Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][CH:6]=1)=[O:4].C([O-])=[O:14].[K+]>CO.CC(C)=O>[OH:14][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][CH:6]=1)=[O:4]
Reactant: O=C[O-]
Reactant: CSc1ccc(C(=O)CBr)cc1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CO
Product: CSc1ccc(C(=O)CO)cc1

Procedure:
119 g of 2-bromo-1-[4-methylthiophenyl]ethanone (prepared according to J. Amer. Chem. Soc., 1952, p. 5475) are dissolved in a mixture of 200 ml of methanol and 300 ml of acetone. 53 g of potassium formate are added and the mixture is heated under reflux for 4 hours. The organic solvents are evaporated, the residual oil is taken up with ethyl acetate and washed with a saturated solution of sodium chloride. The ethyl acetate is evaporated and the residual oil crystallises in isopropyl ether.
Reaction SMILES: ClC(Cl)(Cl)C[O:4][C:5](=[O:35])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][S:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)=[O:22])[CH:15]=1.CC(O)=O>C(Cl)Cl.[Zn]>[F:34][C:31]([F:32])([F:33])[C:28]1[CH:29]=[CH:30][C:25]([CH2:24][O:23][C:21]([CH2:20][C:16]2[CH:15]=[C:14]([S:13][CH2:12][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[C:5]([OH:35])=[O:4])[CH:19]=[CH:18][CH:17]=2)=[O:22])=[CH:26][CH:27]=1
Reactant: O=C(Cc1cccc(SCc2ccccc2C(=O)OCC(Cl)(Cl)Cl)c1)OCc1ccc(C(F)(F)F)cc1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C(Cc1cccc(SCc2ccccc2C(=O)O)c1)OCc1ccc(C(F)(F)F)cc1
Yield: 69.9 %

Procedure:
2-[3-(4-Trifluoromethyl-benzyloxycarbonylmethyl)-phenylsulfanylmethyl]-benzoic acid 2,2,2-trichloro-ethyl ester (105 mg, 0.177 mmol) was dissolved in DCM (8 mL) and zinc (232 mg, 3.55 mmol) was added. After stirring for 5 minutes HOAc, 97% (1 mL, 18 mmol) was added dropwise. The resulting slurry was stirred for 1.5 h before zinc was filtered off and washed with DCM. The organic phase was washed with water, dried through a phase separator and concentrated. The crude was submitted to flash chromatography using heptane and EtOAc (70/30-60/40) as eluent to give the titled compound (57 mg, 70%) as an oil; 1H NMR (400 MHz, CDCl3): δ 3.64 (s, 2H), 4.56 (s, 2H), 5.18 (s, 2H), 7.09-7.14 (m, 1H), 7.16-7.21 (m, 2H), 7.22-7.34 (m, 3H), 7.36-7.43 (m, 3H), 7.60 (d, 2H), 8.00 (d, 1H); Mass spectrum: M−H+ 459.
Reaction SMILES: C([O:8][C@@H:9]1[C@H:14]2[N:15]=[C:16]([NH:18][CH2:19][CH3:20])[O:17][C@H:13]2[CH2:12][C@H:11]([CH2:21][F:22])[C@H:10]1[O:23]CC1C=CC=CC=1)C1C=CC=CC=1.B(Cl)(Cl)Cl.CO.C(Cl)Cl>C(Cl)Cl>[CH2:19]([NH:18][C:16]1[O:17][C@H:13]2[CH2:12][C@H:11]([CH2:21][F:22])[C@@H:10]([OH:23])[C@H:9]([OH:8])[C@H:14]2[N:15]=1)[CH3:20]
Reactant: CCNC1=N[C@@H]2[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H](CF)C[C@@H]2O1
Agent: ClB(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: CCNC1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CF)C[C@@H]2O1
Temperature: 0 °C
Reaction time: 5 h
Yield: 73 %

