Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC[C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1.C([N:11](CC)CC)C.[CH2:16]([O:23][C:24]1[CH:40]=[CH:39][CH:38]=[CH:37][C:25]=1[CH2:26][S:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>ClCCl>[N:5]1[CH:6]=[CH:7][CH:8]=[C:3]([NH:11][C:32](=[O:33])[C:31]2[CH:35]=[CH:36][C:28]([S:27][CH2:26][C:25]3[CH:37]=[CH:38][CH:39]=[CH:40][C:24]=3[O:23][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:29][CH:30]=2)[CH:4]=1
Reactant: O=C(Cl)c1ccc(SCc2ccccc2OCc2ccccc2)cc1
Reactant: CCN(CC)CC
Reactant: NCc1cccnc1
Solvent: ClCCl
Product: O=C(Nc1cccnc1)c1ccc(SCc2ccccc2OCc2ccccc2)cc1
Temperature: 25 °C

Procedure:
To a stirred mixture of 3-aminomethylpyridine (324 mg) and triethylamine (1.51 g) in dichloromethane (20 ml) at 0° C. was added 4-[2-benzyloxybenzylthio]benzoylchloride in CH2Cl2 (10 ml) (3 mmol). The mixture was allowed to warm to ambient temperature, washed with saturated aqueous NaHCO3 (3×20 ml), dried (MgSO4), filtered and evaporated. The residue was triturated with diethyl ether (20 ml) and crystallised from ethyl acetae to give N-(3-pyridyl)-4-[2-benzyloxybenzylthio]benzamide (220 mg). (mpt. 108° C.).
Reaction SMILES: [OH:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.C(N(CC)CC)C.[CH3:18][C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[C:20]=1[S:27](Cl)(=[O:29])=[O:28]>ClCCl>[CH3:18][C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[C:20]=1[S:27]([O:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1)(=[O:28])=[O:29]
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(S(=O)(=O)On2nnc3ccccc32)c(C)c1
Reaction time: 1 h
Yield: 84.2 %

Procedure:
In dichloromethane (70 ml) are added 1-hydroxy-1,2,3-benzotriazole (3.4 g) and further triethylamine (3.7 ml). To the solution is added dropwise a solution of 2,4,6-trimethylbenzenesulfonyl chloride (4.5 g) is dichloromethane (20 ml) at room temperature, and the mixture is stirred for 1 hour. The reaction mixture is washed with water and dried over anhydrous magnesium sulfate, and the solvent is distilled off. The resulting residue is washed with ethyl acetate-n-hexane (1:1; 50 ml) and dried to give colorless crystals of 1-(2,4,6-trimethylbenzenesulfonyloxy)-1,2,3-benzotriazole (5.5 g), melting point: 128°-130° C. The product is recrystallized from dichloromethane-n-hexane to give colorless prisms, melting point: 130°-131° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][S:8][C:4]=2[CH:3]=1.[Br:11]Br.CCOC(C)=O.CCCCCC>CC(O)=O.CCOC(C)=O>[Br:11][C:3]1[C:4]2[S:8][CH:7]=[N:6][C:5]=2[CH:9]=[CH:10][C:2]=1[NH2:1]
Reactant: BrBr
Reactant: Nc1ccc2ncsc2c1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CC(=O)O
Product: Nc1ccc2ncsc2c1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6-aminobenzothiazole (16 g, 107 mmol) in 100 mL of AcOH was added Br2 (2.0 mL, 43 mmol) dropwise and the resulting reaction mixture was stirred for 1 h at 25° C. Reaction mixture was concentrated in vacuo, yielding a yellow solid which was dissolved in EtOAc and washed with aq. NaHCO3. Organic layer was dried over Na2SO4 and concentrated in vacuo, yielding an oil which was subjected to column chromatography (10-50% EtOAc/n-Hexane) to obtain 7.8 g (34 mmol, 80 ) of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([OH:19])=O)[CH:15]=3)[NH:10][N:9]=2)=[CH:4][CH:3]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][NH2:27])[CH:21]=1>CN(C)C=O.Cl.C(N=C=NCCCN(C)C)C>[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][NH:27][C:17]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[NH:10][N:9]=[C:8]3[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[O:19])[CH:21]=1
Reactant: NCc1cccnc1
Reactant: O=C(O)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(NCc1cccnc1)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 53.8 %

