Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([C:30]1[CH:31]=[C:32]([CH:57]=[CH:58][CH:59]=1)[C:33]([C:35]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[N:37]([CH2:44][CH2:45][CH2:46][C:47]([O:49]CC2C=CC=CC=2)=[O:48])[CH:36]=1)=[O:34])[CH:9]([C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH:27]([CH3:29])[CH3:28])=[CH:22][CH:21]=1)[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH:17]([CH3:19])[CH3:18])=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.O1CCOCC1.[Pd]>[CH2:1]([N:8]([C:30]1[CH:31]=[C:32]([CH:57]=[CH:58][CH:59]=1)[C:33]([C:35]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[N:37]([CH2:44][CH2:45][CH2:46][C:47]([OH:49])=[O:48])[CH:36]=1)=[O:34])[CH:9]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH:17]([CH3:19])[CH3:18])=[CH:12][CH:11]=1)[C:20]1[CH:21]=[CH:22][C:23]([CH2:26][CH:27]([CH3:29])[CH3:28])=[CH:24][CH:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)Cc1ccc(C(c2ccc(CC(C)C)cc2)N(Cc2ccccc2)c2cccc(C(=O)c3cn(CCCC(=O)OCc4ccccc4)c4ccccc34)c2)cc1
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)Cc1ccc(C(c2ccc(CC(C)C)cc2)N(Cc2ccccc2)c2cccc(C(=O)c3cn(CCCC(=O)O)c4ccccc34)c2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Benzyl 4-[3-[3-[N-benzyl-N-[bis(4-isobutylphenyl)methyl]amino]benzoyl]indol-1-yl]butyrate (24 mg) was dissolved in a mixture of methanol 93 ml) and 1,4-dioxane (3 ml), and 10% palladium on carbon (12 mg) was added. The mixture was stirred under hydrogen atmosphere at room temperature for 5 hours. The catalyst was removed by filtration and the filtrate was evaporated. The residue was chromatographed on silica gel (2 g) eluting with a mixture of chloroform and methanol (50:1) to give 4-[3-[3-[N-benzyl-N-[bis(4-isobutylphenyl)methyl]amino]benzoyl]indol-1-yl]butyric acid as (14 mg) powder.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[CH3:27][C@H:28]1[NH:33][C@@H:32]([CH3:34])[CH2:31][N:30]([C:35]2[N:39]([CH3:40])[C:38]3[CH:41]=[CH:42][CH:43]=[CH:44][C:37]=3[N:36]=2)[CH2:29]1>>[F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:33]2[C@H:32]([CH3:34])[CH2:31][N:30]([C:35]3[N:39]([CH3:40])[C:38]4[CH:41]=[CH:42][CH:43]=[CH:44][C:37]=4[N:36]=3)[CH2:29][C@@H:28]2[CH3:27])[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: C[C@@H]1CN(c2nc3ccccc3n2C)C[C@H](C)N1
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: C[C@@H]1CN(c2nc3ccccc3n2C)C[C@H](C)N1CCCCC1(C(=O)NCC(F)(F)F)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 2 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 2-(cis-3,5-dimethyl-piperazin-1-yl)-1-methyl-1H-benzimidazole.
Reaction SMILES: [C:1]([C:3]1[C:8](Br)=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].[C:10]1([CH3:19])[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[C:1]([C:3]1[C:8]([C:13]2[CH:14]=[CH:15][C:10]([CH3:19])=[CH:11][CH:12]=2)=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2]
Reactant: Cc1ccc(B(O)O)cc1
Reactant: N#Cc1ncccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2cccnc2C#N)cc1
Yield: 34 %

