Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2([CH3:12])[CH3:11])=[CH:4][C:3]=1[O:13][CH3:14].C([Li])CCC.[Cl:20]N1C(=O)CCC1=O.O>C1COCC1>[Cl:20][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2([CH3:12])[CH3:11])=[CH:4][C:3]=1[O:13][CH3:14]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1cc2c(cc1Br)C(C)(C)CC2
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1cc2c(cc1Cl)C(C)(C)CC2
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6-bromo-5-methoxy-1,1-dimethyl-indan (2.00 g, 7.84 mmol) in THF (30 mL) at −78° C. was slowly added n-butyllithium (4.0 mL, 2.5 M in hexane). The resulting solution was stirred at −78° C. for 0.5 h and a solution of N-chlorosuccinimide (1.26 g, 9.40 mmol) in THF (30 mL) was added. After an additional 2 h at −78° C., the reaction was warmed to room temperature, poured into water (50 mL) and extracted with ethyl acetate (2×70 mL). The combined organic layers were washed with water, brine, dried over sodium sulfate, filtered, and concentrated. Purification by silica gel chromatography (2% ethyl acetate/heptane) afforded the title compound as a yellow oil.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)[CH3:3].[CH2:13]([O:15][C:16](=[O:21])[CH2:17]C([O-])=O)[CH3:14].N1CCCCC1>N1C=CC=CC=1>[CH3:1][N:2]([CH2:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH:17][C:16]([O:15][CH2:13][CH3:14])=[O:21])=[CH:7][CH:6]=1)[CH3:3]
Reactant: CN(C)Cc1ccc(C=O)cc1
Reactant: CCOC(=O)CC(=O)[O-]
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: CCOC(=O)C=Cc1ccc(CN(C)C)cc1
Reaction time: 5 h

Procedure:
A mixture of 4-dimethylaminomethylbenzaldehyde (32.64 g), monoethylmalonate (29.07 g), pyridine (100 ml) and piperidine (2 ml) were heated under reflux with stirring for 5 hr. The pyridine was evaporated at reduced pressure, and the oily residue was extracted with diethyl ether. The combined ether extracts were washed with water and dried over magnesium sulphate. The ether was evaporated at reduced pressure to yield ethyl 4-(dimethylaminomethyl)cinnamate as a light straw coloured oil (46.57 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[C:6]([OH:8])[CH:7]=1.[N+:13]([O-])([OH:15])=[O:14]>C(O)(=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([C:9]([F:10])([F:11])[F:12])[C:5]([N+:13]([O-:15])=[O:14])=[C:6]([OH:8])[CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: Oc1cc(F)cc(C(F)(F)F)c1
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1c(O)cc(F)cc1C(F)(F)F
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 21 %

Procedure:
5-Fluoro-3-(trifluoromethyl)phenol (1.27 g) was dissolved in acetic acid (3 ml) and water (1.5 ml), and nitric acid (3.0 ml) was added thereto. The reaction mixture was stirred at 50° C. for 30 minutes. After cooling, water was added to the reaction mixture, and the mixture was extracted with ether. The extract was washed with an aqueous saturated sodium bicarbonate solution and water, dried over magnesium sulfate, and concentrated. The residue was purified by column chromatography (developing solution:ethyl acetate-hexane=1:3) to obtain the title compound as oil (0.33 g, 21%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[NH2:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][CH:23]=[CH:22]2.Cl.N1C=CC=CC=1>C(OCCO)C>[NH:24]1[C:25]2[C:21](=[CH:20][C:19]([NH:18][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][C:3]=3[C:16]#[N:17])=[CH:27][CH:26]=2)[CH:22]=[CH:23]1
Reactant: Nc1ccc2[nH]ccc2c1
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1cc2ncc(C#N)c(Nc3ccc4[nH]ccc4c3)c2cc1OC

Procedure:
Using an analogous procedure to that described in Example 141, 248.7 mg (1 mmol) of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile, 158.6 mg (1.2 mmol) of 5-aminoindole and 115.6 mg (1 mmol) of pyridine hydrochloride in 10 mL of 2-ethoxyethanol was refluxed for 0.5 hr. The work up gave 338.7 mg (98.5%) of the product as a yellow solid, m.p.>250° C., mass (electrospray, m/e): M+H 344.9. HRCIMS: calcd 344.127 for C20H16N4O2 (M+), obsd 344.1277.
Reaction SMILES: S(Cl)(Cl)=O.[I:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8](O)=[O:9].[CH3:15][NH2:16]>C1(C)C=CC=CC=1>[I:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([NH:16][CH3:15])=[O:9]
Reactant: O=C(O)c1ccccc1I
Reactant: CN
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CNC(=O)c1ccccc1I
Temperature: 0 °C
Reaction time: 16 h

