Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH:14]=[CH:15][CH:16]([OH:26])[CH2:17][C:18](=[O:25])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:12]([CH3:27])[N:11]=[C:10]([CH3:28])[N:9]=2)=[CH:4][CH:3]=1.C(O)(=O)C(C)(C)C.C(B(CC)CC)C.[BH4-].[Na+]>O1CCCC1.O.CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH:14]=[CH:15][CH:16]([OH:26])[CH2:17][CH:18]([OH:25])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:12]([CH3:27])[N:11]=[C:10]([CH3:28])[N:9]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(=O)CC(O)C=Cc1c(C)nc(C)nc1-c1ccc(F)cc1
Agent: CC(C)(C)C(=O)O
Agent: CCB(CC)CC
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCOC(=O)CC(O)CC(O)C=Cc1c(C)nc(C)nc1-c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of 27.5 g (0.071 mol) of [R*, S* (E)]-7-[4-(4-fluorophenyl)-2,6-dimethyl-5-pyrimidinyl]-5-hydroxy-3-oxo-6-heptenoic acid, ethyl ester and 0.73 g (0.0071 mol) of pivalic acid in 140 mL of anhydrous tetrahydrofuran under a dry air atmosphere at room temperature was added a 1M solution of triethylborane (28.4 mL, 0.0784 mol) in a dropwise manner. This solution was stirred for five minutes before 20 mL of air was bubbled through the solution. The mixture was thencooled to -78° C. and 18 mL of methanol and 2.96 g (0.0784 mol) of sodium borohydride were added. This mixture was stirred at -78° C. for six hours and then poured into 140 mL of ice cold 30% hydrogen peroxide solution at 0° C. This mixture was stirred at room temperature overnight and then diluted with water and extracted with ethylacetate.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:21]=[CH:20][C:9]2[NH:10][C:11]([CH2:16][C:17]([OH:19])=O)=[CH:12][S:13](=[O:15])(=[O:14])[C:8]=2[CH:7]=1)(=[O:4])=[O:3].[CH2:22]([O:25][C:26]([C:28]1[N:29]([NH:33][CH2:34][CH2:35][CH:36]([CH3:38])[CH3:37])[CH:30]=[CH:31][CH:32]=1)=[O:27])[CH:23]=[CH2:24].Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.Cl>CN(C)C=O>[CH2:22]([O:25][C:26]([C:28]1[N:29]([N:33]([C:17](=[O:19])[CH2:16][C:11]2[NH:10][C:9]3[CH:20]=[CH:21][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:7][C:8]=3[S:13](=[O:14])(=[O:15])[CH:12]=2)[CH2:34][CH2:35][CH:36]([CH3:38])[CH3:37])[CH:30]=[CH:31][CH:32]=1)=[O:27])[CH:23]=[CH2:24]
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)C=C(CC(=O)O)N2
Reactant: C=CCOC(=O)c1cccn1NCCC(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: C=CCOC(=O)c1cccn1N(CCC(C)C)C(=O)CC1=CS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
(7-Methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,4]thiazin-3-yl)-acetic acid (Example 8i, 0.1 g, 0.3 mmol) was dissolved in anhydrous N,N-dimethylformamide (3 mL). 1-(3-Methyl-butylamino)-1H-pyrrole-2-carboxylic acid allyl ester (Example 1c, 0.07 g, 0.3 mmol) was added followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.06 g, 0.315 mmol). Then N-methylmorpholine (0.07 mL, 0.63 mmol) was added into the above reaction mixture. The mixture was stirred at 25° C. for 4 h. The solution was poured into 1.0 M aqueous hydrochloric acid solution (50 mL). The aqueous layer was extracted with ethyl acetate (2×50 mL). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo to afford the crude desired product, 1-[[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,4]thiazin-3-yl)-acetyl]-(3-methyl-butyl)-amino]-1H-pyrrole-2-carboxylic acid allyl ester (0.3 mmol) as a yellow oil, which was used in the next step without further purification. LC-MS (ESI) calcd for C24H30N4O7S2 550.16. found 551.6 [M+H+].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:32]([O:34][C:35]([C:37]1([C:40]2[CH:45]=[CH:44][C:43](B3OC(C)(C)C(C)(C)O3)=[CH:42][CH:41]=2)[CH2:39][CH2:38]1)=[O:36])[CH3:33]>>[CH2:32]([O:34][C:35]([C:37]1([C:40]2[CH:45]=[CH:44][C:43]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]([O:24][Si:25]([C:28]([CH3:31])([CH3:29])[CH3:30])([CH3:27])[CH3:26])[CH2:15][CH2:16][CH2:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:4][CH:3]=3)=[CH:42][CH:41]=2)[CH2:38][CH2:39]1)=[O:36])[CH3:33]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(CCCc1ccccc1)O[Si](C)(C)C(C)(C)C
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(CCCc4ccccc4)O[Si](C)(C)C(C)(C)C)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using 5-(4-bromo-phenyl)-4-[1-(tert-butyl-dimethyl-silanyloxy)-4-phenyl-butyl]-3-methyl-isoxazole and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3].C(N(CC)CC)C.C[Si](Cl)(C)C.[CH:19]1([C:24](Cl)=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20]1>ClCCl.O>[CH:19]1([C:24]([NH:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3])=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: C[C@H](N)C(=O)O
Reactant: O=C(Cl)C1CCCC1
Agent: C[Si](C)(C)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)C1CCCC1)C(=O)O
Temperature: 40 °C
Reaction time: 1 h