Procedure:
To a solution of (3aS,4R,5R,6S,7aS)-4,5-bis(benzyloxy)-N-ethyl-6-(fluoromethyl)-3a,4,5,6,7,7a-hexahydrobenzo[d]oxazol-2-amine (209 mg, 0.507 mmol) in DCM (5 mL) at −78° C. was added a solution of BCl3 in DCM (1.0 M, 1.27 mL, 1.27 mmol). The mixture was slowly warmed up to 0° C. and stirred at this temperature for 5 h. The reaction was cooled to −78° C. again and a 1:1 mixture of MeOH-DCM (10 mL) was added dropwise to quench the reaction. Solvents were evaporated and the residue was treated with MeOH for three more times. The crude product was purified by silica gel column chromatography, eluted with 5%-15% 2 M NH3 MeOH solution in DCM to give the product (3aR,4R,5R,6S,7aS)-2-(ethylamino)-6-(fluoromethyl)-3a,4,5,6,7,7a-hexahydrobenzo[d]oxazole-4,5-diol (86.0 mg, 73%) as a white solid. MS m/z 233.2 (M+1, 100%); 1H NMR (400 MHz, MeOD) δ 4.60 (dd, J=9.0 Hz, 4.4 Hz, 0.5H), 4.45-4.51 (m, 2H), 4.35 (dd, J=9.0 Hz, 2.5 Hz, 0.5H), 3.47 (t, J=7.1 Hz, 1H), 3.13-3.22 (m, 2H), 3.06-3.12 (m, 2H), 2.12-2.21 (m, 1H), 1.65-1.80 (m, 2H), 1.06 (t, J=7.3 Hz, 3H); 13C NMR (100 MHz, MeOD) δ 163.88, 84.63 (d, J=165.6 Hz), 80.81, 80.65, 71.86 (d, J=4.8 Hz), 68.43, 39.40 (d, J=18.6 Hz), 38.23 (d, J=2.4 Hz), 28.14 (d, J=3.8 Hz), 15.24.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:3]=1[CH:4]=[O:5].C(N(CC)CC)C.[C:19]([C:23](Cl)=[O:24])([Cl:22])([Cl:21])[Cl:20]>C1COCC1>[Cl:20][C:19]([Cl:22])([Cl:21])[C:23]([NH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:3]=1[CH:4]=[O:5])=[O:24]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: COc1cccc(N)c1C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cccc(NC(=O)C(Cl)(Cl)Cl)c1C=O
Temperature: 0 °C
Reaction time: 24 h

Procedure:
A mixture of 2-Amino-6-methoxy-benzaldehyde (6.00 g, 0.04 mol) and triethylamine (4.4 g, 0.044 mol) is dissolved in THF (20 mL) and cooled to 0° C., then CCl3COCl (7.95 g, 0.044 mol) is added and stirred at 25° C. for 24 h. The mixture is extracted from water with ethylacetate to give the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH2:25][CH2:26][CH3:27])=[C:6]([C:8]2[NH:13][C:12](=[O:14])[C:11]3=[C:15]([CH3:23])[N:16]=[C:17]([CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:10]3[N:9]=2)[CH:7]=1.[C:28]([C:30]1[CH:31]=[C:32]([S:36](Cl)(=[O:38])=[O:37])[CH:33]=[CH:34][CH:35]=1)#[N:29].N1C=CC=CC=1>O1CCCC1>[C:28]([C:30]1[CH:31]=[C:32]([S:36]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([O:24][CH2:25][CH2:26][CH3:27])=[C:6]([C:8]3[NH:13][C:12](=[O:14])[C:11]4=[C:15]([CH3:23])[N:16]=[C:17]([CH:18]5[CH2:22][CH2:21][CH2:20][CH2:19]5)[N:10]4[N:9]=3)[CH:7]=2)(=[O:38])=[O:37])[CH:33]=[CH:34][CH:35]=1)#[N:29]
Reactant: CCCOc1ccc(N)cc1-c1nn2c(C3CCCC3)nc(C)c2c(=O)[nH]1
Reactant: N#Cc1cccc(S(=O)(=O)Cl)c1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCCOc1ccc(NS(=O)(=O)c2cccc(C#N)c2)cc1-c1nn2c(C3CCCC3)nc(C)c2c(=O)[nH]1

