I)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1nc(C(F)(F)F)no1)c1cnc(OCC(F)(F)F)c(I)c1
Reaction time: 8 h
Yield: 84 %

Procedure:
5-Iodo-6-(2,2,2-trifluoroethoxy)nicotinic acid (Example 1a, 1 g, 2.88 mmol) was dissolved in DMF (10 mL). C-(3-trifluoromethyl-1,2,4-oxadiazol-5-yl)-methylamine hydrochloride (616 mg, 3.03 mmol), TBTU (981 mg, 3.05 mmol) and N,N-diisopropylethylamine (1.86 g, 2.45 ml, 14.4 mmol) were added. The reaction mixture was stirred overnight, poured into 75 mL 1 M NaOH solution and extracted with i-propyl acetate (2×200 mL). The organic layers were combined, dried over Na2SO4 and concentrated in vacuo to give a brown oil. The crude material was purified by flash chromatography (silica gel, 50 g, 25% i-propyl acetate in n-heptane) to give the title compound (1.2 g, 84%) as light yellow solid; MS (ESI) 497.0 (M+H)+.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][C@H:4]([NH2:8])[C:5]([OH:7])=[O:6].C(N(CC)CC)C.O.[CH2:17]([O:24][C:25](ON1C(=O)CCC1=O)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCOCC1>[CH2:17]([O:24][C:25]([NH:8][C@@H:4]([CH2:3][CH:2]=[CH2:1])[C:5]([OH:7])=[O:6])=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C=CC[C@H](N)C(=O)O
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: C=CC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of L-2-amino-4-pentenoic acid (2.0 g) in Dioxane (80 mL) at RT was added triethylamine (4.3 g), water (2.0 mL), and N-(benzyloxycarbonyloxy)succinimide (9.1 g). The reaction mixture was stirred overnight at RT, concentrated in vacuo, diluted with saturated NaHCO3 and extracted with ether (3×). The basic aqueous layer was acidified to pH 2 with 2N HCl and extracted with EtOAc (3×). The combined EtOAc layer was washed with brine, dried (Na2SO4), filtered and evaporated, then concentrated from Toluene (2×) to give a viscous oil (4.51 g, quantitative). 1H NMR (300 MHz, DMSO-d6) δ 2.31-2.50 (m, 2H), 4.00-4.06 (m, 1H), 5.03 (s, 2H), 5.05-5.12 (m, 2H), 5.71-5.84 (m, 1H), 7.35 (m, 5H), 7.53 (d, 1H), 12.57 (bs, 1H). MS APCI, m/z=250 (M+1). LC/MS 2.30 min., Method A.
Reaction SMILES: BrC1C(Br)=CC(N)=C(N)C=1.O=C(C(OCC)=O)C(OCC)=O.[Br:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][C:33]=1[Br:34])[N:30]=[C:29]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:28](=[O:40])[NH:27]2>C(O)C>[Br:23][C:24]1[C:33]([Br:34])=[CH:32][C:31]2[C:26](=[N:27][C:28](=[O:40])[CH:29]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[N:30]=2)[CH:25]=1
Reactant: CCOC(=O)c1nc2cc(Br)c(Br)cc2[nH]c1=O
Agent: CCOC(=O)C(=O)C(=O)OCC
Agent: Nc1cc(Br)c(Br)cc1N
Solvent: CCO
Product: CCOC(=O)C1N=c2cc(Br)c(Br)cc2=NC1=O

