Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl[C:16]1[CH:21]=[CH:20][N:19]=[C:18](CCl)[CH:17]=1.[C:24](=O)([O-])O.[Na+]>CN(C)C=O>[CH3:3][C:4]([CH2:24][C:16]1[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=1)([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: O=C([O-])O
Reactant: CCOC(=O)C(C)C(=O)OCC
Reactant: ClCc1cc(Cl)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(Cc1ccncc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
N,N-Dimethylformamide (143 ml) was added to sodium hydride (5.36 g, 134 mmol) under a nitrogen atmosphere, and the mixture was stirred under ice-cooling. A solution of diethyl methylmalonate (11.7 g, 67.1 mmol) in N,N-dimethylformamide (40 ml) was added dropwise to the mixture over five minutes, after 10 minutes, 4-chloropicolyl hydrochloride (10.0 g, 61.0 mmol) was added thereto little by little over five minutes, and the temperature was raised to room temperature. After one hour, a saturated aqueous sodium hydrogencarbonate solution (500 ml) was added to the reaction mixture, and the whole was extracted with diethyl ether (400 ml). The organic layer was washed with water (100 ml) and saturated brine (50 ml) successively, dried over magnesium sulfate and concentrated under reduced pressure to give diethyl 2-methyl-2-(4-pyridylmethyl)malonate (17.2 g, quantitatively, containing sodium hydride oil) as a brown oily matter.
Reaction SMILES: CC([C:4]1[CH:9]=[CH:8][CH:7]=[C:6](C(C)C)[C:5]=1[CH2:13][C:14]([C:16]1[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:29])(=[O:28])[NH2:27])[C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=1)=[O:15])C.C([C:36]1[CH:41]=[CH:40][CH:39]=[C:38](C(C)C)[C:37]=1CC(O)=O)(C)C>>[CH:5]1([CH:13]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:14]([C:16]2[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:29])(=[O:28])[NH2:27])[C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=2)=[O:15])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:4]1
Reactant: CC(C)c1cccc(C(C)C)c1CC(=O)c1ccc(C(C)C)c(OS(N)(=O)=O)c1C(C)C
Reactant: CC(C)c1cccc(C(C)C)c1CC(=O)O
Product: CC(C)c1ccc(C(=O)C(c2ccccc2)C2CCCCC2)c(C(C)C)c1OS(N)(=O)=O

Procedure:
This compound was prepared in the same manner as for the title compound of Example 1, except that 2,6-diisopropylphenylacetic acid was replaced with α-phenylcyclohexanecarboxylic acid, mp 127°-137° C.
Reaction SMILES: [C:1](#[N:3])C.[N:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:10](Cl)(Cl)=S>O>[N:3]1[C:1]2[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=2[NH:4][CH:10]=1
Reactant: CC#N
Reactant: S=C(Cl)Cl
Reactant: c1ccncc1
Solvent: O
Product: c1ccc2[nH]cnc2c1
Temperature: 5 °C
Reaction time: 2 h

Procedure:
Into 500 ml of acetonitrile was suspended 40 g (0.217 mol) of N-phenylenediamine in an atmosphere of nitrogen. The suspension was cooled with ice to 5° C. or lower where it was then kept. To the suspension was then added 37 ml (0.477 mol) of pyridine. To the reaction mixture was then added dropwise 25 g (0.217 mol) of thiophosgene while the temperature of the reaction system was being controlled to lower than 10° C. After completion of the dropwise addition, the temperature of the reaction solution was gradually returned to room temperature. The reaction solution was then allowed to undergo at the same temperature for 2 hours. To the reaction solution was then added water. The resulting precipitate was withdrawn by filtration, washed with water, dried, and then recrystallized from methanol to obtain 30.9 g (0.137 mol) of benzimidazole as the target compound (yield: 63%).
Reaction SMILES: C[O:2][C:3](=[O:40])[C@@H:4]([NH:22][C:23]([C:25]1[CH:26]=[C:27]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[C:34]([Cl:39])[CH:33]=2)[CH:28]=[CH:29][C:30]=1[OH:31])=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)=[CH:8][CH:7]=1.[Li+].[OH-].C(OCC)(=O)C.Cl>C1COCC1.CO>[Cl:39][C:34]1[CH:33]=[C:32]([C:27]2[CH:28]=[CH:29][C:30]([OH:31])=[C:25]([C:23]([NH:22][C@@H:4]([CH2:5][C:6]3[CH:11]=[CH:10][C:9]([C:12]4[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:19])[F:20])[CH:13]=4)=[CH:8][CH:7]=3)[C:3]([OH:40])=[O:2])=[O:24])[CH:26]=2)[CH:37]=[CH:36][C:35]=1[F:38]
Reactant: COC(=O)[C@H](Cc1ccc(-c2cccc(C(F)(F)F)c2)cc1)NC(=O)c1cc(-c2ccc(F)c(Cl)c2)ccc1O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(N[C@@H](Cc1ccc(-c2cccc(C(F)(F)F)c2)cc1)C(=O)O)c1cc(-c2ccc(F)c(Cl)c2)ccc1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 96.5 %

