Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[N+]1([O-])CC[O:5]CC1.O[CH:10]1[C:16]([OH:40])([C:17]2[S:18][C:19]([C:22]3[CH:27]=[C:26]([NH:28][C:29]4[N:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][N:30]=4)[CH:25]=[C:24]([CH3:39])[CH:23]=3)=[CH:20][N:21]=2)[CH2:15][CH2:14][NH:13][C:12](=[O:41])[CH2:11]1>CC(C)=O.O.[Os](=O)(=O)(=O)=O>[OH:40][C:16]1([C:17]2[S:18][C:19]([C:22]3[CH:27]=[C:26]([NH:28][C:29]4[N:34]=[C:33]([C:35]([F:36])([F:38])[F:37])[CH:32]=[CH:31][N:30]=4)[CH:25]=[C:24]([CH3:39])[CH:23]=3)=[CH:20][N:21]=2)[CH:15]([OH:5])[CH2:14][NH:13][C:12](=[O:41])[CH2:11][CH2:10]1
Reactant: C[N+]1([O-])CCOCC1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(O)CCNC(=O)CC3O)s2)c1
Agent: O=[Os](=O)(=O)=O
Solvent: CC(C)=O
Solvent: O
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(O)CCC(=O)NCC3O)s2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37 %

Procedure:
The 70:30 mixture of products from Step 1 (100 mg, 0.22 mmol) was dissolved in acetone (1 mL) and water (125 μL). Osmium tetroxide (4% in H2O, 548 μL, 0.09 mmol) and 4-methylmorpholine N-oxide (105 mg, 0.90 mmol) were added and the suspension was stirred for 1 h at room temperature. The reaction was quenched with 5% aqueous sodium thiosulfate and stirred for 15 minutes. The mixture was washed with ethyl acetate (3×), and the combined organic layers were dried over sodium sulfate, filtered, and concentrated to give a mixture of 4,5-dihydroxy-5-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]azepan-2-one and 5,6-dihydroxy-5-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]azepan-2-one (70:30, 40 mg, 0.084 mmol 37% yield) as a brownish-yellow solid. MS ESI: [M+H]+ m/z 480.1. 1H NMR (600 MHz, DMSO-d6) δ 10.13 (s, 1H), 8.80 (d, J=4.9, 1H), 7.93 (s, 1H), 7.90 (s, 1H), 7.53-7.36 (m, 2H), 7.23 (d, J=4.9, 1H), 7.11 (s, 1H), 5.92 (s, 1H), 5.86 (s, 1H), 5.12-5.01 (m, 1H), 4.04-3.99 (m, 1H), 3.58-3.36 (m, 1H), 3.19-3.09 (m, 1H), 2.96-2.75 (m, 1H), 2.30 (s, 3H), 2.04-1.82 (m, 2H) rhSYK activity=+++
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([S:13]([CH3:16])(=[O:15])=[O:14])=[C:11]([C:17]([OH:19])=O)[N:10]=[C:9]2[C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[Cl:27])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)[C:48]2[CH:49]=[CH:50][CH:51]=C[C:47]=2[N:46]=[N:45]1.NN1CCCCC1>CC#N>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([S:13]([CH3:16])(=[O:15])=[O:14])=[C:11]([C:17]([NH:45][N:46]3[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]3)=[O:19])[N:10]=[C:9]2[C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[Cl:27])=[CH:6][CH:7]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CS(=O)(=O)c1c(C(=O)O)nc(-c2ccc(Cl)cc2Cl)n1-c1ccc(Cl)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: NN1CCCCC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1c(C(=O)NN2CCCCC2)nc(-c2ccc(Cl)cc2Cl)n1-c1ccc(Cl)cc1
Reaction time: 16 h
Yield: 84 %

