Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:18][CH2:19][C@H:20]1[N:25]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:24][C@@H:23]([CH:33]([F:44])[CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[N+:41]([O-])=O)[O:22][CH2:21]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.CO.O>C(Cl)Cl.[Fe]>[NH2:41][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=1[CH2:34][CH:33]([C@H:23]1[O:22][CH2:21][C@@H:20]([CH2:19][O:18][Si:1]([C:14]([CH3:17])([CH3:15])[CH3:16])([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:25]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:24]1)[F:44]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](C(F)Cc2ccccc2[N+](=O)[O-])OC[C@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: [Fe]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)N1C[C@@H](C(F)Cc2ccccc2N)OC[C@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reaction time: 0.75 h

Procedure:
A solution of intermediate tert-butyl (2S,5S)-5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2-[1-fluoro-2-(2-nitrophenyl)ethyl]morpholine-4-carboxylate (1 eq.) in a mixture 5:2:1 THF:MeOH:H2O (0.002 M) was warmed up to +59° C. and treated with solid iron (223 eq.). The mixture was further stirred at the same temperature for 45 min, diluted with DCM, washed with sat. NaHCO3, dried over MgSO4, filtered and concentrated. The product was submitted to the next step without further purification. Light yellow oil.
Reaction SMILES: O[CH2:2][CH:3]1[CH:8]([CH3:9])[CH:7]2[CH2:10][CH:4]1[CH2:5][CH2:6]2.CC1C2CC(C=1C)CC2>>[CH3:9][CH:8]1[CH:7]2[CH2:10][CH:4]([CH2:5][CH2:6]2)[C:3]1=[CH2:2]
Reactant: CC1C2CCC(C2)C1CO
Agent: CC1=C(C)C2CCC1C2
Product: C=C1C2CCC(C2)C1C
Yield: 31 %

Procedure:
The same procedure of Example 12 was repeated except that 2-hydroxymethyl-3-methylnorbornane was dehydrated at a reaction temperature of 330° C., and that a product containing 59% 2,3-dimethyl-2-norbornene, and 31% 3-methyl-2-methylenenorbornane was obtained, to obtain 98 g of a fraction having a boiling point of 124° to 127° C./0.2 mmHg.
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.Br[CH:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:11]([NH2:13])=[O:12]>>[I:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([NH2:13])=[O:12])=[CH:4][CH:3]=1
Reactant: NC(=O)C(Br)c1ccccc1
Reactant: Nc1ccc(I)cc1
Product: NC(=O)C(Nc1ccc(I)cc1)c1ccccc1

Procedure:
In accordance with the procedure of example 4 p-iodoaniline and α-bromophenylacetamide were reacted to yield α-(p-iodoanilino)phenylacetamide, Rf =0.65.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]([C:13]2[CH:18]=[C:17]([O:19][C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=3)[CH:16]=[CH:15][N:14]=2)=[O:12])[CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:27]([O-])([OH:29])=[O:28].C([O-])(O)=O.[Na+]>CC(O)=O>[N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]([C:13]2[CH:18]=[C:17]([O:19][C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([N+:27]([O-:29])=[O:28])[CH:21]=3)[CH:16]=[CH:15][N:14]=2)=[O:12])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(NCCCCN1CCCC1)c1cc(Oc2ccc(O)cc2)ccn1
Reactant: O=[N+]([O-])O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(NCCCCN1CCCC1)c1cc(Oc2ccc(O)c([N+](=O)[O-])c2)ccn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-(4-hydroxy-phenoxy)-pyridine-2-carboxylic acid (4-pyrrolidin-1-yl-butyl)-amide (Step C, 2.0 g, 5.6 mmol) in HOAc (32 mL) at RT was added 70% HNO3 (0.56 g, 6.2 mmol). The reaction was stirred at RT for 18 h. An additional amount of 70% HNO3 (0.56 g, 6.2 mmol) was added dropwise over 10 min, and the reaction was stirred for 2 h, after which it was slowly added to saturated aqueous NaHCO3 and extracted with CH2Cl2. The organic layer was washed with NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel chromatography to yield the title compound. MS (MH+)=401.2; Calc'd 400.44 for C20H24N4O5.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13](=[O:29])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:16][CH:15]=1)=[C:8](OS(C(F)(F)F)(=O)=O)[CH:7]=[CH:6]2.[F:38][C:39]1[C:44]([F:45])=[CH:43][CH:42]=[CH:41][C:40]=1B(O)O.[F-].[Cs+]>>[F:38][C:39]1[C:44]([F:45])=[CH:43][CH:42]=[CH:41][C:40]=1[C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([OH:2])[CH:4]=2)[C:9]=1[C:13]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:16][CH:15]=1)=[O:29]
Reactant: OB(O)c1cccc(F)c1F
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Agent: [Cs+]
Agent: [F-]
Product: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(-c2cccc(F)c2F)ccc2cc(O)ccc12
Temperature: 85 °C
Yield: 72.1 %