Procedure:
2-(S)-[(3′-Chloro-4′-fluoro-4-hydroxy-biphenyl-3-carbonyl)-amino]-3-(3′-trifluoromethyl-biphenyl-4-yl)-propionic acid methyl ester (3.0 g, 5.2 mmol) was dissolved in 100 mL of THF-methanol (4-1), cooled to 0° C. and 20 mL 2N LiOH added. The reaction was stirred at 0° C. for 1 hour. Ethyl acetate (100 mL) and 1N HCl (100 mL) were added to the mixture and the organic washed with brine, dried and evaporated to give 2-(S)-[(3′-chloro-4′-fluoro-4-hydroxy-biphenyl-3-carbonyl)-amino]-3-(3′-trifluoromethyl-biphenyl-4-yl)-propionic acid (2.8 g). LC/MS (m/z): 558 [(M+1)+].
Reaction SMILES: O[CH2:2][C@H:3]1[C@@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)[CH2:8][C@H:7]2[N:18]([CH3:19])[C@@H:4]1[CH2:5][CH2:6]2.[CH2:20]([N:22](CC)CC)C.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[C-]#N.[Na+]>C(Cl)Cl.C(OCC)C.O>[ClH:16].[Cl:17][C:12]1[CH:11]=[C:10]([C@H:9]2[CH2:8][C@H:7]3[N:18]([CH3:19])[C@:4]([C:20]#[N:22])([CH2:5][CH2:6]3)[C@@H:3]2[CH3:2])[CH:15]=[CH:14][C:13]=1[Cl:16]
Reactant: CCN(CC)CC
Reactant: CN1[C@H]2CC[C@@H]1[C@@H](CO)[C@@H](c1ccc(Cl)c(Cl)c1)C2
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCOCC
Product: C[C@@H]1[C@@H](c2ccc(Cl)c(Cl)c2)C[C@@H]2CC[C@@]1(C#N)N2C
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of (1R,2S,3S)-2-hydroxymethyl-3-(3,4-dichloro-phenyl)tropane (6.9 g, 23 mmol), triethyl amine (7 ml, 51 mmol) and p-toluenesulphonyl chloride (6.4 g, 34 mmol) in 50 ml methylene chloride was stirred over night at room temperature followed by concentration of the reaction mixture in vacuo. Water (50 ml) and diethylether (50 ml) was added and the mixture was stirred at room temperature for 30 minutes. The ether phase was first washed once with 15 ml 1M sodium hydroxide solution followed by three times water and was finally concentrated in vacuo. The residue was dissolved in ethanol (200 ml) and sodium cyanide-(2.5 g, 51 mmol) was added. The mixture was stirred at reflux temperature for two days followed by concentration in vacuo. The residue was stirred with diethyl ether and water and the ether phase was washed twice with water and concentrated in vacuo. The crude product was subjected to column chromatography using methylene chloride+acetone+methanol (4+1+ 1) as eluent and the fractions containing the product was concentrated in vacuo. The product was dissolved in a small amount of methylene chloride and a solution of hydrochloric acid in diethylether (2M) was added. The mixture was concentrated in vacuo yielding the title compound as a hydroscopic crystals.
Reaction SMILES: [C:1]([O:5][C:6](=[O:62])[CH2:7][N:8]([C:17]1[CH:22]=[CH:21][C:20]([C:23]2([OH:53])[C:36]3[CH:35]=[C:34]([F:37])[C:33]([O:38][CH2:39][O:40][CH2:41][CH2:42][O:43][CH3:44])=[CH:32][C:31]=3[O:30][C:29]3[C:24]2=[CH:25][C:26]([F:52])=[C:27]([O:45][CH2:46][O:47][CH2:48][CH2:49][O:50][CH3:51])[CH:28]=3)=[CH:19][C:18]=1[O:54]CC1C=CC=CC=1)[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([CH3:4])([CH3:3])[CH3:2]>C(O)C.CCOC(C)=O.[Pd]>[C:13]([O:12][C:10](=[O:11])[CH2:9][N:8]([CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:62])[C:17]1[CH:22]=[CH:21][C:20]([C:23]2([OH:53])[C:36]3[CH:35]=[C:34]([F:37])[C:33]([O:38][CH2:39][O:40][CH2:41][CH2:42][O:43][CH3:44])=[CH:32][C:31]=3[O:30][C:29]3[C:24]2=[CH:25][C:26]([F:52])=[C:27]([O:45][CH2:46][O:47][CH2:48][CH2:49][O:50][CH3:51])[CH:28]=3)=[CH:19][C:18]=1[OH:54])([CH3:16])([CH3:15])[CH3:14]
Reactant: COCCOCOc1cc2c(cc1F)C(O)(c1ccc(N(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C)c(OCc3ccccc3)c1)c1cc(F)c(OCOCCOC)cc1O2
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COCCOCOc1cc2c(cc1F)C(O)(c1ccc(N(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C)c(O)c1)c1cc(F)c(OCOCCOC)cc1O2
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.4 %

