Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][CH:2]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:3]([NH:5][C:6]1([C:11]([NH:13][CH:14]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28](SC)=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)[C:15]([OH:17])=[O:16])=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:4].CS[C:39]1[CH:44]=[CH:43][C:42](B(O)O)=[CH:41][CH:40]=1>>[SH:1][CH:2]([CH2:33][CH:34]([CH3:35])[CH3:36])[C:3]([NH:5][C:6]1([C:11]([NH:13][CH:14]([CH2:18][C:19]2([C:41]3[C:40]4[C:39](=[CH:3][CH:2]=[CH:33][CH:34]=4)[CH:44]=[CH:43][CH:42]=3)[CH:24]=[CH:23][C:22]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:21][CH2:20]2)[C:15]([OH:17])=[O:16])=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:4]
Reactant: CSc1ccc(-c2ccc(CC(NC(=O)C3(NC(=O)C(S)CC(C)C)CCCC3)C(=O)O)cc2)cc1
Reactant: CSc1ccc(B(O)O)cc1
Product: CC(C)CC(S)C(=O)NC1(C(=O)NC(CC2(c3cccc4ccccc34)C=CC(c3ccccc3)=CC2)C(=O)O)CCCC1

Procedure:
2-{[1-(2-mercapto-4-methyl-pentanoylamino)-cyclopentanecarbonyl]-amino}-3-(4′-methylthio-biphenyl-4-yl)-propionic acid (from 4-methylthiophenyl-boronic acid; mp 187-189° C.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1([CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.Cl.[CH:27]([C@@H:29]1[C@@H:33]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:32][N:31]([C@H:40]([CH:53]2[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]2)[C:41]([O:43]CC2C=CC(OC)=CC=2)=[O:42])[CH2:30]1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[F:10][C:11]1([CH2:17][CH2:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:16][CH2:15][N:14]([CH2:27][C@@H:29]2[C@@H:33]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH2:32][N:31]([C@H:40]([CH:53]3[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]3)[C:41]([OH:43])=[O:42])[CH2:30]2)[CH2:13][CH2:12]1
Reactant: FC1(CCCc2ccccc2)CCNCC1
Reactant: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](c3ccccc3)[C@@H](C=O)C2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: O=C(O)[C@@H](C1CCCCC1)N1C[C@H](CN2CCC(F)(CCCc3ccccc3)CC2)[C@@H](c2ccccc2)C1
Reaction time: 16 h
Yield: 48 %

