Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.Cl.[NH2:12][CH2:13][C:14]1[N:19]=[C:18]([N:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]2)[C:17]([C:33]([O:35][CH3:36])=[O:34])=[CH:16][CH:15]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH:1]([NH:12][CH2:13][C:14]1[N:19]=[C:18]([N:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]2)[C:17]([C:33]([O:35][CH3:36])=[O:34])=[CH:16][CH:15]=1)=[O:2]
Reactant: COC(=O)c1ccc(CN)nc1N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=CO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: COC(=O)c1ccc(CNC=O)nc1N1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 48 h
Yield: 99.6 %

Procedure:
Formic acid (2.2 mL, 58 mmol) and acetic anhydride (5.2 mL, 58 mmol) were stirred at room temperature for 1 hour. The mixture was added dropwise to a solution of tert-butyl 4-[6-(aminomethyl)-3-(methoxycarbonyl)pyridin-2-yl]piperazine-1-carboxylate hydrochloride (4.9 g, 13 mmol) in methylene chloride (90 mL) at 0° C. and stirred for 48 hours. Evaporation gave the crude material which was treated with sodium bicarbonate and extracted with methylene chloride to give the desired compound (4.9 g, 100%). LCMS calculated for C18H27N4O5 (M+H)+: m/z=379.2. found: 378.9.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.Cl[C:17]1[C:18]2[C:25]([I:26])=[C:24]([CH:27]=[O:28])[N:23]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:19]=2[N:20]=[CH:21][N:22]=1>C(#N)C>[I:26][C:25]1[C:18]2[C:17]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[N:22][CH:21]=[N:20][C:19]=2[N:23]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:34])([CH3:35])[CH3:36])[C:24]=1[CH:27]=[O:28]
Reactant: C1COCCN1
Reactant: C[Si](C)(C)CCOCn1c(C=O)c(I)c2c(Cl)ncnc21
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOCn1c(C=O)c(I)c2c(N3CCOCC3)ncnc21

Procedure:
Morpholine (1.09 g, 12.5 mmol) and N,N-diisopropylethylamine (2.94 g, 22.7 mmol) were added to a solution of 4-chloro-5-iodo-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine-6-carbaldehyde (C28) (5.0 g, 11 mmol) in acetonitrile (20 mL). The reaction mixture was stirred at reflux for 16 hours, whereupon it was cooled and concentrated in vacuo; the residue was purified by chromatography on silica gel (Gradient: 0% to 20% ethyl acetate in petroleum ether) to provide the product as a yellow oil. Yield: 4.0 g, 8.2 mmol, 74%. 1H NMR (400 MHz, CDCl3) δ 9.99 (s, 1H), 8.54 (s, 1H), 6.01 (s, 2H), 3.92-3.98 (m, 4H), 3.70-3.75 (m, 4H), 3.58-3.65 (m, 2H), 0.91-0.96 (m, 2H), −0.05 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].O.[NH2:11][C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1>COCCOC.C(=O)([O-])[O-].[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:11][C:12]1[CH:17]=[C:16]([C:2]2[C:3]([C:4]#[N:5])=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: N#Cc1ccccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: N#Cc1ccccc1-c1cccc(N)c1
Temperature: 80 °C