Procedure:
To a solution of 14 (956 mg, 1.1 mmol) in 95% ethanol (25 mL) and EtOAc (25 mL) was added 10% Pd/C (130 mg). The resulting mixture was stirred at room temperature overnight under H2 (1 atm). The catalyst was then removed by filtration and, after evaporation to dryness, the crude product was purified by flash column chromatography, eluting with 40% EtOAc in hexane (with 0.1% Et3N) to yield 671 mg (78%) of 15 as a light yellow oil. Rf=0.3 (in 40% EtOAc/hexane); 1H NMR (300 MHz, CDCl3) δ 8.1 (s, 1H), 7.18 (d, 1H, J=8.0 Hz), 6.95 (d, 2H, J=7.2 Hz), 6.69 (m, 3H), 6.57 (m, 1H), 5.28 (s, 4H), 4.94 (s, 1H), 3.85 (m, 4H), 3.69 (s, 4H), 3.57 (m, 4H), 3.38 (s, 6H), 1.41 (s, 18H); 13C NMR (75 MHz, CDCl3) δ 171.2, 153.8, 150.6, 147.4, 146.5, 144.8, 144.4, 144.2, 136.3, 126.3, 119.6, 116.7, 116.6, 116.1, 115.8, 115.5, 105.9, 94.6, 81.9, 71.4, 68.0, 59.0, 56.9, 43.1, 27.9; 19F NMR (282 MHz, CDCl3) δ −140.4 (dd, 2 F); mass spectrum, calculated for C46H55F2NO13 (M−17) 761.3, Found 761.7.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](N)=[N:10][CH:9]=[C:8]([CH3:13])[N:7]=1)=[O:5])[CH3:2].[BrH:14].N#N.C([O-])([O-])=O.[Na+].[Na+]>O>[CH2:1]([O:3][C:4]([C:6]1[C:11]([Br:14])=[N:10][CH:9]=[C:8]([CH3:13])[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(C)cnc1N
Reactant: Br
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1nc(C)cnc1Br
Temperature: 5 °C
Reaction time: 1 h

