Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(OC2C=CC=CC=2)C=CC=CC=1.[Br:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][CH:22]=[C:23]([C:29]([O:31]CC)=O)[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:17][CH:16]=1>CCOCC>[Br:14][C:15]1[CH:16]=[C:17]2[C:18](=[CH:19][CH:20]=1)[NH:21][CH:22]=[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:29]2=[O:31]
Reactant: CCOC(=O)C(=CNc1ccc(Br)cc1)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCOCC
Product: CCOC(=O)c1c[nH]c2ccc(Br)cc2c1=O
Temperature: 240 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
Diphenyl ether (870 mL) was heated to 240° C. then diethyl 2-[[(4-bromophenyl)amino]methylidene]propanedioate (75 g, 219.18 mmol) added portionwise. The mixture was stirred at 240° C. for 60 minutes in a flask fitted with clean-stark apparatus. After cooling (25° C.) a crystallized solid was formed. The mixture was diluted with Et2O and the solid was collected by filtration, washed with Et2O and dried to afford the desired material (59.9 g) as a beige crystallized solid, which was used without purification or characterisation.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:21]=[CH:20][C:19]([OH:22])=[CH:18][N:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[O:23]1[C:27]2[CH:28]=[CH:29][C:30]([CH2:32]O)=[CH:31][C:26]=2[O:25][CH2:24]1>>[O:23]1[C:27]2[CH:28]=[CH:29][C:30]([CH2:32][O:22][C:19]3[CH:18]=[N:17][C:16]([C:13]4[CH:14]=[CH:15][C:10]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:11][CH:12]=4)=[N:21][CH:20]=3)=[CH:31][C:26]=2[O:25][CH2:24]1
Reactant: CCCCCCCCOc1ccc(-c2ncc(O)cn2)cc1
Reactant: OCc1ccc2c(c1)OCO2
Product: CCCCCCCCOc1ccc(-c2ncc(OCc3ccc4c(c3)OCO4)cn2)cc1

Procedure:
By Mitsunobu etherification of 2-(4-octyloxyphenyl)pyrimidin-5-ol using benzo[1,3]dioxol-5-ylmethanol analogously to Example 208.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CN(C)[CH:25]=[O:26].[Cl-].[NH4+]>O1CCCC1>[CH2:1]([O:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH:25]=[O:26])=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: Brc1ccc(CCOCc2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=Cc1ccc(CCOCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-(2-benzyloxyethyl)-1-bromobenzene (6.8 g) in tetrahydrofuran (80 mL) was added n-butyl lithium (2.6 mol/L n-hexane solution, 8.98 mL) at −78° C. under an argon atmosphere, and the mixture was stirred for 30 minutes. To the reaction mixture was added N,N-dimethylformamide (20 mL), and the mixture was allowed to warm to 0° C. and stirred for 2 hours. The reaction mixture was poured into a saturated aqueous ammonium chloride solution, and the resulting mixture was extracted with ethylacetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 4-(2-benzyloxyethyl)benzaldehyde (5.6 g). This material was dissolved in methanol (80 mL). To the solution was added sodium borohydride (1.77 g) under ice-cooling, and the mixture was stirred at room temperature overnight. To the reaction mixture was added a saturated aqueous ammonium chloride solution, and the resulting mixture was extracted with diethyl ether. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue (solid) was treated with n-hexane, collected by filtration and dried under reduced pressure to give the title compound (5.41 g).
Reaction SMILES: [CH2:1]([O:19][CH:20]1[CH:25]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH:24]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])[CH2:23][CH:22]([CH2:64][O:65][C:66]2[CH:73]=[CH:72][C:69]([CH:70]=[O:71])=[CH:68][CH:67]=2)[CH2:21]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH3:74][O:75][C:76]1[CH:81]=[CH:80][C:79]([Mg]Br)=[CH:78][CH:77]=1>C1COCC1>[CH3:74][O:75][C:76]1[CH:81]=[CH:80][C:79]([CH:70]([C:69]2[CH:68]=[CH:67][C:66]([O:65][CH2:64][CH:22]3[CH2:21][CH:20]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:25]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH:24]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])[CH2:23]3)=[CH:73][CH:72]=2)[OH:71])=[CH:78][CH:77]=1
Reactant: CCCCCCCCCCCCCCCCCCOC1CC(COc2ccc(C=O)cc2)CC(OCCCCCCCCCCCCCCCCCC)C1OCCCCCCCCCCCCCCCCCC
Reactant: COc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCOC1CC(COc2ccc(C(O)c3ccc(OC)cc3)cc2)CC(OCCCCCCCCCCCCCCCCCC)C1OCCCCCCCCCCCCCCCCCC
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 76.5 %