Procedure:
Alanine (16.8 g, 189 mmol) and 57.8 ml (415 mmol) of triethylamine are dissolved in 200 ml of dichloromethane and 52.7 ml (415 mmol) of trimethylsilyl chloride are added dropwise. After addition is complete, the mixture is stirred for 1 h at room temperature and for 1 h at 40° C. After this, the batch is cooled to −10° C. and cyclopentanecarbonyl chloride (25.0 g, 189 mmol) is added dropwise and the mixture is stirred at this temperature for 2 h. The reaction mixture is treated with 100 ml of water with cooling, stirred for 10 min and and filtered with suction. The residue is washed with water and diethyl ether and dried at 60° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:27][CH2:28]Cl>C1COCC1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2([C:12]([O:14][CH3:15])=[O:13])[CH2:28][CH2:27]2)=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: ClCCBr
Reactant: COC(=O)Cc1ccc(C(C)(C)C)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C1(c2ccc(C(C)(C)C)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.4 %

Procedure:
4 g (19.4 mmol) of Methyl 4-tert-butylphenylacetate, 39 mL (1.0 m, 2 Eq.) of lithium bis(trimethylsilyl)amide, and 3 g (2 Eq.) of 1-bromo-2-chloroethane in 100 mL dry THF were reacted as described in Preparation 11, except that the reaction mixture was stirred for one hour at ambient temperature before work-up. This reaction yielded 4.21 g of a brown oil. This material was purified via silica gel chromatography eluting with a gradient solvent of hexane to hexane/EtOAc 19:1 to yield the title compound 1.57 g (35%) as a pale yellow solid m.p. 58°-60° C. Calculated for C15H20O2: Theory: C, 77.37; H, 8.81 Found: C, 77.54; H, 8.68.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:29])[CH:11]=[C:12]([CH2:17][NH:18][S:19]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[O:13][C:14]=1[CH:15]=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(S(C(N)C2OC(C(O)=O)=C(OCC3C=CC=CC=3)C(=O)C=2)(=O)=[O:37])C=CC=CC=1>>[CH2:1]([O:8][C:9]1[C:10](=[O:29])[CH:11]=[C:12]([CH2:17][NH:18][S:19]([C:22]2[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=2)(=[O:21])=[O:20])[O:13][C:14]=1[C:15]([OH:37])=[O:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(c1cc(=O)c(OCc2ccccc2)c(C(=O)O)o1)S(=O)(=O)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)NCc2cc(=O)c(OCc3ccccc3)c(C=O)o2)cc1
Product: Cc1ccc(S(=O)(=O)NCc2cc(=O)c(OCc3ccccc3)c(C(=O)O)o2)cc1
Yield: 80.14 %