Procedure:
A mixture of 3-amino-6-methyl-pyrazine-2-carboxylic acid ethyl ester (Example C) (2.0 g, 11 mmol), 4 mL water and 3.7 mL (33.1 mmol) hydrobromic acid 48% was cooled to 5° C. 2.5M NaNO2— solution in water (5.3 mL, 13.2 mmol) was added drop wise at 5° C. (N2-evolution!). The reaction mixture was stirred for 1 hr and poured then into ice-water. The reaction mixture was neutralized with Na2CO3 and extracted two times with ethyl acetate (200 mL each). The combined organic extracts were dried with sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (heptane/ethyl acetate 90:10->50:50 gradient). The desired compound was obtained as a colorless liquid (0.53 g, 20%), MS: m/e 245.1 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:45]1[CH2:50][CH2:49][O:48][CH2:47][CH:46]1[C:51]1[C:59]2[S:58][C:57]([NH2:60])=[N:56][C:55]=2[C:54]([O:61][CH3:62])=[CH:53][CH:52]=1>C1COCC1.C(Cl)(Cl)Cl>[O:45]1[CH2:50][CH2:49][O:48][CH2:47][CH:46]1[C:51]1[C:59]2[S:58][C:57]([NH:60][C:9]([C:7]3[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[N:8]=3)=[O:11])=[N:56][C:55]=2[C:54]([O:61][CH3:62])=[CH:53][CH:52]=1
Reactant: COc1cccc(C(=O)O)n1
Reactant: COc1ccc(C2COCCO2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cccc(C(=O)Nc2nc3c(OC)ccc(C4COCCO4)c3s2)n1

Procedure:
From 6-methoxy-2-pyridinecarboxylic acid, HATU and N-ethyldiisopropylamine in THF, then treatment with (+)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine. [α]D20=+20.3° (c=1.08, CHCl3), ES-MS m/e (%): 402 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]([CH:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[C:7]([CH2:9]Cl)=[N:8][C:4]=2[CH:3]=1.[CH3:19][S:20]([C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:25][N:24]=1)(=[O:22])=[O:21].CS(C1C2C(=CN=CC=2)NN=1)(=O)=O>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]([CH:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[C:7]([CH2:9][N:25]3[C:26]4[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:23]([S:20]([CH3:19])(=[O:21])=[O:22])=[N:24]3)=[N:8][C:4]=2[CH:3]=1
Reactant: CS(=O)(=O)c1n[nH]c2ccccc12
Reactant: ClCc1nc2cc(Cl)ccc2n1C1CCOCC1
Agent: CS(=O)(=O)c1n[nH]c2cnccc12
Product: CS(=O)(=O)c1nn(Cc2nc3cc(Cl)ccc3n2C2CCOCC2)c2ccccc12

Procedure:
The title compound was prepared in analogy to Example 2-1 by using 5-chloro-2-chloromethyl-1-(tetrahydro-pyran-4-yl)-1H-benzoimidazole and 3-methanesulfonyl-1H-indazole instead of 5-chloro-2-chloromethyl-1-((S)-1,1-dioxo-tetrahydro-1λ6-thiophen-3-yl)-1H-benzoimidazole and 3-(methylsulfonyl)-1H-pyrazolo[3,4-c]pyridine.
Reaction SMILES: ClC(Cl)(Cl)C([O:6][C:7]([N:9]1[CH:14]2[C:15]([C:36](O)=[O:37])=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][O:27][C:28]4[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=4[Cl:35])=[CH:20][CH:19]=3)[CH2:17][CH:10]1[CH2:11][N:12]([C:39](=[O:41])[CH3:40])[CH2:13]2)=[O:8])(C)C.[Br:44][C:45]1[CH:55]=[CH:54][CH:53]=[CH:52][C:46]=1[CH2:47][NH:48][CH:49]1[CH2:51][CH2:50]1>>[CH:7]([OH:8])=[O:6].[Br:44][C:45]1[CH:55]=[CH:54][CH:53]=[CH:52][C:46]=1[CH2:47][N:48]([CH:49]1[CH2:50][CH2:51]1)[C:36]([C:15]1[C@@H:14]2[NH:9][C@H:10]([CH2:17][C:16]=1[C:18]1[CH:19]=[CH:20][C:21]([O:24][CH2:25][CH2:26][O:27][C:28]3[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=3[Cl:35])=[CH:22][CH:23]=1)[CH2:11][N:12]([C:39](=[O:41])[CH3:40])[CH2:13]2)=[O:37]
Reactant: CC(=O)N1CC2CC(c3ccc(OCCOc4cc(F)ccc4Cl)cc3)=C(C(=O)O)C(C1)N2C(=O)OC(C)(C)C(Cl)(Cl)Cl
Reactant: Brc1ccccc1CNC1CC1
Product: CC(=O)N1C[C@H]2CC(c3ccc(OCCOc4cc(F)ccc4Cl)cc3)=C(C(=O)N(Cc3ccccc3Br)C3CC3)[C@@H](C1)N2
Product: O=CO

