Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:37][C:38]3[CH:43]=[C:42]([CH3:44])[C:41]([OH:45])=[C:40]([CH3:46])[CH:39]=3)[C:19]([N:21]3[CH2:26][CH2:25][CH:24]([CH:27]4[CH2:32][CH2:31][N:30]([CH2:33][C:34]([OH:36])=[O:35])[CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:47]=[CH:48][CH:49]=[CH:50][C:4]=2[NH:3]1.O[CH2:52][CH2:53][N:54]1[CH2:59][CH2:58][CH2:57][CH2:56][C:55]1=[O:60]>C(Cl)Cl>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C@H:18]([CH2:37][C:38]3[CH:43]=[C:42]([CH3:44])[C:41]([OH:45])=[C:40]([CH3:46])[CH:39]=3)[C:19](=[O:20])[N:21]3[CH2:22][CH2:23][CH:24]([CH:27]4[CH2:32][CH2:31][N:30]([CH2:33][C:34]([O:36][CH2:52][CH2:53][N:54]5[CH2:59][CH2:58][CH2:57][CH2:56][C:55]5=[O:60])=[O:35])[CH2:29][CH2:28]4)[CH2:25][CH2:26]3)=[O:16])[CH2:13][CH2:14]2)[CH2:7][CH2:6][C:5]2[CH:47]=[CH:48][CH:49]=[CH:50][C:4]=2[NH:3]1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(C3CCN(CC(=O)O)CC3)CC2)cc(C)c1O
Reactant: O=C1CCCCN1CCO
Solvent: ClCCl
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(C3CCN(CC(=O)OCCN4CCCCC4=O)CC3)CC2)cc(C)c1O

Procedure:
Prepared analogously to Example 3c from 80 mg (0.12 mmol) (R)-2-(1′-carboxymethyl-4,4′-bipiperidinyl-1-yl)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate and 33 mg (0.23 mmol) 1-(2-hydroxyethyl)-piperidin-2-one. After the elimination of the desiccant and solvent the residue was taken up in DCM and again purified by chromatography (silica gel, DCM/EtOH/NH3 95:5:0.5). The fractions containing the product were combined, concentrated by evaporation i. vac., triturated with DIPE, suction filtered and dried.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:9][CH2:10][C:11]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:15][C@H:14]2[CH3:27])=[O:12])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.CN1CCOCC1.[C:35]1(=[O:41])[O:40][C:38](=[O:39])[CH2:37][CH2:36]1>ClCCl>[Cl:8][C:6]1[CH:7]=[C:2]([NH:1][C:35](=[O:41])[CH2:36][CH2:37][C:38]([OH:40])=[O:39])[C:3]([O:9][CH2:10][C:11]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:15][C@H:14]2[CH3:27])=[O:12])=[N:4][CH:5]=1
Reactant: O=C1CCC(=O)O1
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)CCN1C(=O)COc1ncc(Cl)cc1N
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C[C@@H]1CN(Cc2ccc(F)cc2)CCN1C(=O)COc1ncc(Cl)cc1NC(=O)CCC(=O)O
Temperature: 25 °C
Reaction time: 72 h
Yield: 31.2 %

Procedure:
To a solution of 2-(3-amino-5-chloro-pyridin-2-yloxy)-1-[4-(4-fluoro-benzyl)-(2R)-2-methyl-piperazin-1-yl]-ethanone (0.10 g, 0.26 mmol) in dichloromethane (3 mL) was added N-methylmorpholine (0.028 mL, 0.26 mmol) and succinic anhydride (0.026 g, 0.26 mmol). The reaction was stirred at ambient temperature for 3 days. The reaction was diluted with dichlormethane and washed with 1N hydrochloric acid solution. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated in vacuo. Chromatography on silica gel gave the title compound (0.040 g, LRMS: 493.2).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].ClC(Cl)(Cl)C(=N)O[C:16]([CH3:19])([CH3:18])[CH3:17].C(=O)(O)[O-].[Na+]>ClCCl.CCCCCC>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O:11][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:10]
Reactant: CC(C)(C)OC(=N)C(Cl)(Cl)Cl
Reactant: O=C(O)CCCCCCCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)CCCCCCCBr
Temperature: 25 °C
Reaction time: 1 h
Yield: 38 %

