Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[NH2:28][C:29]([CH2:31][N:32]([S:40]([CH3:43])(=[O:42])=[O:41])[C:33]1[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=1)=[O:30]>>[NH2:28][C:29]([CH2:31][N:32]([C:33]1[CH:38]=[CH:37][C:36]([NH:39]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:35][CH:34]=1)[S:40]([CH3:43])(=[O:41])=[O:42])=[O:30]
Reactant: CS(=O)(=O)N(CC(N)=O)c1ccc(N)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(N(CC(N)=O)S(C)(=O)=O)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and N-aminocarbonylmethyl-N-methylsulphonyl-p-phenylenediamine Rf value: 0.7 (silica gel, methylene chloride/methanol=5:1) C26H24N4O6S
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:13]([NH:17][C:18]1[NH:19][C:20](=[O:45])[C:21]2[N:22]=[CH:23][N:24]([C:43]=2[N:44]=1)[C@:25]1([C:33](=[O:42])[CH2:34][O:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[O:32][C@H:29]([CH2:30][OH:31])[C@@H:27]([OH:28])[CH2:26]1)([CH3:16])([CH3:15])[CH3:14]>N1C=CC=CC=1>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([O:31][CH2:30][C@H:29]2[O:32][C@@:25]([C:33](=[O:42])[CH2:34][O:35][C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)([N:24]3[C:43]4[N:44]=[C:18]([NH:17][C:13]([CH3:14])([CH3:16])[CH3:15])[NH:19][C:20](=[O:45])[C:21]=4[N:22]=[CH:23]3)[CH2:26][C@@H:27]2[OH:28])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)Nc1nc2c(ncn2[C@@]2(C(=O)COc3ccccc3)C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Solvent: c1ccncc1
Product: CC(C)(C)Nc1nc2c(ncn2[C@@]2(C(=O)COc3ccccc3)C[C@H](O)[C@@H](COC(=O)c3ccc([N+](=O)[O-])cc3)O2)c(=O)[nH]1

Procedure:
The synthesis of this product is carried out by reacting 1.1 eq of p-nitrobenzoyl chloride with 2-N-t-butylphenoxyacetyldeoxyguanosine for 16 hours in pyridine. After extraction with a dichloromethane/methanol mixture and evaporation to dryness, the product is taken up in chloroform/hexane (8/2) and purified on a silica column (elution 3% methanol). The product obtained is very soluble in organic solvents.
Reaction SMILES: [C:1]([C:3]1[C:4]([I:15])=[C:5]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[S:6][C:7]=1SC)#[N:2].[CH:16]1C=C(Cl)C=C(C(OO)=O)C=1.[S:27]([O-:30])([O-])=[O:28].[Na+].[Na+].C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.C1COCC1>[I:15][C:4]1[C:3]([C:1]#[N:2])=[C:7]([S:27]([CH3:16])(=[O:30])=[O:28])[S:6][C:5]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: O=S([O-])[O-]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)c1sc(SC)c(C#N)c1I
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOC(=O)c1sc(S(C)(=O)=O)c(C#N)c1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.5 %

Procedure:
Ethyl 4-cyano-3-iodo-5-(methylsulfanyl)thiophene-2-carboxylate (7.2 g, 20.4 mmol) was dissolved in DCM (200 mL) and THF (100 mL) and m-CPBA (9.14 g, 40.8 mmol) was added. The reaction mixture was stirred at rt overnight. Sodium sulfite (5.14 g, 40.8 mmol) was added and the mixture was stirred for 10 minutes followed by the addition of potassium carbonate (8.45, 61.2 mmol). The suspension was stirred at rt for 1 hour and filtered through celite, washed with DCM and the solvent was evaporated to afford ethyl 3-iodo-4-cyano-5-(methylsulfonyl)thiophene-2-carboxylate (6.80 g, 78%). LCMS: (FA) ES+ 386. 1H NMR (400 MHz, CDCl3) δ: 4.45 (q, 2H), 3.38 (s, 3H), 1.43 (t, 3H).
