Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:23])[N:16]([CH2:18][CH2:19][C:20]([NH2:22])=[O:21])[CH:17]=2)=O)=[C:4]([CH3:34])[CH:3]=1.Cl.[NH2:36][OH:37].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:24]2[CH:25]=[CH:26][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][CH:29]=2)[CH2:9]/[C:10](/[C:12]2[CH:13]=[CH:14][C:15](=[O:23])[N:16]([CH2:18][CH2:19][C:20]([NH2:22])=[O:21])[CH:17]=2)=[N:36]\[OH:37])=[C:4]([CH3:34])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(CCC(N)=O)c1)c1ccc(S(C)(=O)=O)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(Cl)ccc1C(C/C(=N\O)c1ccc(=O)n(CCC(N)=O)c1)c1ccc(S(C)(=O)=O)cc1

Procedure:
In analogy to example 151, step 3, 3-(5-(3-(4-chloro-2-methylphenyl)-3-(4-(methylsulfonyl)phenyl)propanoyl)-2-oxopyridin-1(2H)-yl)propanamide was reacted with hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate to give the title compound containing less than 10% of the corresponding Z isomer as an off-white solid, MS (ESI+): m/z=516.4 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:14]2[CH2:15][CH2:16][N:17](C)[CH2:18][CH2:19][N:12]3[C:13]=2[C:5]([C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=23)=[CH:4][CH:3]=1.ClC(OC(Cl)C)=O>ClC(Cl)C>[Cl:1][C:2]1[C:14]2[CH2:15][CH2:16][NH:17][CH2:18][CH2:19][N:12]3[C:13]=2[C:5]([C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=23)=[CH:4][CH:3]=1
Reactant: CN1CCc2c(Cl)ccc3c4c(n(c23)CC1)CCCC4
Agent: CC(Cl)OC(=O)Cl
Solvent: CC(Cl)Cl
Product: Clc1ccc2c3c(n4c2c1CCNCC4)CCCC3
Temperature: 25 °C
Yield: 87.3 %

Procedure:
To a solution of 6-chloro-3-methyl-2,3,4,5,9,10,11,12-octahydro-1H-[1,4]diazocino[7,8,1-jk]carbazole (0.36 g, 1.25 mmole) in dichloroethane (80 mL) was added 1-chloroethyl chloroformate (1.2 mL, 10.8 mmole) and the mixture refluxed for 24 hours. The reaction mixture was cooled to room temperature and the solvent removed in vacuo and replaced with methanol (25 mL) and refluxed for another 3 hours. The reaction mixture was then cooled to room temperature and the solvent removed in vacuo. The dark residue was dissolved in methylene chloride (200 mL) and washed with aqueous sodium hydroxide (1N, 150 mL), saturated sodium chloride (150 mL), dried (sodium sulfate) and concentrated. Purification by flash column chromatography (silica gel, 1.5% methanol in dichloromethane) provided 0.30 g of the title compound. 80 mg of this was further treated with one equivalent of fumaric acid in ethanol to form a fumarate salt, mp 208-210° C. MS (ESI) m/z 275 ([M+H]+).
Reaction SMILES: [C:1]([C:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:5](=[CH:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:22](O)=[O:23])[CH:4]=1)#[N:2].[CH3:25][O:26][C:27]1[CH:28]=[C:29]([C:35]([NH2:38])([CH3:37])[CH3:36])[CH:30]=[C:31]([O:33][CH3:34])[CH:32]=1>>[CH3:34][O:33][C:31]1[CH:30]=[C:29]([C:35]([NH:38][C:22]([C@H:12]2[CH2:11][CH2:10][C@H:9]3[C@H:8]4[C@H:17]([CH2:16][CH2:15][C@:13]23[CH3:14])[C@:18]2([CH3:21])[C:5]([CH:4]=[C:3]([C:1]#[N:2])[CH2:20][CH2:19]2)=[CH:6][CH2:7]4)=[O:23])([CH3:36])[CH3:37])[CH:28]=[C:27]([O:26][CH3:25])[CH:32]=1
Reactant: COc1cc(OC)cc(C(C)(C)N)c1
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4C=C(C#N)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)O
Product: COc1cc(OC)cc(C(C)(C)NC(=O)[C@H]2CC[C@H]3[C@@H]4CC=C5C=C(C#N)CC[C@]5(C)[C@H]4CC[C@]23C)c1
Yield: 98 %

