Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([OH:8])[CH2:4][CH2:3]1.[H-].[Na+].F[C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1>CN(C=O)C.CCOC(C)=O>[NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([O:8][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)[CH2:4][CH2:3]1
Reactant: N#Cc1ccc(F)cc1
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(O[C@H]2CC[C@H](N)CC2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of trans-4-aminocyclohexanol (3 g, 26 mmol) in DMF (130 mL) at 0° C. was added 60% sodium hydride in oil. The reaction mixture was stirred at 0° C. for 1 h and then 4-fluorobenzonitrile (3.9 g, 32.6 mmol) was added. It was heated to 60° C. for 2 h and stirred for 12 h at room temperature. The reaction mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried, filtered, and concentrated under reduced pressure to provide the titled compound (2.5 g, 44% yield). 1H NMR (300 MHz, DMSO-d6): δ7.72 (d, J=9 Hz, 2H), 7.09 (d, J=9 Hz, 2H), 4.48-4.34 (m, 1H), 2.68-2.55 (m, 1H), 2.07-1.94 (m, 2H), 1.85-1.71 (m, 2H), 1.46-1.11 (m, 4H).
Reaction SMILES: [NH2:1][C@H:2]([C:8]([NH:10][C@H:11]([C:24]([NH:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[O:25])[CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[OH:6].C(N1C=CN=C1)(N1C=CN=C1)=O.SCC(CC(OC)=O)C([N:49]1[CH2:56][CH2:55][CH2:54][C@H:50]1[C:51]([OH:53])=[O:52])=O.C(N1CCOCC1)C>CN(C)C=O>[NH2:1][C@H:2]([C:8]([NH:10][C@H:11]([C:24]([NH:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[O:25])[CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:9])[CH2:3][CH2:4][C:5](=[O:6])[OH:7].[NH:49]1[CH2:56][CH2:55][CH2:54][C@H:50]1[C:51]([OH:53])=[O:52]
Reactant: COC(=O)CC(CS)C(=O)N1CCC[C@H]1C(=O)O
Agent: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)[C@@H](N)CCC(=O)O)C(=O)NCCC(=O)O
Agent: CCN1CCOCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: O=C(O)[C@@H]1CCCN1
Temperature: -10 °C
Reaction time: 2 h

Procedure:
A solution of 10 mmoles of Nα -pyro-L-glutamyl-Nε -tert-butyloxycarbonyl-L-lysyl-β-alanine in redistilled dimethylformamide (DMF) is cooled in an ice-dry ice-acetone bath at -20° C. To this solution is added a cold solution of 10 mmoles of 1,1'-carbonyldiimidazole in DMF. The solution is stirred at -10° C. for two hours and then mixed with a cold solution of 10 mmoles of N-[3-mercapto-2-(methoxycarbonylmethyl)propanoyl]-L-proline (from Example 82) in DMF which is neutralized with N-ethyl morpholine. The reaction mixture is stirred at -10° C. for an additional hour and then slowly warmed to room temperature. The solvent is removed under reduced pressure to 40° C. and ethyl acetate is added to the residue. The mixture is cooled in an ice water bath and washed with 1N citric acid and then three times with saturated NaCl solution. The solvent is removed with a rotary evaporator after drying over anhydrous MgSO4. The product is purified by LH-20 column chromatography using a 1.2 cm by 95 cm column and eluted with THF:isopropanol, 3:7 (parts by volume). The peak fractions are pooled and the solvent is removed under reduced pressure yielding the product Nα -[(3-[Nα -pyro-L-glutamyl-Nε -tertbutyloxycarbonyl-L-lysyl-β-alanine]-thio-2-(methoxycarbonylmethyl)propanoyl]-L-proline. The tert-butyloxycarbonyl protecting group is removed as described in Example 94 to yield the named product.
Reaction SMILES: ClC[C:3]([C:5]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([OH:9])C(Cl)=O)=[O:4].[CH3:16][CH:17]([CH2:19][CH2:20][CH2:21][C@H:22]([CH2:24][CH2:25][CH2:26][C@H:27]([CH2:29][CH2:30][CH2:31]/[C:32](=[CH:34]/[CH2:35][OH:36])/[CH3:33])[CH3:28])[CH3:23])[CH3:18].C(N(CC)CC)C.NC(N)=S>C(Cl)Cl.CO.C(OCC)(=O)C>[C:3]([O:36][CH2:35]/[CH:34]=[C:32](/[CH2:31][CH2:30][CH2:29][C@@H:27]([CH2:26][CH2:25][CH2:24][C@@H:22]([CH2:21][CH2:20][CH2:19][CH:17]([CH3:16])[CH3:18])[CH3:23])[CH3:28])\[CH3:33])(=[O:4])[CH:5]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[OH:9]
Reactant: C/C(=C\CO)CCC[C@H](C)CCC[C@H](C)CCCC(C)C
Reactant: O=C(Cl)C(O)(C(=O)CCl)c1ccccc1
Agent: NC(N)=S
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCN(CC)CC
Product: C/C(=C\COC(=O)C(O)c1ccccc1)CCC[C@H](C)CCC[C@H](C)CCCC(C)C
Reaction time: 2 h
Yield: 89.5 %