Procedure:
Charge a flask with trifluoromethanesulfonic acid 6-methoxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-naphthalen-2-yl ester (2.0 g, 3.7 mmol), 2,3 difluorophenyl boronic acid (1.17 g, 7.4 mmol) palladium dichloride bis(triphenylphosphine) (518 mg, 0.74 mmol) and cesium fluoride (5.06 g, 33.3 mmol) and add 250 mL degassed acetonitrile. Heat the mixture at 85° C. for two hours, cool the reaction and filter off any solids. Purify on an SCX column eluting with 2N ammonia/methanol. Purify further on a silica gel column eluting with a 0-10% methanol/methylene chloride gradient to give 1.3 g (70%) of the title compound: 1H-NMR (CD3OD, 400 MHz) δ7.92 (d, J=8.8 Hz, 1H); 7.54 (dd, J=8.4, 4.0 Hz, 3H); 7.43 (dd, J=8.4, 1.6 Hz, 1H); 7.31 (d, J=2.8 Hz, 1H); 7.09 (dd, J=9.2, 2.4 Hz, 1H); 7.05-6.92 (m, 3H); 6.79 (d, J=8.8 Hz, 2H); 4.10 (t, J=5.6 Hz, 2H); 3.93 (s, 3H); 2.73 (t, J=5.2 Hz, 2H); 2.50-2.50 (m, 4H); 1.62-1.57 (m, 4H); 1.48-1.43 (m, 2H).
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].C(O)[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O.[CH2:36](O)[C@H:37]1[O:42][C@H:41]([O:43][C@H:44]2[C@H:49]([OH:50])[C@@H:48]([OH:51])[C@@H:47]([O:52][C@H:53]3[C@H:58]([OH:59])[C@@H:57]([OH:60])[C@@H:56]([OH:61])[O:55][C@@H:54]3[CH2:62][OH:63])[O:46][C@@H:45]2[CH2:64][OH:65])[C@H:40]([OH:66])[C@@H:39]([OH:67])[C@@H:38]1[OH:68].C[O-].[Na+]>C(Cl)(Cl)Cl.CO.O>[C@H:11]1([O:12][CH2:36][C@H:37]2[O:42][C@H:41]([O:43][C@@H:44]3[C@@H:45]([CH2:64][OH:65])[O:46][C@H:47]([O:52][C@H:53]([C@@H:54]([CH2:62][OH:63])[OH:55])[C@H:58]([OH:59])[C@@H:57]([OH:60])[CH:56]=[O:61])[C@H:48]([OH:51])[C@H:49]3[OH:50])[C@H:40]([OH:66])[C@@H:39]([OH:67])[C@@H:38]2[OH:68])[O:4][C@H:3]([CH2:2][OH:1])[C@@H:5]([OH:6])[C@H:7]([OH:8])[C@H:9]1[OH:10]
Reactant: OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@@H](O[C@H]3[C@H](O)[C@@H](O)[C@@H](O)O[C@@H]3CO)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: C[O-]
Agent: OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C[C@H](O)[C@@H](O)[C@H](O[C@H]1O[C@H](CO)[C@@H](O[C@H]2O[C@H](CO[C@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)[C@@H](O)[C@H](O)[C@H]2O)[C@H](O)[C@H]1O)[C@H](O)CO
Reaction time: 24 h