Procedure:
200 mg (0.566 mmol) of the compound from example 44A are reaccted with 342 mg (1.70 mmol) of 3-cyanobenzenesulfonyl chloride and 0.46 ml (5.66 mmol) of pyridine in 15 ml of tetrahydrofuran overnight.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([OH:23])[CH:10]([NH2:22])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.[C:24]1([C:34](Cl)=[O:35])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[F:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([OH:23])[CH:10]([NH:22][C:34]([C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=[CH:26][CH:25]=2)=[O:35])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:7][CH:8]=1
Reactant: O=C(Cl)c1cccc2ccccc12
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.1 %

Procedure:
To a solution of (1RS,2RS)-1-(4-fluorophenyl)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)-2-propylamine hydrochloride (150 mg, 0.43 mmol) in ethyl acetate (5 ml) were added 1-naphthoyl chloride (97 mg, 0.64 mmol) and saturated aqueous sodium hydrogen carbonate (5 ml) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (50 ml), and extracted with ethyl acetate (50 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1-1:1), and recrystallized from ethyl acetate-hexane to give the title compound (145 mg, 72%).
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[CH3:23][C:24]1([CH3:38])[C:28]([CH3:30])([CH3:29])[O:27][B:26]([C:31]2[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=2)[O:25]1.[CH2:39]([N:46]1[CH:51]=[C:50]([C:52]2[CH:57]=[CH:56][C:55]([F:58])=[CH:54][CH:53]=2)[C:49](=[O:59])[C:48]([C:60](O)=[O:61])=[CH:47]1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>CN(C=O)C.O>[CH2:39]([N:46]1[CH:51]=[C:50]([C:52]2[CH:53]=[CH:54][C:55]([F:58])=[CH:56][CH:57]=2)[C:49](=[O:59])[C:48]([C:60]([NH:35][C:34]2[CH:36]=[CH:37][C:31]([B:26]3[O:25][C:24]([CH3:38])([CH3:23])[C:28]([CH3:29])([CH3:30])[O:27]3)=[CH:32][CH:33]=2)=[O:61])=[CH:47]1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: O=C(O)c1cn(Cc2ccccc2)cc(-c2ccc(F)cc2)c1=O
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)OB(c2ccc(NC(=O)c3cn(Cc4ccccc4)cc(-c4ccc(F)cc4)c3=O)cc2)OC1(C)C
Temperature: 50 °C
Reaction time: 8 h
Yield: 40.4 %

Procedure:
EDC.HCl (152 mg), HOBt (73 mg) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (128 mg) were added to a solution of 1-benzyl-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (171 mg) in DMF (3 ml) at room temperature. The reaction mixture was stirred at 50° C. overnight. EDC.HCl (76 mg) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (64 mg) were added to the reaction mixture at 50° C. The reaction mixture was stirred at 50° C. overnight. The reaction mixture was stirred at 80° C. overnight. The reaction mixture was returned to room temperature and diluted by adding water. The precipitated solid was collected by filtration. The resulting solid was purified by silica gel column chromatography [hexane:ethyl acetate=5:1->4:1->3:1->1:1 (v/v)] to give 112 mg of the title compound as a solid.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].Cl[C:13]1[CH:18]=[C:17]([C:19]2[CH:24]=[C:23]([N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH:22]=[CH:21][C:20]=2[N+:31]([O-:33])=[O:32])[N:16]=[CH:15][N:14]=1>CN(C=O)C.Cl>[N+:31]([C:20]1[CH:21]=[CH:22][C:23]([N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:24][C:19]=1[C:17]1[N:16]=[CH:15][N:14]=[C:13]([NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=2)[CH:18]=1)([O-:33])=[O:32]
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: O=[N+]([O-])c1ccc(N2CCCCC2)cc1-c1cc(Cl)ncn1
Agent: Cl
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(N2CCCCC2)cc1-c1cc(Nc2cccc(C(F)(F)F)c2)ncn1
Temperature: 90 °C
Yield: 74.5 %