Procedure:
Synthesized according to typical procedures H and E from bicyclononene BN10 and (2-bromobenzyl)cyclopropylamine. LC-MS: Rt=0.90; ES+: 684.11.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH3:11].[NH2:12][C:13]1[CH:18]=[C:17](Cl)[CH:16]=[CH:15][N:14]=1.[H-].[Na+].CS(C)=O>O>[CH3:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([O:1][C:17]3[CH:16]=[CH:15][N:14]=[C:13]([NH2:12])[CH:18]=3)[CH:3]=2)[NH:7][CH:6]=1
Reactant: Nc1cc(Cl)ccn1
Reactant: Cc1c[nH]c2ccc(O)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1c[nH]c2ccc(Oc3ccnc(N)c3)cc12
Temperature: 160 °C
Reaction time: 15 h
Yield: 21 %

Procedure:
A mixture of 5-hydroxy-3-methylindole (4.7 g), 2-amino-4-chloropyridine (4.1 g), sodium hydride (1.3 g), and dimethyl sulfoxide (40 ml) was stirred at 160° C. for 15 hours. Water was added thereto; extraction was performed with ethyl acetate; and purification was performed by silica gel column chromatography (ethyl acetate, sequentially, ethyl acetate:methanol=20:1). The solvent was distilled off to yield the title compound as a brown solid (1.6 g).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH:12]=O)[CH2:8][CH2:7]1.[CH3:24][N:25]([CH3:37])[C:26](=[O:36])[C@H:27]([CH3:35])[NH:28][C:29]1[CH2:33][S:32][C:31](=[O:34])[N:30]=1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9](/[CH:12]=[C:33]2/[C:29]([NH:28][C@H:27]([C:26]([N:25]([CH3:24])[CH3:37])=[O:36])[CH3:35])=[N:30][C:31](=[O:34])[S:32]/2)[CH2:8][CH2:7]1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Reactant: C[C@H](NC1=NC(=O)SC1)C(=O)N(C)C
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: C[C@H](NC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1)C(=O)N(C)C
Temperature: 60 °C
Reaction time: 8 h
Yield: 37.3 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (305 mg) and N,N-dimethyl-N2-(2-oxo-2,5-dihydro-1,3-thiazol-4-yl)-L-alaninamide (213 mg) in 2-propanol (2 mL) was added piperidinium acetate (144 mg) at room temperature. The reaction mixture was stirred at 60° C. overnight. The solvent was evaporated, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (180 mg).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[C:4](O)(=O)C.C=O.[C:10]([C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:26]=1[NH:25][CH:24]=[CH:23]2)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(O)C>[CH3:1][N:2]([CH2:4][C:23]1[C:22]2[C:26](=[C:18]([C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:17])[CH:19]=[CH:20][CH:21]=2)[NH:25][CH:24]=1)[CH3:3]
Reactant: CC(=O)O
Reactant: O=C(c1ccccc1)c1cccc2cc[nH]c12
Reactant: CNC
Agent: C=O
Solvent: CCO
Product: CN(C)Cc1c[nH]c2c(C(=O)c3ccccc3)cccc12