Procedure:
To a solution of DIEA (0.019 mL, 0.11 mmol) in 0.5 mL of 1,2-dichloroethane was added 4fluoro-4-(3-phenylpropyl) piperidine.HCl (21 mg, 0.08 mmol) To this solution, a solution of 2-(R)-((3-(R)-formyl)-4-(S)-phenylpyrrolidin-1-yl)-2-(cyclohexyl)acetic acid, (4-methoxy) benzyl ester (25 mg, 0.052 mmol, from EXAMPLE 33, Step E) was added. A slurry of sodium triacetoxyborohydride (35 mg, 0.17 mmol) in 0.5 mL of 1,2-dichloroethane was then added. The reaction mixture was allowed to stand at rt for 16 hours. The solvent was removed and the product was purified by preprative HPLC (column: YMC Combiprep ODS-A 20×50 mm, gradient: 10% acetonitrile/H2O w/0.1% TFA for 1.5 min then ramp to 90% acetonitrile/H2O w/0.1% TFA over 7.5 min, flow: 20 mL/min). The isolated material was stirred in 3 mL formic acid for 16 h. After removal of solvent, the residue was purified by ion exchange chromatography (0.5 grams Varian SCX resin, 100% MeOH→2.0 M NH3/MeOH) to give 13 mg (48%) of the title compound: 1H NMR (400 MHz, CD3OD) δ 1.15-1.37 (m, 4H), 1.41-1.59 (m, 5H), 1.62-1.69 (m, 5H), 1.72-1.91 (m, 5H), 2.04 (t, J=10, 1H), 2.24 (t, J=11, 1H), 2.32 (dd, J=4.5, 13, 1H), 2.46 (dd, J=10, 13 Hz, 2H), 2.58 (t, J=7.5 Hz, 2H), 2.62-2.65 (m, 1H), 2.77 (m, 1H), 3.16 (dd, J=11, 19, 1H), 3.45 (m, 2H), 3.51 (d, J=3.9, 1H), 3.58-3.64 (m, 2H), 7.12-7.16 (m, 3H), 7.22-7.29 (m, 3H), 7.33-7.37 (m, 4H); ESI-MS: 521 (M+H); HPLC A: 2.65 min.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[C@@H:16]3[CH2:20][C@H:19]([NH:21][C:22](=[O:25])[CH2:23][CH3:24])[C@@H:18]([OH:26])[C@H:17]3[OH:27])=[C:9]([NH:28][CH2:29][CH:30]([C:38]3[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=3)[C:31]3[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=3)[N:8]=2)[CH2:3]1.CN1C(=O)CCC1.[O:52]1[CH2:57][CH2:56][N:55]([C:58]2[CH:66]=[CH:65][C:61]([C:62]([Cl:64])=[O:63])=[CH:60][N:59]=2)[CH2:54][CH2:53]1>C1COCC1>[ClH:64].[ClH:64].[OH:44][C:41]1[CH:42]=[CH:43][C:38]([CH:30]([C:31]2[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=2)[CH2:29][NH:28][C:9]2[N:8]=[C:7]([N:4]3[CH2:5][CH2:6][C@@H:2]([NH:1][C:62](=[O:63])[C:61]4[CH:65]=[CH:66][C:58]([N:55]5[CH2:54][CH2:53][O:52][CH2:57][CH2:56]5)=[N:59][CH:60]=4)[CH2:3]3)[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[C@@H:16]2[CH2:20][C@H:19]([NH:21][C:22](=[O:25])[CH2:23][CH3:24])[C@@H:18]([OH:26])[C@H:17]2[OH:27])=[CH:39][CH:40]=1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccc(O)cc4)c4ccc(O)cc4)nc(N4CC[C@@H](N)C4)nc32)[C@H](O)[C@@H]1O
Reactant: O=C(Cl)c1ccc(N2CCOCC2)nc1
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccc(O)cc4)c4ccc(O)cc4)nc(N4CC[C@@H](NC(=O)c5ccc(N6CCOCC6)nc5)C4)nc32)[C@H](O)[C@@H]1O
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of N-((1S,2R,3S,4R)-4-{2-((R)-3-amino-pyrrolidin-1-yl)-6-[2,2-bis-(4-hydroxy-phenyl)-ethylamino]-purin-9-yl}-2,3-dihydroxy-cyclopentyl)-propionamide (20 mg, 33 μmol) in dry THF is treated with NMP (0.5 ml) followed by TEA (13.4 mg, 0.13 mmol) and 6-morpholinonicotinoyl chloride (8.3 mg, 37 μmol). The reaction mixture is stirred at room temperature for 30 minutes and then the solvent is removed in vacuo. Purification by C-18 reverse phase column chromatography eluting with acetonitrile:water:HCl (0.1%) (gradient of 0 to 100% acetonitrile) yields the title compound. (MH+ 793.4)
Reaction SMILES: C([O:3][C:4](=[O:27])[CH:5]([NH:24]C=O)/[CH:6]=[C:7](\[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)/[CH2:8][P:9]([O:14]CC)([O:11]CC)=[O:10])C>Cl>[NH2:24][CH:5](/[CH:6]=[C:7](\[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)/[CH2:8][P:9]([OH:14])([OH:11])=[O:10])[C:4]([OH:27])=[O:3]
Reactant: CCOC(=O)C(/C=C(\Cc1ccccc1)CP(=O)(OCC)OCC)NC=O
Agent: Cl
Product: NC(/C=C(\Cc1ccccc1)CP(=O)(O)O)C(=O)O