Procedure:
4-(3,4,5-Tris-octadecyloxy-cyclohexylmethoxy)-benzaldehyde (130 mg, 127 μmol) was dissolved in dehydrated THF (2 mL), 4-methoxy-phenyl-magnesiumbromide (350 μmol) was added, and the mixture was stirred at 40° C. for 1.5 hours. After evaporation of the solvent, 1N hydrochloric acid (5 mL) was added to the residue to allow crystallization. The crystals were filtered, and thoroughly washed with hydrochloric acid, water and methanol in this order to give (4-methoxy-phenyl)-[4-(3,4,5-tris-octadecyloxy-cyclohexylmethoxy)-phenyl]-methanol (110 mg, 97.2 μmol, 96%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][N:14]=2)[C@H:10](C(O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC(P([N:37]=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.C(N(CC)CC)C.[OH-].[Na+]>C1(C)C=CC=CC=1>[NH2:37][C@H:10]1[C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][N:14]=2)[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](C(=O)O)[C@H](c2ccc(F)cn2)C1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C[C@@H](N)[C@H](c2ccc(F)cn2)C1
Temperature: 65 °C
Reaction time: 1 h
Yield: 88.1 %

Procedure:
To a solution of the compound (2.29 g) obtained in step 8 in toluene (24.0 mL) were added DPPA (2.44 g) and triethylamine (1.23 mL), and the mixture was stirred at 65° C. for 1 hr. The mixture was cooled to −10° C., 8N aqueous sodium hydroxide solution (9.23 mL) was added dropwise, and the mixture was stirred at −10° C. to 0° C. for 1.5 hr. The mixture was diluted with toluene, and extracted with water and 1N aqueous sodium hydroxide solution. The combined aqueous layer was extracted with ethyl acetate (4 times), dried and concentrated under reduced pressure. The residue was diluted with ethyl acetate, and the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (1.83 g, 88%) as a yellow oil.
Reaction SMILES: [CH2:1]([N:5]([CH2:22][C:23]#[N:24])[C:6]([CH:8]1[CH2:13][CH2:12][C:11]2[C:14]3[C:19](Cl)=[N:18][CH:17]=[N:16][C:15]=3[S:21][C:10]=2[CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].[NH2:25][C:26]1[C:35]([O:36][CH3:37])=[CH:34][C:29]2[NH:30][C:31](=[O:33])[S:32][C:28]=2[CH:27]=1>>[CH2:1]([N:5]([CH2:22][C:23]#[N:24])[C:6]([CH:8]1[CH2:13][CH2:12][C:11]2[C:14]3[C:19]([NH:25][C:26]4[C:35]([O:36][CH3:37])=[CH:34][C:29]5[NH:30][C:31](=[O:33])[S:32][C:28]=5[CH:27]=4)=[N:18][CH:17]=[N:16][C:15]=3[S:21][C:10]=2[CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: COc1cc2[nH]c(=O)sc2cc1N
Reactant: CCCCN(CC#N)C(=O)C1CCc2c(sc3ncnc(Cl)c23)C1
Product: CCCCN(CC#N)C(=O)C1CCc2c(sc3ncnc(Nc4cc5sc(=O)[nH]c5cc4OC)c23)C1

Procedure:
100 mg (276 μmol) (RS)—N-butyl-4-chloro-N-(cyanomethyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxamide (prepared according to intermediate example 88a) were transformed in analogy to example 1 using 6-amino-5-methoxy-1,3-benzothiazol-2(3H)-one to give after working up and purification 15.9 mg (10%) of the title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([CH3:11])([CH3:10])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[S-:12][C:13]#[N:14].[K+]>CN(C)C=O.O>[CH3:10][C:4]([CH3:11])([CH2:3][CH2:2][S:12][C:13]#[N:14])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C(C)(C)CCCl
Reactant: N#C[S-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)(C)CCSC#N
Temperature: 100 °C
Reaction time: 7 h
Yield: 65.9 %