Procedure:
A solution of 15 mg of 3-(trifluoromethyl)aniline and 27 mg intermediate 3.1b in 1 mL of DMF was treated with 1 drop of concentrated hydrochloric acid and heated to 90° C. for 1 h. The solution was cooled and partitioned between ethyl acetate and water. The organic extracts were washed with brine and dried over Na2SO4. The solvent was evaporated at reduced pressure to give 28 mg of product.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([N+:13]([O-:15])=[O:14])[C:8]([CH3:12])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:16][O-:17].[Na+]>CO>[CH3:16][O:17][C:2]1[C:11]2[C:6](=[C:7]([N+:13]([O-:15])=[O:14])[C:8]([CH3:12])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccc2c(Cl)nccc2c1[N+](=O)[O-]
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nccc2c([N+](=O)[O-])c(C)ccc12
Temperature: 25 °C
Yield: 73.8 %

Procedure:
A stirred solution of 1-chloro-6-methyl-5-nitroisoquinoline (1.2 g, 5.4 mmol) and sodium methoxide (0.6 g, 95%, 11 mmol) in methanol (20 mL) in a sealed-tube was heated to 80° C. for 2 h, cooled to room temperature and partitioned between ethyl acetate (3×30 mL) and water (50 mL). The combined organic extracts were washed (water, brine), dried (sodium sulfate) and concentrated in vacuo to give the product as a beige solid (0.87 g, 74%). A sample recrystallised from ethanol gave mp 94° C.; Found: C, 60.45; H, 4.58; N, 12.74%. C11H10N2O3 requires C, 60.55; H, 4.62; N, 12.83%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH3:16])[O:11][C:10]=1[C:17]([OH:19])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH:33]1([NH2:37])[CH2:36][CH2:35][CH2:34]1.CCN(CC)CC>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH3:16])[O:11][C:10]=1[C:17]([NH:37][CH:33]1[CH2:36][CH2:35][CH2:34]1)=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(=O)c(OCc2ccccc2)c(C(=O)O)o1
Reactant: NC1CCC1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(=O)c(OCc2ccccc2)c(C(=O)NC2CCC2)o1
Temperature: 50 °C
Reaction time: 5 h
Yield: 91.8 %

Procedure:
A mixture of 3-(benzyloxy)-6-methyl-4-oxo-4H-pyran-2-carboxylic acid (2.5 g, 9.6 mmol, 1.0 equiv), 1,1′-carbonyldiimidazole (2.49 g, 15.37 mmol, 1.6 equiv) in DMF (20 mL) was stirred at 50° C. for 5 h. The mixture was cooled to room temperature. Cyclobutylamine hydrochloride (1.24 g, 11.52 mmol, 1.2 equiv) and Et3N (1.74 mL, 12.48 mmol, 1.3 equiv) was added, and the mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure. Purification by chromatography (1:1 hexanes/EtOAc, then EtOAc) provided the titled compound (2.76 g, 91.56%) as a yellow solid. M.p. 69.3-71.0° C.; 1H-NMR (CDCl3, 400 MHz) δ 1.51-1.72 (m, 4H, cyclobutyl H), 2.19-2.28 (m, 2H, cyclobutyl H), 2.37 (s, 3H, CH3), 4.39-4.41 (m, 1H, CH), 5.41 (s, 2H, OCH2Ph), 6.30 (s, 1H, CH), 7.39-7.49 (m, 5H, ArH), 7.86 (br, 1H, NH), and MS (m/z) 314 (M++1), 217, 91.
Reaction SMILES: CC(C[AlH]CC(C)C)C.[CH3:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]1[C:24](OC)=[O:25]>C1COCC1>[OH:25][CH2:24][CH:12]1[CH:11]([CH3:10])[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH2:13]1
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1C
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: CC1CCN(C(=O)OC(C)(C)C)CC1CO
Reaction time: 1 h
Yield: 86.4 %