Procedure:
0.44 g of E-2-formylamino-4-benzyl-5-diethylphosphono-3-pentenoic acid ethyl ester are dissolved in 8 ml of 4.5N hydrochloric acid and heated at 85° for 48 hours. After concentration in vacuo, the residue is dissolved in a small amount of ethanol and 1 ml of ethanol/propylene oxide(1:1) is added dropwise thereto. The resulting white precipitate is filtered off and, after recrystallisation from water, E-2-amino-4-benzyl-5-phosphono-3-pentenoic acid is obtained in the form ofcolourless needles, m.p. 196°-198°.
Reaction SMILES: [Cl:1][C:2]1[C:7](I)=[CH:6][N:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[C:16]1([C:22]#[CH:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl.[Cu](I)I>[Cl:1][C:2]1[C:7]([C:23]#[C:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:6][N:5]=[CH:4][N:3]=1
Reactant: C#Cc1ccccc1
Reactant: Clc1ncncc1I
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Clc1ncncc1C#Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 2.1 g of 4-chloro-5-iodopyrimidine, 10 mL of triethylamine, 1.2 mL phenylacetylene, 80 mg copper iodide and 160 mg of dichlorobis(triphenylphosphine was stirred at room temperature for 18 hours. The mixture was diluted with dichloromethane and evaporated in vacuo. The residue was redissolved in a few mL of dichloromethane, 10 mL of triethylamine added and the mixture heated at reflux for one hour. The heterogeneous mixture was evaporated in vacuo and the residue obtained was partitioned between water and dichloromethane. A gelatinous precipitate which formed on shaking the two layers was filtered off, enabling separation of the two layers. The organic extracts were dried over sodium sulfate, filtrated and evaporated in vacuo to yield 2.5 g of a dark brown syrup. The syrup was purified by column chromatography on silica gel, twice, eluting with hexanes, 1:1 hexanes/dichloromethane, dichloromethane and finally ethyl acetate. Like fractions from dichloromethane elution were pooled, obtaining 350 mg of the product, 5-phenylethynyl-4-chloropyrimidine as an oil which solidified to white rosettes.
Reaction SMILES: [C:1]([NH:5][CH2:6][CH2:7][N:8]([CH3:23])[C:9]1[N:14]=[C:13]([NH:15]C(=O)OC(C)(C)C)[CH:12]=[CH:11][CH:10]=1)(=[O:4])[CH:2]=[CH2:3].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:15][C:13]1[N:14]=[C:9]([N:8]([CH3:23])[CH2:7][CH2:6][NH:5][C:1](=[O:4])[CH:2]=[CH2:3])[CH:10]=[CH:11][CH:12]=1
Reactant: C=CC(=O)NCCN(C)c1cccc(NC(=O)OC(C)(C)C)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CC(=O)NCCN(C)c1cccc(N)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
A mixture of 110d (2.0 g, 6.25 mmol) and TFA (2.0 mL) in DCM (10.0 mL) was stirred at rt overnight. The mixture was concentrated and diluted with EA (30 mL), neutralized with 1M NaOH. The organic layer was separated, dried over Na2SO4, filtered and concentrated. The residue was purified by prep-TLC (PE/EA=1/1) to give N-(2-((6-aminopyridin-2-yl)(methyl)amino)ethyl)acrylamide 110e (550 mg, 40%) as yellow oil. ESI-LCMS: m/z=221.2
Reaction SMILES: [F-:1].[K+].C1N2CCOCCOCCN(CCOCCOCC2)CCOCCOC1.[N+]([C:32]1[CH:33]=[C:34]2[C:39](=[CH:40][CH:41]=1)[N:38]=[CH:37][N:36]=[C:35]2[O:42][CH2:43][CH2:44][C:45]1[CH:50]=[CH:49][C:48]([C:51]([CH3:54])([CH3:53])[CH3:52])=[CH:47][CH:46]=1)([O-])=O.O>C1COCC1>[F:1][C:32]1[CH:33]=[C:34]2[C:39](=[CH:40][CH:41]=1)[N:38]=[CH:37][N:36]=[C:35]2[O:42][CH2:43][CH2:44][C:45]1[CH:50]=[CH:49][C:48]([C:51]([CH3:54])([CH3:53])[CH3:52])=[CH:47][CH:46]=1
Reactant: CC(C)(C)c1ccc(CCOc2ncnc3ccc([N+](=O)[O-])cc23)cc1
Reactant: [F-]
Agent: C1COCCN2CCOCCOCCN(CCO1)CCOCCOCC2
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1ccc(CCOc2ncnc3ccc(F)cc23)cc1