Procedure:
In 100 ml of dimethylformamide were dissolved 22.1 g of ethyl 4-chloro-2,2-dimethylbutyrate and 14.5 g of potassium thiocyanate and the solution was stirred at 100° C. for 7 hours. The reaction mixture was poured in 500 ml of water and extracted with ethyl ether. The extract was washed with water and dried (MgSO4) and the solvent was distilled off. The residue was subjected to vacuum distillation to provide 16.4 g of the title compound as colorless oil. b.p. 109°-111° C./0.3 mmHg
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[C:11]([NH:15][OH:16])([CH3:14])([CH3:13])[CH3:12]>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[N+:15]([C:11]([CH3:14])([CH3:13])[CH3:12])[O-:16]
Reactant: COc1ccccc1C=O
Reactant: CC(C)(C)NO
Product: COc1ccccc1C=[N+]([O-])C(C)(C)C

Procedure:
The title compound was prepared according to the procedure described in Example 7 using 2-methoxybenzaldehyde and N-tert-butylhydroxylamine. The title compound was isolated in 82.9% overall yield as white crystals, m.p. 109.1° C. (Rf=0.53 on a silica gel plate using ethyl acetate as the eluant).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].N1C=CC=CC=1.[Br:17][C:18]1[C:19]([Cl:29])=[C:20]([CH2:25][C:26](Cl)=[O:27])[C:21]([Cl:24])=[CH:22][CH:23]=1>C(#N)C>[Br:17][C:18]1[C:19]([Cl:29])=[C:20]([CH2:25][C:26]([NH:1][C:2]2[N:3]=[CH:4][S:5][C:6]=2[C:7]([O:9][CH3:10])=[O:8])=[O:27])[C:21]([Cl:24])=[CH:22][CH:23]=1
Reactant: O=C(Cl)Cc1c(Cl)ccc(Br)c1Cl
Reactant: COC(=O)c1scnc1N
Solvent: c1ccncc1
Solvent: CC#N
Product: COC(=O)c1scnc1NC(=O)Cc1c(Cl)ccc(Br)c1Cl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 74.8 %

Procedure:
2.0 g (12.64 mmol) of methyl 4-amino-1,3-thiazole-5-carboxylate were dissolved in 20 acetonitrile, and 2.05 ml (25.29 mmol) of pyridine were added. After 5 min of stirring at room temperature, a solution of 4.21 g (13.91 mmol) of (3-bromo-2,6-dichlorophenyl)acetyl chloride (obtained from (3-bromo-2,6-dichlorophenyl)acetic acid, see WO9736868) in 10 ml of acetonitrile was added dropwise. The reaction mixture was stirred at RT for 12 h. The precipitate formed was filtered off, washed with water and dried under reduced pressure. The resulting mother liquor was concentrated by evaporation, dissolved in chloroform and chromatographed (ethyl acetate/n-heptane: 20/80 to 80/20). This gives a total of 4.01 g of methyl 4-{[(3-bromo-2,6-dichlorophenyl)acetyl]amino}-1,3-thiazole-5-carboxylate.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[CH:8]3[CH2:17][CH2:16][CH2:15][CH:9]3[C:10](=O)[NH:11][C:12]=2[CH:13]=1)([O-:3])=[O:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:27])=CC=1>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[CH:8]3[CH2:17][CH2:16][CH2:15][CH:9]3[C:10](=[S:27])[NH:11][C:12]=2[CH:13]=1)([O-:3])=[O:2]
Reactant: O=C1Nc2cc([N+](=O)[O-])ccc2C2CCCC12
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: O=[N+]([O-])c1ccc2c(c1)NC(=S)C1CCCC21

Procedure:
7-Nitro-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinolin-4-one (91 mg, 0.30 mmol) is stirred with Lawesson's reagent (170 mg, 0.43 mmol) for 6 hours at room temperature. The batch is concentrated by evaporation in a vacuum, and the residue is purified on silica gel with toluene: 52 mg (54%) of product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH:15]=O)[O:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][N:28]3[CH2:27][CH2:26][N:25]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[O:18][CH3:17])[CH2:30][CH2:29]3)[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: O=CCCc1cc(-c2ccc(Cl)cc2)no1
Reactant: COc1ccccc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccccc1N1CCN(CCCc2cc(-c3ccc(Cl)cc3)no2)CC1
Yield: 101.4 %