Procedure:
Following a procedure similar to that described in Preparation 16a, but using 3-cyanoandrosta-3,5-diene-17β-carboxylic acid [prepared as described in Example 1(b)] and 1-(3,5-dimethoxyphenyl)-1-methylethylamine as starting materials, in relative proportions similar to those used in that Preparation, the title compound was obtained in a yield of 98%.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][CH:8]=[C:9]([C:11](=[O:18])[NH:12][C@H:13]([CH2:16][OH:17])[CH2:14][CH3:15])[N:10]=2)[CH2:3]1.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].N1C=CN=C1>CN(C)C=O>[Si:19]([O:17][CH2:16][C@@H:13]([NH:12][C:11]([C:9]1[N:10]=[C:6]([N:4]2[CH2:5][CH:2]([OH:1])[CH2:3]2)[S:7][CH:8]=1)=[O:18])[CH2:14][CH3:15])([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: CC[C@@H](CO)NC(=O)c1csc(N2CC(O)C2)n1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)c1csc(N2CC(O)C2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.1 %

Procedure:
To a solution of 3-hydroxy-1-{4-[(1S)-1-(hydroxymethyl)-propylcarbamoyl]-1,3-thiazol-2-yl}azetidine (940 mg, 3.50 mmol) (obtained as described in Reference Example 34(3)) in dimethylformamide (47 ml) were added t-butyldimethylsilyl chloride (633 mg, 4.20 mmol) and imidazole (286 mg, 4.20 mmol) in an ice bath, and the reaction mixture was stirred at room temperature for 3 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The obtained organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (2:1→1:3) as the eluant to afford 1-{4-[(1S)-1-(t-butyldimethylsilyloxymethyl)propylcarbamoyl]-1,3-thiazol-2-yl}-3-hydroxyazetidine (1.00 g, yield 74%) as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]2[N:19]3[CH2:20][CH2:21][CH2:22][CH:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:18]3=[N:17][N:16]=2)[CH:6]=[CH:7][C:8]=1[C:9]1[O:13][C:12]([CH3:14])=[N:11][CH:10]=1.[H-].[Na+].[B-](F)(F)(F)[F:32].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.[Cl-].[NH4+]>CN(C=O)C>[F:32][C:23]1([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:22][CH2:21][CH2:20][N:19]2[C:15]([C:5]3[CH:6]=[CH:7][C:8]([C:9]4[O:13][C:12]([CH3:14])=[N:11][CH:10]=4)=[C:3]([O:2][CH3:1])[CH:4]=3)=[N:16][N:17]=[C:18]12
Reactant: CCOC(=O)C1CCCn2c(-c3ccc(-c4cnc(C)o4)c(OC)c3)nnc21
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: [Cl-]
Agent: [H-]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(F)CCCn2c(-c3ccc(-c4cnc(C)o4)c(OC)c3)nnc21
Reaction time: 0.5 h
Yield: 60.6 %

Procedure:
Under an argon atmosphere, ethyl 3-[3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine-8-carboxylate (200 mg) was added to a suspension of sodium hydride (60%, 23 mg) in DMF (2 mL) under ice-cooling. The reaction mixture was stirred for 30 min under ice-cooling, N-fluoro-N′-chloromethyltriethylenediamine bis(tetrafluoroborate) (371 mg) was added under ice-cooling, and the mixture was stirred for 30 min under ice-cooling. The reaction mixture was poured into saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (127 mg).
Reaction SMILES: C(Cl)(=O)C1C=CC(OC)=CC=1.C[O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[S:24][C:23]3[CH:25]=[C:26]([O:29]C)[CH:27]=[CH:28][C:22]=3[C:21]=2[C:31](=[O:40])[C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)=[CH:16][CH:15]=1.B(Cl)(Cl)Cl>ClCCCl>[OH:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[S:24][C:23]3[CH:25]=[C:26]([OH:29])[CH:27]=[CH:28][C:22]=3[C:21]=2[C:31](=[O:40])[C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)=[CH:18][CH:19]=1
Reactant: COc1ccc(C(=O)c2c(-c3ccc(OC)cc3)sc3cc(OC)ccc23)cc1
Agent: COc1ccc(C(=O)Cl)cc1
Agent: ClB(Cl)Cl
Solvent: ClCCCl
Product: COc1ccc(C(=O)c2c(-c3ccc(O)cc3)sc3cc(O)ccc23)cc1
Temperature: 2.5 °C
Reaction time: 7.5 h