Procedure:
Under nitrogen, 13.91 g (76 mmol) of 2-cyano-3-bromopyridine from step 2 and 11.41 g (84 mmol) of 4-tolylboronic acid from step 3 were treated with 2.65 g (2.3 mmol) of tetrakis (triphenylphosphine)palladium zero, 155 mL of toluene, 60 mL of ethanol, and 77 mL of 2M aqueous sodium carbonate. The reaction mixture was heated to reflux and vigorously stirred overnight. The product crystallized from the reaction mixture after several days at ambient temperature. Filtration provided 5.02 g (34%) of 2-cyano-3-(4-tolyl)pyridine as a colorless solid: mp 136°-138° C.; NMR (CDCl3) δ2.44 (s, 3H), 7.34 (d, J=8 Hz, 2H), 7.47 (d, J=8 Hz, 2H), 7.56 (dd, J=8 and 5 Hz, 1H), 7.85 (dd, J=8 and 2 Hz, 1H), 8.68 (dd, J=5 and 2 Hz, 1H); MS (70 eV) m/e (rel intensity) 194 (100).
Reaction SMILES: S(Cl)([Cl:3])=O.N1C(C)=CC=CC=1C.[CH2:13]([O:16][C:17]([N:19]1[CH2:23][C@H:22]([O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[CH2:21][C@H:20]1[CH:32]([C:34]1[CH:35]=[N:36][CH:37]=[N:38][CH:39]=1)O)=[O:18])[CH:14]=[CH2:15].[OH-].[Na+]>ClCCl>[CH2:13]([O:16][C:17]([N:19]1[CH2:23][C@H:22]([O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[CH2:21][C@H:20]1[CH:32]([C:34]1[CH:35]=[N:36][CH:37]=[N:38][CH:39]=1)[Cl:3])=[O:18])[CH:14]=[CH2:15]
Reactant: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C(O)c1cncnc1
Reactant: O=S(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C(Cl)c1cncnc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 47.3 %

Procedure:
To a solution of thionyl chloride (6.05 g) in dichloromethane (70 ml) was added 2,6-lutidine (6.53 g) at 5° C. to 10° C. After the solution was stirred for 30 minutes at the same temperature, the solution of 1-{(2S,4R)-1-allyloxycarbonyl-4-(t-butyldimethylsilyloxy)-pyrrolidin-2-yl}-1-(pyrimidin-5-yl)methanol (20.0 g) in dichloromethane (100 ml) was slowly dropped thereto below 10° C. After the reaction mixture was stirred for an hour below 10° C., it was stirred at room temperature for 2 hours, then thionyl chloride (6.05 g) and 2,6-lutidine (6.53 g) were added to the reaction mixture. After the reaction mixture was stirred another one hour, thionyl chloride (6.05 g) and 2,6-lutidine (6.53 g) were added to the reaction mixture. The reaction mixture was stirred at room temperature for 2 hours, then it was poured into ice-water (500 ml) and dichloromethane (400 ml) and adjusted to pH 5.1 with saturated aqueous sodium hydroxide below 15° C. The organic layer was separated and washed with water (400 ml) at pH 4.3 and brine (350 ml). The organic layer was dried over magnesiumsulfate and evaporated. The residue was subjected to column chromatography on silica gel (200 g) [solvent; hexane:ethyl acetate=5:1 to 2:1 to 1:1] to give 1-{(2S,4R)-1-allyloxycarbonyl-4-(t-butyldimethylsilyloxy)-pyrrolidin-2-yl }-1-(pyrimidin-5-yl)-1-chloromethane (9.9 g) as an oil.
Reaction SMILES: S(=O)(=O)(O)[OH:2].[F:6][C:7]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:8]=1[C:9]#[N:10]>O>[F:6][C:7]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:8]=1[C:9]([NH2:10])=[O:2]
Reactant: N#Cc1c(F)cccc1F
Reactant: O=S(=O)(O)O
Solvent: O
Product: NC(=O)c1c(F)cccc1F
Temperature: 0 °C
Reaction time: 12 h