Procedure:
A mixture of 2-bromobenzonitrile (9.1 g, 50 mmol), 3-aminobenzeneboronic acid monohydrate (11.6 g, 75 mmol) and tetrakis(triphenylphosphine)palladium(0) (1.73 g, 1.5 mmol) in 1,2-dimethoxyethane (50 ml) and 2M sodium carbonate solution (25 ml) was heated at 80° C. for 20h. After cooling to ambient temperature the reaction was partitioned between ethyl acetate (400 ml) and water (400 ml). The organics were washed with brine (400 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel, eluting with isohexane on a gradient of ethyl acetate (0-25%) gave 3′-aminobiphenyl-2-carbonitrile as a colourless oil that solidified on standing to afford a white solid (9.5 g, 98%). 1H NMR (360 MHz, CDCl3) δH 3.79 (2H, br), 6.75 (1H, ddd, J 8, 3 and 1), 6.84 (1H, dd, J 3 and 3), 6.92 (1H, dd, J 8 and 3), 7.25 (1H, dd, J 8 and 8), 7.40 (1H, ddd, J 8, 8 and 1), 7.50 (1H, dd, J 8 and 1), 7.62 (1H, ddd, J 8, 8 and 1), 7.73 (1H, dd, J8 and 1).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][C:10]([NH:12][C:13]2[S:14][C:15]3[CH:21]=[C:20]([SH:22])[CH:19]=[CH:18][C:16]=3[N:17]=2)=[O:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(O)C.SCC(C(CS)O)O.Cl[C:35]1[N:39]2[N:40]=[C:41]([O:44][CH2:45][CH3:46])[CH:42]=[CH:43][C:38]2=[N:37][N:36]=1>O.P([O-])(O)(O)=O.[K+]>[CH2:45]([O:44][C:41]1[CH:42]=[CH:43][C:38]2[N:39]([C:35]([S:22][C:20]3[CH:19]=[CH:18][C:16]4[N:17]=[C:13]([NH:12][C:10]([NH:9][CH2:8][CH2:7][N:1]5[CH2:2][CH2:3][O:4][CH2:5][CH2:6]5)=[O:11])[S:14][C:15]=4[CH:21]=3)=[N:36][N:37]=2)[N:40]=1)[CH3:46]
Reactant: CCOc1ccc2nnc(Cl)n2n1
Reactant: O=C(NCCN1CCOCC1)Nc1nc2ccc(S)cc2s1
Agent: O=P([O-])(O)O
Agent: OC(CS)C(O)CS
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCOc1ccc2nnc(Sc3ccc4nc(NC(=O)NCCN5CCOCC5)sc4c3)n2n1
Yield: 46.8 %

Procedure:
The 1-{6-[(6-ethoxy[1,2,4]triazolo[4,3-b]pyridazin-3-yl)sulphanyl]-1,3-benzothiazol-2-yl}-3-[2-(morpholin-4-yl)ethyl]urea was prepared according to the method described in Example 17a, but using 613 mg of 1-[2-(morpholin-4-yl)ethyl]-3-(6-sulphanyl-1,3-benzothiazol-2-yl)urea, 20 cm3 of degassed ethanol, 7 mg of potassium dihydrogen phosphate in 0.2 cm3 of water, 699 mg of DL-dithiothreitol and 300 mg of 3-chloro-6-ethoxy[1,2,4]triazolo[4,3-b]pyridazine. 354 mg of 1-{6-[(6-ethoxy[1,2,4]triazolo[4,3-b]pyridazin-3-yl)sulphanyl]-1,3-benzothiazol-2-yl}-3-[2-(morpholin-4-yl)ethyl]urea are thus obtained in the form of a white powder, the characteristics of which are as follows:
Reaction SMILES: F[C:2]1[C:3]([C:9](=O)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1.O.[NH2:20][NH2:21]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[F:8][C:6]1[CH:7]=[C:2]2[NH:21][N:20]=[C:9]([CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:3]2=[N:4][CH:5]=1
Reactant: NN
Reactant: O=C(Cc1ccccc1F)c1ncc(F)cc1F
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: Fc1cnc2c(Cc3ccccc3F)n[nH]c2c1

Procedure:
9.07 g (32.4 mmol) of the compound from example 5A were initially charged in pyridine (84 ml). Subsequently, 8.10 g (162 mmol) of hydrazine hydrate and 19.8 mg (0.162 mmol) of 4-dimethylaminopyridine were added, and the mixture was heated at reflux for 30 min. The reaction mixture was diluted with ethyl acetate at RT and washed four times with 10% strength aqueous citric acid solution. The organic phase was subsequently washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. MTBE was added to the residue and the solids were filtered off. The latter were dried under high vacuum and gave 1.79 g (79% pure, 18% of theory) of the title compound. The filtrate was concentrated and gave a further 4.86 g (61% pure, 37% of theory) of the title compound. The two fractions were combined and reacted without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][N:4]=1)#[N:2].[CH2:12]([O:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[C:17]([N+:22]([O-:24])=[O:23])[CH:16]=1)[CH3:13]>>[C:1]([C:3]1[N:4]=[CH:5][C:6]([C:7]([NH:19][C:18]2[CH:20]=[CH:21][C:15]([O:14][CH2:12][CH3:13])=[CH:16][C:17]=2[N+:22]([O-:24])=[O:23])=[O:9])=[CH:10][CH:11]=1)#[N:2]
Reactant: N#Cc1ccc(C(=O)O)cn1
Reactant: CCOc1ccc(N)c([N+](=O)[O-])c1
Product: CCOc1ccc(NC(=O)c2ccc(C#N)nc2)c([N+](=O)[O-])c1