Procedure:
To a 25 ml round bottom flask is added potassium fluoride (82.6 mg, 1.42 mmol) and kryptofix 222 (0.53 g, 1.42 mmol). The above mixture is stirred in THF for 20 minutes after which 6-Nitro-4-(2-(4-tert-butylphenyl)ethoxy)quinazoline (0.1 g, 0.284 mmol) is added to it. The solution is refluxed for 30 minutes after which it is cooled and water is added to it. It is then extracted in dichloromethane, washed with water and dried. Purification by flash chromatography (silica gel; ethyl acetate/hexanes) gives the above compound.
Reaction SMILES: Br[CH2:2][CH:3]=[C:4]([CH2:12][CH3:13])[CH2:5][CH2:6][CH:7]=[C:8]([CH3:11])[CH2:9][CH3:10].[OH:14][C:15]1[CH:24]=[C:23]2[C:18]([CH2:19][CH2:20][CH2:21][O:22]2)=[CH:17][CH:16]=1>>[CH2:12]([C:4]([CH2:5][CH2:6][CH:7]=[C:8]([CH3:11])[CH2:9][CH3:10])=[CH:3][CH2:2][O:14][C:15]1[CH:24]=[C:23]2[C:18]([CH2:19][CH2:20][CH2:21][O:22]2)=[CH:17][CH:16]=1)[CH3:13]
Reactant: Oc1ccc2c(c1)OCCC2
Reactant: CCC(C)=CCCC(=CCBr)CC
Product: CCC(C)=CCCC(=CCOc1ccc2c(c1)OCCC2)CC

Procedure:
Following the procedure of Example 1, 1-bromo-3-ethyl-7-methyl-2,6-nonadiene and 7-hydroxy-chromane are reacted to form 7-(3-ethyl-7-methyl-2,6-nonadienyloxy)-chromane of boiling point 140°-141°C/0.001 mmHg.
Reaction SMILES: [CH2:1]([N:3]([CH2:12][CH3:13])[C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)[CH3:2].[C:14]([CH:18]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:16][CH3:17])=[O:15]>C(#N)C>[CH2:1]([N:3]([CH2:12][CH3:13])[C:4]1[CH:11]=[CH:10][C:7](/[CH:8]=[CH:18]/[C:14]([O:16][CH3:17])=[O:15])=[CH:6][CH:5]=1)[CH3:2]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCN(CC)c1ccc(C=O)cc1
Solvent: CC#N
Product: CCN(CC)c1ccc(/C=C/C(=O)OC)cc1
Yield: 76 %