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[CH:3]=1.[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>CS(C)=O>[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([C:2]2[CH:11]=[CH:10][C:5]3[C:6](=[O:9])[CH2:7][O:8][C:4]=3[CH:3]=2)[CH2:15][CH2:14]1
Reactant: O=C1COc2cc(F)ccc21
Reactant: CN1CCNCC1
Solvent: CS(C)=O
Product: CN1CCN(c2ccc3c(c2)OCC3=O)CC1
Temperature: 25 °C

Procedure:
A mixture of Example 1109B (0.152 g) and 1-methylpiperazine (0.22 g) in DMSO (1 ml) was heated at 150 C for 30 min, allowed to cool to r.t. (room temperature) then partitioned between water and EtOAc. Organics were dried (Na2SO4), concentrated and purified via silica gel chromatography eluting with 5% MeOH-CH2Cl2 to give the title compound. MS ESI(+)m/e 233.0(M+H)+.
Reaction SMILES: [CH2:1]([N:5]1[C:13](=[O:14])[C:12]2[NH:11][C:10]([CH3:15])=[N:9][C:8]=2[N:7]([CH2:16][CH2:17][CH2:18][CH3:19])[C:6]1=[O:20])[CH2:2][CH2:3][CH3:4].[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1.[K+].[Br-]>>[CH2:1]([N:5]1[C:13](=[O:14])[C:12]2[N:11]([S:27]([C:24]3[CH:25]=[CH:26][C:21]([CH3:31])=[CH:22][CH:23]=3)(=[O:29])=[O:28])[C:10]([CH3:15])=[N:9][C:8]=2[N:7]([CH2:16][CH2:17][CH2:18][CH3:19])[C:6]1=[O:20])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)c2[nH]c(C)nc2n(CCCC)c1=O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Br-]
Agent: [K+]
Product: CCCCn1c(=O)c2c(nc(C)n2S(=O)(=O)c2ccc(C)cc2)n(CCCC)c1=O
Yield: 75 %

Procedure:
The title compound was prepared according to the procedure of example 3 except that 1,3-dibutyl-8-methyl-3,7-dihydro-purine-2,6-dione was used in place of 1,3-dibutyl-3,7-dihydro-purine-2,6-dione and p-toluenesulfonyl chloride was used in place of methanesulfonyl chloride. Yield: 75%; mp: 111-113° C.; 1H NMR (300 MHz, CDCl3): δ 0.89-0.96 (m, 6H), 1.29-1.37 (m, 4H), 1.58-1.65 (m, 2H), 1.67-1.72 (m, 2H), 2.48 (s, 3H), 2.86 (s, 3H), 3.93 (t, J=7.6 Hz, 2H), 4.11 (t, J=7.1 Hz, 2H), 7.36 (d, J=8.1 Hz, 2H), 8.13 (d, J=8.5 Hz, 2H); IR (KBr, cm−1): 2960m, 2865m, 1709s, 1674s, 1593m, 1528s, 1479m, 1181m, 1121s, 938m, 760m, 595m; MS (ES) m/z (relative intensity): 433 (M++H, 100).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:14]([Li])[CH2:15][CH2:16]C.[CH2:19]1[CH2:23][O:22][CH2:21][CH2:20]1>>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:21](=[O:22])[CH2:20][CH2:19][CH2:23][CH:15]([CH3:16])[CH3:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [Li]CCCC
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Reactant: C1CCOC1
Product: CC(C)CCCC(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Temperature: 0 °C

Procedure:
To a −78° C. solution of 4(R)-benzyl-2-oxazolidinone (21.28 g, 0.12 mol) in THF (360 mL) was added n-butyllithium (48 mL, 2.5M in hexane, 120 mmol). After 10 minutes Example 8A (19.76 g, 0.134 mol) was added. After 30 minutes the mixture was warmed to 0° C., and quenched with saturated ammonium chloride. The supernatant was decanted and concentrated. The residue was partitioned between water and ethyl acetate and the organic layer was washed sequentially with water, 1M sodium bicarbonate, water, and brine, dried (MgSO4), filtered, and concentrated to provide the desired product. MS (ESI) m/e 290 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[Se]=[O:13].[BH4-].[Na+]>O1CCOCC1>[CH3:8][C:6]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=[C:2]([CH2:1][OH:13])[CH:7]=1