Procedure:
A 100 mL, 3 neck, round bottom flask fitted with a mechanical agitator, glass stopper, and outlet to a caustic scrubber is charged with p-anisoyl chloride (3.47 g, 20.34 mmol), 2-(4-methoxyphenyl)-3-(4-methoxybenzoyl)-6-methoxybenzo[b]thiophene (5.0 g, 18.49 mmol) and 30 mL 1,2-dichloroethane. The mixture is cooled to 0-5° C. and previously condensed boron trichloride (4.7 mL, 55.0 mmol) is added in one portion. The mixture is stirred at 0-50° C. for 7.5 hours then more boron trichloride (4.7 mL, 55.0 mmol) is added. The cooling bath is removed and the reaction mixture is stirred at ambient temperature for 16 hours. After the overnight stir, the mixture is poured into 500 mL of agitated ice/water which caused precipitation of the monomethoxy product. The reaction vessel is rinsed in with 1,2-dichloroethane and the slurry is stirred for 1 hour. Then, 200 mL of methylene chloride is added and the mixture is vacuum filtered washing with methylene chloride. The solid is dried overnight in a vacuum oven at 40° C. to afford 6.3 g (82.4%) of monomethoxy product as a yellow solid. An analytical sample is obtained by chromatography on silica gel (20:1 methylene chloride/methanol). mp 127-128° C. (dec); 1H NMR (300.1 MHz, DMSO-d6) δ 3.76 (s, 3H), 6.66 (d, 2H), 6.85 (dd, 1H), 6.87 (d, 2H), 7.16 (d, 2H), 7.25 (d, 1H), 7.33 (s, 1H), 7.66 (d, 2H), 9.76 (br s, 2H); 13C NMR (75.5 MHz, DMSO-d6) d 55.5, 107.1, 114.0, 115.2, 115.7, 123.3, 123.8, 129.7, 131.8, 132.3, 139.2, 140.4, 155.4, 157.8, 163.5, 192.6; MS (FD+) m/e 376(100), 377(25), 378(7); Analysis calc'd for C22H16O4S: C, 70.20; H, 4.28; S, 8.52; found: C, 70.09; H, 4.27; S, 8.45.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)=O.[CH3:14][NH:15][C:16]([NH2:18])=[S:17]>C(O)C>[CH3:14][NH:15][C:16]1[S:17][CH:2]=[C:3]([C:5]2[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=2)[N:18]=1
Reactant: O=C(O)c1ccc(C(=O)CBr)cc1
Reactant: CNC(N)=S
Solvent: CCO
Product: CNc1nc(-c2ccc(C(=O)O)cc2)cs1
Temperature: 0 °C
Yield: 103.7 %