Procedure:
DIBAL-H (1 M in toluene, 27.3 mL, 27.3 mmol) was added drop-wise to a solution of 1-tert-butyl 3-methyl 4-methylpiperidine-1,3-dicarboxylate (3.35 g, 13.02 mmol, prepared using R from Preparation #Y.1 and P) in THF (40 mL) at about 0° C. The reaction mixture was stirred for about 1 h before quenching with 10% aqueous potassium sodium tartrate solution in water (50 mL). The reaction mixture was allowed to stir for about 1 h before it was concentrated under reduced pressure. The residue was partitioned with EtOAc (200 mL) and brine (3×100 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to constant weight to afford tert-butyl 3-(hydroxymethyl)-4-methylpiperidine-1-carboxylate as a clear oil (2.58 g, 86%): LC/MS (Table 2, Method a) Rt=2.10 min; MS m/z: 230 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]2[N:6]=[C:7]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[C:8]3[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=4[S:11][C:9]=3[NH:10][C:4]=2[C:3]=1[O:27]C.C(S)(S)C.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[F:1][C:2]1[CH:26]=[CH:25][C:5]2[N:6]=[C:7]([N:18]3[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]3)[C:8]3[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=4[S:11][C:9]=3[NH:10][C:4]=2[C:3]=1[OH:27]
Reactant: COc1c(F)ccc2c1Nc1sc3ccccc3c1C(N1CCN(C)CC1)=N2
Agent: CC(S)S
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CN1CCN(C2=Nc3ccc(F)c(O)c3Nc3sc4ccccc4c32)CC1

Procedure:
In the same manner as in Example 62 and using 8-fluoro-7-methoxy-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine, dichloromethane, ethanedithiol and aluminium chloride, 8-fluoro-7-hydroxy-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine is obtained.
Reaction SMILES: [CH2:1]1[N:12]2[C:13]3[C:9]([C@@H:10]4[CH2:17][NH:16][CH2:15][CH2:14][C@@H:11]42)=[CH:8][CH:7]=[CH:6][C:5]=3[CH2:4][S:3][CH2:2]1.Cl[CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1>>[F:29][C:26]1[CH:27]=[CH:28][C:23]([O:22][CH2:21][CH2:20][CH2:19][CH:1]2[N:12]3[C:13]4[C:9]([CH:10]5[CH2:17][NH:16][CH2:15][CH2:14][CH:11]53)=[CH:8][CH:7]=[CH:6][C:5]=4[CH2:4][S:3][CH2:2]2)=[CH:24][CH:25]=1
Reactant: Fc1ccc(OCCCCl)cc1
Reactant: c1cc2c3c(c1)[C@@H]1CNCC[C@@H]1N3CCSC2
Product: Fc1ccc(OCCCC2CSCc3cccc4c3N2C2CCNCC42)cc1