Procedure:
3-Benzyloxy-4-oxo-6-[(toluene-4-sulfonylamino)-methyl]-4H-pyran-2-carboxylic acid (12-06) (2.0 g, 80.14%) was synthesized as a white solid from N-(5-benzyloxy-6-formyl-4-oxo-4H-pyran-2-ylmethyl)-4-methyl-benzenesulfonamide (11-06) (2.4 g, 5.81 mmol) following the procedure described for 6-(benzenesulfonylamino-methyl)-3-benzyloxy-4-oxo-4H-pyran-2-carboxylic acid (12-01).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([CH2:18][N:19]2[CH2:24][CH2:23][N:22]([S:25]([C:28]3[CH2:29][O:30][C:31]4[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:32]=4[CH:33]=3)(=[O:27])=[O:26])[CH2:21][C:20]2=[O:39])([C:14]([O:16][CH3:17])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>C(OCC)(=O)C.CO>[ClH:38].[Cl:38][C:36]1[CH:35]=[CH:34][C:32]2[CH:33]=[C:28]([S:25]([N:22]3[CH2:23][CH2:24][N:19]([CH2:18][C:11]4([C:14]([O:16][CH3:17])=[O:15])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)[C:20](=[O:39])[CH2:21]3)(=[O:27])=[O:26])[CH2:29][O:30][C:31]=2[CH:37]=1
Reactant: COC(=O)C1(CN2CCN(S(=O)(=O)C3=Cc4ccc(Cl)cc4OC3)CC2=O)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)C1(CN2CCN(S(=O)(=O)C3=Cc4ccc(Cl)cc4OC3)CC2=O)CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 196.8 %

Procedure:
To 1-[1-(tert-butoxycarbonyl)-4-methoxycarbonylpiperidin-4-ylmethyl]-4-(7-chloro-2H-benzopyran-3-sulfonyl)-2-piperazinone (260 mg) was added 4N hydrochloric acid in ethyl acetate (10 ml) and methanol (4 ml), and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated to give colorless solid of 4-(7-chloro-2H-benzopyran-3-sulfonyl)-1-(4-methoxycarbonylpiperidin-4-ylmethyl)-2-piperazinone hydrochloride (228 mg). A solution of 4-(7-chloro-2H-benzopyran-3-sulfonyl)-1-(4-methoxycarbonylpiperidin-4-ylmethyl)-2-piperazinone hydrochloride (228 mg), chloropyridine hydrochloride (80 mg) and triethylamine (225 mg) in ethanol (14 ml) was allowed to react in a sealed tube at 150° C. for 15 hours. The reaction solution was concentrated, and the residue was dissolved in dichloromethane. The solution was washed with 1N sodium hydroxide solution, dried and concentrated, and the residue was purified with silica gel column chromatography (dichloromethane:methanol containing 10% ammonia solution=20:1) to give colorless solid of the title compound (126 mg).
Reaction SMILES: FC(F)(F)C(O)=O.CC([NH:16][S:17]([C:20]1[CH:21]=[N:22][C:23]([C:26]2[C:31]([O:32][CH3:33])=[CH:30][CH:29]=[CH:28][C:27]=2[O:34][CH3:35])=[CH:24][CH:25]=1)(=[O:19])=[O:18])(C)CC(C)(C)C>ClCCl>[CH3:33][O:32][C:31]1[CH:30]=[CH:29][CH:28]=[C:27]([O:34][CH3:35])[C:26]=1[C:23]1[N:22]=[CH:21][C:20]([S:17]([NH2:16])(=[O:19])=[O:18])=[CH:25][CH:24]=1
Reactant: COc1cccc(OC)c1-c1ccc(S(=O)(=O)NC(C)(C)CC(C)(C)C)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(OC)c1-c1ccc(S(N)(=O)=O)cn1
Temperature: 25 °C

Procedure:
Trifluoroacetic acid (3.6 ml, 47 mmol) was added to a solution of 6-(2,6-Dimethoxy-phenyl)-pyridine-3-sulfonic acid (1,1,3,3-tetramethyl-butyl)-amide (1.90 g, 4.7 mmol) in 40 ml dichloromethane and stirred at room temperature (monitored by TLC). The mixture was evaporated to dryness, taken up in 10 ml ethyl acetate and washed with aqueous sodium bicarbonate. The organic layer was evaporated to dryness and the residue was purified by flash chromatography (SiO2, heptane-ethyl acetate gradient) to return 1.28 g of the title compound as an off-white solid, m/z=295 (ES+), 293 (ES−).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[Cl:10].[CH:11]1([C:17](Cl)=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>>[CH:11]1([C:17]([NH:1][CH2:2][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[Cl:10])=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: NCCc1ccccc1Cl
Product: O=C(NCCc1ccccc1Cl)C1CCCCC1

Procedure:
1-Amino-2-(2-chlorophenyl)ethane and cyclohexanecarbonyl chloride was reacted in the same way as in step (a) of Example 13 to afford 1-cyclohexylcarbonylamino-2-(2-chlorophenyl)ethane having a melting point of 93.5° to 93.9° C.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)[CH3:2].[Cl:9][C:10]1[N:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>>[Cl:9][C:10]1[N:15]=[CH:14][C:13]([S:16]([N:6]2[CH2:7][CH2:8][N:3]([CH2:1][CH3:2])[CH2:4][CH2:5]2)(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: CCN1CCNCC1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Product: CCN1CCN(S(=O)(=O)c2ccc(Cl)nc2)CC1
Yield: 83 %