Procedure:
Pullulane52 (100 g) was dissolved in water (1 l) by heating and added to a solution of acetic acid (ca 15 ml) and sodium acetate (41 g) in water (5 l). The solution was adjusted to pH 5 and pullulanase and β-amylase (200 and 200000 units respectively) were added. The reaction mixture was stirred at 37° for 24 h (TLC: SiO2, acetone:isopropanol:0.1M lactic acid; 2:2:1) and then heated at 120° for 20 min (autoclave). The solution was concentrated (final volume: 1.5 l) and treated with ion-exchange resin (Duolite C-26 (H+); 0.5 l). The resin was washed with water and the combined water solutions (ca 4 l) were ultrafiltered (Millipore PSAC 14205 NMWL 1000) which gave a colorless solution. Freeze-drying gave 91 (72 g) contaminated with glucose, maltose and maltotriose. Pure 91 was obtained by treating 92 (1.0 g) with methanolic sodium methoxide (50 ml; from ~1 mg of sodium) at room temperature while monitoring the reaction by TLC (SiO2, chloroform:methanol:water 65:35:10, lower phase). After 24 h, the reaction mixture was neutralized with dry Duolite (H+) resin, filtered, concentrated and chromatographed (Waters Preppak-500/C:water) to give 91 (337 mg, 63%, >99.5% pure by HPLC). [α]D25 +165° (c 0.8, water). Lit.25 [α]D20 +179° (c 1.14, water). 1H-NMR (D2O, TSP) δ 5.40, 5.38 (2d, each 1H, J=3.8 and 3.5 Hz, H1' and H1"), 5.26 (d, ~0.3H, J=3.7 Hz, H1), 4.99 (d, 1H, J=3.7 Hz, H1"'), 4.68 (d, ~0.7H, J=7.9 Hz, H1). 13C-NMR (D2O, TSP) δ 102.6, 102.2, 100.8 (C1', C1∆, C1"'), 98.5, 94.7 (Cl), 79.9, 79.8, 79.6, 78.9, 77.3, 76.7, 76.0, 75.97, 75.8, 74.7, 74.6, 74.4, 74.3, 74.2, 74.1, 73.9, 72.7, 72.3, 72.1, 68.6, 63.4, 63.3, 63.2. The structure of 91 was confirmed by methylation analysis26.
Reaction SMILES: C[O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=2)[C:15]([OH:17])=[O:16])[C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1.Br>C(O)(=O)C>[OH:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=2)[C:15]([OH:17])=[O:16])[C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(C[C@@H](CC[C@H](Cc2ccc(OC)cc2)C(=O)O)C(=O)O)cc1
Agent: Br
Solvent: CC(=O)O
Product: O=C(O)[C@H](CC[C@H](Cc1ccc(O)cc1)C(=O)O)Cc1ccc(O)cc1
Temperature: 120 °C
Reaction time: 48 h
Yield: 32.3 %