Procedure:
10 ml of a methylene chloride solution containing 10.0 g of chloroacetylmandelic acid chloride was dropped into a solution of 10.0 g of phytol and 4.5 g of triethylamine dissolved in 30 ml of methylene chloride at 30°-40° C. The resulting mixture was stirred for 2 hours at the same temperature. After the completion of the reaction, the reaction mixture was washed with dilute hydrochloric acid, 3% aqueous sodium hydrogencarbonate solution and water in this order. The solvent was removed by distillation under reduced pressure. The residue obtained was dissolved in 50 ml of methanol. Thereto were added 3.8 g of triethylamine and 2.9 g of thiourea at room temperature. The resulting mixture was stirred for 3 hours at the same temperature. After the completion of the reaction, the solvent was removed by distillation under reduced pressure. The residue obtained was dissolved in ethyl acetate and the resulting solution was washed with dilute hydrochloric acid, 3% aqueous sodium hydrogencarbonate solution and water in this order and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue obtained was purified by a column chromatography (eluant; n-hexane:ethyl acetate=9:1) to obtain 13.0 g (yield: 90%) of oily phytyl mandelate.
Reaction SMILES: [NH2:1][C@H:2]([C:8]([NH:10][C@H:11]([C:20]([NH:22][C@H:23]([C:30]([NH:32][C@H:33]([C:40]([NH:42][C@H:43]([C:50]([NH:52][C@H:53]([C:61]([NH:63][CH2:64][C:65]([NH:67][C@H:68]([C:79]([NH:81][C@H:82]([C:87]([O:89]C(C)(C)C)=[O:88])[CH2:83][C:84](=[O:86])[NH2:85])=[O:80])[CH2:69][C:70]1[C:78]2[C:73](=[CH:74][CH:75]=[CH:76][CH:77]=2)[NH:72][CH:71]=1)=[O:66])=[O:62])[C@@H:54]([CH3:60])[O:55]C(C)(C)C)=[O:51])[CH2:44][O:45]C(C)(C)C)=[O:41])[CH2:34][O:35]C(C)(C)C)=[O:31])[CH2:24][O:25]C(C)(C)C)=[O:21])[CH2:12][C:13](=[O:19])[O:14]C(C)(C)C)=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[OH:6]>FC(F)(F)C(O)=O.O.SCCS>[NH2:1][C@H:2]([C:8]([NH:10][C@H:11]([C:20]([NH:22][C@H:23]([C:30]([NH:32][C@H:33]([C:40]([NH:42][C@H:43]([C:50]([NH:52][C@H:53]([C:61]([NH:63][CH2:64][C:65]([NH:67][C@H:68]([C:79]([NH:81][C@H:82]([C:87]([OH:89])=[O:88])[CH2:83][C:84](=[O:86])[NH2:85])=[O:80])[CH2:69][C:70]1[C:78]2[C:73](=[CH:74][CH:75]=[CH:76][CH:77]=2)[NH:72][CH:71]=1)=[O:66])=[O:62])[C@@H:54]([CH3:60])[OH:55])=[O:51])[CH2:44][OH:45])=[O:41])[CH2:34][OH:35])=[O:31])[CH2:24][OH:25])=[O:21])[CH2:12][C:13](=[O:14])[OH:19])=[O:9])[CH2:3][CH2:4][C:5](=[O:6])[OH:7]
Reactant: C[C@@H](OC(C)(C)C)[C@H](NC(=O)[C@H](COC(C)(C)C)NC(=O)[C@H](COC(C)(C)C)NC(=O)[C@H](COC(C)(C)C)NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)[C@@H](N)CCC(=O)O)C(=O)NCC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CC(N)=O)C(=O)OC(C)(C)C
Agent: SCCS
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: C[C@@H](O)[C@H](NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H](CC(=O)O)NC(=O)[C@@H](N)CCC(=O)O)C(=O)NCC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CC(N)=O)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
850 mg (6.9 mmols) Glu-Asp(OBut)-Ser(But)-Ser(But)-Ser(But)-Thr(But)-Gly-Trp-Asn-OBut are dissolved in a mixture of trifluoroacetic acid, water and 1,2-dimercaptoethane (9:1:1). The batch is abandoned for 1 hour at room temperature, concentrated, and the residue is triturated with ether. Yield 650 mg. For purification, the substance is boiled in 30 ml of methanol, and after cooling to room temperature it is suction-filtered. Yield 430 mg (65%). Amino acid analysis (hydrolysis: 24 hours at 120° C. in 6N HCl):
Reaction SMILES: N#N.CCN=C=NCCCN(C)C.Cl.CCN(CC)CC.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH2:34][CH2:35][C:36]([OH:38])=O)[CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31].[CH2:39]([O:41][C:42]([CH2:44][N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)=[O:43])[CH3:40]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:39]([O:41][C:42](=[O:43])[CH2:44][N:45]1[CH2:50][CH2:49][N:48]([C:36](=[O:38])[CH2:35][CH2:34][C:26]2[CH:27]=[C:28]([O:32][CH3:33])[C:29]([O:30][CH3:31])=[C:24]([O:23][CH3:22])[CH:25]=2)[CH2:47][CH2:46]1)[CH3:40]
Reactant: CCOC(=O)CN1CCNCC1
Reactant: COc1cc(CCC(=O)O)cc(OC)c1OC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CN1CCN(C(=O)CCc2cc(OC)c(OC)c(OC)c2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 83.1 %