Procedure:
The title compound was prepared as described for Example 25 using N-ethylpiperazine and 6-chloropyridine-3-sulfonyl chloride (described in: Naegeli, C. et al. Helv. Chim. Actal. 1938, 21, 1746-1750). Yield:83%: 1H NMR (CDCl3, 400 MHz) δ 8.75 (d, J=3 Hz, 1 H), 7.97 (dd, J=8, 3 Hz, 1 H), 7.50 (d, J=8 Hz, 1 H), 3.16-3.06 (m, 4 H), 2.60-2.46 (m, 4 H), 2.42 (q, J=7 Hz, 2 H), 1.04 (t, J=7 Hz, 3 H); 13C NMR (CDCl3, 100 MHz) δ 155.8, 148.9, 137.8, 131.3, 124.7, 51.9, 51.6, 46.0, 11.9; MS (ES) m/z 290 (M++1).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.N1C=CC=CC=1.[CH3:14][C:15]([NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:17]1[N:21]([CH3:22])[C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])=[N:19][N:18]=1)[CH3:16].Cl>[Cl-].[Na+].O.C(Cl)(Cl)Cl>[CH3:16][C:15]([N:30]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:5](=[O:7])[CH3:6])([C:17]1[N:21]([CH3:22])[C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])=[N:19][N:18]=1)[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccccc1-c1nnc(C(C)(C)Nc2ccccc2)n1C
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(=O)N(c1ccccc1)C(C)(C)c1nnc(-c2ccccc2C)n1C
Temperature: 80 °C
Reaction time: 96 h

Procedure:
Acetic anhydride (0.19 ml) and N,N-dimethylaminopyridine (40 mg) were added to a pyridine (10 ml) solution of N-{1-methyl-1-[4-methyl-5-(2-methylphenyl)-4H-1,2,4-triazol-3-yl]ethyl}aniline (500 mg), followed by stirring at 80° C. for 4 days. After the reaction solution and chloroform were added to a 1M hydrochloric acid solution, the reaction solution and chloroform were added to brine and then the organic layer was separated. Furthermore, the organic layer washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated sodium chloride solution successively, dried over anhydrous magnesium sulfate, and filtered and then the solvent was removed by evaporation under reduced pressure. The resulting crude product was purified by flash column chromatography (chloroform:methanol=99:1 to 96:4) and then the resulting solid was washed with ether to obtain 393 mg of N-{1-methyl-1-[4-methyl-5-(2-methylphenyl)-4H-1,2,4-triazol-3-yl]ethyl}-N-phenylacetamide (pale yellow solid).
Reaction SMILES: [NH2:1][C@H:2]1[C@@H:7]([NH:8][C:9]([C:11]2[NH:12][C:13]([CH2:17][CH3:18])=[C:14]([Cl:16])[N:15]=2)=[O:10])[CH2:6][CH2:5][N:4]([C:19]2[S:20][C:21]3[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=[CH:24][C:22]=3[N:23]=2)[CH2:3]1.[CH:33](=O)[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[Cl:16][C:14]1[N:15]=[C:11]([C:9]([NH:8][C@H:7]2[CH2:6][CH2:5][N:4]([C:19]3[S:20][C:21]4[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=[CH:24][C:22]=4[N:23]=3)[CH2:3][C@H:2]2[NH:1][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[O:10])[NH:12][C:13]=1[CH2:17][CH3:18]
Reactant: CCCCCC=O
Reactant: CCOC(=O)c1cccc2nc(N3CC[C@H](NC(=O)c4nc(Cl)c(CC)[nH]4)[C@H](N)C3)sc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCCCCCN[C@@H]1CN(c2nc3cccc(C(=O)OCC)c3s2)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1