Procedure:
A 5.00 g (22.4 mmol) portion of 8-bromooctanoic acid was dissolved in a mixed solvent of 2 ml dichloromethane and 10 ml hexane, and the solution was mixed with 8.00 ml (44.8 mmol) of tert-butyl 2,2,2-trichloroacetoimidate and 0.45 ml (3.66 mmol) of boron trifluoride-ether complex and stirred at room temperature for 1 hour. The reaction solution was mixed with 10 ml of hexane and 0.031 g (3.66 mmol) of sodium bicarbonate, the resulting precipitate was separated by filtration, and then the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=5/1) to obtain 2.34 g (yield, 38%) of tert-butyl 8-bromooctanoate.
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[OH:27][CH2:28][C:29](O)=[O:30]>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:28](=[O:27])[CH2:29][OH:30])[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Reactant: O=C(O)CO
Agent: Cl
Product: O=C(CO)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1

Procedure:
The title compound, off-white solid (65 mg, 67%), MS (ISP) m/z=387.4 [(M+H)+], mp 154.5° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and 2-hydroxy-acetic acid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][CH2:17][C:18]3[CH:19]=[C:20]([C:24](O)=[O:25])[O:21][C:22]=3[CH3:23])=[CH:12][CH:11]=2)=[N:8][CH:9]=1.[C:27]1([CH3:37])[C:28]([S:33]([NH2:36])(=[O:35])=[O:34])=[CH:29][CH:30]=[CH:31][CH:32]=1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>O1CCCC1.CN(C1C=CN=CC=1)C>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][CH2:17][C:18]3[CH:19]=[C:20]([C:24]([NH:36][S:33]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[CH3:37])(=[O:34])=[O:35])=[O:25])[O:21][C:22]=3[CH3:23])=[CH:12][CH:11]=2)=[N:8][CH:9]=1
Reactant: Cc1ccccc1S(N)(=O)=O
Reactant: COc1ccc(-c2ccc(NCc3cc(C(=O)O)oc3C)cc2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(-c2ccc(NCc3cc(C(=O)NS(=O)(=O)c4ccccc4C)oc3C)cc2)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 2.8 %

Procedure:
A suspension of 4-{[4-(5-methoxy-pyridin-2-yl)-phenylamino]-methyl}-5-methyl-furan-2-carboxylic acid hydrochloride salt (166) (30 mg, 0.08 mmoles) in tetrahydrofuran (5 ml) was treated with toluene-2-sulphonamide (41 mg, 0.24 mmoles), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (34 mg, 0.176 mmoles) and 4-(N,N-dimethylamino)-pyridine (10 mg, 0.08 mmoles) and the mixture stirred at room temperature for 16 hours. Triethylamine (24.3 mg, 0.24 mmoles) was added and the mixture was stirred for a further 18 hours. The reaction mixture was concentrated and the residue was purified by HPLC to afford compound 167 as a yellow glass (1.1 mg)). LC/MS System A; Rt=2.72 mins, m/z (ES+)=492 (M+H for C26H25N3O5S) and m/z (ES−)=490 (M−H for C26H25N3O5S).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.CN(C=O)C.[H-].[Na+].[CH3:22][Si:23]([CH3:30])([CH3:29])[CH2:24][CH2:25][O:26][CH2:27]Cl>>[CH3:1][C:2]1([CH3:14])[C:6]([CH3:7])([CH3:8])[O:5][B:4]([C:9]2[CH:13]=[N:12][N:11]([CH2:27][O:26][CH2:25][CH2:24][Si:23]([CH3:30])([CH3:29])[CH3:22])[CH:10]=2)[O:3]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)OB(c2cnn(COCC[Si](C)(C)C)c2)OC1(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.0 g, 0.010 mol) and DMF (30.0 mL, 0.387 mol) was cooled to 0° C. Sodium hydride (320 mg, 0.013 mol) (60% in oil) was added and the mixture was stirred for 10 min. [β-(Trimethylsilyl)ethoxy]methyl chloride (2.4 mL, 0.013 mol) was added and the resulting mixture was stirred for 20 min at 0° C. and 2 h at room temperature. The reaction was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over Mg SO4 and concentrated to give 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrazole as a crude material. LC/MS (M+H)+: 325, 1H NMR (CDCl3) δ 7.85 (s, 1H), 7.80(s, 1H), 5.45(s, 2H), 3.55(t, 2H), 1.35(s, 12H), 0.95(t, 2H), 0.0(s, 9H).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:32])[C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:31])[C@H:17]([CH2:19][CH:20]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:21](=[O:23])[OH:22])[NH2:18])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:40]1([S:46](Cl)(=[O:48])=[O:47])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C(Cl)Cl>[CH2:2]([O:9][C:10](=[O:32])[C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:31])[C@H:17]([CH2:19][CH:20]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:21](=[O:22])[OH:23])[NH:18][S:46]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)(=[O:48])=[O:47])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: N[C@@H](CC(Cc1ccccc1)C(=O)O)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)C(Cc1ccccc1)C[C@H](NS(=O)(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 92.4 %