Procedure:
(The following reaction is done in an anhydrous N2 atmosphere.) Suspend EDC.HCl (376 mg, 1.96 mmol) and Et3N (275 μL, 1.96 mmol) in anhydrous DCM (2.0 mL) and stir the resulting solution for 5 min at rt. Add 3-(3,4,5-Trimethoxy-phenyl)-propionic acid (346 mg, 1.44 mmol) and DMAP (17 mg, 0.14 mmol) and stir the resulting solution for 15 min. Add 1-(Ethoxycarbonylmethyl)piperazine (43) (224 mg, 1.30 mmol) and stir the reaction solution overnight at rt. Quench reaction solution with water, separate layers and extract aqu. layer with EtOAc (3 times). Filtrate the combined organic layer through a short pad of silica gel and remove solvent. Purify the crude product by preparative radial chromatography (silica gel, EtOAc/MeOH 9+1) to obtain {4-[3-(3,4,5-Trimethoxy-phenyl)-propionyl]-piperazin-1-yl}-acetic acid ethyl ester (45) (426 mg, 83%) as a colorless oil. 1H NMR (400 MHz, CDCl3): 1.26 (t, 3H, J=7.1 Hz); 2.45-2.70 (br.m, 6H); 2.89 (t, 2H, J=7.7 Hz); 3.26 (br.s, 2H); 3.43-3.56 (br.m, 2H); 3.61-3.76 (br.m, 2H); 3.80 (s, 3H); 3.83 (s, 6H); 4.18 (q, 2H, J=7.1 Hz); 6.41 (s, 2H).
Reaction SMILES: C([NH:9][C:10]([NH:12][C:13]1[C:18]([O:19][CH3:20])=[CH:17][N:16]=[C:15]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH:14]=1)=[S:11])(=O)C1C=CC=CC=1.C[O-].[Na+].Cl>O1CCCC1.CO>[CH3:20][O:19][C:18]1[C:13]([NH:12][C:10]([NH2:9])=[S:11])=[CH:14][C:15]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[N:16][CH:17]=1
Reactant: COc1cnc(N2CCOCC2)cc1NC(=S)NC(=O)c1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cnc(N2CCOCC2)cc1NC(N)=S
Reaction time: 2 h
Yield: 83.9 %