Procedure:
To 240 g of concentrated sulfuric acid and 24 ml of water are added dropwise, at room temperature, 100 g (0.72 mol) of 2,6-difluorobenzonitrile. The reaction mixture is stirred at 80°-85° C. for 12 hours, and then poured into 1.2 kg of ice-water; the mixture is stirred for 30 minutes and subsequently filtered. The crystals are washed neutral with water, and are afterwards dried at 85° C. in vacuo; yield: 91.0 g (80.6%), melting point: 140°-141.5° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[C:12](Br)[CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:18]([OH:21])[C:19]#[CH:20]>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]([C:20]#[C:19][CH2:18][OH:21])[CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCc1ccc(F)c(Br)c1
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Product: CC(C)(C)OC(=O)NCc1ccc(F)c(C#CCO)c1
Temperature: 100 °C

Procedure:
A mixture of tert-butoxy-N-[(3-bromo-4-fluorophenyl)methyl]carboxamide (0.6 g, 2.0 mmol, Step A), CuI (38 mg, 0.2 mmol), PdCl2(PPh3)2 (72 mg, 0.1 mmol), propargyl alcohol (0.35 mL, 6.0 mmol) and TEA (12 mL) was heated at 100° C. for 5 h. The resulting mixture was filtered, and the filtrate was concentrated. The residue was purified by SiO2 chromatography to give the title compound. MS (ES+): 297 (M+NH4)+. Calc'd C15H22FN2O3-297.34.
Reaction SMILES: [S:1]1[CH:5]=[N:4][N:3]=[C:2]1[NH2:6].Cl[C:8]([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9].O>CN(C)C(=O)C>[S:1]1[CH:5]=[N:4][N:3]=[C:2]1[NH:6][C:8](=[O:9])[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Nc1nncs1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=C(Nc1nncs1)Oc1ccccc1
Yield: 75.6 %

Procedure:
1,3,4-Thiadiazol-2-amine (253 mg, 2.50 mmol) in N,N-dimethylacetamide (3 mL) was stirred with phenyl chloroformate (392 μL, 3.13 mmol) at room temperature for one day. Water was added to the reaction mixture, and the precipitated solid was collected by filtration, washed with water and hexane and dried under reduced pressure to give the title compound as a colorless solid (418 mg, yield 76%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[N:3]=1.[Cl:27][CH2:28][CH2:29][CH2:30][S:31](Cl)(=[O:33])=[O:32]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:31]([CH2:30][CH2:29][CH2:28][Cl:27])(=[O:33])=[O:32])[CH2:23][CH2:22]2)[N:3]=1
Reactant: O=S(=O)(Cl)CCCCl
Reactant: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CCNCC2)nc1N
Product: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCCl)CC2)nc1N

Procedure:
The compound was prepared from [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(2,3-difluoro-6-methoxy-phenyl)-methanone (Example 107) and chloropropanesulfonyl chloride (Aldrich) in an analogous manner as described in Example 177. HR-MS (ES, m/z) calculated for C20H25N5O4SF2Cl [(M+H)+] 504.1279, observed 504.1284.
Reaction SMILES: C1(C)C(S(O)(=O)=O)=CC=CC=1.[NH2:12][N:13]1[CH2:17][CH:16]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[N:15]([CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[C:14]1=[O:36].Cl.[N:38]1[CH:43]=[CH:42][CH:41]=[C:40]([S:44](Cl)(=[O:46])=[O:45])[CH:39]=1.CN1CCOCC1>ClCCl>[N:38]1[CH:43]=[CH:42][CH:41]=[C:40]([S:44]([NH:12][N:13]2[CH2:17][CH:16]([C:18]3[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=3)[N:15]([CH2:26][CH2:27][C:28]3[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=3)[C:14]2=[O:36])(=[O:46])=[O:45])[CH:39]=1
Reactant: COc1ccc(CCN2C(=O)N(N)CC2c2ccc(OC)cc2)cc1
Reactant: O=S(=O)(Cl)c1cccnc1
Agent: Cc1ccccc1S(=O)(=O)O
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COc1ccc(CCN2C(=O)N(NS(=O)(=O)c3cccnc3)CC2c2ccc(OC)cc2)cc1
Temperature: 80 °C
Yield: 42.9 %