Procedure:
The same operation as in Example (77d) was performed using ethyl cis(±)-2-(3-amino-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}piperidin-1-yl)-1,3-benzothiazole-7-carboxylate obtained by the method described in Example (81e) (30 mg, 0.063 mmol), 1-hexanal (22 μl, 0.18 mmol) and sodium (triacetoxy)borohydride (175 mg, 0.83 mmol), to obtain 28.4 mg of the title compound as a colorless oily substance (80%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]2[O:11][CH2:12][CH2:13][O:14][CH:7]2[CH2:6]1.[Cl:15][C:16]1[CH:17]=[C:18]([NH:23][C:24]2[C:33]3[C:28](=[CH:29][C:30]([O:35][CH3:36])=[C:31]([OH:34])[CH:32]=3)[N:27]=[CH:26][N:25]=2)[CH:19]=[CH:20][C:21]=1[F:22].C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>CN(C=O)C>[Cl:15][C:16]1[CH:17]=[C:18]([NH:23][C:24]2[C:33]3[C:28](=[CH:29][C:30]([O:35][CH3:36])=[C:31]([O:34][CH2:2][CH2:3][CH2:4][N:5]4[CH2:10][CH2:9][CH:8]5[O:11][CH2:12][CH2:13][O:14][CH:7]5[CH2:6]4)[CH:32]=3)[N:27]=[CH:26][N:25]=2)[CH:19]=[CH:20][C:21]=1[F:22]
Reactant: ClCCCN1CCC2OCCOC2C1
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCN1CCC2OCCOC2C1
Temperature: 80 °C
Yield: 25.9 %

Procedure:
A mixture of 6-(3-chloropropyl)octahydro-[1,4]dioxino[2,3-c]pyridine (100 mg, 0.46 mmol, 1 eq), 4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-ol (145 mg, 0.46 mmol, 1 eq) and K2CO3 (128 mg, 0.92 mmol, 2 eq) in DMF (10 mL) was heated at 80° C. overnight under N2, and cooled to room temperature. To this, 100 mL of CH2Cl2 was added. The mixture was washed with brine (20 mL×3) and water (20 mL×2). The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was chromatographed with a silica gel column (20:1 (v/v) CH2Cl2/MeOH) to afford the title compound as a yellow solid (60 mg, 28.00%), HPLC: 95.00%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 503.1 (M+1); 1H NMR (400 MHz, CDCl3) δ: 2.04-2.10 (2H, m), 2.21-2.48 (3H, m), 2.60-2.63 (2H, m), 2.92-3.08 (2H, m), 3.56-3.62 (2H, m), 3.67-3.72 (1H, m), 3.76-3.82 (2H, m), 3.52-3.53 (1H, m), 3.97 (2H, s), 4.08-4.15 (2H, m), 7.10-7.15 (1H, m), 7.21 (1H, s), 7.31 (1H, s), 7.62-7.65 (1H, m), 7.93-7.94 (1H, m), 8.62 (1H, s) ppm.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N:12]4[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]4=[O:19])=[CH:8][N:7]3[C:20]=2[CH3:21])[CH2:3][CH2:2]1.[Br:22][C:23]1[S:27][CH:26]=[C:25]([CH2:28]O)[CH:24]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[Br:22][C:23]1[S:27][CH:26]=[C:25]([CH2:28][O:18][C:15]2[CH:16]=[CH:17][N:12]([C:9]3[CH:10]=[CH:11][C:6]4[N:7]([C:20]([CH3:21])=[C:4]([CH:1]5[CH2:3][CH2:2]5)[N:5]=4)[CH:8]=3)[C:13](=[O:19])[CH:14]=2)[CH:24]=1
Reactant: OCc1csc(Br)c1
Reactant: Cc1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cn12
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cc1c(C2CC2)nc2ccc(-n3ccc(OCc4csc(Br)c4)cc3=O)cn12
Temperature: 60 °C
Reaction time: 3 h
Yield: 26.9 %

Procedure:
To a solution of 1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-hydroxypyridin-2(1H)-one (87 mg), (5-bromo-3-thienyl)methanol (119 mg) and tributylphosphine (188 mg) in THF (4 ml) was added 1,1′-(azodicarbonyl)dipiperidine (234 mg), and the reaction mixture was stirred at 60° C. for 3 h. The reaction mixture was then cooled to room temperature, concentrated, and purified by silica gel column chromatography (hexane/EtOAc then MeOH/EtOAc). The resulting solid was recrystallized from EtOH/hexane to give the title compound (38 mg) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=1)[C:10]([CH3:24])([CH3:23])[CH2:9]2)=[O:5])[CH3:2].[C:25](O)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:25](=[O:32])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:17]=1)[C:10]([CH3:23])([CH3:24])[CH2:9]2)=[O:5])[CH3:2]
Reactant: O=C(O)c1ccccc1
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(N)c1)N2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(NC(=O)c3ccccc3)c1)N2
Temperature: 25 °C
Reaction time: 12 h
Yield: 99.8 %