Procedure:
To a stirred solution of 5.80 g (15.6 mmol) 1-benzoyl-3-(5-methoxy-2-morpholin-4-yl-pyridin-4-yl)-thiourea in 100 ml tetrahydrofuran and 25 ml methanol heated at 60° C. was added dropwise 1.15 ml (6.23 mmol) 5.4 M sodium methylate solution and stirring continued for 2 h at 60° C. 1.2 ml concentrated hydrochloric acid was then added and the reaction mixture concentrated in vacuo. The residue was triturated in 25 ml ether to afford 3.51 g (84%) (5-methoxy-2-morpholin-4-yl-pyridin-4-yl)-thiourea as alight brown crystalline solid. ES-MS m/e (%): 269 (M+H+, 100).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:11]=[N:10][NH:9][C:8]=2[C:12]2[CH:29]=[CH:28][C:15]([O:16][CH2:17][C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)=[CH:14][CH:13]=2)=[CH:3][CH:2]=1.[F:30]C1C=C(OCC2C=CC3C(=CC=CC=3)N=2)C=CC=1C(=O)CC1C=CN=CC=1>>[F:30][C:29]1[CH:28]=[C:15]([CH:14]=[CH:13][C:12]=1[C:8]1[C:7]([C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)=[CH:11][NH:10][N:9]=1)[O:16][CH2:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=1
Reactant: O=C(Cc1ccncc1)c1ccc(OCc2ccc3ccccc3n2)cc1F
Reactant: c1ccc2nc(COc3ccc(-c4[nH]ncc4-c4ccncc4)cc3)ccc2c1
Product: Fc1cc(OCc2ccc3ccccc3n2)ccc1-c1n[nH]cc1-c1ccncc1

Procedure:
Following the procedure for the preparation of 2-[-4-(4-Pyridin-4-yl-2H-pyrazol-3-yl)-phenoxymethyl}-quinoline but substituting 1-{2-Fluoro-4-(quinolin-2-ylmethoxy)-phenyl}-2-pyridin-4-yl-ethanone provided the title compound. 1H NMR (400 MHz, CDCl3) δ 8.47 (d, J=6.5 Hz, 2H), 8.22 (d, J=8.3 Hz, 1H), 8.08 (d, J=8.7 Hz, 1H), 7.84 (s, 1H), 7.82 (m, 1H), 7.74 (m, 1H), 7.65 (d, J=8.7 Hz, 1H), 7.55 (m, 1H), 7.25 (m, 1H), 7.18 (d, J=6.2 Hz, 2H), 6.85 (d, J=10.9, 2H), 5.38 (s, 2H): MS: (M+H m/z=397.2).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:18])[C:4]1[C:12]([I:13])=[C:11]([C:14]#[N:15])[C:10]([I:16])=[C:6]([C:7]([OH:9])=[O:8])[C:5]=1[I:17].C(=O)([O-])[O-].[Na+].[Na+].Cl[CH2:26][CH:27]([OH:30])[CH2:28][OH:29]>CN(C)C=O>[OH:30][CH:27]([CH2:28][OH:29])[CH2:26][O:8][C:7](=[O:9])[C:6]1[C:10]([I:16])=[C:11]([C:14]#[N:15])[C:12]([I:13])=[C:4]([C:3](=[O:18])[NH:2][CH3:1])[C:5]=1[I:17]
Reactant: CNC(=O)c1c(I)c(C#N)c(I)c(C(=O)O)c1I
Reactant: OCC(O)CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNC(=O)c1c(I)c(C#N)c(I)c(C(=O)OCC(O)CO)c1I
Yield: 71.7 %