Procedure:
1-Amino-3-[2-(4-methoxyphenyl)ethyl]-4-(4-methoxyphenyl)-2-imidazolidinone toluenesulfonic acid (0.3 g, 0.58 mmol) is stirred in dichloromethane (6 mL) and 3-pyridylsulfonylchloride HCl (135 mg, 0.63 mmol) is added followed by 4-methylmorpholine (0.2 mL). The mixture is heated in a microwave oven at 80° C. for 25 minutes. The mixture is evaporated and purified over silica (hexane/ethylacetate) to give the afford 0.12 g (41% yield) of the desired product as a white solid. 1H NMR (DMSO-d6) δ 10.3 (s, 1H), 9.0 (s, 1H), 8.9 (d, J=6 Hz, 1H), 8.2 (d, J=7.8 Hz, 1H), 7.65 (m, 1H), 7.2 (d, J=7.8 Hz, 2H), 7.05, (d, J=7.8 Hz, 2H), 6.95 (d, J=7.8 Hz, 2H), 6.8 (d, J=7.8 Hz, 2H), 4.5 (t, J=7 Hz, 1H), 3.8 (s, 3H), 3.75 (s, 3H), 3.3 (m, 1H), 3.2 (m, 1H), 2.75 (m, 2H), 2.4 (m, 2H). Anal. calcd. for C24H26N4O5S: C, 59.74; H, 5.43; N, 11.61; found C, 59.60; H, 5.47; N, 11.37. FAB-HRMS calcd. 483.1702; found 483.1720 (MH+).
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH2:8][CH2:9][CH2:10]Cl)=[N:5][N:4]=[N:3]1.[C:12]1([SH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.[I-].[K+]>[CH3:1][N:2]1[C:6]([S:7][CH2:8][CH2:9][CH2:10][S:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:5][N:4]=[N:3]1
Reactant: Sc1ccccc1
Reactant: Cn1nnnc1SCCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cn1nnnc1SCCCSc1ccccc1
Yield: 95.2 %

Procedure:
1-Methyl-5-(3-chloropropyl)thio-1,2,3,4-tetrazole (1.9 g) and thiophenol (1.1 g) are dissolved in acetone (50 ml). To the mixture are added potassium carbonate (1.5 g) and potassium iodide (0.1 g), and the mixture is refluxed for 3 hours. After acetone is distilled off, water is added to the residue, and the mixture is extracted with ether. The ether solution is washed with diluted aqueous sodium hydroxide and saturated aqueous sodium chloride and dried over sodium sulfate. After ether is distilled off, the residue is purified by silica gel column chromatography (Kieselgel 60), followed by eluting with benzene-chloroform (3:2) to give 1-methyl-5-(3-phenylthiopropyl)thio-1,2,3,4-tetrazole (2.5 g) as colorless liquid, nD18 =1.6008.
Reaction SMILES: [CH2:1]([N:3]1[C:7](/[CH:8]=[CH:9]\[C:10]2[C:11]([O:21][CH2:22][C:23]3[CH:48]=[CH:47][C:26]([O:27][CH2:28][C:29]4[N:30]=[C:31]([C:35]5[CH:40]=[CH:39][C:38]([CH2:41][C:42]([O:44]CC)=[O:43])=[CH:37][CH:36]=5)[O:32][C:33]=4[CH3:34])=[C:25]([O:49][CH3:50])[CH:24]=3)=[N:12][N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:14]=2)=[CH:6][N:5]=[CH:4]1)[CH3:2].[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH2:1]([N:3]1[C:7](/[CH:8]=[CH:9]\[C:10]2[C:11]([O:21][CH2:22][C:23]3[CH:48]=[CH:47][C:26]([O:27][CH2:28][C:29]4[N:30]=[C:31]([C:35]5[CH:36]=[CH:37][C:38]([CH2:41][C:42]([OH:44])=[O:43])=[CH:39][CH:40]=5)[O:32][C:33]=4[CH3:34])=[C:25]([O:49][CH3:50])[CH:24]=3)=[N:12][N:13]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:14]=2)=[CH:6][N:5]=[CH:4]1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C\c4cncn4CC)cc3OC)c(C)o2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCn1cncc1/C=C\c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccc(CC(=O)O)cc3)oc2C)c(OC)c1
Yield: 54.7 %