Procedure:
To a round bottom flask was added (2R,5R)-2,5-bis(4-methoxybenzyl)hexanedioic acid (10 mg, 0.026 mmol) and 30% HBr in acetic acid (0.5 mL). The reaction was stirred at 120° C. for 2 days. The solvent was removed and the residue was purified by RP prep-HPLC. The fraction was concentrated to give (2R,5R)-2,5-bis(4-hydroxybenzyl)hexanedioic acid (3.0 mg, 8.4 μmol, 32% yield) as an off-white solid. Anal. Calcd. for C20H22O6 m/z 358.3. found: 357.3 (M−H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH:8]([OH:10])[CH3:9])[CH:5]=[CH:4][N:3]=1.O.[NH2:12][NH2:13]>CO.CCOCC>[NH:12]([C:2]1[CH:7]=[C:6]([CH:8]([OH:10])[CH3:9])[CH:5]=[CH:4][N:3]=1)[NH2:13]
Reactant: CC(O)c1ccnc(Cl)c1
Reactant: NN
Solvent: CO
Solvent: O
Solvent: CCOCC
Product: CC(O)c1ccnc(NN)c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
1-(2-chloropyridin-4-yl)ethanol (5d) (14.3 g) was dissolved in hydrazine hydrate (275 mL). The resulting mixture was heated at 100° C. with stirring overnight. The mixture was concentrated under vacuum to give a yellow oil that was dissolved in a small volume of methanol and ether was added, which resulted in precipitation of a white solid. The obtained suspension was stirred for 30 minutes and filtered, and the residue (hydrazine hydrochloride) was discarded. The filtrate was concentrated under vacuum to give the title compound (13.7 g) as a light-brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:32])[NH:20][C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[C:26]([Cl:31])[CH:27]=4)[N:22]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:33]([O:35]CC)=[O:34].[OH-].[Na+]>C1COCC1.C(O)C.C(OCC)(=O)C.Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19](=[O:32])[NH:20][C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[C:26]([Cl:31])[CH:27]=4)[N:22]=3)=[CH:17][CH:18]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:33]([OH:35])=[O:34]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4ccc5cc(Cl)ccc5n4)cc3)c(Cl)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(Nc1ccc2cc(Cl)ccc2n1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.7 %

Procedure:
To ethyl 6-chloro-7-(4-(6-chloroquinolin-2-ylcarbamoyl)phenoxy)chroman-4-carboxylate (1.31 g, 2.44 mmol) in THF (12 mL) and ethanol (6 mL) was added NaOH (6.09 mL, 12.2 mmol) and the reaction stirred at ambient temperature for 3 hours. The reaction was diluted with ethyl acetate (25 mL) and 1N aqueous HCl (20 mL). THF was added as needed to keep the organic layer clear. The organic layer was separated, washed with brine, dried over magnesium sulfate and concentrated. The residue was triturated with DCM and the resulting solids were collected by filtration to provide the desired product (0.98 g, 1.92 mmol, 78.9% yield). MS (APCI)=509.0 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]2[C:17]([Cl:18])=[CH:16][C:15]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[CH:14][C:13]=2[Cl:25])=[C:6]([N+:26]([O-])=O)[CH:5]=1>C(OP(OCC)OCC)C>[CH3:1][O:2][C:3]([C:4]1[CH:5]=[C:6]2[C:7]([CH:10]=[C:11]([C:12]3[C:17]([Cl:18])=[CH:16][C:15]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[CH:14][C:13]=3[Cl:25])[NH:26]2)=[CH:8][CH:9]=1)=[O:29]
Reactant: COC(=O)c1ccc(/C=C/c2c(Cl)cc(N3CCOCC3)cc2Cl)c([N+](=O)[O-])c1
Agent: CCOP(OCC)OCC
Product: COC(=O)c1ccc2cc(-c3c(Cl)cc(N4CCOCC4)cc3Cl)[nH]c2c1
Temperature: 160 °C