Procedure:
To 25 ml of ethanol were added 4-(2-bromoacetyl)benzoic acid (486 mg, 2 mmole) and N-methyl thiourea (180 mg, 2 mmole). The reaction mixture was refluxed for 3 hr and the TLC showed the disappearing of the starting materials and the formation of a fluorescent product. The reaction was cooled on ice. The product was collected on filtration and washed with ethanol pre-cooled to 0° C. twice (2×3 ml), followed by diethyl ether. After drying, 486 mg product was obtained. 1H NMR (DMSO-d6, 400 MHz) δ 7.97 (2H, d), 7.89 (2H, d), 7.32 (1H, s), 2.96 (3H, s).
Reaction SMILES: C(OC(=O)C)(=O)C.[CH2:8]([C:16]1[CH:31]=[CH:30][C:19]([O:20][CH2:21][CH:22]([OH:29])[CH2:23][N:24]2[CH:28]=[CH:27][CH:26]=[N:25]2)=[CH:18][CH:17]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C(=O)([O-])O.[Na+].[Na+].[Cl-]>CS(C)=O>[CH2:8]([C:16]1[CH:31]=[CH:30][C:19]([O:20][CH2:21][C:22](=[O:29])[CH2:23][N:24]2[CH:28]=[CH:27][CH:26]=[N:25]2)=[CH:18][CH:17]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCCc1ccc(OCC(O)Cn2cccn2)cc1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(=O)OC(C)=O
Product: CCCCCCCCc1ccc(OCC(=O)Cn2cccn2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
0.154 g (1.51 mmol) acetic anhydride is mixed with 5 ml absolute DMSO, stirred at room temperature for 10 min and added drop-wise to a solution of 0.050 g (0.152 mmol) 1-(4-octylphenoxy)-3-(pyrazol-1-yl)propan-2-ol in 10 ml absolute DMSO. Having stirred at room temperature for 18 hours, the solution is poured into a mixture of 5% sodium hydrogen carbonate solution and saturated NaCl solution (1:1, v/v) and hydrolyzed for 10 min. Four extractions using diethyl ether, combination of the organic phases, concentration to half the volume on the rotary evaporator, three wash steps with saturated NaCl solution, drying on sodium sulfate, filtration and reconcentration on the rotary evaporator leave as a crude product a yellowish solid which is purified on silica gel by means of column chromatography (flow agent: petroleum ether/ethyl acetate 90:10) and yields the product as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=1.[F:15][C:16]([F:41])([F:40])[CH2:17][NH:18][C:19]([C:21]1([CH2:35][CH2:36][CH2:37][CH2:38]Br)[C:34]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:28][C:27]2[C:22]1=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:20]>>[F:41][C:16]([F:15])([F:40])[CH2:17][NH:18][C:19]([C:21]1([CH2:35][CH2:36][CH2:37][CH2:38][N:12]2[CH2:13][CH2:14][N:9]([C:7]3[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[N:8]=3)[CH2:10][CH2:11]2)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=2[O:28][C:29]2[C:34]1=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:20]
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2Oc2ccccc21
Reactant: COc1cccc(N2CCNCC2)n1
Product: COc1cccc(N2CCN(CCCCC3(C(=O)NCC(F)(F)F)c4ccccc4Oc4ccccc43)CC2)n1

Procedure:
Prepared analogously to Example 2 b from 1-(6-methoxy-pyridin-2-yl)-piperazine and 9-(4-bromo-butyl)-9H-xanthene-9-carboxylic acid-(2,2,2-trifluoroethyl)-amide.
Reaction SMILES: Cl.C[O:3][C:4]1[CH:5]=[C:6]([S:10][C:11]2[CH:12]=[C:13]([O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:14]([NH:17][C:18]3[S:19][CH:20]=[C:21]([CH3:23])[N:22]=3)=[N:15][CH:16]=2)[CH:7]=[CH:8][CH:9]=1.BrB(Br)Br.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:23][C:21]1[N:22]=[C:18]([NH:17][C:14]2[N:15]=[CH:16][C:11]([S:10][C:6]3[CH:5]=[C:4]([OH:3])[CH:9]=[CH:8][CH:7]=3)=[CH:12][C:13]=2[O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[S:19][CH:20]=1
Reactant: COc1cccc(Sc2cnc(Nc3nc(C)cs3)c(Oc3ccccc3)c2)c1
Agent: BrB(Br)Br
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Product: Cc1csc(Nc2ncc(Sc3cccc(O)c3)cc2Oc2ccccc2)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 65.3 %