Procedure:
To a magnetically stirred suspension of 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-methylsulfonyl-1H-imidazole-4-carboxylic acid (2.23 g, 5.01 mmol) in anhydrous CH3CN (50 ml) was successively added N,N-diisopropylethylamine (Hunig's base) (1.90 ml, 11.0 mmol), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU) (2.27 g, 5.99 mmol) and 1-aminopiperidine (0.65 ml, 6.03 mmol). After stirring for 16 h, the resulting mixture was concentrated in vacuo. The residue was dissolved in EtOAc, successively washed with aqueous NaHCO3 solution, water and brine, dried over Na2SO4, filtered and concentrated to give a crude solid. This solid was further purified by flash chromatography (silicagel, EtOAc) and triturated with methyl-tert-butyl ether to give 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-methylsulfonyl-N-(piperidin-1-yl)-1H-imidazole-4-carboxamide in 84% yield, mp 181–185° C. (dec); 1H-NMR (600 MHz, DMSO-d6) δ 1.35–1.41 (m, 2H), 1.61–1.66 (m, 4H), 2.80–2.84 (m, 4H), 3.52 (s, 3H), 7.38 (d, J=8 Hz, 2H), 7.42 (dd, J=8 and 2 Hz, 1H), 7.46 (d, J=8 Hz, 2H), 7.57 (d, J=2 Hz, 1H), 7.62 (d, J=8 Hz, 1H), 9.40 (s, 1H); HRMS (C22H22Cl3N4O3S) [M+H]+: found m/z 527.0469, calcd 527.0478.
Reaction SMILES: [CH3:1][CH:2]([N:12]([CH3:14])[CH3:13])[CH2:3][CH2:4]OC1C=CC=CC=1.[BrH:15]>C(Cl)(Cl)Cl>[BrH:15].[CH3:1][CH:2]([N:12]([CH3:14])[CH3:13])[CH2:3][CH2:4][Br:15]
Reactant: CC(CCOc1ccccc1)N(C)C
Agent: Br
Solvent: ClC(Cl)Cl
Product: CC(CCBr)N(C)C
Yield: 79 %

Procedure:
5 g of the 1-methyl-3-phenoxypropyldimethylamine thus obtained was reacted with 30 ml of 40% hydrobromic acid at 150° C. for 7 hours with stirring. The reaction solution was cooled, 20 ml of chloroform was added and then the solution was separated. The hydrobromic acid was removed under reduced pressure and the residue was recrystallized from 5 ml of ethyl alcohol to give 4.46 g of 1-methyl-3-bromopropyldimethylamine hydrobromide in a yield of 79%.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:27])[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-]S(C(F)(F)F)(=O)=O.C([B+]CCCC)CCC.[CH2:45]([O:52][C:53]1[CH:60]=[CH:59][C:56]([CH:57]=[O:58])=[CH:55][CH:54]=1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>ClCCl.C(N(CC)CC)C>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:27])[C@@H:15]([O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([CH3:24])([CH3:26])[CH3:25])=[CH:19][CH:18]=1)[C@@H:57]([C:56]1[CH:59]=[CH:60][C:53]([O:52][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)=[CH:54][CH:55]=1)[OH:58])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)c1ccc(OCC(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)cc1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Agent: CCCC[B+]CCCC
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)c1ccc(O[C@H](C(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)[C@H](O)c2ccc(OCc3ccccc3)cc2)cc1

Procedure:
The target compound (30.0 g) was obtained as a colorless oil by carrying out the reaction and the post-treatment according to Reference example 20(b) using (S)-4-benzyl-3-[(4-t-butylphenoxy)acetyl]oxazolidin-2-one (28.2 g) obtained from Reference example 21(a), a solution of dibutylboron triflate in dichloromethane (1M, 92.1 ml), triethylamine (13.9 ml) and 4-benzyloxybenzaldehyde (17.9 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]3[CH2:23][CH2:22][CH2:21][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C-]#N.[K+].[CH:28]1(O)[CH2:32]CC[CH2:29]1>>[Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]3[CH2:23][CH2:22][CH2:21][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH:19]3[CH2:32][CH2:28][CH2:29][CH2:20]3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: OC1CCCC1
Reactant: CCOC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Agent: [C-]#N
Agent: [K+]
Product: O=C(OC1CCCC1)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2

