Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([I:10])[CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[C:11]([O-])([O-])=O.[Cs+].[Cs+].IC>CN(C=O)C>[CH3:11][O:1][C:2]1[CH:9]=[C:8]([I:10])[CH:7]=[CH:6][C:3]=1[CH2:4][OH:5]
Reactant: OCc1ccc(I)cc1O
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cc(I)ccc1CO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Hydroxy-4-iodo-benzylalcohol from Step 3 (1.0 g, 4.0 mmol), Cs2CO3 (1.3 g, 4.0 mmol) and iodomethane (0.25 mL, 4.0 mmol) were dissolved in DMF and heated to 80° for 1 hour and then stirred at room temperature for 2 hours. The DMF was removed in vacuo and the residue was partitioned between H2O and EtOAc. The aqueous layer was extracted with EtOAc (2×). The organic layers were combined, washed with H2O and brine, dried (MgSO4), filtered and concentrated to yield an oil. This oil was purified by flash chromatography eluting product with 30% EtOAC/Hexane to give the title compound.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][N:7]([CH3:24])[C:8](=[O:23])[C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][C:12](Cl)=[N:11][CH:10]=1.CC(=O)CC.[IH:39].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][N:7]([CH3:24])[C:8](=[O:23])[C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][C:12]([I:39])=[N:11][CH:10]=1
Reactant: Cc1ccccc1-c1cc(Cl)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCC(C)=O
Product: Cc1ccccc1-c1cc(I)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 80 °C
Yield: 93.6 %

Procedure:
To a solution of 1.00 g (2.05 mmol) N-(3,5-bis-trifluoromethyl-benzyl)-6-chloro-N-methyl-4-o-tolyl-nicotinamide in 10 ml 2-butanone 1.1 g (7.2 mmol) sodium iodide and 0.28 ml (2.1 mmol) hydroiodic acid (57% in water) were added at room temperature. The mixture was heated at 80° C. for 2 h. After cooling to room temperature the mixture was diluted with ethyl acetate and treated with saturated aqueous sodium bicarbonate solution. The layers were separated, the organic layer washed with water, dried with magnesium sulfate and concentrated to give 1.5 g of crude product. Flash column chromatography gave 1.11 g (93.6%) of the title compound as a yellow oil.
Reaction SMILES: C([O:8][C:9]1[CH:40]=[CH:39][C:12]([O:13][CH2:14][C:15]([C@@H:17]2[CH2:21][CH2:20][CH2:19][N:18]2[C:22](=[O:38])[C@@H:23]2[CH2:27][CH2:26][CH2:25][N:24]2[C:28](=[O:37])[CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:16])=[CH:11][CH:10]=1)C1C=CC=CC=1.O.C(O)(=O)C>CO.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH2:14][C:15]([C@@H:17]2[CH2:21][CH2:20][CH2:19][N:18]2[C:22](=[O:38])[C@@H:23]2[CH2:27][CH2:26][CH2:25][N:24]2[C:28](=[O:37])[CH2:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[O:16])=[CH:39][CH:40]=1
Reactant: O=C(COc1ccc(OCc2ccccc2)cc1)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)CCc1ccccc1
Agent: [Pd]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: O=C(COc1ccc(O)cc1)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)CCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 59.2 %

Procedure:
To a solution of (2S)-2-[4-(benzyloxy)phenoxyacetyl]-1-[N-(3-phenylpropionyl)-L-prolyl]pyrrolidine (1.44 g) in a mixture of methanol (50 ml), water (30 ml) and acetic acid (20 ml) was added Pd-Black (300 mg), and the mixutre was stirred at room temperature under hydrogen atmosphere for 4 hours. The reaction mixture was concentrated, and the concentrate was poured into saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium bicarbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (eluate: chloroform-methanol) to give 0.71 g of the title compound.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.CN(C=O)C.C1(C)C=CC=CC=1.S(Cl)([Cl:38])=O>>[Cl:38][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: COc1cc2c(O)ncnc2cc1OCCCN1CCOCC1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Yield: 66 %