Procedure:
An 18.0 g (0.16 mole) portion of 40% aqueous dimethylamine was cooled to 5° C. and 24 g (0.4 mole) of glacial acetic acid was added. To this mixture, held at 5° C., was added 12.2 g (0.15 mole) of 37% formalin. This aqueous mixture was added to a mixture of 33.1 g (0.15 mole) of 7-benzoyl-1H-indole and 20 ml of acetic acid. After 100 ml of absolute ethanol was added to the mixture, it was warmed on a steam bath for 1/2 hr. Isolation of the product was accomplished by concentrating the mixture under reduced pressure, partitioning between dilute sodium hydroxide and methylene chloride and concentrating the organic solution. The residue was recrystallized from isopropyl alcohol to give 29 g (70 %) of light yellow crystals, m.p. 111.0°-113.5° C.
Reaction SMILES: [N:1]1([C:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]([CH3:25])[C:17](=[O:26])[C:16]=1[C:27]#[N:28]>C1(C)C=CC=CC=1>[CH3:25][N:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:15]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([C:9]3[S:10][CH:11]=[CH:12][CH:13]=3)=[O:8])[CH2:2][CH2:3]2)=[C:16]([C:27]#[N:28])[C:17]1=[O:26]
Reactant: Cn1c(=O)c(C#N)c(Cl)c2ccccc21
Reactant: O=C(c1cccs1)N1CCNCC1
Solvent: Cc1ccccc1
Product: Cn1c(=O)c(C#N)c(N2CCN(C(=O)c3cccs3)CC2)c2ccccc21
Temperature: 120 °C
Yield: 97.7 %

Procedure:
Piperazine-1-yl-thiophen-2-yl-methanone (600 mg, 3.06 mmol) was added to a solution of Compound 3 (319 mg, 1.46 mmol) in toluene (40 mL) and heated overnight at 120° C. The solvent was removed under vacuum. The residue was suspended in water, sonicated, and filtered to yield 540 mg (98%) of white solids. M.P. 247° C. 1H NMR (DMSO-d6): δ 3.58 (s, 3H), 3.63 (m, 4H), 3.92 (m, 4H), 7.16 (t, J=4.8 Hz, 1H), 7.33 (t, J=7.5 Hz, 1H), 7.48 (d, J=3.5 Hz, 1H), 7.59 (d, J=8.5 Hz, 1H), 7.75 (t, J=7.25, 2H), 7.79 (d, J=4.8 Hz, 1H) 7.92 (d, J=7.5 Hz, 1H). EIMS m/z 379 (M+1), 401 (M+23). Anal. (C20H18N4O2S) C, H, N.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][Si:5]([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8].Cl[CH2:16][CH2:17][N:18]=[C:19]=[O:20].[C:21]([O-])(=[S:23])C.[K+]>C(O)C>[Si:5]([CH2:4][CH2:3][CH2:2][NH:1][C:19]([NH:18][CH2:17][CH2:16][S:23][CH3:21])=[O:20])([O:12][CH2:13][CH3:14])([O:6][CH2:7][CH3:8])[O:9][CH2:10][CH3:11]
Reactant: O=C=NCCCl
Reactant: CCO[Si](CCCN)(OCC)OCC
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CCO
Product: CCO[Si](CCCNC(=O)NCCSC)(OCC)OCC
Temperature: -78 °C
Yield: 105.3 %

Procedure:
3-Aminopropyltriethoxysilane (132.82 g, 0.60 mol, 1.00 eq) is initially charged in ethanol (300 ml) in a three-neck flask with precision glass stirrer, internal thermometer, dropping funnel and reflux condenser, and cooled to −78° C. 2-Chloroethyl isocyanate (63.34 g, 0.60 mol, 1.00 eq) is added dropwise at −78 to −68° C. within 1.75 h and then the mixture is heated to 50° C. Potassium thioacetate (68.53 g, 0.60 mol, 1.00 eq) is added in five portions and the mixture is heated to reflux. After a reaction time of 2.25 h, the mixture is cooled to room temperature and the suspension is filtered. The filtrate is freed of the solvent on a rotary evaporator and dried under reduced pressure. The (EtO)3Si—CH2CH2CH2—NH—CO—NH—CH2CH2—S—CH3 product (213.91 g, 97.3% of theory) is obtained as a waxy white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:28])[C:12]3[S:19][C:18]([CH:20]=[O:21])=[C:17]([CH2:22][O:23][CH2:24][CH2:25][O:26][CH3:27])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:28])[C:12]3[S:19][C:18]([CH2:20][OH:21])=[C:17]([CH2:22][O:23][CH2:24][CH2:25][O:26][CH3:27])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:29][CH:30]=1
Reactant: COCCOCc1c(C=O)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COCCOCc1c(CO)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.4 %