Procedure:
A suspension of 4-[(E)-2-(2,6-dichloro-4-morpholin-4-yl-phenyl)-vinyl]-3-nitrobenzoic acid methyl ester (1.25 g, 2.86 mmol) in triethylphosphite (10 mL) was heated at 160° C. for 1 h. The mixture was concentrated under reduced pressure and the residue was triturated to afford 2-(2,6-dichloro-4-morpholin-4-yl-phenyl)-1H-indole-6-carboxylic acid methyl ester as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 11.72 (d, J=1.52 Hz, 1H), 8.02 (d, J=1.01 Hz, 1H), 7.64 (s, 2H), 7.15 (s, 2H), 6.53 (dd, J=1.96, 0.82 Hz, 1H), 3.86 (s, 3H), 3.70-3.76 (m, 4H), 3.25-3.30 (m, 4H). MS (m/z) 405.1 (M+1).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][NH:5][C:6]([C:8]1[CH:9]=[N:10][N:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:21][CH2:20][CH2:19][C@@H:18]3[C:22]3[C:23]([OH:29])=[N:24][CH:25]=[C:26]([F:28])[CH:27]=3)=[N:13][C:12]=12)=[O:7].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[F:28][C:26]1[CH:27]=[C:22]2[C:23](=[N:24][CH:25]=1)[O:29][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:7])[C:8]1=[C:12]3[N:13]=[C:14]([CH:15]=[CH:16][N:11]3[N:10]=[CH:9]1)[N:17]1[C@@H:18]2[CH2:19][CH2:20][CH2:21]1
Reactant: O=C(NCCCCl)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)cnc3O)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C1NCCCOc2ncc(F)cc2[C@H]2CCCN2c2ccn3ncc1c3n2
Temperature: 85 °C
Yield: 43.6 %

Procedure:
A DMF (1 mL) suspension of (R)-N-(3-chloropropyl)-5-(2-(5-fluoro-2-hydroxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (5 mg, 0.012 mmol) and Cs2CO3 (4 mg, 0.06 mmol) was heated at 85° C. overnight. The reaction mixture was filtered through a GF/F paper and directly purified on reverse phase column chromatography (Biotage SP4 system C-18 12+M column, 5 to 60% acetonitrile/water), to provide the title product as white solid (2 mg, 44% yield). MS (apci) m/z=383.3 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:20]=O)=[CH:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[CH:22]1([NH2:25])[CH2:24][CH2:23]1.CO.[BH4-].[Na+]>C(OCC)(=O)C>[CH:22]1([NH:25][CH2:20][C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=2)[CH2:24][CH2:23]1
Reactant: NC1CC1
Reactant: COC(=O)c1ccc(C=C(C=O)c2ccc(F)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1ccc(C=C(CNC2CC2)c2ccc(F)cc2)cc1
Reaction time: 0.5 h

Procedure:
A mixture of methyl 4-(2-(4-fluorophenyl)-3-oxoprop-1-en-1-yl)benzoate (0.568 g. 2 mmol) and cyclopropylamine (0.17 g, 3 mmol) were stirred with MeOH (50 mL) for 3 hours. NaBH4 (0.114 g, 3 mmol) was added to the reaction mixture and it was stirred for 30 minutes. Subsequently the reaction mixture was diluted with ethyl acetate (300 mL) and washed with water (3×50 mL) and brine (100 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated to afford the pure title compound as a pale yellow sticky compound (0.51 g, 76% yield).
Reaction SMILES: [CH2:1]([C:5]1[NH:9][C:8]2[C:10](=[O:17])[C:11]([CH3:16])=[C:12]([CH3:15])[C:13](=[O:14])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].[C:20]([O:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]1[CH:38]=[CH:37][C:36]([CH2:39]Br)=[CH:35][CH:34]=1)=[O:26])([CH3:23])([CH3:22])[CH3:21].[Cl-].[NH4+]>CN(C)C=O>[C:20]([O:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]1[CH:38]=[CH:37][C:36]([CH2:39][N:9]2[C:8]3[C:10](=[O:17])[C:11]([CH3:16])=[C:12]([CH3:15])[C:13](=[O:14])[C:7]=3[N:6]=[C:5]2[CH2:1][CH2:2][CH2:3][CH3:4])=[CH:35][CH:34]=1)=[O:26])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Reactant: CCCCc1nc2c([nH]1)C(=O)C(C)=C(C)C2=O
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCCCc1nc2c(n1Cc1ccc(-c3ccccc3C(=O)OC(C)(C)C)cc1)C(=O)C(C)=C(C)C2=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 56.3 %