Procedure:
A solution of 4-hydroxy-6-methoxy-7-(3-morpholinopropoxy)quinazoline (2.87 g, 9 mmol) and DMF (1 ml) in thionyl chloride (35 ml) was refluxed for 45 minutes. After addition of toluene, the volatiles were removed by evaporation. The residue was partitioned between ethyl acetate and water and the aqueous layer was adjusted to pH8 with 2M aqueous sodium hydroxide. The organic layer was washed with water and brine, dried (MgSO4) and the volatiles were removed by evaporation. The solid residue was purified by column chromatography eluting with a mixture of methylene chloride, acetonitrile and methanol (50/47.5/2.5) to give 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (2 g, 66%).
Reaction SMILES: [CH:1]([CH:3]([CH2:8][C:9]1[CH:10]=[N:11][CH:12]=[N:13][CH:14]=1)[C:4]([O:6]C)=O)=O.C([O-])([O-])=O.[K+].[K+].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][N:37]([CH3:41])[C:38]([NH2:40])=[NH:39])=[CH:31][CH:30]=2)=[CH:24][C:23]=1[C:42]([F:45])([F:44])[F:43]>CN1C(=O)CCC1>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][N:37]([CH3:41])[C:38]3[NH:40][CH:1]=[C:3]([CH2:8][C:9]4[CH:10]=[N:11][CH:12]=[N:13][CH:14]=4)[C:4](=[O:6])[N:39]=3)=[CH:31][CH:30]=2)=[CH:24][C:23]=1[C:42]([F:43])([F:44])[F:45]
Reactant: CN(CCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1)C(=N)N
Reactant: COC(=O)C(C=O)Cc1cncnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CN(CCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1)c1nc(=O)c(Cc2cncnc2)c[nH]1
Temperature: 200 °C
Yield: 27.4 %

Procedure:
To the mixture of methyl 2-formyl-3-(5-pyrimidinyl)propanoate (67.9 mg, 0.350 mmol) and K2CO3 (149 mg, 1.076 mmol) in NMP (2 mL) was added neat N-[2-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)ethyl]-N-methylguanidine (100 mg, 0.269 mmol). The reaction mixture was heated with a microwave reactor at 200° C. for 3 h. Purification via MDAP then afforded the title compound as a white solid (38 mg, 22.4% yield). LCMS: rt=3.02 min, [M+H+]=516.0
Reaction SMILES: [CH3:1][C@@:2]12[CH2:19][CH2:18][C@@H:17]3[C@:12]([CH3:22])([CH2:13][CH2:14][CH2:15][C:16]3([CH3:21])[CH3:20])[C@H:11]1[CH2:10][S:9][C:8]1[C:3]2=[C:4]([OH:24])[CH:5]=[C:6]([OH:23])[CH:7]=1.[CH3:25][Si](C=[N+]=[N-])(C)C>CO.C(Cl)Cl>[CH3:25][O:23][C:6]1[CH:7]=[C:8]2[C:3]([C@@:2]3([CH3:1])[C@H:11]([CH2:10][S:9]2)[C@:12]2([CH3:22])[C@H:17]([C:16]([CH3:20])([CH3:21])[CH2:15][CH2:14][CH2:13]2)[CH2:18][CH2:19]3)=[C:4]([OH:24])[CH:5]=1
Reactant: CC1(C)CCC[C@]2(C)[C@H]3CSc4cc(O)cc(O)c4[C@]3(C)CC[C@@H]12
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: ClCCl
Solvent: CO
Product: COc1cc(O)c2c(c1)SC[C@@H]1[C@@]3(C)CCCC(C)(C)[C@@H]3CC[C@@]21C