Procedure:
3.45 g (10 mmol) of ethyl (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate and 70 mg of powdered potassium cyanide in 10 ml of cyclopentanol are stirred at the boiling point overnight, the excess cyclopentanol is removed in vacuo, the residue is taken up in chloroform, filtered and evaporated. By recrystallization from ethyl acetate/hexane there is obtained cyclopentyl (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate of melting point 210.5°-212°.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][CH:6]=1)[CH3:2].[N+:13]([O-])([OH:15])=[O:14]>OS(O)(=O)=O>[I:11][C:8]1[CH:9]=[CH:10][C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:12])=[CH:6][C:7]=1[N+:13]([O-:15])=[O:14]
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(I)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl-4-iodobenzoate ( 10.0 g, 36.2 mmol) in H2SO4 (20 ml) at 0° C. was added dropwise HNO3 ( 4.7 ml, 72.4 mmol). Reaction was stirred at room temperature for 1 h, cooled to 0° C., quenched with ice, diluted with EtOAc, washed with H2O, brine, dried over Na2SO4, concentrated in vacuo to yield the crude title compound as a yellow solid.
Reaction SMILES: [CH:1]1(/[CH:6]=[CH:7]/[C@H:8]([C@@H:10]2[O:14][C:13](=[O:15])[C@H:12]([O:16][CH3:17])[C@@H:11]2[OH:18])[OH:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:20][C@@H:21]1[C:27](=[O:28])[N:26]([CH3:29])[C:25]2[CH:30]=[CH:31][CH:32]=[CH:33][C:24]=2[N:23]([CH3:34])[CH2:22]1.C(C(CCCC)C([O-])=O)C.[Na+]>C1COCC1>[CH:1]1(/[CH:6]=[CH:7]/[C@@H:8]([OH:9])[C@H:10]([OH:14])[C@@H:11]([OH:18])[C@@H:12]([O:16][CH3:17])[C:13]([NH:20][C@@H:21]2[C:27](=[O:28])[N:26]([CH3:29])[C:25]3[CH:30]=[CH:31][CH:32]=[CH:33][C:24]=3[N:23]([CH3:34])[CH2:22]2)=[O:15])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CO[C@H]1C(=O)O[C@@H]([C@H](O)/C=C/C2CCCC2)[C@H]1O
Reactant: CN1C[C@H](N)C(=O)N(C)c2ccccc21
Agent: CCCCC(CC)C(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CO[C@@H](C(=O)N[C@H]1CN(C)c2ccccc2N(C)C1=O)[C@H](O)[C@@H](O)[C@H](O)/C=C/C1CCCC1
Temperature: 25 °C

Procedure:
208 mg of 32 (852 μmol), 198 mg of 18 (0.712 mmol) and 473 mg of sodium 2-ethylhexanoate (2.848 mmol) in 5 mL of THF are successively introduced into a 25 mL round-bottomed flask, with stirring and under an argon atmosphere. The stirring is maintained at RT for 2 days. The mixture is concentrated under vacuum. The crude product is chromatographed on a silica cartridge [50 g, eluent AcOEt/AcOEt-isopropanol (50/50), in an AcOEt-isopropanol (50/50) gradient: 0 to 30%]). 172 mg of expected product Ex15 are recovered.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[CH3:25][O:26][CH2:27][CH2:28][CH2:29][CH2:30][NH2:31].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.[Cl-].[NH4+]>CN(C=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:31][CH2:30][CH2:29][CH2:28][CH2:27][O:26][CH3:25])=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2]
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: COCCCCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCCCCNC(=O)c1ccc(-n2ncc(-c3ccc(C#N)cc3C)c2O)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.5 %