Procedure:
4,5-Dibromo-o-phenylenediamine was cyclized to the corresponding quinoxaline carboxylic acid ester by the procedure of Preparation 1 utilizing 4.1 g. of the diamine and 2.7 g. of diethyl ketomalonate in 75 ml. of anhydrous ethanol. Ethyl 6,7-dibromo-3,4-dihydro-3-oxo-2-quinoxaline carboxylate thus prepared melted at 235°-236° C. (yield=3.9 g.).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]1([CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([CH:21]([C:23]3[S:27][C:26]4[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=4[CH:24]=3)[OH:22])[CH2:17][CH2:16]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>C(Cl)Cl.CS(C)=O>[S:27]1[C:23]([C:21]([CH:18]2[CH2:19][CH2:20][N:15]([CH2:14][CH2:13][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:16][CH2:17]2)=[O:22])=[CH:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]1=2
Reactant: OC(c1cc2ccccc2s1)C1CCN(CCc2ccccc2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C(c1cc2ccccc2s1)C1CCN(CCc2ccccc2)CC1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
Dissolve oxalyl chloride (4.22 g, 33.28 mmol) in methylene chloride (200 mL), place under an argon atmosphere and cool to -78° C. Add, by dropwise addition, dimethylsulfoxide (5.4 2 g, 69.33 mmol) and stir at -78° C. for 15 minutes. Add, by dropwise addition, a solution of α-[1-(2-phenylethyl)-4-piperidinyl]-2-benzo[b]thiophenemethanol (9.75 g, 27.73 mmol) in dimethylsulfoxide (150 mL). Stir at -78° C. for 30 minutes, add triethylamine (15.18 g, 0.150 mol) and stir at -78° C. for 1 hour. Remove the ice bath and stir for an additional 1.5 hours. Evaporate the solvent in vacuo and recrystallize (isopropanol) to give the title compound as fluffy white crystalline solid; mp 129°-130° C.
Reaction SMILES: [H-].[Na+].[CH3:3]I.[C:5]([O:9][C:10]([N:12]1[CH2:16][CH:15]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:14]([OH:24])[CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6]>O1CCCC1>[C:5]([O:9][C:10]([N:12]1[CH2:16][CH:15]([NH:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:14]([O:24][CH3:3])[CH2:13]1)=[O:11])([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)N1CC(O)C(Nc2ccccc2)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1CN(C(=O)OC(C)(C)C)CC1Nc1ccccc1
Temperature: 25 °C
Yield: 79.7 %

Procedure:
To 10 ml of anhydrous tetrahydrofuran was added 0.34 g (0.0085 mole) of a 60% sodium hydride-mineral oil, and while stirring the mixture at 45° to 50° C., 1.21 g (0.0085 mole) of methyl iodide was added thereto. To the mixture was added dropwise a solution of 2.37 g of 1-t-butoxycarbonyl-3-hydroxy-4-phenylaminopyrrolidine obtained in Reference example 17 (1) dissolved in 10 ml of anhydrous tetrahydrofuran, and the mixture was further stirred at the same temperature for 1 hour. After the mixture was cooled to room temperature, the solvent was removed under reduced pressure, and the residue was spplied to silica gel column chromatography (the eluent used was a mixture of methyl acetate:toluene=1:4) to obtain 1.98 g of 1-t-butoxycarbonyl-3-methoxy-4-phenylaminopyrrolidine as white crystals.
Reaction SMILES: C([N:8]1[CH2:13][C@@H:12]2[CH2:14][CH:9]1[CH2:10][N:11]2[C:15](=[O:43])[CH2:16][NH:17][C:18](=[O:42])[C:19]1[CH:24]=[CH:23][C:22]([S:25](=[O:41])(=[O:40])[NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:21][CH:20]=1)C1C=CC=CC=1>C(O)(=O)C.[Pd]>[C@H:12]12[CH2:14][CH:9]([NH:8][CH2:13]1)[CH2:10][N:11]2[C:15](=[O:43])[CH2:16][NH:17][C:18](=[O:42])[C:19]1[CH:20]=[CH:21][C:22]([S:25](=[O:40])(=[O:41])[NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[CH:23][CH:24]=1
Reactant: O=C(NCC(=O)N1CC2C[C@H]1CN2Cc1ccccc1)c1ccc(S(=O)(=O)Nc2ccccc2Oc2ccccc2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: O=C(NCC(=O)N1CC2C[C@H]1CN2)c1ccc(S(=O)(=O)Nc2ccccc2Oc2ccccc2)cc1
Reaction time: 2 h
Yield: 97.2 %

Procedure:
A stirred mixture of N-[2-((S)-5-benzyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-2-oxo-ethyl]-4-(2-phenoxy-phenylsulfamoyl)-benzamide (Example 2.61) (46 mg, 0.077 mmol) and 10% Pd/C (10 mg) in acetic acid (5 mL) was hydrogenated at 5 bar at room temperature for 2 h. The catalyst was filtered off and the filtrate was concentrated in vacuo. The residue was purified by column chromatography using Kieselgel 60 (0.015-0.040 mm) (Merck) as adsorbent and chloroform:methanol:ammonium hydroxide=9:1:0.1 as eluent to yield 37.9 mg (97%) of the title compound. MS (EI) 507.1 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH:5]([N:8]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[S:28]([NH2:31])(=[O:30])=[O:29])=[CH:18][CH:17]=1)[C:9](=[O:14])[CH2:10][CH2:11][CH2:12][CH3:13])[C:6]#[N:7])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:39]([N:42]=[C:43]=[O:44])[CH2:40][CH3:41].Cl>CC(C)=O.ClCCl>[CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:6]#[N:7])[N:8]([CH2:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[S:28]([NH:31][C:43]([NH:42][CH2:39][CH2:40][CH3:41])=[O:44])(=[O:29])=[O:30])=[CH:20][CH:21]=1)[C:9](=[O:14])[CH2:10][CH2:11][CH2:12][CH3:13])[CH3:2]
Reactant: CCCN=C=O
Reactant: CCCCC(=O)N(Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1)C(C#N)C(=O)OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: ClCCl
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)NCCC)cc1)C(C#N)C(=O)OCC