Procedure:
Thionyl chloride (29.4 mL, 404 mmol) is added to a solution of (2-iodo-benzoic acid (50.0 g, 202 mmol) in dry toluene (600 mL). The mixture is heated to reflux for 4 hours and the solvent is removed in vacuo. The remanence is redissolved in dry toluene (600 mL) and cooled to 0° C. 40% methylamine (aq., 94.1 mL, 1.21 mol) is added dropwise at 0-5° C. during 30 minutes. The mixture is then stirred at ambient temperature for 16 hours, poured onto water (300 mL) and extracted with ethyl acetate (3×300 mL) The combined organic fractions are washed successively with saturated sodium bicarbonate solution (250 mL) and brine (250 mL), dried (MgSO4) and concentrated in vacuo. This gives 50.8 g (96%) of crystalline 2-iodo-N-methyl-benzamide.
Reaction SMILES: CO[CH:3]1[CH:7]([CH:8]=[O:9])[CH2:6][CH:5](OC)O1.Cl.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1>O>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH:5]=[CH:6][C:7]([CH:8]=[O:9])=[CH:3]2)=[CH:17][CH:16]=1
Reactant: COC1CC(C=O)C(OC)O1
Reactant: COc1ccc(N)cc1
Agent: Cl
Solvent: O
Product: COc1ccc(-n2ccc(C=O)c2)cc1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
2,5-Dimethoxytetrahydrofuran-3-carbaldehyde (7.31 g) and p-anisidine hydrochloride (7.28 g) were added to water (100 ml) and stirred at 60° C. for three hours. The precipitated yellow solid were filtered at the same temperature, washed with water (50 ml), saturated aqueous solution of sodium bicarbonate (50 ml), and further water (50 ml) to give 1-(4-methoxyphenyl)pyrrole-3-carb aldehyde.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=1[F:23])[CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[CH3:38][C@H:39]1[NH:45][CH2:44][C@@H:43]([CH3:46])[CH2:42][NH:41][C:40]1=[O:47]>C(#N)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=1[F:23])[CH2:10][C:11]([N:45]1[CH2:44][C@@H:43]([CH3:46])[CH2:42][NH:41][C:40](=[O:47])[C@H:39]1[CH3:38])=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)c(F)cc1F
Reactant: C[C@H]1CNC(=O)[C@@H](C)NC1
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: ClCCCl
Product: C[C@H]1CNC(=O)[C@@H](C)N(C(=O)C[C@@H](Cc2cc(F)c(F)cc2F)NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of (3R)-3-[(tert-butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (Intermediate 3, 120 mg, 0.36 mmol) in acetonitrile (10 mL) was added HOBT (60 mg, 0.43 mmol) and EDC (75 mg, 0.4 mmol). The reaction was stirred at room temperature for 1 h and then treated with (3R,6R)-hexahydro-3,6-dimethyl-2H-1,4-diazepin-2-one (Intermediate 23, 50 mg, 0.35 mmol). The reaction was stirred at room temperature overnight. After removal of solvent, the crude product was purified by flash chromatography on a Biotage® system (silica, 6% methanol in dichloromethane) to yield the title compound as white solid. MS (M+1−Boc): 358.0
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH:10]([OH:15])[C:11]([F:14])([F:13])[F:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Br:23][CH:24]([CH3:28])[C:25](Cl)=[O:26]>C(Cl)Cl>[CH2:1]([N:8]([CH2:9][CH:10]([OH:15])[C:11]([F:14])([F:13])[F:12])[C:25](=[O:26])[CH:24]([Br:23])[CH3:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC(CNCc1ccccc1)C(F)(F)F
Reactant: CC(Br)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(Br)C(=O)N(Cc1ccccc1)CC(O)C(F)(F)F
Reaction time: 0.08 h