Procedure:
To a solution of 150 mg of 3-(4-fluorophenyl)-1H-5-indazolecarboxylic acid produced in Production Example I-14 in 2.5 ml dimethylformamide were added a solution of 70 mg of 3-picolylamine in 0.5 ml dimethylformamide and 124 mg of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (═WSC.HCl), and the mixture was stirred at room temperature for four days. After removing the solvent by distillation, the residue was dissolved in 25 ml of ethyl acetate. The mixture was sequentially washed with water and brine, dried over anhydrous magnesium sulfate and the solvent was removed. The resulting crude crystals were recrystallized from ethyl acetate-diisopropyl ether, to give 109 mg of the title compound as pale yellow crystals.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:21]([O-:23])=[O:22])=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH:7]=1.[Cl:24][C:25]1[CH:26]=[C:27]([CH:30]=[C:31]([Cl:33])[CH:32]=1)[CH2:28][NH2:29].C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:24][C:25]1[CH:26]=[C:27]([CH:30]=[C:31]([Cl:33])[CH:32]=1)[CH2:28][NH:29][C:2]1[CH:3]=[CH:4][C:5]([N+:21]([O-:23])=[O:22])=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(F)ccc2[N+](=O)[O-])CC1
Reactant: NCc1cc(Cl)cc(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(c2cc(NCc3cc(Cl)cc(Cl)c3)ccc2[N+](=O)[O-])CC1
Yield: 41 %

Procedure:
t-Butyl 4-(5-fluoro-2-nitrophenyl)piperazine-1-carboxylate (1.3 mmol), 3,5-dichlorobenzylamine (1.3 mmol), N,N-diisopropylethylamine (1.3 mmol) were stirred at 80° C. in dry acetonitrile (25 mL) for 72 h. The solvent was evaporated and the residue was dissolved in dichloromethane and washed with water. The dichloromethane was evaporated and the crude compound was purified by silica chromatography using 25% ethyl acetate in hexanes to afford the title compound (41%). 1H NMR (400 MHz, CDCl3): δ 9.38 (br, 1H), 7.67 (d, 1H), 7.31 (s, 1H), 7.21 (s, 2H), 6.13 (dd, 1H), 5.70 (d, 1H), 4.42 (d, 2H), 3.54 (m, 4H), 3.38 (m, 4H), 1.49 (s, 9 H). MS (ESI) m/z: Calculated: 481.37; Observed: 482.6 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:31])=[C:6]([C@:8]23[CH2:17][O:16][C@@H:15](/[CH:18]=[CH:19]/[O:20][CH3:21])[CH2:14][C@H:13]2[CH2:12][S:11][C:10]([NH:22][C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:9]3)[CH:7]=1.[CH:32](OC)([O:35][CH3:36])[O:33][CH3:34].[C:39](=O)(O)[O-:40].[Na+]>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:31])=[C:6]([C@:8]23[CH2:17][O:16][C@@H:15]([CH:18]([CH:32]([O:35][CH3:36])[O:33][CH3:34])[CH:19]([O:40][CH3:39])[O:20][CH3:21])[CH2:14][C@H:13]2[CH2:12][S:11][C:10]([NH:22][C:23](=[O:30])[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[N:9]3)[CH:7]=1
Reactant: CO/C=C/[C@H]1C[C@H]2CSC(NC(=O)c3ccccc3)=N[C@@]2(c2cc(Br)ccc2F)CO1
Reactant: O=C([O-])O
Reactant: COC(OC)OC
Agent: [Na+]
Solvent: ClCCl
Product: COC(OC)C(C(OC)OC)[C@H]1C[C@H]2CSC(NC(=O)c3ccccc3)=N[C@@]2(c2cc(Br)ccc2F)CO1
Reaction time: 1.5 h