Procedure:
(1R,10R,11S,16S)-1,11,15,15-Tetramethyl-8-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-triene-3,5-diol (Compound No. 26) (346 mg, 1.0 mmol) was dissolved in MeOH (4 mL) and CH2Cl2 (12 mL). Trimethylsilyl diazomethane (0.80 mL, 2.0 M in ether, 1.6 mmol) was added portionwise over 29 h at room temperature, monitoring the reaction by 1H NMR. The mixture was then concentrated and purified by chromatography on silica gel (Hexanes/EtOAc, 4:1) followed by recrystallization from MeOH/water to give (1R,10R,11S,16S)-5-methoxy-1,11,15,15-tetramethyl-8-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-trien-3-ol (Compound No. 29) (142 mg, 39%) as a white solid. 1H NMR (CDCl3): δ 6.21 (d, 1H), 5.95 (d, 1H), 4.72 (s, 1H), 3.69 (s, 3H), 3.30 (m, 1H), 2.91 (m, 1H), 2.78 (m, 1H), 1.85-1.40 (m, 8H), 1.39 (s, 3H), 1.20-1.00 (m, 2H), 0.96 (s, 3H), 0.95 (m, 1H), 0.85 (s, 3H), 0.84 (s, 3H). MS m/z 359 (C22H32O2S−H+).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](/[CH:11]=[CH:12]/[C:13]([OH:15])=O)=[CH:3]1.[F:16][C:17]1[CH:18]=[C:19]([CH:27]=[CH:28][CH:29]=1)[C:20]([NH:22][NH:23][CH:24]([CH3:26])[CH3:25])=[O:21].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.CCOC(C)=O>[F:16][C:17]1[CH:18]=[C:19]([CH:27]=[CH:28][CH:29]=1)[C:20]([NH:22][N:23]([CH:24]([CH3:26])[CH3:25])[C:13](=[O:15])/[CH:12]=[CH:11]/[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:2]([CH3:1])[CH:3]=1)=[O:21]
Reactant: CC(C)NNC(=O)c1cccc(F)c1
Reactant: Cn1cc(/C=C/C(=O)O)c2ccccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)N(NC(=O)c1cccc(F)c1)C(=O)/C=C/c1cn(C)c2ccccc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To solution containing (E)-3-(1-methyl-1H-indol-3-yl)acrylic acid (140.0 mg, 0.70 mmol), 3-fluoro-N′-isopropylbenzohydrazide (209.0 mg, 1.05 mmol) and HATU (399.2 mg, 1.05 mmol) dissolved in DMF (3.0 ml), N,N-diisopropylethylamine (DIPEA)(0.18 ml, 1.05 mmol) was slowly drop-wise added and stirred at room temperature for 12 hr. The reaction mixture was diluted with EtOAc, washed with water and brine, dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was separated through silica gel chromatography (30% EtOAc) for refinement and dried so that ivory (E)-3-fluoro-N′-isopropyl-N′-(3-(1-methyl-1H-indol-3-yl)acryloyl)benzohydrazide was obtained (37.0 mg, 13.9%).
Reaction SMILES: [CH2:1]([N:5]([CH2:7][C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([C:18]2[O:19][CH:20]=[CH:21][N:22]=2)[CH:17]=1)[C:11]([O:13]C)=O)[CH3:6])[CH2:2][CH2:3][CH3:4].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[ClH:56].Cl.[NH2:58][C@@H:59]([CH2:75][C:76]1[CH:81]=[C:80]([F:82])[CH:79]=[C:78]([F:83])[CH:77]=1)[C@H:60]([OH:74])[CH2:61][NH:62][C:63]1([C:66]2[CH:71]=[CH:70][CH:69]=[C:68]([C:72]#[CH:73])[CH:67]=2)[CH2:65][CH2:64]1>O1CCCC1.CO.O.O.[OH-].[Li+].C(OCC)(=O)C>[ClH:56].[ClH:56].[CH2:1]([N:5]([CH2:7][C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([C:18]2[O:19][CH:20]=[CH:21][N:22]=2)[CH:17]=1)[C:11]([NH:58][C@@H:59]([CH2:75][C:76]1[CH:77]=[C:78]([F:83])[CH:79]=[C:80]([F:82])[CH:81]=1)[C@H:60]([OH:74])[CH2:61][NH:62][C:63]1([C:66]2[CH:71]=[CH:70][CH:69]=[C:68]([C:72]#[CH:73])[CH:67]=2)[CH2:65][CH2:64]1)=[O:13])[CH3:6])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(C)Cc1cc(C(=O)OC)cc(-c2ncco2)c1
Reactant: C#Cc1cccc(C2(NC[C@@H](O)[C@@H](N)Cc3cc(F)cc(F)c3)CC2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: C#Cc1cccc(C2(NC[C@@H](O)[C@H](Cc3cc(F)cc(F)c3)NC(=O)c3cc(CN(C)CCCC)cc(-c4ncco4)c3)CC2)c1
Reaction time: 16 h