Procedure:
A solution of 4-(diethylamino) benzaldehyde (10 g) and carbomethoxymethylenetriphenylphosphorane (20 g) in dry acetonitrile (100 ml) was stirred at reflux under nitrogen for 24 h. The solvent was evaporated and the residual oil was treated with ER (100 ml). The precipitate was filtered, the filtrate was concentrated to an oil and the ER treatment was repeated. After filtration and evaporation the resulting orange oil was purified by [FCS] eluting with cyclohexane/EA/triethylamine 80:20:1) to give the title compound (10.0 g). T.l.c. (cyclohexane/EA/triethylamine 80:20:1) Rf 0.33.
Reaction SMILES: O[C:2]1[C:7]([CH3:8])=[N:6][N:5]([CH3:9])[C:4](=[O:10])[CH:3]=1.O=P(Cl)(Cl)[Cl:13]>>[Cl:13][C:2]1[C:7]([CH3:8])=[N:6][N:5]([CH3:9])[C:4](=[O:10])[CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nn(C)c(=O)cc1O
Product: Cc1nn(C)c(=O)cc1Cl
Temperature: 85 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
A mixture of 5-hydroxy-2,6-dimethylpyridazin-3(2H)-one (736 mg, 5.25 mmol) and POCl3 (4.5 mL) was stirred at 85° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to give the crude material that was quenched with saturated aqueous Na2CO3. The resulting mixture was stirred for 2 hours and extracted with EtOAc (3×). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to give 587 mg (70%) of the desired product that was used directly without further purification.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[N:18][C:19]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)=[CH:20][CH:21]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[Cl:28]C1C=CC=CC=1B(O)O.O1C2C=CC(C3(C(NC4C=NC(Br)=CC=4)=O)CC3)=CC=2OC1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[N:18][C:19]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=5[Cl:28])=[CH:20][CH:21]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: OB(O)c1ccccc1Cl
Reactant: O=C(Nc1ccc(-c2ccccc2)nc1)C1(c2ccc3c(c2)OCO3)CC1
Agent: O=C(Nc1ccc(Br)nc1)C1(c2ccc3c(c2)OCO3)CC1
Product: O=C(Nc1ccc(-c2ccccc2Cl)nc1)C1(c2ccc3c(c2)OCO3)CC1

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(6-(2-chlorophenyl)pyridin-3-yl)cyclopropanecarboxamide was synthesized using the procedure of 1-(benzo[d][1,3]dioxol-5-yl)-N-(6-phenylpyridin-3-yl)cyclopropanecarboxamide from 2-chlorophenylboronic acid and 1-(benzo[d][1,3]dioxol-5-yl)-N-(6-bromopyridin-3-yl)cyclopropanecarboxamide.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][S:13][C:14]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][N:21]=2)[N:17]2[N:30]=[CH:31][N:32]=[C:16]2[N:15]=1.[OH-:33].[Na+]>>[CH3:12][S:13]([C:14]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:22][N:21]=2)[N:17]2[N:30]=[CH:31][N:32]=[C:16]2[N:15]=1)(=[O:9])=[O:33]
Reactant: CSc1cc(-c2ccc(C(F)(F)F)cn2)n2ncnc2n1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: [OH-]
Agent: [Na+]
Product: CS(=O)(=O)c1cc(-c2ccc(C(F)(F)F)cn2)n2ncnc2n1

Procedure:
700 mg of m-chloroperbenzoic acid was added to a chroloform 120 mL solution of 420 mg of 5-(methylthio)-7-(5-(trifluoromethyl)pyridin-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidine, followed by reflux with heating for 2 hours. After completion of the reaction, the reaction liquid was returned to room temperature, a 1N sodium hydroxide aqueous solution was added to the reaction liquid, followed by extraction with chloroform, the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/1) to obtain 420 mg of the desired product.
Reaction SMILES: [OH:1][C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:12][CH2:13][CH:14]2[O:16][CH2:15]2)[N:3]=1.[NH2:17][CH2:18][CH2:19][C:20]1[NH:21][C:22]2[CH:28]=[C:27]([C:29]3[CH:30]([CH3:36])[CH2:31][C:32](=[O:35])[NH:33][N:34]=3)[CH:26]=[CH:25][C:23]=2[N:24]=1>>[OH:1][C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:12][CH2:13][CH:14]([OH:16])[CH2:15][NH:17][CH2:18][CH2:19][C:20]2[NH:21][C:22]3[CH:28]=[C:27]([C:29]4[CH:30]([CH3:36])[CH2:31][C:32](=[O:35])[NH:33][N:34]=4)[CH:26]=[CH:25][C:23]=3[N:24]=2)[N:3]=1
Reactant: OC1=Nc2cccc(OCC3CO3)c2CC1
Reactant: CC1CC(=O)NN=C1c1ccc2nc(CCN)[nH]c2c1
Product: CC1CC(=O)NN=C1c1ccc2nc(CCNCC(O)COc3cccc4c3CCC(O)=N4)[nH]c2c1