Procedure:
7.2 g of the product of Stage A, 6.5 g of anhydrous potassium carbonate and 1.48 ml of n-propyl isocyanate were stirred in 180 ml of acetone at reflux for 2 hours 30 minutes. After cooling, the solution was treated with 2N hydrochloric acid and the residue obtained was dissolved in an aqueous mixture of dichloromethane. After extraction with methylene chloride, the extracts were dried and the solvents were eliminated under reduced pressure and the product was crystallized from ethyl acetate to obtain 6.5 g of the expected product as a white solid with a Rf (SiO2, ethyl acetate)=0.48 and melting at 131°-133° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1[C:13]([NH2:14])=[CH:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])=[C:10]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C([O:33][C:34](=O)[CH2:35][C:36](=[O:56])[C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([N:43]2[C:47]([CH2:48][O:49][CH:50]3[CH2:55][CH2:54][CH2:53][CH2:52][O:51]3)=[CH:46][N:45]=[N:44]2)[CH:38]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1[C:13]([NH:14][C:34](=[O:33])[CH2:35][C:36](=[O:56])[C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([N:43]3[C:47]([CH2:48][O:49][CH:50]4[CH2:55][CH2:54][CH2:53][CH2:52][O:51]4)=[CH:46][N:45]=[N:44]3)[CH:38]=2)=[CH:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])=[C:10]([O:22][CH2:23][C:24]([F:25])([F:26])[F:27])[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(-c2ccccc2F)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2nncc2COC2CCCCO2)c1
Product: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(-c2ccccc2F)cc1NC(=O)CC(=O)c1cccc(-n2nncc2COC2CCCCO2)c1

Procedure:
The title compound was prepared from [5-amino-2′-fluoro-2-(2,2,2-trifluoro-ethoxy)-biphenyl-4-yl]-carbamic acid tert.-butyl ester (Example J5) (200 mg, 0.5 mmol) and (RS)-3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionic acid tert-butyl ester (Example K5) (220 mg, 0.55 mmol) according to the general procedure M. Obtained as a yellow oil(100 mg).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:21]1[C:26]([F:27])=[CH:25][CH:24]=[CH:23][N:22]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([CH:14]2[CH2:15][CH2:16][N:17]([C:21]3[C:26]([F:27])=[CH:25][CH:24]=[CH:23][N:22]=3)[CH2:18][CH2:19]2)(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)C2CCNCC2)cc1
Reactant: Fc1cccnc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc(S(=O)(=O)C2CCN(c3ncccc3F)CC2)cc1
Yield: 9.6 %