Procedure:
A mixture of N-(5-(3-methoxyphenylthio)-3-phenoxypyridin-2-yl)-4-methylthiazol-2-amine (prepared according to Example 56; 1.1 g, 2.6 mmol) and CH2Cl2 (20 mL) was cooled to 0° C. and tribromoborane (1M in CH2Cl2, 7.83 mL, 7.83 mmol) was added and stirred at 0° C. for 1 hour. The reaction was slowly poured into saturated aqueous sodium bicarbonate and extracted with 10% methanol in CH2Cl2. The organic layer was dried with sodium sulfate, filtered and concentrated. The residue was purified on silica gel (50 to 80% EtOAc in hexanes) to afford 3-(6-(4-methylthiazol-2-ylamino)-5-phenoxypyridin-3-ylthio)phenol (692 mg, 65.1% yield) as a white solid. 1H NMR (d6-DMSO) δ 8.18 (dd, 1H), 7.37 (m, 2H), 7.31 (d, 1H), 7.19 (m, 1H), 7.16 (dd, 1H), 7.11-7.02 (m, 3H), 6.69-6.61 (m, 3H), 6.45 (m, 1H), 2.33 (s, 3H); Mass spectrum (esi) m/z=408.2 (M+H).
Reaction SMILES: O.O.O.[N+]([O-])([O-])=O.[Tl+3].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[CH:17]([O:22][CH3:23])([O:20]C)OC.Cl.[C:25]([C:28]1[CH:37]=[C:36]2[C:31]([CH2:32][CH2:33][N:34]([CH2:38][CH2:39][CH2:40][CH2:41][NH:42][C:43](=[O:56])[C:44]3[CH:49]=[CH:48][C:47]([C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)=[CH:46][CH:45]=3)[CH2:35]2)=[CH:30][CH:29]=1)(=O)C>CO.ClCCl>[CH3:23][O:22][C:17]([CH2:25][C:28]1[CH:37]=[C:36]2[C:31]([CH2:32][CH2:33][N:34]([CH2:38][CH2:39][CH2:40][CH2:41][NH:42][C:43](=[O:56])[C:44]3[CH:45]=[CH:46][C:47]([C:50]4[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=4)=[CH:48][CH:49]=3)[CH2:35]2)=[CH:30][CH:29]=1)=[O:20]
Reactant: CC(=O)c1ccc2c(c1)CN(CCCCNC(=O)c1ccc(-c3ccccc3)cc1)CC2
Reactant: COC(OC)OC
Agent: Cl
Agent: O=[N+]([O-])[O-]
Agent: [Tl+3]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: COC(=O)Cc1ccc2c(c1)CN(CCCCNC(=O)c1ccc(-c3ccccc3)cc1)CC2
Reaction time: 4 h
Yield: 29.9 %

Procedure:
A mixture of thallium (III) nitrate trihydrate (0.73 g, 1.6 mmol), K10 clay (1.65 g) and trimethyl orthoformate (1.8 ml, 1.6 mmol) in methanol (3 ml) was stirred at room temperature for 15 min. The solvent was evaporated in vacuo and dichloromethane (5 ml) was added to the residue. To this mixture was added a solution of 7-acetyl-2-(4-(4-phenylbenzoylamino)butyl)-1,2,3,4-tetrahydroisoquinoline, hydrochloride (0.50 g, 1.1 mmol) in dichloromethane (15 ml) and the reaction mixture was stirred for 4 h. The suspended solid was removed by filtration and the filtrate was washed with saturated aqueous potassium carbonate (2×30 ml), then brine (30 ml). Drying (Na2SO4) and evaporation in vacuo afforded a yellow gum which was chromatographed on silica using 20-100% ethyl acetate--pentane gradient elution to afford the title compound as an off-white solid (0.15 g, 30%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5](OCCCCCCC)=[C:6]([CH:38]=1)[C:7]([NH:9][C@@H:10]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2OC2C=CC(C(F)(F)F)=CC=2)=[CH:17][CH:16]=1)[C:11]([OH:13])=[O:12])=[O:8].[Cl:47][C:48]1[CH:49]=[C:50](B(O)O)[CH:51]=[CH:52][C:53]=1[F:54]>>[C:18]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:17]=[CH:16][C:15]([CH2:14][C@H:10]([NH:9][C:7]([C:6]2[CH:38]=[CH:2][C:3]([C:50]3[CH:51]=[CH:52][C:53]([F:54])=[C:48]([Cl:47])[CH:49]=3)=[CH:4][CH:5]=2)=[O:8])[C:11]([OH:13])=[O:12])=[CH:20][CH:19]=1
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: CCCCCCCOc1ccc(Br)cc1C(=O)N[C@@H](Cc1ccc(-c2ccccc2Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)O
Product: O=C(N[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)O)c1ccc(-c2ccc(F)c(Cl)c2)cc1
Yield: 81.6 %