Procedure:
Methyl 3-{[butyl(methyl)amino]methyl}-5-(1,3-oxazol-2-yl)benzoate (30 mg, 0.1 mmol) is dissolved in 2:1:1 tetrahydrofuran/methanol/water (4 mL), and lithium hydroxide monohydrate is added (10 mg, 0.2 mmol), and the reaction stirred 16 h. The solution is concentrated under reduced pressure. The residue is redissolved in DMF (1 mL), and diisopropylethylamine (70 μL, 0.4 mmol), HATU (57 mg, 0.15 mmol), and (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-{[1-(3-ethynylphenyl)cyclopropyl]amino}butan-2-ol dihydrochloride (203 mg, 0.5 mmol) are added. The reaction stirred at room temperature 2 h. The reaction mixture is diluted with ethyl acetate, washed with water, saturated sodium bicarbonate, brine, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 9-10% methanol/methylene chloride) provides the title compound as the free base. The residue is dissolved in diethyl ether (3 mL) and 1N hydrochloric acid in diethyl ether (1 mL) is added. The mixture is concentrated under reduced pressure to yield the title compound. ESI MS m/z 627.3 [M+H]+.
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH2:8][C@@H:9]([C:17]([N:19]1[CH2:33][CH2:32][CH2:31][C@H:20]1[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)C(C)C)(C)C.[CH2:43]([N:45]=[C:46]=[O:47])[CH3:44]>ClCCl>[CH2:43]([NH:45][C:46]([NH:8][C@@H:9]([C:17]([N:19]1[CH2:33][CH2:32][CH2:31][C@H:20]1[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:47])[CH3:44]
Reactant: CCN=C=O
Reactant: N[C@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCNC(=O)N[C@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reaction time: 16 h
Yield: 107 %

Procedure:
To a solution of TFA.D-Phe-Pro-OBzl (10 g, 21.4 mmol) in dichloromethane (150 mL) was added N,N-diisopropylethylamine (3.73 mL, 21.4 mmol) followed by ethyl isocyanate (1.86 mL, 23.5 mmol). After stirring for 16 h, the solution was washed three times with 1N HCl, dried over Na2SO4, filtered and concentrated in vacuo to give 9.7 g (107%) of white foam.
Reaction SMILES: C([O:8][C:9]([C:11]1[CH:16]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)[C:15]([C:26]([O:28][CH2:29][CH2:30][C:31]#[N:32])=[O:27])=[C:14]([CH2:33][CH3:34])[NH:13][C:12]=1[CH2:35][CH3:36])=[O:10])C1C=CC=CC=1.C(O)=O.CO>C(Cl)(Cl)Cl.[Pd]>[C:31]([CH2:30][CH2:29][O:28][C:26]([C:15]1[CH:16]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)[C:11]([C:9]([OH:10])=[O:8])=[C:12]([CH2:35][CH3:36])[NH:13][C:14]=1[CH2:33][CH3:34])=[O:27])#[N:32]
Reactant: CCC1=C(C(=O)OCCC#N)C(c2ccc([N+](=O)[O-])cc2)C(C(=O)OCc2ccccc2)=C(CC)N1
Agent: [Pd]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: O=CO
Product: CCC1=C(C(=O)O)C(c2ccc([N+](=O)[O-])cc2)C(C(=O)OCCC#N)=C(CC)N1

Procedure:
The solution of 3-benzyloxycarbonyl-5-(2-cyanoethoxy) carbonyl-2,6-diethyl-1,4-dihydro-4-(4-nitrophenyl)pyridine (6.30 g, 13.0 mmol) in 250 ml of 4.4% (w/w) formic acid/MeOH mixture was stirred with Pd/C (10%, 6.0 g) for 30 min., the reaction was quenched by addition of 100 ml of CHCl3. The mixture was filtered and concentration of filtrate give a yellow powder, which was dissolved in CHCl3, washed with water and 1N HCl. After filtration and removal of solvent, 3-(2-cyanoethoxy)carbonyl-2,6-diethyl-1,4-dihydro-4-(4-nitrophenyl)pyridine-5-carboxylic acid was obtained as a yellow powder (4.5 g, 87%).
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N+:11]([O-:13])=[O:12].[NH:14]1[C:22]2[C:17](=[C:18]([N:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15]1.C(N(CC)CC)C.CN(C=O)C>O>[N+:11]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[NH:4][CH2:3][CH2:2][N:26]1[CH2:27][CH2:28][N:23]([C:18]2[CH:19]=[CH:20][CH:21]=[C:22]3[C:17]=2[CH:16]=[CH:15][NH:14]3)[CH2:24][CH2:25]1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1ccccc1NCCCl
Reactant: c1cc(N2CCNCC2)c2cc[nH]c2c1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1NCCN1CCN(c2cccc3[nH]ccc23)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 39.2 %