Procedure:
The title compound was prepared from 6-cyanonicotinic acid and 4-ethoxy-2-nitroaniline as a yellow solid as described in Example 15. 1H NMR (CDCl3): 11.22 (s, 1H), 9.31-9.30 (m, 1H), 8.81 (d, J=9.3, 1H), 8.42-8.38 (m, 1H), 7.90-7.87 (m, 1H), 7.76 (d, J=3.0, 1H), 7.34-7.30 (m, 1H), 4.12 (q, J=6.9, 2H), 1.47 (t, J=6.9, 3H).
Reaction SMILES: [Mg].[C:2]1([CH2:8][CH2:9][C:10]2[CH:11]=[C:12](Br)[CH:13]=[CH:14][CH:15]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17](O)(=[O:19])[CH3:18]>O1CCCC1>[C:2]1([CH2:8][CH2:9][C:10]2[CH:11]=[C:12]([C:17](=[O:19])[CH3:18])[CH:13]=[CH:14][CH:15]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cccc(CCc2ccccc2)c1
Reactant: CC(=O)O
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(=O)c1cccc(CCc2ccccc2)c1
Reaction time: 1 h
Yield: 92 %

Procedure:
A Grignard compound synthesized from 1.0 g of magnesium and 10.0 g of 3-(2-phenylethyl)-bromobenzene in 30 ml of tetrahydrofuran was dropped at -60° C. under stirring for 3 min into 7.6 g of anhydrous acetic acid dissolved in 20 ml of tetrahydrofuran in a nitrogen atmosphere and stirred for further one hour. Then, the reaction solution was poured into a mixture of ice and an aqueous saturated solution of ammonium chloride and extracted with toluene. After separating the solution, it was washed with an aqueous 2N-solution of sodium hydroxide and saturated saline solution successively, dried over anhydrous sodium sulfate and then concentrated to solid. The residue was purified by silica gel column chromatography, using benzene/n-hexane (1:1) as an elute, to obtain 7.9 g of 1-(3-(2-phenylethyl)-phenyl)ethanone as an oily product. Then, by using 5.0 g of the thus obtained acetophenone compound, 3.8 g of (Z)-2-(4-methylpiperazin-1-yl)-1-(3-(2-phenylethyl)-phenyl-ethanone oxime hydrochloride with the melting point of from 185° to 188° C. (decomposition) and 0.5 g of (E)-2-(4-methylpiperazin-1-yl)-1-(3-(2-phenylethyl)-phenyl)-ethanone oxime with the melting point from 133° to 134° C. were obtained in the same manner as in Example 33.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14](O)=O)[C@H:12]2[CH2:17][C@@H:9]1[CH2:10][C@@H:11]2[OH:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C(Cl)(=O)OCC(C)C.[NH2:34][C:35]1[CH:39]=[C:38]([Br:40])[S:37][C:36]=1[C:41]([NH2:43])=[O:42]>O1CCCC1.O>[Br:40][C:38]1[S:37][C:36]2[C:41](=[O:42])[NH:43][C:14]([C@@H:13]3[C@H:12]4[CH2:17][C@H:9]([CH2:10][C@@H:11]4[OH:18])[N:8]3[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[N:34][C:35]=2[CH:39]=1
Reactant: NC(=O)c1sc(Br)cc1N
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@H]([C@H]1C(=O)O)[C@@H](O)C2
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)N1[C@@H]2C[C@H]([C@H]1c1nc3cc(Br)sc3c(=O)[nH]1)[C@@H](O)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.7 %