Procedure:
3-Biphenyl-4-yl-(2S)-[(5-bromo-benzoyl-amino)-propionic acid (100 mg, 0.23 mmol) was reacted with 3-chloro-4-fluoro-phenyl boronic acid (0.123 mg, 0.69 mmol) by following general procedure D to afford title compound (89 mg, 80%) as a white solid. 1H NMR (400 MHz, CD3COCD3): 4.05 (dd, 2H), 5.00 (m, 1H), 7.32 (m, 1H), 7.44 (m, 4H), 7.62 (m, 4H), 7.71 (m, 1H), 7.74 (m, 2H), 7.84 (m, 1H), 7.96 (m, 3H). LC/MS (m/z): 474 (M+1)+.
Reaction SMILES: [Br-].[O:2]1[CH2:7][CH2:6][CH2:5][O:4][CH:3]1[CH2:8][CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1.CC(C)([O-])C.[K+].[F:40][C:41]1[CH:42]=[C:43]([CH:48]2[CH2:53][CH2:52][CH:51]([CH:54]3[CH2:59][CH2:58][CH2:57][CH2:56][C:55]3=O)[CH2:50][CH2:49]2)[CH:44]=[CH:45][C:46]=1[F:47]>CCOCC>[O:4]1[CH2:5][CH2:6][CH2:7][O:2][CH:3]1[CH2:8][CH:9]=[C:57]1[CH2:56][CH2:55][CH:54]([CH:51]2[CH2:50][CH2:49][CH:48]([C:43]3[CH:44]=[CH:45][C:46]([F:47])=[C:41]([F:40])[CH:42]=3)[CH2:53][CH2:52]2)[CH2:59][CH2:58]1
Reactant: O=C1CCCCC1C1CCC(c2ccc(F)c(F)c2)CC1
Reactant: c1ccc([P+](CCC2OCCCO2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Fc1ccc(C2CCC(C3CCC(=CCC4OCCCO4)CC3)CC2)cc1F
Reaction time: 1 h

Procedure:
Into a three-necked flask equipped with a dropping funnel, a three-way cock and a thermometer was placed 2-(1,3-dioxan-2-yl)ethyltriphenylphosphonium bromide (12.3 g, 27 mmols), followed by adding tetrahydrofuran (100 ml), suspending, and stirring under ice cooling till the liquid temperature reached 10° C. The reaction mixture was added potassium t-butoxide (3.0 g, 27 mmols), followed by elevating the temperature up to room temperature under ice cooling for one hour, stirring for one hour, and dropwise adding a tetrahydrofuran (50 ml) solution of (4-(3,4-difluorophenyl)cyclohexylcyclohexanone (7.3 g, 25 mmols) over 30 minutes from the dropping funnel. Further, the resulting reaction mixture was stirred for 5 hours after completion of the dropwise addition, followed by adding ether (100 ml), allowing to stand for one hour, filtering off deposited insoluble substance, concentrating the filtrate under reduced pressure and isolating and purifying the resulting pale brown oil by means of silica gel column chromatography, to obtain 1-(2-(1,3-dioxan-2-yl)ethylidene)-4-(4-(3,4-difluorophenyl)cyclohexyl)cyclohexane.
Reaction SMILES: [OH:1][C:2]([CH3:21])([CH3:20])[C:3]#[C:4][CH2:5][C@H:6]([C:8]1[C@:9]2([CH3:19])[C@@H:14]([CH2:15][CH2:16][CH:17]=1)[C:13](=[O:18])[CH2:12][CH2:11][CH2:10]2)[CH3:7].[Si:22](C1NC=CN=1)([CH3:25])([CH3:24])[CH3:23]>C(Cl)Cl>[CH3:23][Si:22]([CH3:25])([CH3:24])[O:1][C:2]([CH3:20])([CH3:21])[C:3]#[C:4][CH2:5][C@H:6]([C:8]1[C@:9]2([CH3:19])[C@@H:14]([CH2:15][CH2:16][CH:17]=1)[C:13](=[O:18])[CH2:12][CH2:11][CH2:10]2)[CH3:7]
Reactant: C[Si](C)(C)c1ncc[nH]1
Reactant: C[C@H](CC#CC(C)(C)O)C1=CCC[C@H]2C(=O)CCC[C@]12C
Solvent: ClCCl
Product: C[C@H](CC#CC(C)(C)O[Si](C)(C)C)C1=CCC[C@H]2C(=O)CCC[C@]12C
Reaction time: 24 h

Procedure:
446 mg (1.55 mmol) of (4aS,8aR)-5-((R)-5-hydroxy-1,5-dimethyl-hex-3-ynyl)-4a-methyl-3,4,4a,7,8,8a-hexahydro-2H-naphthalen-1-one in 12 ml of abs. CH2Cl2 was treated with 2.03 ml (9 eq.) of TMS-imidazole and kept at RT for 24 h. Pouring onto crushed ice, twofold extraction with ether, washing with water and brine, and drying over sodium sulfate left a crude product, which was purified by flash chromatography (SiO2, hexane/AcOEt=9/1). Thereby, 561 mg of the title compound was obtained as colorless oil.
Reaction SMILES: Br[C:2]1[N:9]2[C:5](=[N:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=32)[S:4][N:3]=1.[CH3:14][O-:15].[Na+]>CO>[CH3:14][O:15][C:2]1[N:9]2[C:5](=[N:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=32)[S:4][N:3]=1
Reactant: C[O-]
Reactant: Brc1nsc2nc3ccccc3n12
Agent: [Na+]
Solvent: CO
Product: COc1nsc2nc3ccccc3n12
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.1 %