Procedure:
A mixture of 2-(3-amino-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (745 mg, 2.3 mmol), benzoic acid (337 mg, 2.76 mmol) and o-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.31 g, 3.45 mmol) in dichloromethane (10 mL) and triethyl-amine (0.8 mL, 5.75 mmol) was stirred at 25° C. for 12 h. Then the reaction mixture was extracted with dichloromethane (2×100 mL), washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-(3-benzoylamino-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (984 mg, 100%) as a brown oil which was used for next step without further purification: LC/MS m/e calcd for C27H28N2O3 (M+H)+: 429.54, observed: 429.1.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[Cl:13][C:14]1[N:19]=[CH:18][N:17]=[C:16]([C:20](Cl)=[O:21])[CH:15]=1.CCOC(C)=O>C1COCC1>[Cl:13][C:14]1[N:19]=[CH:18][N:17]=[C:16]([C:20]([N:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:4]([CH3:3])=[CH:5]2)=[O:21])[CH:15]=1
Reactant: Cc1c[nH]c2ccccc12
Reactant: O=C(Cl)c1cc(Cl)ncn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cn(C(=O)c2cc(Cl)ncn2)c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under a nitrogen atmosphere 120 mg (3.00 mmol) sodium hydride (60% in mineral oil) were added batchwise to 380 mg (2.90 mmol) 3-methylindole in 15 mL THF and the mixture was stirred for 30 min at RT. 500 mg (2.83 mmol) 6-chloropyrimidine-4-carboxylic acid chloride were added batchwise and then the reaction mixture was stirred for 2 h at RT. Then 50 mL EtOAc were added and the mixture was washed with 50 mL saturated sodium hydrogen carbonate solution (1×), 30 mL water and with 50 mL 1 M hydrochloric acid. The organic phase was dried on sodium sulphate, filtered and then evaporated down i. vac. The product was used in the next step without further purification.
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([C:8]2[N:9]=[C:10]([NH:13][C:14](=[O:18])[CH:15]([CH3:17])[CH3:16])[S:11][CH:12]=2)[N:5]=[C:4]2[C:19]3[C:25]([Cl:26])=[C:24]([O:27][CH3:28])[CH:23]=[CH:22][C:20]=3[O:21][C:3]=12.O=P(Cl)(Cl)[Cl:31]>>[Cl:31][C:2]1[CH2:7][CH:6]([C:8]2[N:9]=[C:10]([NH:13][C:14](=[O:18])[CH:15]([CH3:17])[CH3:16])[S:11][CH:12]=2)[N:5]=[C:4]2[C:19]3[C:25]([Cl:26])=[C:24]([O:27][CH3:28])[CH:23]=[CH:22][C:20]=3[O:21][C:3]=12
Reactant: COc1ccc2oc3c(O)cc(-c4csc(NC(=O)C(C)C)n4)nc3c2c1Cl
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc2oc3c(c2c1Cl)=NC(c1csc(NC(=O)C(C)C)n1)CC=3Cl
Reaction time: 0.17 h

Procedure:
A mixture of 11G (300 mg, 0.72 mmol) in POCl3 (5 mL) was refluxed for 30 min. After reaction completed, POCl3 was evaporated under reduced pressure. The residue was poured into crushed ice and stirred for 10 min. The solids were collected by filtration and dried to give 161 mg of product (M11).
Reaction SMILES: F[C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[C:4]([F:10])[C:3]=1[C:11]([F:14])([F:13])[F:12].[NH3:15]>O1CCCC1>[NH2:15][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[C:4]([F:10])[C:3]=1[C:11]([F:14])([F:13])[F:12]
Reactant: Fc1cc(F)c(C(F)(F)F)c(F)c1F
Reactant: N
Solvent: C1CCOC1
Product: Nc1c(F)c(F)cc(F)c1C(F)(F)F
Temperature: 100 °C

Procedure:
110 g of 2,3,4,6-tetrafluoro-benzotrifluoride in 200 ml of tetrahydrofuran were initially introduced into a 0.7 l stainless steel autoclave and it was pressurized using 30 ml of liquid ammonia. The mixture was subsequently heated at 100° C. for 3 hours, a maximum pressure of 10 bar being adjusted. After cooling, the pressure was released and the liquid phase was subjected to a fractional distillation. 42 g of 2-amino-3,4,6-trifluorobenzotrifluoride were first obtained with a boiling point of 47° to 48° C. at 8 mbar, then after an intermediate run, 46 g of 2,5,6-trifluoro-4-amino-benzo-trifluoride with a boiling point of 75° to 78° C. at 8 mbar.