Procedure:
A mixture of ethyl {4-[4-({4-[({4-[(Z)-2-(1-ethyl-1H-imidazol-5-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}acetate (385 mg), 1N aqueous sodium hydroxide solution (5 mL), tetrahydrofuran (10 mL) and ethanol (10 mL) was heated under reflux for 30 min. After cooling, the reaction mixture was neutralized with 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. Recrystallization of the obtained crystal from ethyl acetate-hexane gave {4-[4-({4-[({4-[(Z)-2-(1-ethyl-1H-imidazol-5-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}acetic acid as colorless crystals (202 mg, yield 55%). melting point: 148-149° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.P(Cl)(Cl)(Cl)=O.CN(C)[CH:25]=[O:26]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:25]=[O:26])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1
Reactant: CN(C)C=O
Reactant: Fc1ccc(-c2cn3cc(Br)ccc3n2)cc1
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c(-c2ccc(F)cc2)nc2ccc(Br)cn12

Procedure:
6-Bromo-2-(4-fluorophenyl)imidazo[1,2-a]pyridine (7 g, 0.024 moles) was treated with phosphorous oxychloride (3.4 mL, 36 mmol) in N,N-dimethylformamide in a similar manner as described in Example 2 to give, after recrystallization from acetonitrile, 6-bromo-2-(4-fluorophenyl)imidazo[1,2-a]pyridine-3-carbaldehyde (6.12 g, 80%) as a white solid. 1H NMR (CDCl3): δ 10.08 (s, 1H), 9.88 (s, 1H), 7.86 (q, 2H), 7.72 (m, 2H), 7.28 (t, 2H); 19F NMR (CDCl3) δ −110.6; MS m/z 320 (M+1).
Reaction SMILES: [B:1]([OH:4])([OH:3])[OH:2].[CH2:5](O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>O.C(O)C1C=CC=CC=1>[B:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([O:3][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[O:2][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: OCc1ccccc1
Reactant: OB(O)O
Solvent: O
Product: c1ccc(COB(OCc2ccccc2)OCc2ccccc2)cc1
Temperature: 70 °C

Procedure:
A mixture of 186g of boric acid and 990g of benzyl alcohol was heated at 70° C. During the reaction 180ml of a water/benzyl alcohol azeotrope were distilled over. The residue was distilled under a pressure of 0.5-10mm Hg and in this manner 950g of the title compound were obtained as a clear liquid.
Reaction SMILES: [CH2:1]([N:8]([CH2:19][CH:20]=[CH2:21])[CH:9]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]([C:16](O)=[O:17])[CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[Li].[H-]>>[CH2:1]([N:8]([CH2:19][CH:20]=[CH2:21])[CH:9]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]([CH2:16][OH:17])[CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: C=CCN(CCCCCCC)C1CCCCC(C(=O)O)C1
Agent: [H-]
Agent: [Li]
Product: C=CCN(CCCCCCC)C1CCCCC(CO)C1

Procedure:
In a manner similar to Preparation 5, react 3-[heptyl-(2-propenyl)amino]cycloheptanecarboxylic acid with lithium aluminun hydride to obtain the title compound.
Reaction SMILES: [ClH:1].C([NH:5][C:6]1[CH:7]=[C:8]([N:12]2[C:16]3[CH:17]=[CH:18][C:19]([C:21]([NH:23][CH2:24][C:25]4[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=4)=[O:22])=[CH:20][C:15]=3[N:14]=[CH:13]2)[CH:9]=[CH:10][CH:11]=1)(=O)C>>[ClH:1].[ClH:1].[NH2:5][C:6]1[CH:7]=[C:8]([N:12]2[C:16]3[CH:17]=[CH:18][C:19]([C:21]([NH:23][CH2:24][C:25]4[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=4)=[O:22])=[CH:20][C:15]=3[N:14]=[CH:13]2)[CH:9]=[CH:10][CH:11]=1
Reactant: CC(=O)Nc1cccc(-n2cnc3cc(C(=O)NCc4cccnc4)ccc32)c1
Agent: Cl
Product: Nc1cccc(-n2cnc3cc(C(=O)NCc4cccnc4)ccc32)c1
Reaction time: 0.67 h