Procedure:
A mixture containing 0.49 g of N-(2-chloroethyl)-2-nitroaniline, prepared according to the procedure described by Ramage G. R. et al. in J. Chem. Soc. 4406-4409 (1952), 0.55 g of 1-(4-indolyl)piperazine (prepared according to WO 95/33743), 1 mL of triethylamine and 3 mL of DMF was heated at reflux while stirring under nitrogen for 2.5 h. After cooling at room temperature, the mixture was poured into H2O, extracted with CH2Cl2, and the organic phase dried on anhydrous Na2SO4 and evaporated to dryness. The residue was purified via flash chromatography (EtOAc-petrolium ether 3:7) giving 0.35 g (40%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[BH4-].[Na+].Cl.[OH-].[NH4+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][NH:9]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc2cccnc2c1
Agent: Cl[Ni]Cl
Agent: Cl
Agent: [BH4-]
Solvent: CO
Solvent: O
Product: Cc1ccc2c(c1)NCCC2
Temperature: 0 °C
Reaction time: 1 h
Yield: 102.5 %

Procedure:
To a cooled solution of 7-methyl quinoline (5.00 g, 35 mmol) and nickel (II) chloride hexahydrate (1.40 g, 6 mmol) in methanol (130 mL) was added sodium borohydride (5.50 g, 140 mmol) portionwise. The reaction mixture was stirred at 0° C. for 1 hour and then at room temperature for 3 hours. Hydrochloric acid (2N, 200 mL) was added to the black residue and the mixture stirred at room temperature until disappearance of the black precipitate. The acidic solution was neutralized with concentrated ammonium hydroxide and extracted with ether. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, filtered and evaporated to give 5.28 g of 7-methyl-1,2,3,4-tetrahydro-quinoline (100%), used without further purification. A mixture of 7-methyl-1,2,3,4-tetrahydro-quinoline (1.20 g, 8.2 mmol), potassium carbonate (2.3 g, 16.4 mmol) and isopropyl iodide (3.3 mL, 32.8 mmol) in N,N-dimethylformamide (10 mL) was heated at 60° C. with stirring for 24 hours. The solution was cooled to room temperature and washed successively with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated to give 1.28 g (82%) of 1-isopropyl-7-methyl-1,2,3,4-tetrahydro-quinoline. To a solution of 1-isopropyl-7-methyl-1,2,3,4-tetrahydro-quinoline (1.04 g, 5.5 mmol) in dichloromethane was added tetrabutylammonium tribromide (2.65 g, 5.5 mmol) and the solution stirred at room temperature for 5 hours. The solution was washed successively with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was chromatographed and silica gel (ethyl acetate/hexane, 1:9) to give 1.00 g of 6-bromo-1-isopropyl-7-methyl-1,2,3,4-tetrahydro-quinoline (67%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[C:25]([N:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1)=[O:26])[C:5]([NH:7][C@H:8]([C:10]1[NH:14][C:13]2[CH:15]=[CH:16][C:17]([N+:19]([O-])=O)=[CH:18][C:12]=2[N:11]=1)[CH3:9])=[O:6].[H][H]>CO.[Pd]>[CH3:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[C:25]([N:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1)=[O:26])[C:5]([NH:7][C@H:8]([C:10]1[NH:14][C:13]2[CH:15]=[CH:16][C:17]([NH2:19])=[CH:18][C:12]=2[N:11]=1)[CH3:9])=[O:6]
Reactant: [H][H]
Reactant: Cc1cc(C(=O)N[C@@H](C)c2nc3cc([N+](=O)[O-])ccc3[nH]2)ccc1C(=O)N1CCCC1
Agent: [Pd]
Solvent: CO
Product: Cc1cc(C(=O)N[C@@H](C)c2nc3cc(N)ccc3[nH]2)ccc1C(=O)N1CCCC1
Yield: 83 %

Procedure:
40 mg of 3-methyl-N-[(1S)-1-(5-nitro-1H-benzimidazol-2-yl)ethyl]-4-(pyrrolidin-1-ylcarbonyl)benzamide if dissolved in 40 mL of methanol, combined with 10 mg of palladium on activated charcoal (10%), and hydrogenated for 3 hours with hydrogen (3 bar). Then the catalyst is filtered off and the solvent is distilled off. Yield: 83%; Rf value: 0.50 (silica gel; dichloromethane/ethanol=4:1); C22H25N5O2 (391.47); mass spectrum: (M+H)+=392 and (M−H)−=390
Reaction SMILES: [NH2:1][C:2]1[C:17]([F:18])=[CH:16][C:5]2[O:6][C:7]([F:15])([F:14])[C:8](=[O:13])[N:9]([CH2:10][C:11]#[CH:12])[C:4]=2[CH:3]=1.Cl[C:20]([O:22][CH2:23][CH3:24])=[O:21].CCOC(C)=O.CCCCCCC>C1(C)C=CC=CC=1>[F:15][C:7]1([F:14])[C:8](=[O:13])[N:9]([CH2:10][C:11]#[CH:12])[C:4]2[CH:3]=[C:2]([NH:1][C:20](=[O:21])[O:22][CH2:23][CH3:24])[C:17]([F:18])=[CH:16][C:5]=2[O:6]1
Reactant: C#CCN1C(=O)C(F)(F)Oc2cc(F)c(N)cc21
Reactant: CCOC(=O)Cl
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C#CCN1C(=O)C(F)(F)Oc2cc(F)c(NC(=O)OCC)cc21
Yield: 40.6 %