Procedure:
A solution of 3-(Benzylamino)-1,1,1-trifluoropropan-2-ol (2.68 g, 12.3 mmol) and triethylamine (1.7 mL, 12.2 mmol) in CH2Cl2 is cooled to 0° C. The solution is treated drop wise with 2-bromopropanoyl chloride (1.2 mL, 12 mmol, Aldrich) and stirred for 5 minutes. The solution is diluted to 100 mL with CH2Cl2 and washed sequentially with 1.0M HCl, saturated NaHCO3, and brine (100 mL each). The organic layer is dried over Na2SO4 and filtered. The solvent is removed by rotary evaporation yielding (N-benzyl-2-bromo-N-(3,3,3-trifluoro-2-hydroxypropyl)propanamide as a golden oil. Dry NaH is suspended in dry, inhibitor free THF (25 ml) in a flame dried flask and the mixture is cooled to 0° C. with stirring on an ice bath. The N-benzyl-2-bromo-N-(3,3,3-trifluoro-2-hydroxypropyl)propanamide (4.25 g, 12 mmol) is added as a solution in dry, inhibitor free THF (25 ml) and the resultant suspension is warmed to RT. After stirring for one hour the reaction is quenched with MeOH over an ice bath until no more gas evolved and the mixture is poured into 1.0M HCl (200 mL). The aqueous mixture is extracted into MTBE (200 mL) and the organic layer is washed with saturated NaHCO3 and brine (200 mL each). The organic layer is dried over Na2SO4 and filtered, and the solvent is removed by rotary evaporation yielding an amber oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:9]=2[F:15])[N:5]=[CH:4][N:3]=1.[CH3:16][C:17]([CH3:23])([CH3:22])[C:18]#[C:19][CH2:20][OH:21].[H-].[Na+].O>CN(C)C=O>[CH3:16][C:17]([CH3:23])([CH3:22])[C:18]#[C:19][CH2:20][O:21][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:9]=2[F:15])[N:5]=[CH:4][N:3]=1
Reactant: Fc1cccc(-c2cc(Cl)ncn2)c1F
Reactant: CC(C)(C)C#CCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)C#CCOc1cc(-c2cccc(F)c2F)ncn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.6 %

Procedure:
In 6 ml of N,N-dimethylformamide were dissolved 199 mg of 4-chloro-6-(2,3-difluorophenyl)pyrimidine and 118 mg of 4,4-dimethyl-2-pentyn-1-ol, to which 43 mg of sodium hydride (60% in oil) was added, followed by stirring at room temperature for 3 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The resulting residue was subjected to silica gel column chromatography to give 190 mg of 4-(4,4-dimethyl-2-pentynyloxy)-6-(2,3-difluorophenyl)pyrimidine (the present compound (119)).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:16][CH:15]3[CH2:17][N:11]4[CH2:12][CH:13]([CH2:18][CH:9]2[CH2:10]4)[CH2:14]3)[CH:5]=[N:6][CH:7]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28]>>[CH3:30][O:29][C:25]1[CH:24]=[C:23]([C:2]2[CH:3]=[C:4]([N:8]3[CH2:16][CH:15]4[CH2:17][N:11]5[CH2:12][CH:13]([CH2:18][CH:9]3[CH2:10]5)[CH2:14]4)[CH:5]=[N:6][CH:7]=2)[CH:22]=[C:21]([O:20][CH3:19])[C:26]=1[O:27][CH3:28]
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Reactant: Brc1cncc(N2CC3CC4CC2CN(C4)C3)c1
Product: COc1cc(-c2cncc(N3CC4CC5CC3CN(C5)C4)c2)cc(OC)c1OC

Procedure:
The title compound was prepared from the product of Example 65A and 3,4,5-trimethoxyphenylboronic acid according to General Method B: 1H NMR (500 MHz, CDCl3) δ ppm 8.16 (s, 2 H), 7.03 (s, 1 H), 6.73 (s, 2 H), 4.1 (s, 1 H), 3.91 (s, 9H.), 3.73-3.37 (m, 5 H), 3.05-3.00 (m, 4 H), 2.27-2.17 (m, 5 H); LC-MS Method D (ESI+) m/z 396.0 (M+H)+, retention time 1.32 minutes.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([NH:16][C:17]3[CH:21]=[C:20]([CH2:22][C:23]([OH:25])=[O:24])[NH:19][N:18]=3)=[N:11][CH:12]=[N:13]2)=[CH:8][C:7]=1[O:26][CH3:27].[OH:28][CH2:29][CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.Cl>CC(N(C)C)=O>[OH:28][CH2:29][CH:30]1[CH2:35][CH2:34][N:33]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:15]=[C:14]3[C:9]([C:10]([NH:16][C:17]4[CH:21]=[C:20]([CH2:22][C:23]([OH:25])=[O:24])[NH:19][N:18]=4)=[N:11][CH:12]=[N:13]3)=[CH:8][C:7]=2[O:26][CH3:27])[CH2:32][CH2:31]1
Reactant: COc1cc2c(Nc3cc(CC(=O)O)[nH]n3)ncnc2cc1OCCCCl
Reactant: OCC1CCNCC1
Agent: Cl
Solvent: CC(=O)N(C)C
Product: COc1cc2c(Nc3cc(CC(=O)O)[nH]n3)ncnc2cc1OCCCN1CCC(CO)CC1
Reaction time: 0.5 h
Yield: 69.1 %