Procedure:
To a solution of N-{(4aR,6R,8aS)-8a-(5-bromo-2-fluorophenyl)-6-[(E)-2-methoxyethenyl]-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl}benzamide (C43) (0.54 g, 1.1 mmol) in dichloromethane (2 mL) at 0° C., was added trimethyl orthoformate (0.239 mL, 2.19 mmol) followed by drop-wise addition of boron trifluoride-diethyl etherate (0.136 mL, 1.08 mmol), without letting the reaction temperature exceed 3° C. The resulting solution was allowed to stir at the same temperature for 1.5 hours. The reaction mixture was diluted with dichloromethane (200 mL) and a saturated aqueous solution of sodium bicarbonate (200 mL). The organic layer was separated and resulting aqueous layer was extracted with further dichloromethane (200 mL). The combined organics were washed with brine (200 mL), dried over sodium sulfate, filtered and concentrated to give the product (0.65 g) as a white solid, which was taken directly to the following step. 1H NMR (400 MHz, CD3OD) characteristic peaks: δ 8.23 (br d, J=7.0 Hz, 2H), 7.41-7.52 (m, 5H), 6.99 (dd, J=1.7, 9.0 Hz, 1H), 4.52 (dd, J=17.7, 4.2 Hz, 1H), 4.13 (d, J=12.5 Hz, 1H), 4.04 (d, J=8.4 Hz, 1H), 3.79 (d, J=11.9 Hz, 1H), 3.13-3.19 (m, 1H), 2.98 (dd, J=13.1, 2.7 Hz, 1H), 2.64 (dd, J=13.1, 1.3 Hz, 1H).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][C@H:16]([CH2:24][CH3:25])[C:17]([N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:18].[CH:26]([C:28]1[CH:33]=[CH:32][N:31]=[C:30]2[N:34]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH:35]=[C:36]([C:37]([O:39][CH3:40])=[O:38])[C:29]=12)=O>ClCCCl.C(O)(=O)C>[O:18]=[C:17]([N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)[C@H:16]([NH:15][CH2:26][C:28]1[CH:33]=[CH:32][N:31]=[C:30]2[N:34]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH:35]=[C:36]([C:37]([O:39][CH3:40])=[O:38])[C:29]=12)[CH2:24][CH3:25]
Reactant: COC(=O)c1cn(C(=O)OC(C)(C)C)c2nccc(C=O)c12
Reactant: CC[C@@H](N)C(=O)N1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC[C@@H](NCc1ccnc2c1c(C(=O)OC)cn2C(=O)OC(C)(C)C)C(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
A mixture of sodium triacetoxyborohydride (237 mg, 1.116 mmol) and (R)-2-amino-1-(pyrrolidin-1-yl)butan-1-one (131 mg, 0.837 mmol) in DCE (2 mL) was stirred at room temperature for 30 min. The reaction mixture was cooled to 0° C. A solution of 1-tert-butyl 3-methyl 4-formyl-1H-pyrrolo[2,3-b]pyridine-1,3-dicarboxylate (200 mg, 0.657 mmol) in DCE (2 mL) was added, followed by acetic acid (1 drop). The reaction was stirred at 0° C. for 30 min and then at room temperature for 3 h. Purification by silica column chromatography (EtOAc/DCM, 0-10%) afforded the title compound as a yellow oil (260 mg, 93%). [M+H] calc'd for C23H32N4O5, 445; found, 445.5.
Reaction SMILES: C([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[C:7](Br)[C:6]=1[O:14][CH3:15])(=O)C.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[OH:24].C(=O)([O-])[O-].[Cs+].[Cs+]>N1C=CC=CC=1.[Cu]=O>[OH:4][C:5]1[C:6]([O:14][CH3:15])=[CH:7][C:8]([CH:9]=[O:10])=[C:11]([O:24][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[O:17][CH3:16])[CH:12]=1
Reactant: COc1ccccc1O
Reactant: COc1c(OC(C)=O)ccc(C=O)c1Br
Agent: O=[Cu]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: c1ccncc1
Product: COc1cc(C=O)c(Oc2ccccc2OC)cc1O
Temperature: 130 °C