Procedure:
About 2 min after dissolving 3-[3-(4-chlorophenyl)isoxazol-5-yl]propanal (10 mg, 0.04 mmol) and 1-(2-methoxyphenyl)piperazine (16.2 mg, 0.08 mmol) in 2 mL of dry methylene chloride, were added NaBH(OAc)3 (26.7 mg, 0.13 mmol) and molecular sieves (5 beads). The reaction mixture was reacted for 16.5 hr and followed the same processes as in Example 1 to obtain 16.7 mg (96.5%) of the target compound.
Reaction SMILES: COC1C=CC(C[O:8][CH2:9][CH2:10][C:11]2[NH:15][N:14]=[C:13]([NH2:16])[CH:12]=2)=CC=1>C(O)(C(F)(F)F)=O>[NH2:16][C:13]1[CH:12]=[C:11]([CH2:10][CH2:9][OH:8])[NH:15][N:14]=1
Reactant: COc1ccc(COCCc2cc(N)n[nH]2)cc1
Solvent: O=C(O)C(F)(F)F
Product: Nc1cc(CCO)[nH]n1
Temperature: 25 °C
Yield: 30.6 %

Procedure:
A solution 5-(2-((4-methoxy-benzyl)oxy)-ethyl)-1H-pyrazol-3-amine (66 g, 334.4 mmol) in TFA (300 mL) was heated under reflux for 16 h. After being cooled to RT, the solvent was removed in vacuo, and the residue was partitioned between DCM (400 mL) and 2 N aqueous NaHCO3 (200 mL). The organic layer was separated and the aqueous layer was extracted with DCM (3×100 mL). The combined organic layers were washed with brine, dried (Na2SO4) and then concentrated in vacuo to afford 13 g (38%) of 2-(3-amino-1H-pyrazol-5-yl)ethanol as a yellow solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:9][C@@H:8]2[C@@H:4]([N:5]([C:10]3[CH:15]=[CH:14][C:13]([C:16]4[CH:21]=[CH:20][C:19]([N:22]5[C:27](=[O:28])[CH:26]=[CH:25][CH:24]=[N:23]5)=[CH:18][CH:17]=4)=[CH:12][CH:11]=3)[CH2:6][CH2:7]2)[CH2:3]1.[OH:29]O>C(Cl)Cl.CO>[CH3:1][N@@+:2]1([O-:29])[CH2:9][C@@H:8]2[C@@H:4]([N:5]([C:10]3[CH:15]=[CH:14][C:13]([C:16]4[CH:21]=[CH:20][C:19]([N:22]5[C:27](=[O:28])[CH:26]=[CH:25][CH:24]=[N:23]5)=[CH:18][CH:17]=4)=[CH:12][CH:11]=3)[CH2:6][CH2:7]2)[CH2:3]1
Reactant: OO
Reactant: CN1C[C@H]2CCN(c3ccc(-c4ccc(-n5ncccc5=O)cc4)cc3)[C@H]2C1
Solvent: CO
Solvent: ClCCl
Product: C[N@@+]1([O-])C[C@H]2CCN(c3ccc(-c4ccc(-n5ncccc5=O)cc4)cc3)[C@H]2C1
Temperature: 50 °C