Reactant: Cc1cc(C)c([N+](=O)[O-])cn1
Reactant: O=[Se]
Agent: [BH4-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1cc(CO)ncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the mixture of 2,4-dimethyl-5-nitropyridine (3.0 g, 20 mmol) in 30 ml of dioxane, was selenium oxide (2.8 g, 25 mmol) added at an ambient temperature. The reaction was refluxed for 10 hrs. The reaction was cooled to room temperature and concentrated under vacuum. The residue was poured into water and extracted with ethyl acetate. The organic layer was dried over MgSO4 and concentrated under vacuum. The crude mixture of the aldehyde was diluted in methanol (30 mL) and sodium borohydride (0.74 g, 20 mmol) was added portionwise at 0° C. After stirred for 1 hr, the reaction was quenched with water (20 mL) and concentrated under vacuum. The reaction was extracted with ethyl acetate and dried over MgSO4. The ethyl acetate was dried under vacuum and purified under SiO2 with 50% ethyl acetate in hexane to afford (4-methyl-5-nitropyridin-2-yl)methanol in 83% (2.7 g). 1HNMR (CDCl3, 400 MHz) δ 2.65 (s, 1H), 4.60 (d, J=8.1, 2H), 5.81 (t, J=8.1, 1H), 7.67 (s, 1H), 9.21 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C(Cl)Cl>[CH3:18][S:19]([O:7][CH2:6][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[C:9]([CH3:10])[CH:8]=1)(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(CO)ccc1Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(COS(C)(=O)=O)ccc1Br
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of compound 2 (2.0 g, 9.95 mmol), Et3N (6.94 mL, 49.7 mmol), and CH2Cl2 (100 mL) was cooled to 0° C. and treated with methanesulfonyl chloride (1.54 mL, 19.9 mmol). The solution was stirred at room temperature for 3 hours. The volatiles were removed under reduced pressure and the resultant crude product was used without further purification.
Reaction SMILES: [C:1]1([CH:7]2[NH:11][C@H:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:9][S:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][C:19]1[CH:20]=[C:21]([NH:25][C:26](=[O:32])[NH:27][CH2:28][C:29](O)=[O:30])[CH:22]=[CH:23][CH:24]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(#N)C>[CH3:18][C:19]1[CH:20]=[C:21]([NH:25][C:26](=[O:32])[NH:27][CH2:28][C:29]([SH:8]2[CH2:9][C@@H:10]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:11][CH:7]2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:30])[CH:22]=[CH:23][CH:24]=1
Reactant: c1ccc(C2N[C@H](c3ccccc3)CS2)cc1
Reactant: Cc1cccc(NC(=O)NCC(=O)O)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC#N
Product: Cc1cccc(NC(=O)NCC(=O)[SH]2C[C@@H](c3ccccc3)NC2c2ccccc2)c1
Yield: 45.5 %

Procedure:
By proceeding in a fashion similar to that described in Example 41 §A, but starting from 1.2 g of (2RS,4R)-2,4-diphenylthiazolidine, 1.04 g of 2-[3-(3-methylphenyl)ureido]acetic acid and 1.03 g of N,N'-dicyclohexylcarbodiimide in 15 cm3 of acetonitrile, and after treatment, 0.98 g of (2RS,4R)-1-{2-[3-(3-methylphenyl)ureido]acetyl}-2,4-diphenylthiazolidine is obtained in the form of a meringue-like product.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[I:44][C:45]1[CH:50]=[CH:49][C:48]([CH2:51][N:52]2[CH:56]=[CH:55][C:54]([NH2:57])=[N:53]2)=[C:47]([C:58]([F:61])([F:60])[F:59])[CH:46]=1>CN(C=O)C.CO>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:57][C:54]1[CH:55]=[CH:56][N:52]([CH2:51][C:48]2[CH:49]=[CH:50][C:45]([I:44])=[CH:46][C:47]=2[C:58]([F:61])([F:59])[F:60])[N:53]=1)=[O:6]
Reactant: Nc1ccn(Cc2ccc(I)cc2C(F)(F)F)n1
Reactant: O=C(O)c1ccccc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(Nc1ccn(Cc2ccc(I)cc2C(F)(F)F)n1)c1ccccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 2-fluorobenzoic acid (22 mg, 0.157 mmol, Aldrich) was added a solution of HATU (58 mg, 0.153 mmol, Advanced asymmetrics) in DMF (0.5 ml), DIPEA (0.062 ml, 0.355 mmol) and then a solution of 1-{[4-iodo-2-(trifluoromethyl)phenyl]methyl}-1H-pyrazol-3-amine (for a preparation see Intermediate 39)(43 mg, 0.117 mmol) in DMF (0.5 ml). The resulting yellow solution was stirred at ambient temperature overnight. The reaction mixture was diluted with methanol (1 ml) and purified by MDAP on Sunfire C18 column (Method B) using Acetonitrile-Water with a Formic acid modifier. The solvent was evaporated in vacuo to give the title compound as a white solid (40 mg); LCMS: (System 4) MH+=490, tRET=3.38 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([NH2:18])[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([CH2:15][CH3:16])[CH:14]=1)[NH:11][N:10]=[C:9]2[CH3:17].[C:20](C1NC=CN=1)(C1NC=CN=1)=[O:21].[NH:32]1[CH2:37][CH2:36][CH:35]([N:38]2[CH2:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[NH:40][C:39]2=[O:48])[CH2:34][CH2:33]1>O1CCCC1>[CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:18][C:20]([N:32]1[CH2:33][CH2:34][CH:35]([N:38]2[CH2:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[NH:40][C:39]2=[O:48])[CH2:36][CH2:37]1)=[O:21])[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([CH2:15][CH3:16])[CH:14]=1)[NH:11][N:10]=[C:9]2[CH3:17]
Reactant: O=C1Nc2ccccc2CN1C1CCNCC1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: CCc1cc(CC(N)C(=O)OC)cc2c(C)n[nH]c12
Solvent: C1CCOC1
Product: CCc1cc(CC(NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C(=O)OC)cc2c(C)n[nH]c12
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A stirred solution of (±)-2-amino-3-(7-ethyl-3 methyl-1H-indazol-5-yl)-propionic acid methyl ester (0.55 g, 2.1 mmol) in tetrahydrofuran (6 mL) at 0° C. was treated with carbonyl diimidazole (0.37 g, 1.1 equiv). The reaction was stirred for 5 min at 0° C., warmed to room temperature, stirred 10 min, and treated with 3-piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one (0.53 g, 1.1 equiv). The mixture was stirred at room temperature overnight. The solvent was evaporated and the residue purified by column chromatography to give 0.94 g (86%) as a white powder. 1H-NMR (DMSO-d6) δ 1.26 (t, J=7.5, 3H), 1.49 (m, 1H), 2.44 (s, 3H), 2.83 (dd, J=7.3, 7.6, 1H), 2.84 (dd, J=115.0, 7.6, 1H), 2.88-3.10 (m, 1.5H), 3.18 (d, J=5.5, 0.5H), 3.61 (s, 3H), 4.04-4.16 (m, 3H), 4.28 (m, 2H), 6.76 (d, J=7.9, 1H), 6.86 (m, 2H), 7.04-7.25 (m, 3H), 7.36 (s, 1H), 7.40 (s, 1H), 9.18 (s, 1H), 12.59 (s, 1H). Mass spec.: 519.37 (MH)+.