Procedure:
60 g 5-cyano-2,4,6-triiodoisophthalic acid monomethylamide is heated in 150 ml of dimethylformamide with 22 g of sodium carbonate (anhydrous) and 28 g of 1-chloro-2,3-propanediol for 4 hours to 90° C. The mixture is then cooled, vacuum-filtered from the precipitated sodium chloride, and concentrated to dryness under vacuum. The residue is dissolved in 250 ml of ethyl acetate, the solution is filtered over active carbon, and the filtrate is concentrated to half its volume. The product is cooled in an ice bath and gently combined with such an amount of diisopropyl ether that crystallization sets in. After stirring for several, hours in an ice bath, the crystallized product is vacuum-filtered, washed with diisopropyl ether, and dried at 50° C., thus obtaining 48.5 g (=74% of theory) of 5-cyano-3-methylcarbamoyl-2,4,6-triiodobenzoic acid (2,3-dihydroxypropyl)ester as a white powder, mp 117-120° C.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[F:9].[C:10](=O)(O)[O-:11].[Na+].ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]=[C:10]=[O:11])=[CH:4][C:3]=1[F:9]
Reactant: O=C([O-])O
Reactant: Nc1ccc(Cl)c(F)c1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [Na+]
Solvent: ClCCl
Product: O=C=Nc1ccc(Cl)c(F)c1
Temperature: 0 °C

Procedure:
4-Chloro-3-fluoroaniline (2 g, 13.7 mmol) was dissolved in 60 mL of dichloromethane. Under ice bath, saturated sodium bicarbonate solution (60 mL) was added. The mixture was stirred at 0° C. and triphosgene (1.36 g, 4.58 mmol) was added. The mixture was stirred at 0° C. for 1 h and then extracted with dichloromethane and water. The organic layer was dried with sodium sulfate and filtered. The filtrate solution was concentrated and the residue was treated with 50 mL of hexanes. The hexane solution was concentrated to remove all solvents. The residue was taken up in 12 mL of hexanes and filtered. The solution was concentrated and dried to give 1-chloro-2-fluoro-4-isocyanatobenzene as an off white solid (1.69 g). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 6.82-6.90 (m, 1H) 6.93 (dd, J=9.22, 2.65 Hz, 1H) 7.31-7.41 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[NH:11][C:12](=[O:24])[C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=1.[Br:26][CH2:27][CH2:28][CH2:29]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:29][CH2:28][CH2:27][Br:26])=[CH:6][C:5]=1[NH:11][C:12](=[O:24])[C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:22])([F:21])[F:23])=[CH:15][CH:14]=1
Reactant: COC(=O)c1ccc(O)cc1NC(=O)c1ccc(OC(F)(F)F)cc1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OCCCBr)cc1NC(=O)c1ccc(OC(F)(F)F)cc1
Yield: 74.7 %

Procedure:
This compound was produced using similar methods as those used in Step 4, example 27, starting with 4-hydroxy-2-(4-trifluoromethoxy-benzoylamino)-benzoic acid methyl ester (1.49 g, 4.19 mmol), 1,3-dibromopropane (3.39 g, 16.8 mmol) and potassium carbonate (2.90 g, 21.0 mmol) in acetone (85 mL). The crude oil was purified by flash chromatography through silica gel using ethyl acetate/hexanes (0/100 gradient to 12/88) to give 4-(3-bromo-propoxy)-2-(4-trifluoromethoxy-benzoylamino)-benzoic acid methyl ester (1.49 g, 75%) as a white powder. 1H NMR (400 MHz, CDCl3); δ 12.30 (s, 1H), 8.57 (d, 1H), 8.10 (d, 2H), 8.02 (d, 1H), 7.36 (d, 2H), 6.65 (dd, 1H), 4.24 (t, 2H), 3.93 (s, 3H), 3.61 (t, 2H), 2.35 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:24])=[CH:4][C:5]([O:22]C)=[C:6]([S:8]([N:11]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]3[CH:18]=[CH:19][CH:20]=[CH:21][C:12]2=3)(=[O:10])=[O:9])[CH:7]=1.B(Br)(Br)Br>C(Cl)Cl>[Br:1][C:2]1[C:3]([Cl:24])=[CH:4][C:5]([OH:22])=[C:6]([S:8]([N:11]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]3[CH:18]=[CH:19][CH:20]=[CH:21][C:12]2=3)(=[O:10])=[O:9])[CH:7]=1
Reactant: COc1cc(Cl)c(Br)cc1S(=O)(=O)N1CCCCc2ccccc21
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=S(=O)(c1cc(Br)c(Cl)cc1O)N1CCCCc2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.2 %