Procedure:
Prepared analogously to Example 1 from 1-(3,4-dihydro-2-hydroxy-quinolin-5-yloxy)-2,3-epoxypropane and 6-[2-(2-aminoethyl)benzimidazol-5-yl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23](=[O:33])[NH:24][CH2:25][CH:26]([CH3:32])[CH2:27][C:28]([F:31])([F:30])[F:29])[CH:21]=2)[N:16]([CH3:34])[CH:15]=1)[C:6]([O:8]C)=[O:7].O.[OH-].[Li+]>CO.O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23](=[O:33])[NH:24][CH2:25][CH:26]([CH3:32])[CH2:27][C:28]([F:30])([F:29])[F:31])[CH:21]=2)[N:16]([CH3:34])[CH:15]=1)[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1ccc(Cc2cn(C)c3ccc(C(=O)NCC(C)CC(F)(F)F)cc23)c(OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1cc(C(=O)O)ccc1Cc1cn(C)c2ccc(C(=O)NCC(C)CC(F)(F)F)cc12
Reaction time: 18 h
Yield: 88.5 %

Procedure:
A solution of methyl 3-methoxy-4-[1-methyl-5-(2-methyl-4,4,4-trifluorobutylcarbamoyl)indol-3-ylmethyl]benzoate (0.64 g) in methanol (3.5 mL), tetrahydrofuran (3.5 mL) and water (1.3 mL) was treated with lithium hydroxide monohydrate (0.34 g). The mixture was stirred for 18 hours and the organic solvents evaporated. The resulting aqueous solution was acidified with 10% (w/v) hydrochloric acid. The white precipitate which formed was collected by filtration, washed with water and dried under vacuum to give 3-methoxy-4-[1-methyl-5-(2-methyl-4,4,4-trifluorobutylcarbamoyl)indol-3-ylmethyl]benzoic acid as a white powder (0.55 g, 88%); partial NMR (300 MHz, DMSO-d6): 1.00 (d, 3H, CHCH3) 3.21 (m, 2H, NCH2), 3.76 (s, 3H, NCH3), 3.91 (s, 3H, OCH3), 4.07 (s, 2H, CH2), 7.15 (m, 2H, ArH), 7.46 (m, 3H, ArH), 7.68 (dd, 1H, ArH), 8.10 (d, 1H, ArH), 8.44 (t, 1H, NHCO).
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:5]=[C:6]([C:10]2([CH2:16][CH2:17][N:18]3[CH:23]4[CH2:24][CH2:25][CH:19]3[CH2:20][CH:21]([N:26]3[C:30]5[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=5[N:28]=[C:27]3[CH3:35])[CH2:22]4)[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1.[F:36][C:37]([F:47])([F:46])[C:38]1[C:42]([C:43]([OH:45])=O)=CNN=1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.[N:64]1(OC(N(C)C)=[N+](C)C)[C:68]2N=CC=[CH:72][C:67]=2N=N1>CN(C)C=O>[F:3][C:4]1[CH:5]=[C:6]([C:10]2([CH2:16][CH2:17][N:18]3[CH:23]4[CH2:24][CH2:25][CH:19]3[CH2:20][CH:21]([N:26]3[C:30]5[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=5[N:28]=[C:27]3[CH3:35])[CH2:22]4)[CH2:11][CH2:12][N:13]([C:43]([C:42]3[C:38]([C:37]([F:36])([F:46])[F:47])=[CH:72][CH:67]=[CH:68][N:64]=3)=[O:45])[CH2:14][CH2:15]2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(O)c1c[nH]nc1C(F)(F)F
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2cccc(F)c2)CCNCC1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2cccc(F)c2)CCN(C(=O)c2ncccc2C(F)(F)F)CC1
Reaction time: 2 h
Yield: 20 %