Procedure:
Combined 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid (50 mg, 0.156 mmol) and 4-methoxybutan-1-amine (29.0 mg, 0.281 mmol) in DMF (1 mL). Then added a solution of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (50 mg, 0.261 mmol) and triethylamine (0.121 mL, 0.868 mmol) in DMF (0.5 mL), and a solution of HOBT (35 mg, 0.259 mmol) in DMF (0.5 mL). The mixture was then stirred overnight at room temperature. Into the reaction mixture was then poured 20 mL of saturated ammonium chloride solution and was rigorously stirred for 1 hour to give a solid. The solid was collected on by filtration, washed three times with saturated ammonium chloride solution, and then twice with ether, before being dried to give the title compound (49 mg, 77% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.50-1.61 (m, 4 H) 2.42 (s, 3 H) 3.23 (s, 3 H) 3.25-3.45 (m, 8 H) 7.42-7.47 (m, 1 H) 7.49 (s, 1 H) 7.80 (s, 1 H) 8.19 (dd, J=8.72, 2.40 Hz, 1 H) 8.27 (d, J=8.34 Hz, 1 H) 8.49-8.57 (m, 2 H) 8.83 (d, J=2.02 Hz, 1 H). MS m/z [M+H]+ 406.2.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[C:11]([O:22]C)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.N>C(O)(=O)C>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[C:11]([OH:22])[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cnn(Cc2ccccc2)c(=O)c1-c1ccc(F)cc1
Agent: Br
Agent: N
Solvent: CC(=O)O
Product: O=c1c(-c2ccc(F)cc2)c(O)cnn1Cc1ccccc1

Procedure:
The product from Example 6 (1.24 g; 4 mmol) in 20 mL of acetic acid was treated with aqueous 48% HBr (25 mL). The mixture was heated at reflux for about 5 to about 8 hours (TLC analysis). The mixture was concentrated in vacuo. The product was dissolved in ethyl acetate, washed with 10% bicarbonate, brine and concentrated in vacuo. The residue was treated with diethyl ether-hexanes (2:1) and the solid was filtered to provide an almost pure product (yield: 1.16 g; 98%). 1H NMR (300 MHz, DMSO-d6) δ 5.24 (2H), 7.21 (m, 2H), 7.30 (m, 5H), 7.55 (m, 2H), 7.85 (s, 1H), 11.31 (br s, 1H). MS (DCI/NH3) m/z 296 (M+H)+, 314 (M+NH4)+.
Reaction SMILES: [C:1]([N:20]1[CH2:24][C@@H:23]2[C@H:25]([NH2:28])[CH2:26][CH2:27][C@@H:22]2[CH2:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1([O:35][C:36](=O)[NH:37][C:38]2[CH:43]=[C:42]([C:44]3[N:48]([CH3:49])[N:47]=[N:46][N:45]=3)[CH:41]=[C:40]([CH2:50][CH3:51])[CH:39]=2)C=CC=CC=1.C(N(CC)CC)C.C(#N)C>CN(C)C=O>[CH2:50]([C:40]1[CH:39]=[C:38]([NH:37][C:36]([NH:28][CH:25]2[CH:23]3[CH:22]([CH2:21][N:20]([C:1]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)([C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[CH2:24]3)[CH2:27][CH2:26]2)=[O:35])[CH:43]=[C:42]([C:44]2[N:48]([CH3:49])[N:47]=[N:46][N:45]=2)[CH:41]=1)[CH3:51]
Reactant: N[C@@H]1CC[C@@H]2CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)C[C@@H]21
Reactant: CCc1cc(NC(=O)Oc2ccccc2)cc(-c2nnnn2C)c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCc1cc(NC(=O)NC2CCC3CN(C(c4ccccc4)(c4ccccc4)c4ccccc4)CC32)cc(-c2nnnn2C)c1
Yield: 87 %