Procedure:
The title compound of EXAMPLE 5 was prepared from (7bR,11aS)-1,2,7b,8,9,10,11,11a-octahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indole and 1-(3-chloropropoxy)-4-fluorobenzene following the procedure described in EXAMPLE 4. 1H NMR (CDCl3, 300 MHz): δ 7.0-6.78 (m, 6H), 6.65 (t, 1H, J=7.3 Hz), 3.95 (t, 2H, J=6.2 Hz), 3.84 (dd, 2H, J=16.4 Hz), 3.59 (m, 2H), 3.25 (m, 2H), 3.15 (m, 2H), 2.85 (m, 2H), 2.65 (m, 2H), 2.45 (m, 4H), 2.30 (m, 2H) ppm. LRMS (ES)+: 399 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([CH2:6][NH:7][C:8]([CH:10]2[C:15]3[N:16]=[C:17]([NH:19][C:20](=[O:28])[CH2:21][CH:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)[S:18][C:14]=3[CH2:13][CH2:12][CH2:11]2)=[O:9])[CH2:2]1.[Cl:29][C:30]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:31]=1[CH:32]=O>C(Cl)Cl>[Cl:29][C:30]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:31]=1[CH2:32][N:1]1[CH2:5][CH2:4][CH:3]([CH2:6][NH:7][C:8]([CH:10]2[C:15]3[N:16]=[C:17]([NH:19][C:20](=[O:28])[CH2:21][CH:22]4[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]4)[S:18][C:14]=3[CH2:13][CH2:12][CH2:11]2)=[O:9])[CH2:2]1
Reactant: O=Cc1c(Cl)cccc1Cl
Reactant: O=C(CC1CCCCC1)Nc1nc2c(s1)CCCC2C(=O)NCC1CCNC1
Solvent: ClCCl
Product: O=C(CC1CCCCC1)Nc1nc2c(s1)CCCC2C(=O)NCC1CCN(Cc2c(Cl)cccc2Cl)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Compound 2-(2-cyclohexylacetylamino)-4,5,6,7-tetrahydrobenzthiazol-4-carboxylic acid (1-pyrrolidin-3-yl)methylamide (1) (1.66 mmol) was dissolved in DCM (15 mL) under a blanket of nitrogen. 2,6-Dichlorobenzaldehyde (320 mg, 1.82 mmol) and sodium triacetoxyboron hydride (530 mg, 2.48 mmol) were added. The reaction mixture was stirred overnight at RT under a blanket of nitrogen. Following removal of the solvent in vacuo and purification by column chromatography (SiO2, DCM/MeOH 95:5), there were obtained 623 mg (1.11 mmol, 67% of theory) of the desired product 2-(2-cyclohexylacetylamino)-4,5,6,7-tetrahydrobenzthiazol-4-carboxylic acid [1-(2,6-dichlorobenzyl)-pyrrolidin-3-yl]methylamide (K).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.CCN(C(C)C)C(C)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>O1CCCC1>[CH3:16][S:17]([N:4]1[CH2:5][CH2:6][C@H:2]([O:1][S:17]([CH3:16])(=[O:19])=[O:18])[CH2:3]1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: O[C@H]1CCNC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)O[C@H]1CCN(S(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(S)-3-Hydroxypyrrolidine (2 g, 23 mmol) is dissolved in 40 mL of tetrahydrofuran. DIPEA (10 mL, 57.36 mmol) is added and the reaction mixture is stirred for 30 min at room temperature. The reaction mixture is cooled to 0° C., methanesulfonyl chloride (3.73 mL, 48.21 mmol) is added dropwise and the reaction mixture is allowed to reach room temperature. After stirring for 2 h, the reaction mixture is concentrated under vacuum, water is added and the reaction mixture is extracted with ethyl acetate. The organic phase is collected, dried over sodium sulfate, separated and concentrated under vacuum. The crude product obtained is triturated with a solution of cyclohexane/dichloromethane 1:1 to give the title compound. (Yield: 2.2 g).
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10](C(OC(C)(C)C)=O)[CH:11]([CH3:13])[CH3:12].FC(F)(F)C(O)=O>C(Cl)Cl>[F:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][NH:10][CH:11]([CH3:12])[CH3:13]
Reactant: CC(C)N(CCCCOCc1ccccc1F)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)NCCCCOCc1ccccc1F