Procedure:
A mixture of 6-amino-2,2,7-trifluoro-4-(prop-2-ynyl)-2Hbenzo[b][1,4]oxazin-3(4H)-one (2.0 g, 7.8 mmol) and ethyl chloroformate (1.14 g, 10.5 mmol) in dry toluene was heated to reflux for 2 hours. The mixture was evaporated to dryness to obtain a brown solid. Column chromatography (silica, EtOAc: heptane, 1:3) gave the product (1.04 g), which was used without further purification in the next step 1.8a.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][CH2:11][N:12]2[CH2:17][CH:16]=[C:15]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[NH:20][CH:19]=3)[CH2:14][CH2:13]2)=[CH:2]1.[CH3:27][CH2:28][CH2:29]CCC.C(Br)C=C>C1COCC1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][CH2:11][N:12]2[CH2:13][CH:14]=[C:15]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]([CH2:29][CH:28]=[CH2:27])[CH:19]=3)[CH2:16][CH2:17]2)=[CH:2]1
Reactant: CCCCCC
Reactant: C1=C(c2c[nH]c3ccccc23)CCN(CCc2csc3ccccc23)C1
Solvent: C1CCOC1
Solvent: C=CCBr
Product: C=CCn1cc(C2=CCN(CCc3csc4ccccc34)CC2)c2ccccc21
Reaction time: 5.5 h

Procedure:
3-{1-[2-(1-benzothiophene-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1H-indole (358 mg, 1 mmol) (obtained from example 29, step 2) in dry THF (50 ml) was slowly added to a stirred suspension of hexane and washed with 60% sodium hydride (44 mg) at 0° C. After the addition, the reaction mixture was stirred for 330 min and allyl bromide (183 mg, 1.5 mmol) was added. The reaction mixture was stirred for 4 hrs and quenched carefully with ice cold water. The reaction mixture was extracted with chloroform; washed well with water; dried over anhydrous MgSO4; filtered and concentrated. The residue obtained was purified by silica-gel column chromatography by eluting it with 50% ethyl acetate:hexane. Yellow semi-solid. Yield: 195 mg (48%); 399 (M+H); 1HNMR (400 MHz, CDCl3): δ 7.99˜7.87 (m, 3H); 7.42˜6.99 (m, 6H); 6.22˜6.21 (s, 1H); 5.22˜5.21 (d, J=1.3 Hz, 2H); 5.20˜5.19 (d, J=1.3 Hz, 2H); 4.71˜4.65 (d, 1.6 Hz, 2H); 3.49˜2.67 (m, 10H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[C:35](Cl)[N:34]=[N:33][C:32]=2[CH2:38][CH2:39][CH2:40][CH3:41])=[CH:27][CH:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:35]2[N:34]=[N:33][C:32]([CH2:38][CH2:39][CH2:40][CH3:41])=[C:31]([C:28]3[CH:27]=[CH:26][C:25]([O:24][CH2:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:30][CH:29]=3)[CH:36]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCc1nnc(Cl)cc1-c1ccc(OCc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCc1nnc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1-c1ccc(OCc2ccccc2)cc1
Reaction time: 0.17 h

Procedure:
To a stirred solution of 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (227 mg, 1.13 mmol) in THF (4.0 mL) at room temperature was added NaH (100 mg, 4.5 mmol). Stirring was continued for 10 min. To this solution was added 4-(4-benzyloxy-phenyl)-3-butyl-6-chloro-pyridazine (200 mg, 0.56 mmol) and the resulting mixture was stirred at 50-55° C. overnight. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with water followed by brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography using 30% ethyl acetate in hexanes to provide 4-[5-(4-benzyloxy-phenyl)-6-butyl-pyridazin-3-yloxy]-piperidine-1-carboxylic acid tert-butyl ester.