Procedure:
To a cooled mixture of 3-bromo-1,2,4-thiadiazolo[4,5-a]benzimidazole (4.55 g, 17.9 mmole) in 50 mL of methanol, sodium methoxide (0.967 g, 17.9 mmole) was added in one portion and stirred for 4 h at room temperature. The reaction mixture was evaporated to dryness under vacuum and the residue was taken-up in ethyl acetate and washed with water. The organic layer was dried with sodium sulfate, filtered and evaporated to yield 3.64 g (94%) of 3-methoxy-1,2,4-thiadiazolo[4,5-a]benzimidazole as colourless crystals: mp 172-175° C.; 1H NMR (CDCl3) δ 7.83 (d, 1H), 7.75 (d, 1H), 7.42 (t, 1H), 7.27 (t, 1H), 4.32 (s, 3H) ppm; 13C NMR (CDCl3) δ 163.2, 150.3, 148.1, 128.119.2, 111.7, 57.5119.2, 111.7, 57.5 ppm; IR (KBr) ν 3418, 2942, 1595, 1492, 1404, 1275, 1255, 1206, 1083, 755 cm-1. Anal. Calcd for C9H7N3OS: C, 52.67; H, 3.44; N, 20.49. Found: C, 52.28; H, 3.36; N, 20.45.
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[CH2:7][N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH2:12][CH2:11][C@H:10]([NH:19][C:20]([C:22]2([CH2:27][CH:28]([CH2:32][C:33]([NH:35][CH:36]([CH3:38])[CH3:37])=[O:34])[C:29]([OH:31])=[O:30])[CH2:26][CH2:25][CH2:24][CH2:23]2)=[O:21])[C:9]1=[O:39])([CH3:4])([CH3:3])[CH3:2].[CH3:41][O:42][CH2:43][CH2:44][O:45][CH2:46]Cl.C(N(CC)CC)C>ClCCl.CN(C1C=CN=CC=1)C>[CH3:41][O:42][CH2:43][CH2:44][O:45][CH2:46][C:28]([CH2:27][C:22]1([C:20]([NH:19][C@H:10]2[CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:8]([CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:40])[C:9]2=[O:39])=[O:21])[CH2:26][CH2:25][CH2:24][CH2:23]1)([CH2:32][C:33]([NH:35][CH:36]([CH3:37])[CH3:38])=[O:34])[C:29]([OH:31])=[O:30]
Reactant: COCCOCCl
Reactant: CC(C)NC(=O)CC(CC1(C(=O)N[C@H]2CCc3ccccc3N(CC(=O)OC(C)(C)C)C2=O)CCCC1)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCOCC(CC(=O)NC(C)C)(CC1(C(=O)N[C@H]2CCc3ccccc3N(CC(=O)OC(C)(C)C)C2=O)CCCC1)C(=O)O
Reaction time: 8 h

Procedure:
300 mg 2-{[1-({[(3S)-1-(2-tert. butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}-carbonyl)cyclopentyl]methyl}-4-(isopropylamino)-4-oxobutyric acid (for preparation see Example 12) was dissolved in 5 ml dichloromethane. 33 mg DMAP, 74 μl methoxyethoxymethyl chloride and 90 μl triethylamine were added to this receiving solution. The reaction mixture was stirred overnight, then diluted with 5 ml dichloromethane and the organic phase was washed in succession once each with 3 ml dilute aqueous KHSO4 solution and saturated aqueous common salt solution. The organic phase was dried over magnesium sulfate, the solvent was largely evaporated at reduced pressure and the remaining residue was chromatographed on silica gel (mobile phase: EA/cyclohexane 2:1 v/v). Drying the product fractions in an oil pump vacuum yielded 191 g of the title compound, MS: [M+H]+: 646; m/z: 590, 540, 484, 425.