Procedure:
A mixture of (3aR,4R,6aS)-2-trityloctahydrocyclopenta[c]pyrrol-4-amine (prepared following the procedures of Patent publication EP 0 359 172 A1; 250 mg, 678 μmol), [3-ethyl-5-(1-methyl-1H-tetrazol-5-yl)phenyl]-carbamic acid phenyl ester (219 mg, 678 μmol), triethylamine (189 μL, 1.36 mmol), acetonitrile (3 mL) and N,N-dimethylformamide (0.5 mL) was stirred at room temperature for 18.5 hours. The mixture was concentrated under vacuum, and the residue was dissolved in ethyl acetate. The solution was washed with 1.0 N aqueous sodium hydroxide, and the organic phase was dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography, eluting with 40% ethyl acetate/hexane, to provide a white solid (353 mg, 87%). 1H NMR (300 MHz, CDCl3) δ8.04 (s, 1H), 7.67 (s, 1H), 7.53 (s, 1H), 7.46 (d, J=7 Hz, 6H), 7.18 (t, J=7 Hz, 6H), 7.07 (t, J=7 Hz, 3H), 6.97 (s, 1H), 6.11 (d, J=7 Hz, 1H), 4.04 (s, 3H), 2.74 (m, 1H), 2.6-2.4 (m, 4H), 2.4-2.1 (m, 3H), 1.91 (m, 1H), 1.8-1.7 (m, 3H), 1.58 (m, 1H), 1.12 (t, J=7 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[S:6][C:7]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:8]=3[CH:9](O)[CH2:10][C:4]=2[CH:3]=1.[Cl-:19].[Ca+2].[Cl-].Cl>C1C=CC=CC=1>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[S:6][C:7]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:8]=3[CH:9]([Cl:19])[CH2:10][C:4]=2[CH:3]=1
Reactant: OC1Cc2cc(Cl)ccc2Sc2ccc(F)cc21
Reactant: [Cl-]
Agent: Cl
Agent: [Ca+2]
Solvent: c1ccccc1
Product: Fc1ccc2c(c1)C(Cl)Cc1cc(Cl)ccc1S2

Procedure:
58.3 G. of 2-chloro-8-fluoro-10,11-dihydro-dibenzo[b,f]thiepin-10-ol 300 ml. of benzene and 21 g. of finely pulverized calcium chloride are saturated with hydrochloric acid over a period of 2 hours at 15°. The resulting precipitate is filtered, washed with benzene and evaporated under reduced pressure, whereby there is obtained 2,10-dichloro-8-fluoro-10,11-dihydro-dibenzo[b,f]thiepin as white crystals, having a melting point of 84°-85°.
Reaction SMILES: [CH:1](NC(C)C)(C)[CH3:2].C([Li])CCC.CN(C)P(N(C)C)(N(C)C)=O.[CH:24]1([C:33]([O:35][CH3:36])=[O:34])[CH2:28][CH2:27][CH:26]([C:29]([O:31][CH3:32])=[O:30])[CH2:25]1.BrCCCl>C1COCC1>[C:26]12([C:29]([O:31][CH3:32])=[O:30])[CH2:25][C:24]([C:33]([O:35][CH3:36])=[O:34])([CH2:1][CH2:2]1)[CH2:28][CH2:27]2
Reactant: COC(=O)C1CCC(C(=O)OC)C1
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: ClCCBr
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)C12CCC(C(=O)OC)(CC1)C2
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 50.7 %