Procedure:
340 mg (1.5 mmol) Of the benzimidazol-4,7-dione was dissolved in 15 ml of dimehtylformarnide, and this was cooled to 0° C. After 65 mg (1.6 mmol) of 60% sodium hydride was added and the mixture was stirred for 30 min. A solution of 503 mg (1.5 mmol) of (2'-t-butoxycarbonylbiphenyl-4-yl)methyl bromide in 2 ml of dimethylformamide was added dropwise and the mixture was stirred for 1 hour. To the reaction mixture was added an aqueous saturated solution of ammonium chloride, and this was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated sodium chloride solution, and this was dried over anhydrous sodium sulphate, and the solvent was distilled off under the reduced pressure. The resultant crude product was purified by silica gel chromatography (ethyl acetate: n-hexane=5:1) to obtain 421 mg of 1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-2-n-butyl-5,6-dimethyl-1H-benzimidazol-4,7-dione as yellow oily material (Yield 58%). This has the following NMR spectrum. δ ppm (CDCl3): 0.91 (3H, t, J=7 Hz), 1.21 (9H, s), 1.35-1.43 (H, s), 1.76-1.82 (2H, m), 2.04 (3H, s), 2.10 (3H, s), 5.62 (2H, s), 7.10 (2H, d, J=8 Hz), 7.27-7.30 (3H, m), 7.39-7.42 (1H, m), 7.45-7.48 (1H, m), 7.78 (1H, dd, J=6, 1 Hz)
Reaction SMILES: [CH:1]1([CH:7]([N:20]2[C:24]3[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:23]=3[N:22]=[C:21]2[C:31]2[C:32]([O:39][CH3:40])=[N:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=2)[CH2:8][O:9][C:10]2[C:17]([CH3:18])=[CH:16][C:13]([C:14]#[N:15])=[CH:12][C:11]=2[CH3:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.C(N(CC)CC)C.[N-:49]=[N+:50]=[N-:51].[Na+].Cl>CC1C=CC=CC=1C>[CH:1]1([CH:7]([N:20]2[C:24]3[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:23]=3[N:22]=[C:21]2[C:31]2[C:32]([O:39][CH3:40])=[N:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=2)[CH2:8][O:9][C:10]2[C:11]([CH3:19])=[CH:12][C:13]([C:14]3[NH:51][N:50]=[N:49][N:15]=3)=[CH:16][C:17]=2[CH3:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(-c2nc3cc(F)c(F)cc3n2C(COc2c(C)cc(C#N)cc2C)C2CCCCC2)c(OC)n1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: CCN(CC)CC
Product: COc1ccc(-c2nc3cc(F)c(F)cc3n2C(COc2c(C)cc(-c3nnn[nH]3)cc2C)C2CCCCC2)c(OC)n1
Temperature: 145 °C
Reaction time: 8 h

Procedure:
To a solution of 0.18 g (0.33 mmol) 4-{2-cyclohexyl-2-[2-(2,6-dimethoxy-pyridin-3-yl)-5,6-difluoro-benzoimidazol-1-yl]-ethoxy}-3,5-dimethyl-benzonitrile in 3 ml o-xylene were added 0.227 g (1.65 mmol) triethylamine hydrochloride and 0.107 g (2.65 mMol) sodium azide and the solution was heated for 7 h at 145° C. (oil bath temperature). The reaction was allowed to cool down to room temperature overnight and then was poured onto 1M aqueous hydrochloric acid solution and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The remaining oil was dissolved in acetonitrile, the solution was completely evaporated and the residue dissolved in 20 ml tert-butyl methyl ether under warming to 45° C. The solution was partially evaporated, then stored at 4° C. overnight. The resulting suspension was filtered, washed with tert-butyl methyl ether and dried under high vacuum. Light brown solid (75%). MS (Turbo Spray): m/z=590.44 [M+H].
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=2[C:17]2[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=2)=[O:9])[C@@H:3]1[CH2:23][NH:24][C:25]1[CH:30]=[CH:29][C:28](C(F)(F)F)=[CH:27][N:26]=1.ClC1C=CC=C([C:42]([F:45])([F:44])[F:43])N=1>>[CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=2[C:17]2[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=2)=[O:9])[C@@H:3]1[CH2:23][NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:42]([F:45])([F:44])[F:43])[N:26]=1
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)cn2)c1
Reactant: FC(F)(F)c1cccc(Cl)n1
Product: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2cccc(C(F)(F)F)n2)c1