Procedure:
To a mixture of 4-acetoxy-2-bromo-3-methoxybenzaldehyde (546 mg, 2 mmol; prepared in example 105, step a), 2-methoxy-phenol (280 mg, 2 mmol) and cesium carbonate (1.3 g, 4 mmol) in 16 mL of pyridine was added copper oxide(320 mg, 4 mmol)under argon. The mixture was purged with argon for 10 min, heated at 130° C. overnight and then quenched with 5% HCl solution. The mixture was extracted with ethyl acetate, washed with 1N NaOH solution and water before drying over sodium sulfate. After the removal of the solvent, the residue was chromatographed to give the product, 4-hydroxy-5-methoxy-2-(2-methoxy-phenoxy)-benzaldehyde.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([S:10][CH2:11][C:12]([OH:14])=O)=[CH:2]1.[NH2:15][C:16]1[CH:20]=[C:19]([CH3:21])[O:18][N:17]=1.C1CN(C(Cl)=[N+]2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.ClC(Cl)C>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([S:10][CH2:11][C:12]([NH:15][C:16]2[CH:20]=[C:19]([CH3:21])[O:18][N:17]=2)=[O:14])=[CH:2]1
Reactant: O=C(O)CSc1c[nH]c2ccccc12
Reactant: Cc1cc(N)no1
Agent: ClC(N1CCCC1)=[N+]1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(NC(=O)CSc2c[nH]c3ccccc23)no1
Yield: 71 %

Procedure:
2-((1H-indol-3-yl)thio)acetic acid (650 mg, 3.14 mmol) from Step B, 3-amino-5-methyl-isoxazole (616 mg, 6.28 mmol), PyClu (2.00 g, 6.28 mmol), and DIEA (1.36 mL, 7.85 mmol) were added to dichloroethane (25 mL) and microwave irradiated at 110° C. for 20 minutes. The solvent was removed in vacuo and the remaining residue purified on a silica gel column (0-70% ethyl acetate:hexanes over 33 min) to yield the desired product (642 mg, 2.23 mmol, 71% yield). LCMS>99% at 214 nm, RT=1.23 min, m/z=288 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:13]([CH3:14])=[CH:12][C:11]([OH:15])=[CH:10][C:9]2=[O:16])[C:5]([CH3:17])=[CH:4][N:3]=1.[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Cl)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C.CCCCCCC>CN(C)C=O.C1OCCOCCOCCOCCOCCOC1>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH2:24][C:23]3[CH:26]=[CH:27][C:20]([O:19][CH3:18])=[CH:21][CH:22]=3)=[CH:10][C:9]2=[O:16])[C:5]([CH3:17])=[CH:4][N:3]=1
Reactant: Cc1cnc(Cl)cc1-n1c(C)cc(O)cc1=O
Reactant: COc1ccc(CCl)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(COc2cc(C)n(-c3cc(Cl)ncc3C)c(=O)c2)cc1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
To a solution of 2′-chloro-4-hydroxy-6,5′-dimethyl-[1,4′]bipyridinyl-2-one of part A (6.0 g, 20.1 mmol) in N,N-dimethylformamide (20 mL) was added 4-methoxybenzylchloride (2.73 mL, 20.1 mmol), potassium carbonate (6.93 g, 50.2 mmol) and 18-crown-6 (100 mg). The slurry was heated at 60° C. for 3 h and was stirred at ambient temperature for 18 h. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water and brine and dried over magnesium sulfate. The solution was concentrated in vacuo to provide a brown oil. Normal phase chromatography (ethyl acetate/heptane) provided the alkylated product as a light yellow solid (4.6 g): MS (ES) m/e 371 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)[CH:3]=1.C(N(CC)CC)C.[CH:29]1([C:34]2[CH:35]=[C:36]3[N:41]([C:42]=2[C:43](=[O:47])[C:44](Cl)=[O:45])[CH2:40][CH2:39][CH2:38][CH2:37]3)[CH2:33][CH2:32][CH2:31][CH2:30]1>C1COCC1>[CH:29]1([C:34]2[CH:35]=[C:36]3[N:41]([C:42]=2[C:43](=[O:47])[C:44]([NH:21][C:18]2[CH:19]=[CH:20][C:15]([N:12]4[CH2:13][CH2:14][N:9]([C:4]5[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[N:5]=5)[CH2:10][CH2:11]4)=[CH:16][CH:17]=2)=[O:45])[CH2:40][CH2:39][CH2:38][CH2:37]3)[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: Cc1cc(C)nc(N2CCN(c3ccc(N)cc3)CC2)c1
Reactant: O=C(Cl)C(=O)c1c(C2CCCC2)cc2n1CCCC2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(C)nc(N2CCN(c3ccc(NC(=O)C(=O)c4c(C5CCCC5)cc5n4CCCC5)cc3)CC2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 45.5 %