Reaction SMILES: [C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:11][CH2:12][CH2:13][NH:14][CH3:15])[C:8]([NH2:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:22][C:23]1[CH:31]=[CH:30][C:26]([CH2:27][CH2:28]Br)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:11][CH2:12][CH2:13][N:14]([CH2:28][CH2:27][C:26]2[CH:30]=[CH:31][C:23]([Cl:22])=[CH:24][CH:25]=2)[CH3:15])[C:8]([NH2:10])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Clc1ccc(CCBr)cc1
Reactant: CNCCCC(C(N)=O)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(CCCC(C(N)=O)(c1ccccc1)c1ccccc1)CCc1ccc(Cl)cc1

Procedure:
A mixture containing 2,2-diphenyl-5-methylaminopentanamide (0.3 g-see Preparation 3), 4-chlorophenethyl bromide (0.234 g-see Preparation 7), anhydrous potassium carbonate (0.4 g) and acetonitrile (10 ml) was heated under reflux for 5 hours. The mixture was concentrated in vacuo and the residue partitioned between dichloromethane (30 ml) and 10% aqueous potassium carbonate (30 ml). The layers were separated and the aqueous layer extracted with dichloromethane (3×20 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give a gum which was purified by column chromatography on silica eluting with dichloromethane containing methanol (5% up to 10%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a gum, yield 0.306 g.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[CH:14]=[C:13]2[C:7]([CH2:8][N+:9]([O-])=[C:10]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[C:11]3[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:12]=32)=[CH:6]1)=[O:4].[C:28]([O:31]C(=O)C)(=[O:30])[CH3:29]>>[CH3:1][O:2][C:3]([N:5]1[CH:14]=[C:13]2[C:7]([CH:8]([O:31][C:28](=[O:30])[CH3:29])[N:9]=[C:10]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[C:11]3[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:12]=32)=[CH:6]1)=[O:4]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)n1cc2c(c1)-c1ccc(Cl)cc1C(c1ccccc1Cl)=[N+]([O-])C2
Product: COC(=O)n1cc2c(c1)C(OC(C)=O)N=C(c1ccccc1Cl)c1cc(Cl)ccc1-2
Reaction time: 5 h

Procedure:
A mixture of 7.6 g (19 mmol) of 8-chloro-6-(2-chlorophenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepine-2-carboxylic acid methyl ester 5-oxide and 200 ml of acetic anhydride was stirred at 70° for 12 hr and at 105° for 5 hr. The acetic anhydride solution was concentrated at reduced pressure. The residue was dissolved in methylene chloride and washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated at reduced pressure to give an oil. Purification by column chromatography (50 g, neutral alumina; 5% ether in methylene chloride, eluent) gave a tan solid, mp 175°-177°. Recrystallization from ether gave an off-white solid, mp 177°-178°.
Reaction SMILES: [O:1]=[S:2]1(=[O:15])[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[Br:16]N1C(=O)CCC1=O.CCOC(C)=O>C(Cl)Cl.CO.C(Cl)Cl>[Br:16][C:12]1[CH:13]=[C:8]([CH:5]2[CH2:6][CH2:7][S:2](=[O:15])(=[O:1])[CH2:3][CH2:4]2)[CH:9]=[CH:10][C:11]=1[NH2:14]
Reactant: Nc1ccc(C2CCS(=O)(=O)CC2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CO
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Nc1ccc(C2CCS(=O)(=O)CC2)cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