Procedure:
A solution of the product from Example 1G (5 g, 13.44 mmol) in DCM (80 mL) and MeOH (40 mL) was treated with hydrogen peroxide (5.2 mL, 30% in H2O, 53.8 mmol). The mixture was heated to 50° C. for 48 hours. The mixture was concentrated under reduced pressure to a smaller volume while still in a solution. The solution was loaded onto an ANALOGIX SuperFlash silica gel column (ANALOGIX is a registered trademark of Analogix Inc. of Burlington, Wis.) and eluted with NH4OH/MeOH/DCM (1/10/90) to obtain the faster moving component (comparing with Example 1I) as the title product. 1H NMR (300 MHz, DMSO) δ ppm 8.06 (m, 1H), 7.69 (d, J=9 Hz, 2 H), 7.57 (d, J=9 Hz, 4 H), 7.50 (d, J=6 Hz, 1 H), 7.08 (dd, dd, J=9, 4.0 Hz, 1 H), 6.70 (d, J=9 Hz, 2 H), 4.72 (d, J=6 Hz, 1 H), 3.75-3.82 (m, 1 H), 3.52-3.59 (m, 2 H), 3.36-3.45 (m, 3 H), 3.15-3.21 (m, 1 H), 3.14 (s, 3 H), 2.05-2.12 (m, 1 H), 1.80-1.86 (m, 1 H); MS (DCI,) M+=388.
Reaction SMILES: O.[CH2:2]([N:4]([CH2:20][CH3:21])[C:5]([CH2:7][NH:8][C:9]1[CH:14]=[C:13]([N+:15]([O-])=O)[CH:12]=[CH:11][C:10]=1[O:18][CH3:19])=[O:6])[CH3:3]>[Fe].C(O)(=O)C>[CH2:20]([N:4]([CH2:2][CH3:3])[C:5]([CH2:7][NH:8][C:9]1[CH:14]=[C:13]([NH2:15])[CH:12]=[CH:11][C:10]=1[O:18][CH3:19])=[O:6])[CH3:21]
Reactant: CCN(CC)C(=O)CNc1cc([N+](=O)[O-])ccc1OC
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: CCN(CC)C(=O)CNc1cc(N)ccc1OC
Temperature: 90 °C

Procedure:
Into 120 ml of water, one adds 28 g of iron powder and 10 ml of acetic acid. The mixture is brought to a temperature of 85° C. under agitation. Then one adds, little by little, 0.1 mol (28 g) of 2-diethylcarbamylmethylamino-4-nitro anisole. The reaction medium is maintained for 10 minutes at a temperature of 90° C. Then one adds 14 ml of 10 N. soda solution. It is filtered boiling on a heated filter. By cooling the filtrate the expected product crystallizes. After recrystallization in water and vacuum drying it melts at 111° C.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C@H:11]([N:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:19](=[O:22])[CH2:20][CH3:21])[CH2:10][C@@H:9]2[CH3:29])=[O:7])=[CH:4][CH:3]=1.[CH2:32]([CH:34]([CH2:37][CH3:38])[CH:35]=O)[CH3:33].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCl>[CH2:32]([CH:34]([CH2:37][CH3:38])[CH2:35][NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C@H:11]([N:18]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:19](=[O:22])[CH2:20][CH3:21])[CH2:10][C@@H:9]2[CH3:29])=[O:7])=[CH:30][CH:31]=1)[CH3:33]
Reactant: CCC(=O)N(c1ccccc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(N)cc2)c2ccccc21
Reactant: CCC(C=O)CC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCC(=O)N(c1ccccc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(NCC(CC)CC)cc2)c2ccccc21
Temperature: 25 °C
Yield: 83 %

Procedure:
(±)-Cis-N-{1-[4-(2-ethyl-butylamino)-benzoyl]-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl}-N-phenyl-propionamide was prepared from (±)-cis-N-[1-(4-amino-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-N-phenyl-propionamide. To a solution of (±)-cis-N-[1-(4-Amino-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-N-phenyl-propionamide (75 mg, 0.145 mmol) in dichloromethane (3 mL) was added 2-ethylbutyraldehyde (26 uL, 0.2 mmol) in one portion. The mixture was stirred at room temperature for a 0.5 h before a solution of sodium triacetoxyborohydride (74 mg, 0.348 mmol) 1 ml DCM was added slowly. A single drop of acetic acid was added and the reaction was allowed to stir at room temperature over night. Excess reagent was quenched by the addition of saturated aqueous sodium bicarbonate. The resulting mixture was extracted three times with 20 mL dichloromethane. The combined extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. Crude product was purified by HPLC to afford the title compound (60 mg, 83%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1.[C:15]([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])#[N:16].N1CCCCC1>CCO>[C:15](/[C:17](=[CH:11]/[C:10]1[CH:13]=[CH:14][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[CH:8][CH:9]=1)/[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])#[N:16]
Reactant: O=Cc1ccc(-c2ccccn2)cc1
Reactant: CC(C)(C)OC(=O)CC#N
Solvent: C1CCNCC1
Solvent: CCO
Product: CC(C)(C)OC(=O)/C(C#N)=C\c1ccc(-c2ccccn2)cc1
Temperature: 73 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
To a solution of 4-(pyridin-2-yl)-benzaldehyde (300 mg, 1.638 mmol) in EtOH (5 ml) at room temperature was added tert-butyl 2-cyanoacetate (0.281 ml, 1.965 mmol) followed by piperidine (0.016 ml, 0.164 mmol). The mixture was stirred at 73° C. overnight. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. To the obtained mixture was added water and then extracted with DCM. The combined organic layer was washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by flash chromatography (silica gel, 15 to 30% EtOAc/Heptane) and gave the title compound: 350 mg (yield: 70%). LCMS (condition B): 307.2 (M+1); retention time=1.30 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:27][CH3:28])[C:22](OCC)=[O:23])[C:11](=[O:29])[C@@H:10]([CH2:30][C:31]([OH:33])=[O:32])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[BH4-].[Li+].CO>CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:27][CH3:28])[CH2:22][OH:23])[C:11](=[O:29])[C@@H:10]([CH2:30][C:31]([OH:33])=[O:32])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)[C@H](CC)N1C(=O)[C@@H](CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOCC
Solvent: CO
Product: CC[C@@H](CO)N1C(=O)[C@@H](CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reaction time: 0.33 h