Procedure:
To a solution of DCM (25.0 mL) containing 1-(5-bromo-4-chloro-2-methoxy-benzenesulfonyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine (2.15 g, 5 mmol) at −78° C. was added BBr3 (12.5 mL, 1M in DCM, 12.5 mmol) dropwise. The mixture was gradually warmed to rt while it was stirred for 4 hrs. The mixture was concentrated and partitioned between ethyl acetate (100 mL) and sat. NaHCO3 solution (100 mL). The organic layer was further washed with brine (2×50 mL), dried over MgSO4, and evaporated. The purification of the crude material by silica gel column chromatography eluting with hexane/ethyl acetate (6/1) yielded 4-bromo-5-chloro-2-(2,3,4,5-tetrahydro-benzo[b]azepine-1-sulfonyl)-phenol as a white solid (1.9 g). NMR (CDCl3), δ, 7.739 (1H, s), 7.186-7.259 (4H, m), 7.127 (1H, s), 3.692 (2H, m), 2.502-2.539 (2H, m), 1.802-1.868 (2H, m), 1.601-1.676 (2H, m).
Reaction SMILES: CN(C)C1CCCCC1.[Cl:10][C:11]1[CH:17]=[C:16]([SH:18])[CH:15]=[CH:14][C:12]=1[NH2:13].[C:19](Br)([CH3:22])([CH3:21])[CH3:20].O>C(Cl)Cl>[Cl:10][C:11]1[CH:17]=[C:16]([S:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:15]=[CH:14][C:12]=1[NH2:13]
Reactant: Nc1ccc(S)cc1Cl
Reactant: CC(C)(C)Br
Solvent: CN(C)C1CCCCC1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)Sc1ccc(N)c(Cl)c1
Temperature: 25 °C
Reaction time: 68 h

Procedure:
Dimethylcyclohexylamine (22.86 g., 0.18 mole) in methylene chloride (125 ml.) is added dropwise to a stirred solution of 2-chloro-4-mercaptoaniline (27.0 g., 0.17 mole) and tert-butyl bromide (22.86 g., 0.18 mole) in methylene chloride (125 ml.) and the mixture is allowed to stir at room temperature for about 68 hours. An additional quantity of dimethylcyclohexylamine (2.3 g.) and tert-butyl bromide (2.5 g., 0.018 mole) is added and stirring is continued overnight. The reaction is poured into water, and the product is extracted with methylene chloride. The combined extracts are washed with dilute hydrochloric acid, water and dried. Removal of the drying agent and methylene chloride gives impure 2-chloro-4-tert-butylthioaniline as a beige solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([O:20][CH2:21][CH3:22])C>>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14]([OH:17])([C:2]2[CH:1]=[CH:22][C:21]([O:20][CH3:18])=[CH:4][CH:3]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CCOCC
Product: COc1ccc(C2(O)CCN(C(=O)OCc3ccccc3)CC2)cc1
Reaction time: 15 h