Procedure:
To a solution of (1R*,3S,4R*,5S)-2-(tert-butoxycarbonyl)-5-hydroxy-2-azabicyclo[2.2.1]heptane-3-carboxylic acid (349 mg) and triethylamine (0.190 mL) in tetrahydrofuran (4 mL) was added 2-methylpropyl chlorocarbonate (0.178 mL) at 0° C., and the mixture was stirred at room temperature for 30 min. To the reaction system was added a solution of 3-amino-5-bromothiophene-2-carboxamide (200 mg) produced in Example 1, step D, in tetrahydrofuran (2 mL), and the mixture was stirred at 60° C. for 18 hr. Water was added to the reaction mixture, and the separated aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. Insoluble material was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by basic silica gel column chromatography (ethyl acetate/hexane). To the obtained pale-yellow amorphous solid (307 mg) were added 2M aqueous sodium hydroxide solution (1.81 mL) and ethanol (4.0 mL), and the mixture was stirred at 70° C. for 5 hr. The reaction system was neutralized with 1M hydrochloric acid at 0° C. To the reaction system was added water (2 mL), and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was washed with ethyl acetate (2 mL) to give the title compound (211 mg) as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:59]=[CH:58][C:6]([CH2:7][O:8][C:9](=[O:57])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24](=[O:56])[N:25]([CH2:31][C:32]2[CH:37]=[C:36]([O:38][CH2:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH:35]=[C:34]([O:47][CH2:48][C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH:33]=2)[CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.[B-](F)(F)(F)F.CN(C(O[N:82]1[C:87](=[O:88])[CH2:86][CH2:85][C:83]1=[O:84])=[N+](C)C)C>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9](=[O:57])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24](=[O:56])[N:25]([CH2:31][C:32]2[CH:33]=[C:34]([O:47][CH2:48][C:49]([O:51][C:52]([CH3:53])([CH3:55])[CH3:54])=[O:50])[CH:35]=[C:36]([O:38][CH2:39][C:40]([O:42][C:43]([CH3:44])([CH3:45])[CH3:46])=[O:41])[CH:37]=2)[CH2:26][CH2:27][C:28]([O:30][N:82]2[C:87](=[O:88])[CH2:86][CH2:85][C:83]2=[O:84])=[O:29])=[CH:58][CH:59]=1
Reactant: COc1ccc(COC(=O)CCCCCCCCCCCCCCC(=O)N(CCC(=O)O)Cc2cc(OCC(=O)OC(C)(C)C)cc(OCC(=O)OC(C)(C)C)c2)cc1
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(COC(=O)CCCCCCCCCCCCCCC(=O)N(CCC(=O)ON2C(=O)CCC2=O)Cc2cc(OCC(=O)OC(C)(C)C)cc(OCC(=O)OC(C)(C)C)c2)cc1
Temperature: 0 °C
Yield: 76.6 %

Procedure:
15-[(3,5-Bis-tert-butoxycarbonylmethoxybenzyl)-(2-carboxyethyl)carbamoyl]pentadecanoic acid 4-methoxybenzyl ester (190 mg, 0.23 mmol) was dissolved in THF (5 mL). The mixture was cooled with an ice bath. Diisopropylethylamin (0.047 mL, 0.28 mmol) and O—(N-succinimidyl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (83 mg, 0.28 mmol) was added. The mixture was stirred under nitrogen at 0° C. After 30 minutes the ice cooling was removed and the mixture was stirred for an additional 3 hours. Solvent removed in vacuo. The crude product was dissolved in ethyl acetate (50 mL), washed with aqueous phosphate buffer (pH=5.5) (3×25 mL). The organic phase was dried (Na2SO4), solvent removed in vacuo to yield the title compound (163 mg) which was used in subsequent step.
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:12][CH2:11][C@@H:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[CH2:9]1.[C:21]1([CH2:27][CH2:28][CH2:29][CH:30]=O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)(Cl)Cl>[C:21]1([CH2:27][CH2:28][CH2:29][CH2:30][N:8]2[CH2:12][CH2:11][C@@H:10]([S:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[CH2:9]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Oc1ccc(S[C@@H]2CCNC2)cc1
Reactant: O=CCCCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: Oc1ccc(S[C@@H]2CCN(CCCCc3ccccc3)C2)cc1