To a suspension of 4-(1,1-dioxo-hexahydro-1λ6-thiopyran-4-yl)-phenylamine (as prepared in the previous step, 174 mg, 0.77 mmol) in 20 mL of 3:1 DCM/MeOH at 0° C. was added N-bromosuccinimide (NBS) (137 mg, 0.77 mmol) in 5 mL of DCM under Ar. The mixture was warmed to RT and stirred for 1 h under Ar. Treated with 100 mL of EtOAc, the mixture was washed with H2O (2×20 mL), brine (20 mL) and dried (Na2SO4). Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (2-3% EtOAc/DCM) gave 155 mg (66%) of the title compound as a white solid. 1H-NMR (CDCl3; 400 MHz): δ 7.28 (d, 1H, J=2.0 Hz), 6.97 (dd, 1H, J=8.3, 2.0 Hz), 6.73 (d, 1H, J=8.3 Hz), 4.07 (br s, 2H), 3.09-3.14 (m, 4H), 2.66 (dddd, 1H, J=12.1, 12.1, 3.3, 3.3 Hz), 2.26-2.39 (m, 2H), 2.12-2.21 (m, 2H). Mass spectrum (ESI, m/z): Calcd. for C11H14BrNO2S, 304.0 (M+H). found 304.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[C:13]([C:17]1[S:21][C:20](=[NH:22])[N:19]([CH2:23][CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH:18]=1)([CH3:16])([CH3:15])[CH3:14].N>>[C:13]([C:17]1[S:21]/[C:20](=[N:22]\[C:7](=[O:9])[C:6]2[CH:10]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:11][CH3:12])/[N:19]([CH2:23][CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH:18]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: COc1ccc(Cl)cc1C(=O)O
Reactant: CC(C)(C)OC(=O)NCCn1cc(C(C)(C)C)sc1=N
Agent: N
Product: COc1ccc(Cl)cc1C(=O)/N=c1\sc(C(C)(C)C)cn1CCNC(=O)OC(C)(C)C

Procedure:
The title compound was prepared according to the procedure described in Example 54A by substituting 5-chloro-2-methoxybenzoic acid for Example 26B and the product of Example 70A for Example 16A. 1H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.35 (s, 9H) 1.39 (s, 9H) 3.57 (q, J=5.82 Hz, 2H) 3.90 (s, 3H) 4.33 (t, J=5.75 Hz, 2H) 5.41 (s, 1H) 6.64 (s, 1H) 6.91 (d, J=9.12 Hz, 1H) 7.34 (dd, J=8.72, 2.78 Hz, 1H) 7.93 (d, J=2.78 Hz, 1H). MS (DCI/NH3) m/z 468.2 (M+H)+.
Reaction SMILES: C1(P(C2CCCCC2)C2(OC)[CH2:13][CH:12]=[CH:11][C:10](OC)=[C:9]2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)CCCCC1.Br[C:31]1[C:32]2[C:37]([C:38](Br)=[C:39]3[C:44]=1[CH:43]=[CH:42][CH:41]=[CH:40]3)=[CH:36][CH:35]=[CH:34][CH:33]=2.[CH:46]12[CH2:59][CH:49]([C:50]3[C:51](B(O)O)=[CH:52][CH:53]=[CH:54][C:55]=31)[CH2:48][CH2:47]2.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O>[CH:46]12[CH2:59][CH:49]([C:50]3[C:55]1=[CH:54][CH:53]=[CH:52][C:51]=3[C:31]1[C:32]3[C:37]([C:38]([C:21]4[CH:20]=[CH:19][CH:18]=[C:17]5[C:16]=4[CH:9]4[CH2:10][CH:11]5[CH2:12][CH2:13]4)=[C:39]4[C:44]=1[CH:43]=[CH:42][CH:41]=[CH:40]4)=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:48][CH2:47]2
Reactant: COC1=C(c2ccccc2)C(OC)(P(C2CCCCC2)C2CCCCC2)CC=C1
Reactant: Brc1c2ccccc2c(Br)c2ccccc12
Reactant: OB(O)c1cccc2c1C1CCC2C1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: c1cc(-c2c3ccccc3c(-c3cccc4c3C3CCC4C3)c3ccccc23)c2c(c1)C1CCC2C1

Procedure:
915 my (1 mmol) of tris(dibenzylidenacetone)dipalladium(0) and 821 mg (2 mmol) of 2-dicyclohexylphosphino-2,6-dimethoxybiphenyl are added to a suspension of 16.8 g (50 mmol) of 9,10-dibromoanthracene, 21.6 g (115 mol) of 1,2,3,4-tetrahydro-1,4-methanonaphthalene-5-boronic acid and 66.9 g (315 mmol) of tripotassium phosphate in 400 ml of anhydrous toluene, and the mixture is refluxed for 16 h. After the reaction mixture has been cooled, 400 ml of water are added, and the precipitate is filtered off with suction, washed three times with 200 ml of water each time, washed three times with 200 ml of ethanol each time, dried under reduced pressure and subsequently chromatographed on silica gel (eluent heptane/toluene 8:2, v/v, column temperature 500C). Sublimation: p=1×10−5 mbar, 300° C. Yield: 13.1 g (28 mmol), 56.6% of theory; purity: 99.5% according to 1H-NMR (including all isomers).