Procedure:
The title compound was synthesized following the same general protocol as described for ((2S,3R)-3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone in Example A1, using 2-chloro-6-(trifluoromethyl)pyridine. ESI-MS (m/z): 472 [M+1]+.
Reaction SMILES: BrC1C=C(C=CC=1)C=O.[Br-].C(CC[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(O)=O.[Br:35][C:36]1[CH:37]=[C:38]([CH:42]=[CH:43][CH2:44][C:45](O)=[O:46])[CH:39]=[CH:40][CH:41]=1>>[Br:35][C:36]1[CH:37]=[C:38]([CH2:42][CH2:43][CH2:44][CH2:45][OH:46])[CH:39]=[CH:40][CH:41]=1
Reactant: O=C(O)CC=Cc1cccc(Br)c1
Agent: O=C(O)CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=Cc1cccc(Br)c1
Agent: [Br-]
Product: OCCCCc1cccc(Br)c1

Procedure:
3-bromobenzaldehyde and 2-carboxyethyltriphenylphosphonium bromide were reacted to synthesize 4-(3-bromophenyl)-3-butenoic acid, then this compound was esterified and then reduced to synthesize the desired compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[CH2:5][NH:6][C:7]([C:9]1O[CH:11]=[C:12]([Br:24])[C:13](=[O:23])[C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:8].C(O)C.[NH2:31][CH2:32][CH2:33][OH:34]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[CH2:5][NH:6][C:7]([C:9]1[N:31]([CH2:32][CH2:33][OH:34])[CH:11]=[C:12]([Br:24])[C:13](=[O:23])[C:14]=1[O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:8]
Reactant: NCCO
Reactant: O=C(NCc1cccc(Cl)c1)c1occ(Br)c(=O)c1OCc1ccccc1
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(NCc1cccc(Cl)c1)c1c(OCc2ccccc2)c(=O)c(Br)cn1CCO
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-benzyloxy-5-bromo-4-oxo-4H-pyran-2-carboxylic acid 3-chlorobenzylamide (2.0 g) obtained in Example 161, Step 1 in tetrahydrofuran (10 ml)-ethanol (10 ml) was added 2-aminoethanol (0.33 ml) and the mixture was stirred at room temperature and at 50° C. respectively for 30 min. The solvent was evaporated and the residue was crystallized from ethyl acetate-diisopropyl ether to give 3-benzyloxy-5-bromo-1-(2-hydroxyethyl)-4-oxo-1,4-dihydropyridine-2-carboxylic acid 3-chlorobenzylamide (1.95 g).
Reaction SMILES: [CH:1]([C:3]1[CH:7]=[CH:6][NH:5][CH:4]=1)=[O:2].[H-].[Na+].[C:10](Cl)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O1CCCC1.O>[C:10]([N:5]1[CH:6]=[CH:7][C:3]([CH:1]=[O:2])=[CH:4]1)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=Cc1cc[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1ccn(C(=O)c2ccccc2)c1
Reaction time: 0.25 h

Procedure:
500 mg of 3-formyl-pyrrole were dissolved in 10 ml of tetrahydrofuran and then, at +20° C., 227 mg of sodium hydride dispersed at 55% in vaseline oil were added all at once. Gas evolved and after stirring for 15 minutes, a solution of 0.58 ml of benzoyl chloride in 2 ml of tetrahydrofuran was introduced dropwise at +5° C. The mixture was stirred for 2 hours at 20° C. and diluted with water. Extracting with ether, concentrating to dryness by distillation under reduced pressure and chromatographing the residue over silica and eluting with a mixture of hexane and ethyl acetate (7-3) yielded 558 mg of 1-benzoyl-3-formyl-pyrrole.