Procedure:
The title compound, MS: m/e=328.3 (M+H+) and [α]D20 +10.15° (c=0.56, chloroform) was prepared from (R)-4-(pyrrolidin-3-yl-sulfanyl)-phenol trifluoroacetic acid salt and 4-phenyl-butyraldehyde.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:39][S:40]([CH2:43][CH2:44][CH:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)(=[O:42])=[O:41]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:48]3[CH2:49][CH2:50][CH:45]([CH2:44][CH2:43][S:40]([CH3:39])(=[O:42])=[O:41])[CH2:46][CH2:47]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)CCC1CCNCC1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Agent: Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CCS(C)(=O)=O)CC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with 4-(2-methanesulfonyl-ethyl)-piperidine hydrochloride to give the title compound. HR-MS (ES, m/z) calculated for C37H47N4O4SCl2 [(M+H)+] 713.2690, observed 713.2689.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=1)[C:10]([OH:12])=[O:11])=O)(C)(C)C.O=S(Cl)Cl.[CH3:26]O>>[ClH:20].[CH3:26][O:12][C:10](=[O:11])[CH:9]([NH2:8])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=1
Reactant: CO
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(Cl)c(Cl)c1)C(=O)O
Solvent: O=S(Cl)Cl
Product: COC(=O)C(N)Cc1ccc(Cl)c(Cl)c1
Product: Cl
Temperature: 25 °C
Yield: 99 %

Procedure:
To a stirred solution of (S)-2-tert-butoxycarbonylamino-3-(3,4-dichloro-phenyl)-propionic acid (0.67 g, 2.00 mmol) in MeOH (13 mL) at 0° C. was added SOCl2 (0.29 mL, 4.00 mmol). The reaction mixture was allowed to stir and warm to rt overnight. The mixture was concentrated to provide the product as a white solid (0.56 g, 99%). 1H NMR (400 MHz, DMSO-d6): 8.66 (br s, 2H), 7.65-7.60 (m, 2H), 7.26 (dd, J=8.2, 1.9, 1H), 4.37 (br s, 1H), 3.72 (s, 3H), 3.18-3.14 (m, 2H).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:11]([CH2:21][NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[C:10]2[C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=1)(=O)=O.C(N(CC)CC)C.[C:46]([O:50][CH2:51][CH3:52])(=[O:49])[CH:47]=[CH2:48].O>CN(C)C=O>[C:26]([O:25][C:23]([NH:22][CH2:21][C:11]1[C:12]([CH2:17][CH:18]([CH3:20])[CH3:19])=[N:13][C:14]2[C:9]([C:10]=1[C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=1)=[CH:8][C:7](/[CH:48]=[CH:47]/[C:46]([O:50][CH2:51][CH3:52])=[O:49])=[CH:16][CH:15]=2)=[O:24])([CH3:29])([CH3:28])[CH3:27]
Reactant: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(OS(=O)(=O)C(F)(F)F)cc23)cc1
Reactant: C=CC(=O)OCC
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1ccc2nc(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c3ccc(C)cc3)c2c1
Temperature: 70 °C
Reaction time: 6 h
Yield: 61.8 %

Procedure:
To a solution of 3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-4-(4-methylphenyl)quinolin-6-yl trifluoromethanesulfonate (1.5 g, 2.8 mmol) in N,N-dimethylformamide (10 ml) were added dichlorobistriphenylphosphine palladium (0.021 g, 0.030 mmol), triethylamine (4.2 ml, 30 mmol) and ethyl acrylate (0.65 ml, 6.0 mmol) and the mixture was stirred at 70° C. for 6 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give ethyl (2E)-3-[3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-4-(4-methylphenyl)quinolin-6-yl]acrylate (0.87 g, yield 62%) as pale-yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:5][NH:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][NH:16][CH3:17])[N:14]=1)=[O:8].[CH3:22][O:23][C:24]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:25]=1[CH:26]=O.C([BH3-])#N.[Na+].CO>C(Cl)Cl.C(O)(=O)C>[NH3:6].[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:5][NH:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][N:16]([CH2:26][C:25]2[CH:28]=[CH:29][C:30]([O:32][CH3:33])=[CH:31][C:24]=2[O:23][CH3:22])[CH3:17])[N:14]=1)=[O:8]
Reactant: CNCc1csc(NC(=O)NCc2ccc(Cl)c(Cl)c2)n1
Reactant: COc1ccc(C=O)c(OC)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1ccc(CN(C)Cc2csc(NC(=O)NCc3ccc(Cl)c(Cl)c3)n2)c(OC)c1
Product: N
Temperature: 25 °C