Procedure:
A solution of 4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenylamine (prepared as described in Reference Example 94; 0.20 g, 0.71 mmol) and triethylamine (0.3 mL, 2.1 mmol) in THF (5 mL) was cooled to 0° C. A solution of (2-cyclopentyl-5,6,7,8-tetrahydro-indolizin-3-yl)-oxo-acetyl chloride (prepared as described in Reference Example 22, 0.24 g, 0.85 mmol) in THF (2 mL) was added and the mixture stirred under N2 atmosphere at 0° C. for 1 h and then at room temperature for 1 h. The mixture was quenched with sodium bicarbonate solution and extracted twice with ethyl acetate. The combined organic phases were washed with water and brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (60-120 mesh) eluting with 12% ethyl acetate/chloroform to afford 2-(2-cyclopentyl-5,6,7,8-tetrahydro-indolizin-3-yl)-N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide (0.17 g, 46%) as a solid.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O)(=[O:3])[CH3:2].C([N:16]([CH2:19][CH3:20])[CH2:17]C)C.ClC(OCC)=O.[CH3:27][C:28]1([CH3:35])[O:32]C(CN)C[O:29]1>ClCCl.O>[CH3:27][C:28]1([CH3:35])[O:32][CH:19]([N:16]([CH3:17])[C:7](=[O:9])[C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[O:4][C:1](=[O:3])[CH3:2])[CH2:20][O:29]1
Reactant: CC1(C)OCC(CN)O1
Reactant: CCN(CC)CC
Reactant: CC(=O)Oc1ccccc1C(=O)O
Agent: CCOC(=O)Cl
Solvent: ClCCl
Solvent: O
Product: CC(=O)Oc1ccccc1C(=O)N(C)C1COC(C)(C)O1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
The solution from 2-acetoxybenzoic acid (216 mg, 1.2 mmol) in dichloromethane (4 ml) is treated with triethylamine (0.15 ml, 1.2 mmol), cooled to 0° C., treated dropwise with ethyl chloroformate (0.144 ml, 1.0 mmol), stirred at 0° C. for 2 h and filtered. The filtrate is added at room temperature to a solution of 2,2-dimethyl-4-aminomethyl-1,3-dioxolane (293 mg, 1.0 mmol) and triethylamine (0.14 ml) in dichloromethane (4 ml). After 4 h, water (10 ml) is added and the mixture is stirred. The organic phase is washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and water, dried over magnesium sulphate and concentrated. The residue is purified by column chromatography on silica gel 60 (gradient hexane/ethyl acetate=3/1→1/1). Yield: 143 mg.
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([S:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:20]=[CH:21][C:22]4[NH:27][C:26](=[O:28])[O:25][CH2:24][C:23]=4[CH:29]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:30]O>>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([S:13]([CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:20]=[CH:21][C:22]4[NH:27][C:26](=[O:28])[O:25][CH2:24][C:23]=4[CH:29]=3)=[O:30])=[CH:11][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OO
Reactant: O=C1Nc2ccc(OCCCCSc3ccc(C4CCCCC4)cc3)cc2CO1
Product: O=C1Nc2ccc(OCCCCS(=O)c3ccc(C4CCCCC4)cc3)cc2CO1