Procedure:
An aqueous HCl (2M, 5 mL) solution of 1-[3-(acetylamino)phenyl]-N-(pyridin-3-ylmethyl)-1H-benzimidazole-5-carboxamide (0.47 g) was heated at reflux. After 40 min, the crude reaction mixture was evaporated under reduced pressure at rt and dried in vacuo to afford 1-(3-aminophenyl)-N-(pyridin-3-ylmethyl)-1H-benzimidazole-5-carboxamide dihydrochloride as a purple solid. 1H-NMR (DMSO-d6, 400 MHz): δ 4.00 (brs, 2H), 4.72 (d, J=5.2 Hz, 2H), 7.24 (d, J=7.6 Hz, 1H), 7.39 (d, J=7.6 Hz, 1H), 7.44 (s, 1H), 7.56 (t, J=8.4 Hz, 1H), 7.82 (d, J=8.4 Hz, 1H), 8.10-8.50 (m, 2H), 8.47 (s, 1H), 8.59 (d, J=8.0 Hz, 1H), 8.85 (1H, J=5.6 Hz, 1H), 8.96 (s, 1H), 9.25 (s, 1H), 9.64 (t, J=5.6 Hz, 1H). MS (ES+): m/z 344 [MH+].
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][OH:4].N1C=CN=C1.[Si:11](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CN(C)C=O.C(OCC)(=O)C>[Si:11]([O:4][CH2:3][CH2:2][CH2:1][OH:5])([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OCCCO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OCCCO)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 1,3-propanediol (1.25 g, 16.4 mmol) in N,N-dimethylformamide (50 mL) was added imidazole (2.23 g, 32.8 mmol) and tert-butyldiphenylsilyl chloride (4.97 g, 18.1 mmol). The reaction was stirred for 3 days at room temperature, then was diluted with ethyl acetate and was washed with water and brine. Concentration in vacuo afforded the crude product as a thick colorless oil which was used directly in the next step.
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[C:8]2[CH:7]=[C:6]([C:18]#[C:19][C:20]3[CH:30]=[CH:29][C:23]([C:24]([O:26]CC)=[O:25])=[CH:22][CH:21]=3)[CH:5]=[CH:4][C:3]1=2.O[Li].O>C1COCC1.O>[CH3:1][C:2]1([CH3:31])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[C:8]2[CH:7]=[C:6]([C:18]#[C:19][C:20]3[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:29][CH:30]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccccn2)=CCC3(C)C)cc1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)CC=C(c2ccccn2)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc21

Procedure:
A solution of 80.0 mg (0.196 mmol) of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(2-pyridyl)-2-naphthalenyl)ethynyl]benzoate (Compound 10) and 20.6 mg (0.491 mmol) of LiOH—H2O in 3 ml of THF/water (3:1, v/v), was stirred overnight at room temperature. The reaction was quenched by the addition of saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated in vacuo to give the title compound as a colorless solid. 1H NMR (d6-DMSO): δ 8.64 (1H, m), 7.94 (2H, d, J=8.3 Hz), 7.87 (1H, dt, J=1.7, 7.8 Hz), 7.58 (2H, d, J=8.3 Hz), 7.50 (1H, d, J=8.2 Hz), 7.47 (2H, s), 7.37 (1H, m), 7.25 (1H, s), 6.30 (1H, t, J=4.6 Hz), 2.39 (2H, d, J=4.6 Hz), 1.31 (6H, s).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([F:8])[CH:7]=1.I[CH2:11][CH3:12].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:11]([O:9][C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=1)[CH3:12]
Reactant: Oc1cc(F)cc(F)c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1cc(F)cc(F)c1
Yield: 62.5 %