Procedure:
1-(3,4-Dichloro-benzyl)-3-(4-methylaminomethyl-thiazol-2-yl)-urea (Example 132) was taken up in DCM with 1.5 equivalents of 2,4-Dimethoxy-benzaldehyde and several drops of acetic acid. Reaction was stirred for several hours at ambient temperature. Sodium cyanoborohydride (1.5 equivalents) was added at once and the reaction was stirred overnight at ambient temperature. An aqueous work-up with dichloromethane and chromatography (silica, DCM, 0-10% MeOH saturated with NH3) afforded the title compound. 1H NMR (400 MHz, DMSO-d6): 10.65 (br s, 1H), 7.60 (d, 1H), 7.54 (d, 1H), 7.29 (dd, 1H), 7.27 (br d, 1H), 7.12 (br s, 1H), 6.58 (br s, 1H), 6.56-6.46 (m, 2H), 4.33 (d, 2H), 3.75 (s, 6H), 3.46 (br s, 4H), 2.12 (br s, 3H). MS (ES+): M/Z 495 and 497 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([Cl:13])=[C:11]([CH2:14][C:15]#N)[N:10]=[C:9]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=[O:31])=CC=1.[CH2:35]([OH:37])[CH3:36]>>[ClH:13].[CH2:1]([N:8]1[C:12]([Cl:13])=[C:11]([CH2:14][C:15]([O:37][CH2:35][CH3:36])=[O:31])[N:10]=[C:9]1[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCc1nc(-c2ccccc2)n(Cc2ccccc2)c1Cl
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCO
Solvent: O
Product: CCOC(=O)Cc1nc(-c2ccccc2)n(Cc2ccccc2)c1Cl
Product: Cl

Procedure:
3.1 g of 1-benzyl-5-chloro-2-phenyl-4-cyanomethylimidazole, together with 2.1 g of p-toluenesulfonic acid monohydrate, was boiled in 100 ml of ethanol for 10 hours. The reaction solution was evaporated to dryness under reduced pressure, and the residue was dissolved in 50 ml of chloroform, followed by washing with 50 ml each of a 5% aqueous sodium bicarbonate solution and water to evaporate the chloroform layer to dryness under reduced pressure. The residue was chromatographed on a column of 60 g of silica gel, and eluted with chloroform. The fractions of the objective compound were collected and evaporated to dryness under reduced pressure, followed by dissolving the residue in 2 ml of 20% hydrogen chloride-ethanol. Upon addition of 50 ml of ether, there was obtained 1.5 g of ethyl 1-benzyl-5-chloro-2-phenylimidazole-4-acetate hydrochloride as colorless prisms, m.p. 120°-124° C.
Reaction SMILES: [F:1][C:2]([F:19])([CH:8](O)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(OCC)(=O)C.O.COCCN(S(F)(F)[F:37])CCOC>C(Cl)Cl>[F:1][C:2]([F:19])([CH:8]([F:37])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(F)(F)C(O)c1cccc([N+](=O)[O-])c1
Reactant: COCCN(CCOC)S(F)(F)F
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C(F)(F)C(F)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of ethyl 2,2-difluoro-3-hydroxy-3-(3-nitrophenyl)propanoate (C29, 1.02 g) in methylene chloride (22 mL), bis(2-methoxyethyl)aminosulfur trifluoride (1.6 mL) was added under ice cooling, and the mixture was stirred at room temperature for 16 hours. To the reaction mixture, ethyl acetate and water were added. The organic layer was separated, washed successively with 1.0 mol/L aqueous hydrochloric acid, saturated aqueous sodium hydrogencarbonate and saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain ethyl 2,2,3-trifluoro-3-(3-nitrophenyl)propanoate (C30, 1.19 g).