Procedure:
A 22-L, 3-neck, round bottom flask was equipped with a J-KEM temperature controller, a mechanical stirrer, a nitrogen inlet, and an addition funnel. The flask was flushed with nitrogen then charged with anhydrous THF (5 L) and diisopropylamine (731 mL, 5.219 mol). The solution was cooled to −20° C. using a dry ice/acetone bath. The stirring mixture was slowly treated with 1.6 M n-butyllithium in hexanes (3.02 L, 4.833 mol) via cannula over 1 h maintaining the temperature between −20° C. and −27° C. The reaction mixture was cooled to −40° C. and hexamethylphosphoramide (2.7 L, 16.317 mol) was slowly added via addition funnel over 40 min. The reaction mixture was cooled to −73° C. and dimethyl cyclopentane-1,3-dicarboxylate (360 g, 1.933 mol) dissolved in anhydrous THF (2 L) was slowly added via addition funnel over 2 h. The reaction mixture was warmed to −10° C. and stirred at that temperature for 30 min, then cooled to 70° C. and treated with 1-bromo-2-chloroethane (267 mL, 3.209 mol) via addition funnel over 4 h. The reaction mixture was allowed to slowly warm to room temperature over 12 h and then was quenched with saturated aqueous ammonium chloride (2 L) over 90 min. The reaction mixture was diluted with hexane (2 L), the layers were separated, and the aqueous layer was further extracted with hexane (3×2 L). The combined organic layers were washed with brine (2×1 L), dried over sodium sulfate, filtered, and concentrated to a brown oil. The crude product was purified by silica gel purification (0-10% ethyl acetate/hexane). The product containing fractions were concentrated to near dryness and diluted with hexanes. The resulting crystalline solids were filtered and washed with hexane (200 mL) providing pure product as a clear crystalline solid. Additional batches of product were obtained from the filtrate in a similar manner. All product batches were combined to provide 208 g (51%) of dimethyl bicyclo[2.2.1]heptane-1,4-dicarboxylate as a clear crystalline solid. 1H NMR (500 Hz, CDCl3) δ ppm 3.68 (s, 6H), 2.03 (d, J=6.4 Hz, 4H), 1.90 (s, 2H), 1.67 (d, J=7.0, 4H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:21][CH2:22][C:23](Cl)=[O:24]>C(Cl)Cl>[Cl:21][CH2:22][C:23]([N:11]1[CH2:12][CH2:13][N:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH2:9][CH2:10]1)=[O:24]
Reactant: O=C(Cl)CCl
Reactant: Fc1ccc(N2CCNCC2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCl)N1CCN(c2ccc(F)cc2)CC1
Temperature: 0 °C

Procedure:
1-(4-Fluorophenyl) piperazine (2.8 mmol) was dissolved in 10 mL of CH2Cl2. Triethylamine (5.5 mmol) was added to it and the reaction was cooled to 0° C. Chloroacetylchloride (4.2 mmol) was added to it slowly, and the reaction was warmed to room temperature overnight. After completion, the reaction was quenched with brine solution and reaction mixture was extracted with methylene chloride. The combined organic phases were washed with brine and water and dried over magnesium sulfate. The solvent was evaporated and the compound purified by column chromatography (hexane/ethyl acetate=1.5/1) to afford the title compound as a white solid. 1H NMR (400 MHz, CDCl3): δ 6.9–7.2 (m, 2H), 6.82–6.92 (m, 2H), 4.1 (s, 2H), 6.62–3.8 (m, 4H), 3.46–3.6 (m, 4H). 13C NMR (400 MHz, CDCl3): 164, 158, 156.2, 148.5, 118.2, 116.8, 52.6, 52.2, 48, 46, 42.1, 40.6.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:11][C:12]1[N:17]=[CH:16][C:15]([CH:18]([CH2:21][C:22]2([C:25]([F:28])([F:27])[F:26])[CH2:24][CH2:23]2)[CH2:19][NH2:20])=[CH:14][N:13]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:20][CH2:19][CH:18]([C:15]1[CH:16]=[N:17][C:12]([CH3:11])=[N:13][CH:14]=1)[CH2:21][C:22]1([C:25]([F:26])([F:27])[F:28])[CH2:24][CH2:23]1)=[O:6]
Reactant: Cc1ncc(C(CN)CC2(C(F)(F)F)CC2)cn1
Reactant: O=C(O)c1ccccc1Cl
Product: Cc1ncc(C(CNC(=O)c2ccccc2Cl)CC2(C(F)(F)F)CC2)cn1

Procedure:
The racemic mixture which was prepared in a similar manner to example 3a from 2-chlorobenzoic acid and 2-(2-methyl-pyrimidin-5-yl)-3-(1-trifluoromethyl-cycl opropyl)-propylamine was separated into the two enantiomers by preparative SFC to yield the title compound. LCMS (MH+): m/z=398.1, tR (minutes, Method F)=2.55. [α]D20=−25.5 (c=5.1 mg/mL,CHCl3)
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)([OH:3])=O.O=S(Cl)Cl.[NH:16]([CH2:19][CH3:20])[CH2:17][CH3:18]>>[CH2:17]([N:16]([CH2:19][CH3:20])[C:1](=[O:3])[C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)[CH3:18]
Reactant: CCNCC
Reactant: O=Cc1ccc(C(=O)O)cc1
Solvent: O=S(Cl)Cl
Product: CCN(CC)C(=O)c1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.3 %