Procedure:
Using the procedure from Example 7A, 4-[(4-tert-butylphenyl)sulfonyl]piperidine (100 mg, 0.36 mmol) was reacted with 2-chloro-3-fluoropyridine (74 μl, 0.72 mmol), DIEA (0.25 ml, 1.44) and 1,4-dioxane (0.3 ml) at 185° C. to afford the title compound (13 mg), a white solid, in 10% yield.
Reaction SMILES: [OH:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C@H:11]2[S:15][C@H:14]([C:16]3[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=3)[CH2:13][S:12]2)=[CH:4][C:3]=1[O:28][CH3:29].[CH2:30](Br)[CH:31]=[CH2:32].C1OCCOCCOCCOCCOCCOC1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:32]([O:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C@H:11]2[S:15][C@H:14]([C:16]3[CH:17]=[C:18]([O:26][CH3:27])[C:19]([O:24][CH3:25])=[C:20]([O:22][CH3:23])[CH:21]=3)[CH2:13][S:12]2)=[CH:4][C:3]=1[O:28][CH3:29])[CH:31]=[CH2:30]
Reactant: C=CCBr
Reactant: COc1cc([C@@H]2SC[C@@H](c3cc(OC)c(OC)c(OC)c3)S2)cc([N+](=O)[O-])c1O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1c(OC)cc([C@@H]2SC[C@@H](c3cc(OC)c(OC)c(OC)c3)S2)cc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
Trans-2-(4-hydroxy-3-methoxy-5-nitrophenyl)-4-(3,4,5-trimethoxy-phenyl)-1,3-dithiolane (21) (2.50 g, 5.69 mmole) was dissolved in 30 ml dry DMF and allyl bromide (0.963 g, 7.97 mmole) was added by syringe. To this solution was added 100 mg of 18-crown-6 and potassium carbonate (0.785 g, 5.69 mmole). The reaction was stirred at 50° C. under an argon atmosphere for 4 hours. The reaction was quenched with 10% HCl and extracted with diethyl ether. The organic layer was dried over MgSO4, and concentrated to a yellow oil in vacuo which was purified by flash column chromatography with 3:1-2:1 hexane/ethyl acetate as eluent. (2.60 g, 95% yield: colorless oil).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]#N)=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15])(=[O:3])[CH3:2].[BH4-].[Na+].[H-].[Na+].Cl.BrC1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1>O.CC(C)=O.CN(C)C=O>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15])(=[O:3])[CH3:2]
Reactant: Brc1ccncc1
Reactant: CC(=O)Nc1ccc(SC#N)cc1[N+](=O)[O-]
Agent: Cl
Agent: [BH4-]
Agent: [H-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CC(=O)Nc1ccc(Sc2ccncc2)cc1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
A solution of 9.6 g. of 1-acetamido-2-nitro-4-thiocyanatobenzene in 60 ml. dimethylformamide is treated, under nitrogen, with 1.52 g. sodium borohydride at less than 25° C. The mixture is stirred for 1 hour at 20°-25° C., then 15 ml. of acetone is added and stirring continued for 2 hours. 2.5 G. of 57% sodium hydride in oil suspension is added at 20°-30° C., followed by 11.7 g. of 4-bromopyridine hydrochloride. The mixture is warmed slowly and kept at 120°-130° C. for several hours, then cooled and diluted with water, and extracted with chloroform. The chloroform solution is treated with charcoal, stripped and the residue recrystallized from methanol and washed with pentene affording 1-acetamido-2-nitro-4-(pyrid-4-ylthio)benzene.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C@@H:9]([NH:17][C:18]([C:20]1[C:32]2[CH2:31][CH2:30][C:29]3[CH:28]=[N:27][CH:26]=[CH:25][C:24]=3[C:23]=2[N:22]([CH2:33][C:34]([F:37])([F:36])[F:35])[CH:21]=1)=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(C)(C)C.Cl.C(OCC)C>O1CCOCC1>[NH2:7][CH2:8][C@@H:9]([NH:17][C:18]([C:20]1[C:32]2[CH2:31][CH2:30][C:29]3[CH:28]=[N:27][CH:26]=[CH:25][C:24]=3[C:23]=2[N:22]([CH2:33][C:34]([F:37])([F:36])[F:35])[CH:21]=1)=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)NC[C@H](Cc1ccccc1)NC(=O)c1cn(CC(F)(F)F)c2c1CCc1cnccc1-2
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: NC[C@H](Cc1ccccc1)NC(=O)c1cn(CC(F)(F)F)c2c1CCc1cnccc1-2
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
To a solution of tert-butyl[(2S)-3-phenyl-2-({[1-(2,2,2-trifluoroethyl)-4,5-dihydro-1H-pyrrolo[2,3-f]isoquinolin-3-yl]carbonyl}amino)propyl]carbamate L8 (0.38 mmol) in dry dioxane (20 mL), 4M HCl in dioxane (5 mL) was added. The reaction mixture was stirred at rt overnight. The solvent was removed and the residue dissolved with DCM and washed with aq NaHCO3. The organic layer was dried (Na2SO4) and concentrated. Purification by chromatography on silica gel (eluant: DCM/MeOH 19:1) gave, after trituration with diethylether, the title compound (75% yield). ESI (+) MS: m/z 429 (MH+). 1H-NMR: 4.06-4.18 (m, 1H), 5.32 (q, J=8.98, 2H), 7.18 (m, 1H), 7.48 (d, J=5.24, 1H), 7.57 (s, 1H), 7.71 (d, J=8.41, 1H), 8.38 (d, J=5.24, 1H), 8.40 (s, 1H).
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][C:13](Br)=[CH:14][CH:15]=2)[O:10][C:9]([C:18]2[N:19]=[CH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:8]1)(C)(C)C.[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]#[CH:37])=[CH:32][CH:31]=1>>[CH:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:27]=[C:18]([C:9]2[O:10][C:11]3[C:16]([C:7](=[N:6][OH:5])[CH:8]=2)=[CH:15][CH:14]=[C:13]([C:37]#[C:36][C:33]2[CH:34]=[CH:35][C:30]([O:29][CH3:28])=[CH:31][CH:32]=2)[CH:12]=3)[N:19]=1
Reactant: C#Cc1ccc(OC)cc1
Reactant: CC(C)(C)ON=c1cc(-c2cc3ccccc3cn2)oc2cc(Br)ccc12
Product: COc1ccc(C#Cc2ccc3c(=NO)cc(-c4cc5ccccc5cn4)oc3c2)cc1