Procedure:
Prepared analogously to Example 2 from 6-[4-(4-cyclohexyl-phenylmercapto)-butoxy]-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: CC([N:5]([CH2:9][CH:10]([NH:18][C:19]([C:21]1[S:22][CH:23]=[C:24]([C:26]2[N:30]([CH3:31])[N:29]=[CH:28][C:27]=2[Cl:32])[CH:25]=1)=[O:20])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)C(=O)[O-])(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:5][CH2:9][CH:10]([NH:18][C:19]([C:21]1[S:22][CH:23]=[C:24]([C:26]2[N:30]([CH3:31])[N:29]=[CH:28][C:27]=2[Cl:32])[CH:25]=1)=[O:20])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Cn1ncc(Cl)c1-c1csc(C(=O)NC(Cc2ccccc2)CN(C(=O)[O-])C(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1ncc(Cl)c1-c1csc(C(=O)NC(CN)Cc2ccccc2)c1
Reaction time: 0.5 h

Procedure:
A solution of 1,1-dimethylethyl[2-({[4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thienyl]carbonyl}amino)-3-phenylpropyl]carbamate (crude from part c) in TFA-DCM (3 mL, 1:2) was stirred at 25° C. After 30 min, the solution was concentrated and the residue neutralized through a silica plug (4% MeOH in DCM (1% NH4OH)) affording the free base of the title compound.
Reaction SMILES: [Cl-].[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11]C(O)=O)=[CH:7][CH:6]=1)([O-:4])=[O:3].[N-:15]=[N+]=[N-].[Na+].C[C:20](C)=[O:21]>C(Cl)(Cl)Cl>[N+:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][N:15]=[C:20]=[O:21])=[CH:9][CH:10]=1)([O-:4])=[O:3]
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)=O
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: O=C=NCc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C

Procedure:
The chloride of 4-nitrophenylacetic acid in solution in dry acetone (7.5 ml) is slowly added to an aqueous solution of 0.75 g (11.5 mmoles) of sodium azide, cooled down to 0° C. Agitation of the medium is maintained for one hour after the addition is completed, at 0-5° C. The reaction medium is then diluted with 30 ml of chloroform, decanted and the organic phase washed with water (20 ml) followed by a saturated solution of sodium chloride (20 ml). After drying over sodium sulphate, the organic solution is filtered and partly concentrated ( 20 ml) under vacuum.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH2:3]N1CCCCC1.C([N:14](CC)CC)C.ClC1C=CC([S:26](Cl)(=[O:28])=[O:27])=CC=1>ClCCCl>[F:1][C:2]([F:11])([F:10])[CH2:3][S:26]([NH2:14])(=[O:28])=[O:27]
Reactant: CCN(CC)CC
Reactant: FC(F)(F)CN1CCCCC1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: ClCCCl
Product: NS(=O)(=O)CC(F)(F)F
Yield: 114.1 %

Procedure:
b)To a solution of O-protected trifluoroethyl piperidine (1.13 g, 3.6 mmol) in DCE (15 mL) was added triethylamine (0.6 mL, 4.3 mmol) then 4-chlorobenzenesulfonyl chloride (1.13 g, 5.4 mmol) and the reaction was heated at reflux overnight. The final mixture was concentrated and directly purified by flash chromatography over silica gel (eluting hexane to DCM) to afford 0.67 g (38%) of O-protected trifluoroethyl sulfonamide.
Reaction SMILES: [C:1]1([CH3:8])[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:9](Cl)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[OH-].[K+]>O.C(O)C>[CH2:9]([O:7][C:6]1[C:1]([CH3:8])=[CH:2][CH:3]=[CH:4][CH:5]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cc1ccccc1O
Reactant: ClCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1ccccc1OCc1ccccc1
Yield: 76.4 %