Procedure:
γ-Benzyl-L-glutamyl-L-proline benzylester hydrochloride (2.30 g, 5 mmole) was dissolved in methylene chloride (30 ml), and triethylamine (1.11 g, 11 mole) was added thereto at -30 ° C. Methylene chloride (10 ml) solution of benzene sulfonyl chloride (0.86 g, 5 mmole) was added dropwise thereto. The solution was stirred for 1 hour at less than 0° C., and then for 5 hours at room temperature, and methylene chloride (60 ml) was added thereto. The solution was washed with 55 aqueous sodium bicarbonate (100 ml, twice), 1N aqueous hydrochloric acid (100 ml, twice), and water (100 ml) in the order given, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give N-benzenesulfonyl-γ-benzyl-L-glutamyl-L-proline benzylester (yield: 2.61 g, 92.4%)
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].FC1C=CC(I)=C(C=1)C(O)=O>>[N:12]1[N:11]([C:5]2[CH:4]=[CH:3][CH:2]=[CH:10][C:6]=2[C:7]([OH:9])=[O:8])[N:15]=[CH:14][CH:13]=1
Reactant: O=C(O)c1cc(F)ccc1-n1nccn1
Agent: O=C(O)c1cc(F)ccc1I
Product: O=C(O)c1ccccc1-n1nccn1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 41, substituting 2-iodo-benzoic acid for 5-fluoro-2-iodo-benzoic acid. 1H NMR (400 MHz, CD3OD): 7.91 (s, 2H), 7.85-7.82 (m, 1H), 7.75 (dd, J=8.1, 1.0 Hz, 1H), 7.69 (td, J=7.7, 1.5 Hz, 1H), 7.60-7.55 (m, 1H).
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.Cl.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28](B(O)O)[C:27]=1[CH3:35]>>[Cl:22][C:17]1[CH:16]=[C:15]([C:13]2[N:14]=[C:10]([C:8]3[CH:7]=[CH:6][C:5]([C:28]4[C:27]([CH3:35])=[N:26][CH:31]=[CH:30][CH:29]=4)=[C:4]([CH:9]=3)[C:3]([OH:2])=[O:24])[S:11][CH:12]=2)[CH:20]=[CH:19][C:18]=1[Cl:21]
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Reactant: Cc1ncccc1B(O)O
Agent: Cl
Product: Cc1ncccc1-c1ccc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)cc1C(=O)O
Yield: 58.9 %

Procedure:
Using the conditions of General Procedure C for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 111 mg, 0.25 mmol) was reacted with 2-picoline-3-boronic acid hydrochloride salt (available from Combi-Blocks Inc.; 87 mg, 0.5 mmol). The resulting ester was hydrolyzed and the acid was purified to give 5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-2-(2-methyl-pyridin-3-yl)-benzoic acid (65 mg, 59%). 1H NMR (400 MHz, DMSO-d6) δ 8.56 (d, J=1.8 Hz, 1H), 8.49 (s, 1H), 8.34 (d, J=2.0 Hz, 1H), 8.30 (dd, J=7.9, 1.9 Hz, 1H), 8.09 (dd, J=8.5, 2.0 Hz, 1H), 7.77 (d, J=8.3 Hz, 1H), 7.43 (d, J=8.0 Hz, 1H), 7.21-7.30 (m, 1H), 2.08 (s, 3H).
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([Cl:17])=[C:5]([CH:10]=[CH:11][C:12]=1[S:13]([CH3:16])(=[O:15])=[O:14])[C:6]([O:8][CH3:9])=[O:7].[C:18]([O-:21])(=[O:20])[CH3:19].[Na+]>CN(C=O)C>[C:18]([O:21][CH2:2][C:3]1[C:4]([Cl:17])=[C:5]([CH:10]=[CH:11][C:12]=1[S:13]([CH3:16])(=[O:15])=[O:14])[C:6]([O:8][CH3:9])=[O:7])(=[O:20])[CH3:19]
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(CBr)c1Cl
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(S(C)(=O)=O)c(COC(C)=O)c1Cl
Temperature: 100 °C
Reaction time: 2 h
Yield: 89.5 %