Procedure:
4-Carboxybenzaldehyde (1.07 g, 7.13 mmol) was added into SOCl2 (5 ml). The mixture was refluxed for 6 hours until the solid was totally dissolved in solution. Then SOCl2 was evaporated under reduced pressure. Toluene (10 ml) was added to the residue and then removed under reduced pressure. The resulting residue was dissolved in anhydrous DCM (10 ml). Et2NH (20 mmol, 2.07 ml) was added dropwise. The solution was stirred at room temperature overnight. The solvent was removed under reduced pressure and the resulting residue was subjected to flash chromatography (EtOAc/Hexanes=30%˜50%) to give compound (1) (1.32 g, 6.44 mmol, yield 90%). 1H NMR (CDCl3) δ 10.06 (s, 1H), 7.95 (d, 2H), 7.55 (d, 2H), 3.58 (quart, 2H), 3.23 (quart, 2H), 1.28 (t, 3H), 1.13 (t, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:12][C:13]([O:15]CC)=[O:14])=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30](=[NH:32])[NH2:31])=[CH:26][CH:25]=1.[OH-].[Na+]>>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:12][C:13]([OH:15])=[O:14])=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:22][CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30](=[NH:31])[NH2:32])=[CH:28][CH:29]=1
Reactant: CCOC(=O)CN(c1ccc2c(c1)nc(CCc1ccc(C(=N)N)cc1)n2C)S(C)(=O)=O
Agent: [Na+]
Agent: [OH-]
Product: Cn1c(CCc2ccc(C(=N)N)cc2)nc2cc(N(CC(=O)O)S(C)(=O)=O)ccc21

Procedure:
Prepared analogously to Example 3 from 1-methyl-2-[2-(4-amidinophenyl)-ethyl]-5-[N-(ethoxycarbonylmethyl)-methanesulphonylamino]-benzimidazole and sodium hydroxide solution.
Reaction SMILES: [ClH:1].FC1C=C2C(C(C3C=NN(C4CCNCC4)C=3)=CN2S(C2C=CC=CC=2)(=O)=O)=CC=1.[F:32][C:33]1[CH:41]=[C:40]2[C:36]([C:37]([C:51]3[CH:52]=[N:53][N:54]([CH:56]4[CH2:59][N:58](C(OC(C)(C)C)=O)[CH2:57]4)[CH:55]=3)=[CH:38][N:39]2[S:42]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)(=[O:44])=[O:43])=[CH:35][CH:34]=1>>[ClH:1].[NH:58]1[CH2:57][CH:56]([N:54]2[CH:55]=[C:51]([C:37]3[C:36]4[C:40](=[CH:41][C:33]([F:32])=[CH:34][CH:35]=4)[N:39]([S:42]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)(=[O:43])=[O:44])[CH:38]=3)[CH:52]=[N:53]2)[CH2:59]1
Reactant: CC(C)(C)OC(=O)N1CC(n2cc(-c3cn(S(=O)(=O)c4ccccc4)c4cc(F)ccc34)cn2)C1
Agent: Cl
Agent: O=S(=O)(c1ccccc1)n1cc(-c2cnn(C3CCNCC3)c2)c2ccc(F)cc21
Product: O=S(=O)(c1ccccc1)n1cc(-c2cnn(C3CNC3)c2)c2ccc(F)cc21

Procedure:
Following the general method as outlined in Intermediate 17, starting from tert-butyl 3-(4-(6-fluoro-1-(phenylsulfonyl)-1H-indol-3-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate (Intermediate 23; 1.32 g; 2.66 mmol), 1.30 g of the title compound was obtained as a brown solid, which was used directly without further purification.