Procedure:
To a cold (0° C.), stirred solution of 1.05 g of N-(4-chlorobenzyl)-2-formyl-3-[(2-methoxyethoxy)methyl]-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide in 20 mL of CH2Cl2 is added 0.67 mL of acetic acid and 1.5 g of sodium triacetoxyborohydride. The mixture is allowed to warm to room temperature and stirred for 2 h, then partitioned between CH2Cl2 and aqueous NaHCO3. The organic phase is dried (Na2SO4) and concentrated under reduced pressure. Flash chromatography of the residue on silica using 2.5-4% MeOH in CH2Cl2 affords 1.08 g (100%) of the title compound as a yellow crystalline solid. Recrystallization from acetonitrile affords white spars.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7](F)=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1[NH2:28].Cl>O.CN(C=O)C>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([NH:28][CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27][CH:22]2[CH3:21])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1
Reactant: CC1CCCCC1N
Reactant: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(NC2CCCCC2C)c([N+](=O)[O-])c1
Reaction time: 16 h
Yield: 100.1 %

Procedure:
To a solution of 20.0 g of 4-fluoro-3-nitro-benzoic acid methyl ester in 100 ml of abs. DMF was added 27.8 g of potassium carbonate, followed by 12.5 g of 2-methylcyclohexylamine. After 16 h at rt, the mixture was poured into water, the pH was adjusted to 4 by the addition of 2 M aqueous hydrochloric acid, and the reaction mixture was extracted with ethyl acetate three times. The combined organic phases were washed with water, dried over sodium sulphate and concentrated to yield 29.4 g (100%) of 4-(2-Methyl-cyclohexylamino)-3-nitro-benzoic acid methyl ester. C15H20N2O4 (292.34), LCMS (method 7—1—1): Rt=1.85 min, m/z=293.25 [M+H]+
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OCC)=O)=O)C.[Cl:32][C:33]1[CH:34]=[C:35]([NH:40][C:41]([C:43]2[S:51][C:46]3=[N:47][CH2:48][CH2:49][CH2:50][N:45]3[C:44]=2[OH:52])=[O:42])[CH:36]=[C:37]([Cl:39])[CH:38]=1.[CH2:53]([O:55][C:56](=[O:59])[CH2:57]O)[CH3:54]>O1CCCC1>[Cl:39][C:37]1[CH:36]=[C:35]([NH:40][C:41]([C:43]2[S:51][C:46]3=[N:47][CH2:48][CH2:49][CH2:50][N:45]3[C:44]=2[O:52][CH2:57][C:56]([O:55][CH2:53][CH3:54])=[O:59])=[O:42])[CH:34]=[C:33]([Cl:32])[CH:38]=1
Reactant: CCOC(=O)CO
Reactant: O=C(Nc1cc(Cl)cc(Cl)c1)C1=C(O)N2CCCN=C2S1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)COC1=C(C(=O)Nc2cc(Cl)cc(Cl)c2)SC2=NCCCN21
Temperature: -78 °C
Reaction time: 1 h

Procedure:
In 40 ml of tetrahydrofuran was dissolved 916 mg of triphenylphosphin. To the solution was added 550 μl of azodicarboxylic acid diethylester under cooling with ice, followed by cooling to -78° C. To the reaction mixture was added 1.0 g of N-(3,5-dichlorophenyl)-6,7-dihydro-3-hydroxy-5H-thiazolo[3,2-a]pyrimidine-2-carboxamide obtained in Example 111 and 400 μl of hydroxyacetic acid ethylester, followed by raising the reaction temperature to room temperature by the degree. After stirring at room temperature for 1 hour, the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (silica gel:50 g) using chloroform and metanol (20:1 by volume) as an eluent to obtain 1.00 g of the titled compound.