Procedure:
50 ml of a DMF solution containing 5.0 g of methyl 3-bromomethyl-2-chloro-4-methanesulfonylbenzoate and 1.2 g of sodium acetate, was stirred for 2 hours at 100° C. After cooling, the reaction mixture was poured into ice water and extracted with chloroform. After washing the extract with water and drying it, the solvent was distilled off to obtain 4.2 g of the desired product. Melting point: 165°-168° C.
Reaction SMILES: F[C:2]1[C:10]2[S:9][C:8]([C:11]3[C:12]([NH2:28])=[N:13][CH:14]=[C:15]([C:17]4[CH:18]=[N:19][N:20]([CH:22]5[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]5)[CH:21]=4)[CH:16]=3)=[N:7][C:6]=2[C:5]([C:29]([F:32])([F:31])[F:30])=[CH:4][CH:3]=1.I[C:34]1SC2C(C)=CC=C(C(F)(F)F)C=2N=1>>[CH3:34][C:2]1[C:10]2[S:9][C:8]([C:11]3[C:12]([NH2:28])=[N:13][CH:14]=[C:15]([C:17]4[CH:18]=[N:19][N:20]([CH:22]5[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]5)[CH:21]=4)[CH:16]=3)=[N:7][C:6]=2[C:5]([C:29]([F:32])([F:30])[F:31])=[CH:4][CH:3]=1
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2c(C(F)(F)F)ccc(F)c2s1
Reactant: Cc1ccc(C(F)(F)F)c2nc(I)sc12
Product: Cc1ccc(C(F)(F)F)c2nc(-c3cc(-c4cnn(C5CCNCC5)c4)cnc3N)sc12

Procedure:
Following the procedure for 3-(7-fluoro-4-trifluoromethylbenzothiazol-2-yl)-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine, using 2-iodo-7-methyl-4-trifluoromethyl-1,3-benzothiazole and conducting the Suzuki coupling at 55° C. for 3 h, the title compound was obtained as a yellow-green solid. 1H NMR (400 MHz, DMSO-d6): δ=2.10-2.31 (m, 4H), 2.70 (s, 3H), 3.07-3.18 (m, 2H), 3.37-3.44 (m, 2H), 3.54 (brs, 2H), 4.47-4.56 (m, 1H), 7.53 (d, J=9.2 Hz, 1H), 7.88 (d, J=7.6 Hz, 1H), 8.08 (d, J=0.8 Hz, 1H), 8.41-8.46 (m, 2H), 8.57 (d, J=2.4 Hz, 1H), 8.76 (brs, 1H), 8.96 (brs, 1H), MS(ES+): m/z=459.09 (100) [MH+]. HPLC: tR=2.32 min (ZQ3, polar—5 min).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([S:17]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][C@@H:21]2[C:26](O)=[O:27])(=[O:19])=[O:18])[CH2:13][CH2:12]1.Cl.[CH2:30]([O:37][NH2:38])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.CN1CCOCC1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:30]([O:37][NH:38][C:26]([C@H:21]1[CH2:22][CH2:23][CH2:24][CH2:25][N:20]1[S:17]([N:14]1[CH2:15][CH2:16][CH:11]([C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=3)[NH:7][CH:6]=2)[CH2:12][CH2:13]1)(=[O:18])=[O:19])=[O:27])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(O)[C@H]1CCCCN1S(=O)(=O)N1CCC(c2c[nH]c3ccc(F)cc23)CC1
Reactant: NOCc1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: O=C(NOCc1ccccc1)[C@H]1CCCCN1S(=O)(=O)N1CCC(c2c[nH]c3ccc(F)cc23)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a solution of 1-[4-(5-fluoroindol-3-yl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxylic acid (0.46 g, 1.12 mmol) [prepared as described Step 2 above] in methylene chloride (10 ml) was added O-benzylhydroxylamine hydrochloride salt (0.54 g, 3.36 mmol), followed by 4-dimethylaminopyridine (0.15 g, 1.23 mmol), 4-methylmorpholine (0.38 ml, 3.47 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimlide (0.43 g, 2.24 mmol). The reaction was stirred at RT for 2 h, diluted with methylene chloride (50 ml) and washed with 1M HCl. The organic layer was washed with brine, dried over MgSO4, and concentrated to give N-benzyloxy-1-[4-(5-fluoroindol-3-yl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxamide (95%) as a clear oil. This material was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12](O)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH:63]1([N:69]([CH2:71][CH:72]2[CH2:77][CH2:76][CH2:75][CH2:74][NH:73]2)[CH3:70])[CH2:68][CH2:67][CH2:66][CH2:65][CH2:64]1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:73]1[CH2:74][CH2:75][CH2:76][CH2:77][CH:72]1[CH2:71][N:69]([CH:63]1[CH2:68][CH2:67][CH2:66][CH2:65][CH2:64]1)[CH3:70])=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Reactant: CN(CC1CCCCN1)C1CCCCC1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc2cc(C(=O)N3CCCCC3CN(C)C3CCCCC3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and N-cyclohexyl-N-methyl-piperidin-2-ylmethyl-amine in DMSO at ambient temperature.
Reaction SMILES: [C:1]([Si:5]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[O:6][C@@H:7]1[CH2:11][C@@H:10](O)[C@@H:9]([O:13][CH:14]([CH3:16])[CH3:15])[CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[N:29]1C=CC=C[CH:30]=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>C(Cl)Cl>[C:1]([Si:5]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[O:6][C@@H:7]1[CH2:11][C@H:10]([C:30]#[N:29])[C@@H:9]([O:13][CH:14]([CH3:15])[CH3:16])[CH2:8]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)O[C@H]1C[C@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C[C@H]1O
Reactant: c1ccncc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: CC(C)O[C@H]1C[C@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C[C@@H]1C#N
Temperature: -35 °C
Reaction time: 5 h
Yield: 60 %