Procedure:
mixture to a temperature of about 20° C., a solution of N-benzyloxycarbonyl-4-piperidone (48.2 g) in ethyl ether (450 cc) is poured in. Stirring is continued for 15 hours at this temperature. The reaction medium is then hydrolysed with a saturated solution of ammonium chloride to pH 6-7, the extracted with diethyl ether (3×500 cc). The organic phase is dried over anhydrous magnesium sulphate and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa). The residual oil is purified by flash-chromatography on a silica column, under a current of argon at medium pressure (0.5-1.5 bar) with dichloromethane and then a mixture of dichloromethane and methanol (90-10 vol) as eluant. N-Benzyloxycarbonyl-4-hydroxy-4-(4-methoxyphenyl)piperidine (21.2 g), m.p. 98° C. is thus obtained, which is used in the crude state in the subsequent syntheses.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9](OC)[N:8]=[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:6]=1)=[O:4].P(Cl)(Cl)([Cl:20])=O>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([Cl:20])[N:8]=[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:6]=1)=[O:4]
Reactant: CCOC(=O)c1cc(C(=O)OC)cc(OC)n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(C(=O)OC)cc(Cl)n1
Temperature: 85 °C
Yield: 78 %

Procedure:
Mix 6-methoxypyridine-2,4-dicarboxylic acid 2-ethyl ester 4-methyl ester (239 mg, 1.0 mmol), phosphorous oxychloride (0.46 mL, 4.93 mmol) in DMF (1.9 mL) and heat to 85° C. for 24 h. Cool to room temperature and quench with saturated aqueous sodium acetate solution (5 mL). Extract with ethyl acetate, wash with water, dry (sodium sulfate), concentrate and purify (silica gel chromatography, eluting with ethyl acetate and hexanes) to give the title compound (190 mg, 78%).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1)=[O:3].[CH2:11](O)[CH2:12][OH:13].CO>ClCCl.C1C(=O)N(Br)C(=O)C1>[Cl:10][C:7]1[CH:8]=[CH:9][C:4]([C:2]2([CH3:1])[O:13][CH2:12][CH2:11][O:3]2)=[CH:5][CH:6]=1
Reactant: OCCO
Reactant: CC(=O)c1ccc(Cl)cc1
Agent: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: CO
Product: CC1(c2ccc(Cl)cc2)OCCO1
Temperature: 25 °C
Reaction time: 70 h
Yield: 55.4 %

Procedure:
To a stirred mixture of 4-chloroacetophenone (1.3 mL, 10 mmol), triethylformate (2.0 mL, 12 mmol), ethylene glycol (1.7 mL, 30 mmol) and dry methanol (1.2 mL) in dry dichloromethane (50 mL) was added NBS (53 mg, 0.30 mmol). The mixture was protected from light and stirred at room temperature under an inert atmosphere of nitrogen for 70 h. After the mixture was washed with saturated sodium bicarbonate solution (20 mL), the aqueous phase was extracted with dichloromethane (3×30 mL). The combined organic solution was washed with water (2×20 mL), brine (1×20 mL), then dried (Na2SO4) and concentrated under reduced pressure. Flash column chromatography of the residue, eluting with 37% aqueous ammonia:ether:hexane (0.02:1:6) afforded 2-(4-chlorophenyl)-2-methyl-1,3-dioxolane (21) as a colourless oil (1.1 g, 51%). 1H nmr (300 MHz, CDCl3) 1.63 (s, 3H, CH3), 3.72-3.82 (m, 2H, OCH2), 3.98-4.09 (m, 2H, OCH2), 7.42 (d, J=8.6 Hz, 2H, 2×ArH), 7.30 (d, J=8.6 Hz, 2H, 2×ArH).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8](OS(C(F)(F)F)(=O)=O)[CH:9]=2)[C:4](=[O:19])[CH2:3]1.[Cl:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[C:26]([Cl:28])[CH:27]=1>>[Cl:21][C:22]1[CH:23]=[C:24]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[C:4](=[O:19])[CH2:3][C:2]3([CH3:20])[CH3:1])[CH:25]=[C:26]([Cl:28])[CH:27]=1
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Reactant: CC1(C)CC(=O)c2ccc(OS(=O)(=O)C(F)(F)F)cc21
Product: CC1(C)CC(=O)c2ccc(-c3cc(Cl)cc(Cl)c3)cc21

Procedure:
The title compound was prepared from trifluoro-methanesulfonic acid 3,3-dimethyl-1-oxo-indan-5-yl ester and 3,5-dichlorophenyl boronic acid according to the procedure described in example 21. MS (ES) m/z 305.1; HRMS: calcd for C17H14Cl2O+H+, 305.04944; found (ESI, [M+H]+), 305.0509.