Procedure:
The desired intermediate was prepared from the deprotection of 4-(2-fluorobenzyloxy)-N-(t-butoxycarbonyl)-N-(isopropyl)butylamine using standard techniques. The 4-(2-fluorobenzyloxy)-N-(t-butoxycarbonyl)-N-(isopropyl)butylamine was admixed with a 4:1 mixture of methylene chloride and trifluoroacetic acid. The progress of the reaction was monitored by thin layer chromatography.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.II.[I:17](O)(O)(O)(O)(O)=O.S(=O)(=O)(O)O>O.C(O)(=O)C>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([I:17])=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1
Reactant: [O-][I+](O)(O)(O)(O)O
Reactant: Brc1ccc2c(c1)Cc1ccccc1-2
Agent: II
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: Brc1ccc2c(c1)Cc1cc(I)ccc1-2
Temperature: 60 °C
Yield: 333.6 %

Procedure:
Charged were 2-bromofluorene 25.0 g, iodine 11.5 g, orthoperiodic acid 4.88 g, acetic acid 150 ml, conc. sulfuric acid 3 ml and water 10 ml, and the mixture was heated at 60° C. for 30 minutes while stirring. Further, the temperature was elevated up to 90° C., and the mixture was heated for 3 hours while stirring. The reaction solution was left cooling down to room temperature and poured into 500 ml of water. The precipitate formed was filtered and washed with ethanol and water. The solid matter thus obtained was recrystallized from ethanol to obtain 26.5 g of yellow crystal of 2-bromo-7-iodofluorene.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.O>CN(C)C=O>[CH3:11][O:10][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[O:1][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: BrCCCCCCOCCCCc1ccccc1
Reactant: COc1ccc(C=O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C=O)cc1OCCCCCCOCCCCc1ccccc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 98.9 %

Procedure:
To a stirred solution of 3-hydroxy-4-methoxybenzaldehyde (4.8 grams) in dimethylformamide (100 ml) at room temperature is added potassium carbonate (4.9 grams) and 1-bromo-6-(4-phenylbut-1-yloxy)hexane (10.0 grams). After stirring at 80° C. over 4 hours the reaction mixture is poured into water and extracted with ethyl acetate. The combined organics are washed with 1N sodium hydroxide and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting amber oil is filtered through a 5×10 cm pad of silica gel, eluting with a 1:3 mixture of ethyl acetate and hexane, to give 12.0 grams of a colorless oil. MS (m/z) 384.
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[CH2:11][CH2:10][CH2:9][NH:8]2)[CH:2]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>>[F:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([N:8]2[CH2:9][CH2:10][CH2:11][CH:7]2[C:3]2[CH:2]=[C:1]([CH3:12])[CH:6]=[CH:5][CH:4]=2)(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: Cc1cccc(C2CCCN2)c1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Product: Cc1cccc(C2CCCN2S(=O)(=O)c2ccc(F)cc2)c1

Procedure:
The title compound, off-white solid, m.p. 80° C. and MS: m/e=319(M+) was prepared in accordance with the general method of example 1e from (RS)-2-m-tolyl-pyrrolidine and 4-fluoro-benzenesulfonyl chloride.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:14]=2[CH2:20]Br)[CH:7]=1)[CH3:2].[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]2[CH2:34][NH:33][C:32](=[O:35])[CH2:31]2)=[CH:26][CH:25]=1>>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:14]=2[CH2:20][N:33]2[CH2:34][CH:30]([C:27]3[CH:28]=[CH:29][C:24]([Cl:23])=[CH:25][CH:26]=3)[CH2:31][C:32]2=[O:35])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cccc(Oc2ccc(Br)cc2CBr)c1
Reactant: O=C1CC(c2ccc(Cl)cc2)CN1
Product: CCOC(=O)Cc1cccc(Oc2ccc(Br)cc2CN2CC(c3ccc(Cl)cc3)CC2=O)c1

Procedure:
Prepared according to the procedure described in Example 116, Step 1, using the following starting materials: [3-(4-bromo-2-bromomethyl-phenoxy)-phenyl]-acetic acid ethyl ester and 4-(4-chloro-phenyl)-pyrrolidin-2-one.