Procedure:
(1S,2R,4S) and (1R,2S,4R)-4-(tert-Butyl-diphenyl-silanyloxy)-2-isopropoxy-cyclopentanol (510 mg, 1.28 mmol) was dissolved in DCM (12 ml) and pyridine was added (206 μl, 2.56 mmol). The mixture was cooled to −35° C. and a solution of trifluoromethanesulfonic anhydride (253 μl, 1.54 mmol) in DCM (3 ml) was added. After the reaction mixture had been stirred for 5 h at −20° C. it was concentrated and passed trough a short plug of silica gel and then evaporated to dryness. The remaining oil was dissolved in THF (12 ml) and a solution of tertrabutylammonium cyanide in THF (3 ml) was added dropwise at −45° C. The reaction mixture was stirred at room temperature over night and then evaporated. The remaining yellow oil was purified by silica column chromatography (heptane/EtOAc 9:1) to obtain the title compound (311 mg, 60%) as colorless oil. MS (EI): 408.4 (M+H)+.
Reaction SMILES: Cl[CH2:2][N:3]1[C:13](=[O:14])[C:12]2[C:7](=[C:8]([O:19][CH3:20])[CH:9]=[C:10]([O:17][CH3:18])[C:11]=2[CH2:15][CH3:16])[S:4]1(=[O:6])=[O:5].[Na].[C:22]1([N:28]2[C:32]([SH:33])=[N:31][N:30]=[N:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>CN(C)C=O>[C:22]1([N:28]2[C:32]([S:33][CH2:2][N:3]3[C:13](=[O:14])[C:12]4[C:7](=[C:8]([O:19][CH3:20])[CH:9]=[C:10]([O:17][CH3:18])[C:11]=4[CH2:15][CH3:16])[S:4]3(=[O:6])=[O:5])=[N:31][N:30]=[N:29]2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Sc1nnnn1-c1ccccc1
Reactant: CCc1c(OC)cc(OC)c2c1C(=O)N(CCl)S2(=O)=O
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1c(OC)cc(OC)c2c1C(=O)N(CSc1nnnn1-c1ccccc1)S2(=O)=O
Yield: 74 %