Procedure:
To a solution of 3,5-difluoro-phenol (10.0 g, 76.87 mmol, 1.0 equiv) and iodo-ethane (28.77 g, 14.91 mL, 184.49 mmol, 2.4 equiv) in aceton (150 mL) was added portionwise potassium carbonate (31.87 g, 230.6 mmol, 3.0 equiv) and the reaction mixture heated to reflux for 6 h. The reaction mixture was filtered, the filtrate poured into ice water and then extracted with ethyl acetate. The organic layer was washed with water, dried over Na2SO4 and concentrated by evaporation under reduced pressure yielding 7.60 g (63%) of the title compound. 1H NMR (300 MHz, CDCl3): δ1.41 (t, J=7.5 Hz, 3H), 3.99 (q, J=7.5 Hz, 2H), 6.36-6.43 (m, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[NH:6].[Cl:11][C:12]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:13]=1[CH:14]=[C:15]([C:18]#[N:19])[C:16]#[N:17]>>[NH2:19][CH2:18][C:15]1[C:16]([NH2:17])=[N:6][C:5]([C:4]2[CH:3]=[C:2]([CH3:1])[CH:10]=[CH:9][CH:8]=2)=[N:7][C:14]=1[C:13]1[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:12]=1[Cl:11]
Reactant: N#CC(C#N)=Cc1ccc(Cl)cc1Cl
Reactant: Cc1cccc(C(=N)N)c1
Product: Cc1cccc(-c2nc(N)c(CN)c(-c3ccc(Cl)cc3Cl)n2)c1

Procedure:
The title compound, MS: m/e=359.1 (M+H+), was prepared from 3-methyl-benzamidine and 2-(2,4-dichloro-benzylidene)-malononitrile in analogy to the process described in Example 11 as a solid.
Reaction SMILES: [CH:1]1([CH2:4][C:5]([OH:7])=O)[CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH:44]([C:47]1[CH:52]=[CH:51][C:50]([NH:53][C:54]([CH:56]2[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]2)=[O:55])=[CH:49][CH:48]=1)([CH3:46])[CH3:45]>C(#N)C>[CH:44]([C:47]1[CH:48]=[CH:49][C:50]([NH:53][C:54]([CH:56]2[CH2:61][CH2:60][N:59]([C:5](=[O:7])[CH2:4][CH:1]3[CH2:2][CH2:3]3)[CH2:58][CH2:57]2)=[O:55])=[CH:51][CH:52]=1)([CH3:46])[CH3:45]
Reactant: O=C(O)CC1CC1
Reactant: CC(C)c1ccc(NC(=O)C2CCNCC2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1ccc(NC(=O)C2CCN(C(=O)CC3CC3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.3 %

Procedure:
Cyclopropylacetic acid (0.055 g) was dissolved in acetonitrile (6 ml), ethyl-diisopropyl-amine (0.129 g), BOP (0.221 g) was added at RT under an argon atmosphere and the mixture was stirred for 30 minutes at RT. Then piperidine-4-carboxylic acid (4-isopropyl-phenyl)-amide (0.123 g) in acetonitrile (2 ml) was added dropwise at RT and the reaction mixture was stirred for 12 h until completion of the reaction. It was then partitioned between ethyl acetate and aqueous 1M HCl, the layers were separated and the aqueous layer washed with 2M aqueous KHCO3 then dried over Na2SO4. The solvent was evaporated off, the residue purified by flash chromatography (AcOEt/heptane, gradient from 0 to 60%) to give 1-(2-cyclopropyl-acetyl)-piperidine-4-carboxylic acid (4-isopropyl-phenyl)-amide (0.158 g) as an off-white solid. MS (ESI): 329.17 (MH+).