Procedure:
o-Cresol (50 g), 70 g of benzyl chloride and 38.5 g of potassium hydroxide were boiled in a mixture of 100 ml of water and 500 ml of ethanol for 4 hours. The solvent was then distilled off and the residue was shaken with 500 ml each of water and diethyl ether. The diethyl ether layer was washed with 10% sodium hydroxide and water in that order, and distilled under reduced pressure to give 70 g of an O-benzylcresol fraction boiling at 130°-133° C./5 mmHg.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:23]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][NH2:30])[CH:24]=1.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C>[C:23]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][NH:30][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[N:3][CH:4]=2)[CH:24]=1
Reactant: NCc1cccc(-c2ccccc2)c1
Reactant: O=C(O)c1ccc(Cl)nc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(NCc1cccc(-c2ccccc2)c1)c1ccc(Cl)nc1
Temperature: 100 °C
Reaction time: 0.75 h
Yield: 80.8 %

Procedure:
6-Chloronicotinic acid (0.29 g) and 1,1′-carbonylbis(1H-imidazole) (0.34 g) were dissolved in N,N-dimethylformamide (5 mL), and the solution was heated with stirring at 100° C. for 45 minutes. The reaction solution was brought back to room temperature. 1-Biphenyl-3-ylmethanamine (0.37 g) and triethylamine (0.51 mL) were added thereto, and the mixture was stirred at 70° C. for 2 hours. Ethyl acetate was added thereto, and the organic layer was washed with water and dried over sodium sulfate. After concentration under reduced pressure, the obtained residue was purified by silica gel column chromatography (Moritex Corporation, elution solvent: hexane/ethyl acetate) to obtain the title compound (0.48 g) as a white solid (yield: 81%).
Reaction SMILES: [CH2:1]([C:8]1([OH:14])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:22]([O:27][C@@H:28]([C:30]1[N:35]=[C:34](OS(C)(=O)=O)[CH:33]=[CH:32][N:31]=1)[CH3:29])(=[O:26])[CH2:23]CC>ClCCl>[C:22]([O:27][C@@H:28]([C:30]1[N:31]=[C:32]([N:11]2[CH2:12][CH2:13][C:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)([OH:14])[CH2:9][CH2:10]2)[CH:33]=[CH:34][N:35]=1)[CH3:29])(=[O:26])[CH3:23]
Reactant: CCCC(=O)O[C@H](C)c1nccc(OS(C)(=O)=O)n1
Reactant: OC1(Cc2ccccc2)CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)O[C@H](C)c1nccc(N2CCC(O)(Cc3ccccc3)CC2)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-benzyl-4-hydroxypiperidine (0.95 g, 5.0 mmol) and triethylamine (0.51 g, 5.0 mmol) in dichloromethane (10 mL) was added (R)-1-(4-methanesulfonyloxy-pyrimidin-2-yl)-ethyl butyrate (prepared according to the method of Preparation Eight, 1.23 g, 4.0 mmol) and stirred at ambient temperature for 18 h. The mixture was washed once with water, once with saturated aqueous sodium chloride and the organic layer was dried over sodium sulfate and filtered. The filtrate was evaporated to an oil which was purified by flash chromatography (95:5 dichloromethane:methanol) to give the title compound of Example 174, Step A as a viscous oil, 0.99 g (52%). 1H NMR (CDCl3, 300 MHz) δ 0.95 (t, 3H), 1.53 (d, 3H), 1.65-1.78 (m, 4H), 1.88 (m, 2H), 2.08 (m, 2H), 2.48 (t, 2H), 3.45 (m, 2H), 4.42 (br s, 1H), 5.68 (q, 1H), 6.41 (d, 1H), 7.30-7.48 (m, 5H), 8.18 (d, 1H); MS (CI) 384 (MH+).