Procedure:
A solution of 2-chloromethyl-4-ethyl-5,7-dimethoxysaccharin (Example 22L, 0.4 g) and 1-phenyltetrazol-5-thiol sodium salt (0.28 g) in dimethylformamide (3 mL) was heated at 110° C. for two hours, then poured into water. Recrystallization of the resulting solid from ethanol-water afforded 2-(1-phenyltetrazol-5-yl)thiomethyl-4-ethyl-5,7-dimethoxysaccharin, 0.44 g, 74% yield, mp 162°-164° C.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9](=O)OC(C)(C)C.C([O-])(=O)C.[Na+].COC1[CH2:27][CH2:26][CH:25](OC)O1.O1CCOCC1.[ClH:36]>C(O)(=O)C>[ClH:36].[N:8]1([C@@H:3]2[CH2:4][CH2:5][CH2:6][CH2:7][C@H:2]2[NH2:1])[CH:9]=[CH:27][CH:26]=[CH:25]1
Reactant: COC1CCC(OC)O1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@H]1N
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: N[C@@H]1CCCC[C@H]1n1cccc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
tert-Butyl N-[(1R,2R)-2-aminocyclohexyl]carbamate (1.06 g, 4.93 mmol), sodium acetate (1.70 g, 20.7 mmol) and 2,5-dimethoxytetrahydrofuran (764 μL, 5.91 mmol) were combined in acetic acid (10.6 mL). The reaction mixture was heated at 80° C. for 16 hours. The reaction mixture was then evaporated to dryness and the residue was partitioned between ethyl acetate and a saturated aqueous solution of sodium bicarbonate. The layers were separated, and the organic layer was washed twice with a saturated aqueous solution of sodium chloride, dried over sodium sulfate, and evaporated to dryness to yield a brown solid. This solid was then dissolved in HCl in dioxane (10.3 mL of 4.0 M, 41.1 mmol) and was allowed to stand for 3 hours. The solvent was then removed to yield trans-2-(1H-pyrrol-1-yl)cyclohexanamine hydrogen chloride (989 mg, 99%) as a brown solid. ESI-MS m/z calc. 164.1, found 165.2 (M+1)+; Retention time: 0.27 minutes (4 min run).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:16]=[CH:15][C:8]2[O:9][CH2:10][CH:11]([CH2:13][OH:14])[O:12][C:7]=2[C:6]=1[CH3:17])=[O:4].C(N(CC)CC)C.[CH3:25][O:26][C@:27]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:31]([F:34])([F:33])[F:32])[C:28](Cl)=[O:29]>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:16]=[CH:15][C:8]2[O:9][CH2:10][CH:11]([CH2:13][O:14][C:28](=[O:29])[C:27]([O:26][CH3:25])([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:31]([F:33])([F:34])[F:32])[O:12][C:7]=2[C:6]=1[CH3:17])=[O:4]
Reactant: CO[C@](C(=O)Cl)(c1ccccc1)C(F)(F)F
Reactant: COC(=O)c1ccc2c(c1C)OC(CO)CO2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1C)OC(COC(=O)C(OC)(c1ccccc1)C(F)(F)F)CO2

Procedure:
To a round bottom flask equipped with magnetic stirring and a nitrogen inlet was added 3-hydroxymethyl-5-methyl-2,3-dihydrobenzo[1,4]dioxine-6-carboxylic acid methyl ester (0.10 g, 0.44 mmol) and dry methylene chloride (1.5 mL). The mixture was cooled in an ice bath and triethylamine (0.12 mL, 0.87 mmol) was added followed by (R)-(−)-α-methoxy-α-trifluoromethylphenylacetyl chloride (0.09 mL, 0.48 mmol). The mixture was stirred for 2 hours at which point TLC showed the reaction to be incomplete. More (R)-(−)-α-methoxy-α-trifluoromethylphenylacetyl chloride (0.09 mL, 0.48 mmol) was added and the reaction was allowed to stir 1 hour at room temperature. The mixture was diluted with methylene chloride, washed once with 1N HCl, once with saturated sodium bicarbonate, dried over magnesium sulfate, filtered and evaporated. The residue was chromatographed on silica gel eluting with methylene chloride to give a clear oil, 5-methyl-3-(3,3,3-trifluoro-2-methoxy-2-phenyl-propionyl oxymethyl)-2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid methyl ester, for which a yield was not determined. 1H-NMR (300 MHz, CD3COCD3) c (ppm): 2.38 (s, 3H), 3.58 (s, 3H), 3.81 (s, 3H), 4.10 (m, 1H), 4.48 (dd, 1H), 4.65 (m, 2H), 4.86 (m, 1H) 6.78 (d, 1H) 7.47 (m, 5H), 7.60 (d, 1H); 19F-NMR (300 MHz, CD3COCD3) δ (ppm): −72.89 (s); both 1H- and 19F-NMR indicate the presence of only one stereo- and regioisomer; TLC: Rf=0.62 (1:1 ethyl acetate/hexane).