Procedure:
To a solution of 1-(8-{2-[4-(3-fluoro phenyl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole dihydrochloride II (130 mg, 0.25 mmol, 1 eq.) in dimethylformamide (4 mL) was added 3-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 1a, (50 mg, 0.27 mmol, 1 eq.) and N,N-diisopropylethyl amine (180 μL, 1.0 mmol, 4 eq.). After stirring at RT for several min, O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyl-uroniumhexafluorophosphate (95 mg, 0.25 mmol, 1 eq.) was added and the reaction was stirred for 2 h. The mixture was partitioned between dichloromethane and satd. aq. NaHCO3. The organic layer was dried and concentrated and the residue was purified by prep. HPLC (Method Y) to provide 1-{8-[2-(4-(3-fluorophenyl)-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}piperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-2-methyl-1H-benzimidazole 1 as a white solid (30 mg, 20% yield).
Reaction SMILES: O1CCCC1.Cl.[NH2:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=2)[N:11]=[C:10]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[N:9]=1.[C:28](Cl)(=[O:33])[CH2:29][CH2:30][CH:31]=[CH2:32]>C(N(CC)CC)C>[NH2:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=2)[N:11]=[C:10]([N:22]2[CH2:27][CH2:26][N:25]([C:28](=[O:33])[CH2:29][CH2:30][CH:31]=[CH2:32])[CH2:24][CH2:23]2)[N:9]=1
Reactant: C=CCCC(=O)Cl
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CCCC(=O)N1CCN(c2nc(N)c3cc(OC)c(OC)cc3n2)CC1
Reaction time: 0.33 h
Yield: 41.7 %

Procedure:
To 20 ml of tetrahydrofuran were added 2.4 g of 4-amino-6,7-dimethoxy-2-(1-piperazinyl)quinazoline hydrochloride and 2.6 g of triethylamine, after which the mixture was stirred for 20 minutes. There was then added 0.78 g of 4-pentenoyl chloride, after which the mixture was stirred at room temperature for 15 hours. The resulting crystals were collected by filtration, washed with water and recrystallized from ethanol, to give 1.02 g of the desired Compound No. 6 in the form of pale brown needles melting at 219°-220° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:13]([OH:15])=O)[C:5](=[CH:10][C:11]=1[CH3:12])[CH2:6][C:7]([OH:9])=O.[CH:16]([NH2:19])([CH3:18])[CH3:17].C>C(O)C>[CH:16]([N:19]1[C:7](=[O:9])[CH2:6][C:5]2[C:4](=[CH:3][C:2]([CH3:1])=[C:11]([CH3:12])[CH:10]=2)[C:13]1=[O:15])([CH3:18])[CH3:17]
Reactant: Cc1cc(CC(=O)O)c(C(=O)O)cc1C
Reactant: CC(C)N
Agent: C
Solvent: CCO
Product: Cc1cc2c(cc1C)C(=O)N(C(C)C)C(=O)C2
Temperature: 25 °C

Procedure:
A mixture of 4,5-dimethylhomophthalic acid (104 g., 0.5 mole) and isopropylamine (59 g., 1 mole) is heated by an oil bath until molten for 90 minutes. The hot mixture is then poured into 600 ml. of ethanol, treated with carbon black and filtered. The mixture is concentrated to about 300 ml. and slowly cooled to room temperature. 2-Isopropyl-6,7-dimethylisoquinoline-1,3(2H,4H)-dione precipitates and is collected by filtration.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]=[C:12]=[O:13])=[O:4].[CH3:14][NH:15][CH2:16][CH2:17][OH:18]>C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12]([N:15]([CH3:14])[CH2:16][CH2:17][OH:18])=[O:13])=[O:4]
Reactant: COC(=O)c1ccccc1N=C=O
Reactant: CNCCO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccccc1NC(=O)N(C)CCO
Yield: 72.5 %

Procedure:
A solution of 2-methoxycarbonyl phenylisocyanate (21.7 g) in ethyl acetate (116 g) is added dropwise to N-methylethanolamine (22.5 g), the mixture being stirred and cooled to keep the temperature below 36° C. The upper layer of the resulting mixture is separated and distilled at 60° C. under reduced pressure to remove ethyl acetate. The white solid residue remaining is triturated with ether, filtered, washed with ether and then dried in air to give N-(2-methoxycarbonylphenyl)-N'-methyl-N'-(2-hydroxyethyl)urea (22.4 g), m.pt. 90° C.