Procedure:
To a solution of 300 mg (0.61 mmol) of 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-ethoxy-1-oxobutan-2-yl)-2-oxopiperidin-3-yl)acetic acid (Example 3) in 12 mL of Et2O was added lithium tetrahydroborate (39.8 mg, 1.83 mmol) at 0° C. After being stirred for 20 min, methanol (37.0 μl, 914 μmol) was added at 0° C. and the resulting solution was stirred at 25° C. for 2 h. The reaction was quenched (10% citric acid), extracted (2×EtOAc) and washed (1×sat. aq. NaCl solution). The combined organic layers were washed with sat. NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. Purification by reversed phase preparatory HPLC (Gemini™ Prep C18 5 μm column, Phenomenex, Torrance, Calif.; eluent: 35 to 75% acetonitrile+0.1% TFA in water+0.1% TFA, gradient elution) provided the title compound as a white foam.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]([C:18]2[C:26]3[N:25]=[C:24]([CH:27]([CH3:29])[CH3:28])[NH:23][C:22]=3[CH:21]=[CH:20][CH:19]=2)=[O:17])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]([C:18]2[C:26]3[N:25]=[C:24]([CH:27]([CH3:29])[CH3:28])[NH:23][C:22]=3[CH:21]=[CH:20][CH:19]=2)=[O:17])[CH2:10][CH2:9]1
Reactant: CC(C)c1nc2c(C(=O)NCC3CCN(C(=O)OC(C)(C)C)CC3)cccc2[nH]1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1nc2c(C(=O)NCC3CCNCC3)cccc2[nH]1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 88.9 %

Procedure:
To a solution of 4-{[(2-isopropyl-1H-benzoimidazole-4-carbonyl)amino]methyl}-piperidine-1-carboxylic acid tert-butyl ester (10.8 g, 27.0 mmol) dissolved in dichloromethane (50 mL) at 0° C. was slowly added trifluoroacetic acid (50 mL) in 5 mL portions. The solution was allowed to warm to room temperature, stirred for an additional 20 minutes then evaporated in vacuo. Excess trifluoroacetic acid was removed by co-evaporation with toluene. The residue was then dissolved in a minimal volume of dichloromethane and slowly added to diethyl ether (1 L) at 0° C. The resulting slurry was stirred for 2 h at room temperature then filtered to afford the bis-trifluoroacetate salt of the title compound as a light brown solid (12.7 g, 24.0 mmol, 89%). (m/z): [M+H]+ calcd for C17H24N4O 301.21; found 301.5. Retention time (anal. HPLC: 2-50% MeCN/H2O over 6 min)=1.65 min. 1H NMR (300 MHz, MeOD-d3): δ (ppm) 1.59 (d, 6H), 1.60 (m, 1H), 2.03 (m, 2H), 2.04 (m, 1H), 3.00 (m, 2H), 3.43 (m, 2H), 3.45 (m, 2H), 3.63 (septet, 1H), 7.63 (t, 1H), 7.90 (d, 1H), 7.96 (d, 1H), 9.04 (t, 1H).