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:7][N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH:10]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:9]1.I[CH3:31]>O1CCCC1>[Cl:3][C:4]1[CH:5]=[C:6]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:7][N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH:10]([N:18]([CH3:31])[C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:24])[CH3:22])[CH2:9]1
Reactant: CI
Reactant: CC(C)(C)OC(=O)NC1Cc2ccccc2N(Cc2ccc(Cl)c(Cl)c2)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)C1Cc2ccccc2N(Cc2ccc(Cl)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (0.1 g, 4.16 mmol) was added to a 0° C. solution of tert-butyl 1-(3,4-dichlorobenzyl)-1,2,3,4-tetrahydroquinolin-3-ylcarbamate (0.85 g, 2.09 mmol) and iodomethane (95%, 2.97, 10 eq) in anhydrous tetrahydrofuran (10 mL). The mixture was stirred at room temperature for 1 hour. The mixture was quenched by slowly adding few drops of water. The resulting mixture was dried over anhydrous sodium sulfate and the solvent evaporated. The residue was purified by flash chromatography (eluted with 5% EtOAc in hexane) to give tert-butyl 1-(3,4-dichlorobenzyl)-1,2,3,4-tetrahydroquinolin-3-yl(methyl)carbamate as white solid (789 mg). 1H NMR (DMSO) 400 MHz δ 7.57 (d, J=4 Hz, 1H), 7.61 (brd, J=6.4 Hz, 1H), 7.47 (d, J=1.6, 1H), 7.23 (dd, J=2.0 Hz and 8.4 Hz, 1H), 6.95 (d, J=7.6 Hz, 1H), 6.91 (m, 1H), 6.53 (m, 1H), 6.45 (d, 8.4 Hz, 1H), 4.45 (brd, J=10.4 Hz, 1H), 4.29 (br, 1H), 3.40 (t, 10.4 Hz, 1H), 3.21 (m, 1H), 3.02 (m, 1H), 2.74 (m, 1H), 2.72 (s, 3H), 1.36 (m, 9H). LCMS m/e 422 (M+H).
Reaction SMILES: C([O:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([C:16]2[O:17][C:18]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH:28]([CH3:30])[CH3:29])=[C:23]([CH3:31])[CH:22]=3)=[N:19][N:20]=2)=[CH:11][C:10]=1[CH2:32][CH3:33])C1C=CC=CC=1>C1COCC1.CCO.[Pd]>[CH2:32]([C:10]1[CH:11]=[C:12]([C:16]2[O:17][C:18]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH:28]([CH3:29])[CH3:30])=[C:23]([CH3:31])[CH:22]=3)=[N:19][N:20]=2)[CH:13]=[C:14]([CH3:15])[C:9]=1[OH:8])[CH3:33]
Reactant: CCc1cc(-c2nnc(-c3ccc(OC(C)C)c(C)c3)o2)cc(C)c1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCc1cc(-c2nnc(-c3ccc(OC(C)C)c(C)c3)o2)cc(C)c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.5 %

Procedure:
To a solution of 2-(4-benzyloxy-3-ethyl-5-methyl-phenyl)-5-(4-isopropoxy-3-methyl-phenyl)-[1,3,4]oxadiazole (1.25 g, 2.82 mmol) in THF (10 mL), Pd/C (100 mg, 10% Pd) in EtOH (10 mL) is added. The mixture is stirred at rt under 1 atmosphere of H2 for 16 h before the catalyst is removed by filtration. The filtrate is concentrated and separated by CC on silica gel eluting with heptane:EA 4:1 to 1:1 to give 2-ethyl-4-[5-(4-isopropoxy-3-methyl-phenyl)-[1,3,4]oxadiazol-2-yl]-6-methyl-phenol (0.79 g) as a greenish solid; LC-MS: tR=1.12 min, [M+1]+=353.17, 1H NMR (D6-DMSO): δ 9.02 (s br, 1H), 7.90-7.86 (m, 2H), 7.70-7.66 (m, 2H), 7.13 (d, J=9.4 Hz, 1H), 4.72 (hept, J=5.0^9 Hz, 1H), 2.65 (q, J=7.6 Hz, 2H), 2.26 (s, 3H), 2.20 (s, 3H), 1.31 (d, J=5.9 Hz, 6H), 1.17 (t, J=7.6 Hz, 3H).