Procedure:
2-isoquinolin-3-yl-7-(4-methoxyphenyl)ethynyl-chromen-4-one oxime was prepared in 9% overall yield using the method described in example 24, starting from 7-bromo-2-isoquinolin-3-yl-chromen-4-one O-tert-butyl oxime (example 2B) and 4-methoxyphenylacetylene. The title compound was purified by preparative HPLC (gradient 35-20% Water/acetonitrile+0.05% trifluoroacetic acid) and isolated as a yellow solid and as a 95/05 mixture of Z/E oxime isomers.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.Cl[CH2:17][C:18]1[N:19]=[C:20]([C:23]2[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=2)[O:21][CH:22]=1>>[C:29]([C:26]1[CH:25]=[CH:24][C:23]([C:20]2[O:21][CH:22]=[C:18]([CH2:17][O:1][C:2]3[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]4[CH:15]=[CH:14][N:13]=[CH:12]4)=[CH:4][CH:3]=3)[N:19]=2)=[CH:28][CH:27]=1)#[N:30]
Reactant: N#Cc1ccc(-c2nc(CCl)co2)cc1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Product: N#Cc1ccc(-c2nc(COc3ccc(CCCn4ccnc4)cc3)co2)cc1
Yield: 72 %

Procedure:
In substantially the same manner as in Working Example 48, 1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with 4-chloromethyl-2-(4-cyanophenyl) oxazole to give 2-(4-cyanophenyl)-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazole. The yield was 72%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 98-99° C.
Reaction SMILES: Cl[CH2:2][CH2:3][S:4]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)(=[O:6])=[O:5].[CH3:14][C:15]1[CH:28]=[CH:27][C:18]([CH2:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH:21]2[OH:26])=[CH:17][CH:16]=1>>[OH:13][C:10]1[CH:11]=[CH:12][C:7]([S:4]([CH2:3][CH2:2][N:23]2[CH2:24][CH2:25][CH:20]([CH2:19][C:18]3[CH:27]=[CH:28][C:15]([CH3:14])=[CH:16][CH:17]=3)[CH:21]([OH:26])[CH2:22]2)(=[O:6])=[O:5])=[CH:8][CH:9]=1
Reactant: O=S(=O)(CCCl)c1ccc(O)cc1
Reactant: Cc1ccc(CC2CCNCC2O)cc1
Product: Cc1ccc(CC2CCN(CCS(=O)(=O)c3ccc(O)cc3)CC2O)cc1
Yield: 30 %

Procedure:
The title compound was prepared from 4-(2-chloro-ethanesulfonyl)-phenol and (3SR,4SR)-4-(4-methyl-benzyl)-piperidin-3-ol in 30% yield as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9]C(C)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:12]([OH:15])(=[O:14])[CH3:13]>O.O.O.O.C([O-])(=O)C.[Co+2].C([O-])(=O)C.[Br-].[Na+]>[C:1]([C:5]1[CH:10]=[CH:9][C:13]([C:12]([OH:15])=[O:14])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)O
Reactant: Cc1ccc(C(C)(C)C)cc1
Agent: [Co+2]
Agent: CC(=O)[O-]
Agent: [Br-]
Solvent: O
Product: CC(C)(C)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Yield: 86.4 %

Procedure:
Analogously to Example 1, 300 g of p-tert-butyltoluene (93.3% pure) was oxidized in the presence of 50 g of acetic acid, 3 g of cobalt acetate tetrahydrate and 1.5 g of sodium bromide at 25 bar and 115°-135° C. by passing air through it to produce a gas exhaust rate of 1.5 liters per minute. The oxygen absorption ended after a reaction period of 300 minutes; then 450 g of 74.5% acetic acid was added, the dilute reaction mixture was cooled with stirring to room temperature and filtered, and the crystallizate was washed with 450g of 70% acetic acid. 311.5 g of p-tert-butylbenzoic acid resulted, in the form of white crystals of a purity of 99.6 percent by weight as determined by gas chromatography, with a terephthalic acid content of 0.16%.