Procedure:
(3-{[7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl]amino}-1H-pyrazol-5-yl)acetic acid (7.83 g, 20 mmol) in dimethylacetamide (30 ml) was reacted with 4-(hydroxymethyl)piperidine (8.05 g, 70 mmol) at 100° C. for 2 hours. The solvent was evaporated, and the residue triturated with a mixture of dichloromethane:ethyl acetate (1:1). The paste was recovered, and dissolved in a mixture of dichloromethane:methanol. Ethanolic HCl (7.0 N) (10 ml, 70 mmol) was added to the mixture and the solvents were evaporated. Methanol (200 ml) was added to the solid and the mixture was stirred for 0.5 hour. The reaction mixture was reduced in volume and dichloromethane added. The resultant solid was recovered by filtration and dried to yield {3-[(7-{3-[4-(hydroxymethyl)piperidin-1-yl]propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetic acid (6.5 g, 60% yield) as a yellow solid:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[F:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15](Cl)=[O:16].S1C=CC=C1C(Cl)=O>>[F:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1)=[O:16]
Reactant: O=C(Cl)c1ccccc1F
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Agent: O=C(Cl)c1cccs1
Product: O=C(Nc1ccc(F)c([N+](=O)[O-])c1)c1ccccc1F

Procedure:
4-Fluoro-3-nitro-phenylamine was reacted with 2-fluorobenzoyl chloride according to the procedure of Example 256a substituting 2-fluorobenzoyl chloride for thiophene-2-carbonyl chloride to provide 2-fluoro-N-(4-fluoro-3-nitro-phenyl)-benzamide which was then reacted according to the procedures of Examples 256b and 256c to provide the title product.
Reaction SMILES: [OH:1]S(O)(=O)=O.[F:6][C:7]1[CH:8]=[C:9]([N+:17]([O-:19])=[O:18])[C:10]([OH:16])=[C:11](C(=O)C)[CH:12]=1>O1CCOCC1>[F:6][C:7]1[CH:12]=[C:11]([OH:1])[C:10]([OH:16])=[C:9]([N+:17]([O-:19])=[O:18])[CH:8]=1
Reactant: O=S(=O)(O)O
Reactant: CC(=O)c1cc(F)cc([N+](=O)[O-])c1O
Solvent: C1COCCO1
Product: O=[N+]([O-])c1cc(F)cc(O)c1O
Temperature: 28 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
H2SO4 (50 mL) was added to a solution of H3BO3 (89.3 g, 1.4 mol) in 1,4-Dioxane (300 mL) at 0° C. and stirred at 28° C. for 1 h. 1-(5-fluoro-2-hydroxy-3-nitrophenyl)ethanone (50 g, 289 mmol) was added portion wise to the above solution over 1 h, maintaining the temperature at 0° C., after addition was complete, the reaction mixture was warmed to 25° C. and stirred for 16 h. Reaction mixture was quenched with cold water, solid separated was collected by filtration. The solid was suspended in diethyl ether (500 mL) and filtered to remove insoluble inorganic mass, ether layer was washed with cold water (2 to 3 times) followed by brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the crude sticky solid. The crude solid was triturated over n-Hexane and filtered to afford 5-fluoro-3-nitrobenzene-1,2-diol (Int-25) (36 g, 86% yield) as pale yellow solid. MS (ESI): m/z 171.9 (M−1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([CH2:17][CH:18](O)[CH2:19][CH2:20][C:21]3[CH:22]=[N:23][CH:24]=[C:25]([Cl:27])[CH:26]=3)(=[O:16])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl.CN(C)C.C(N(CC)CC)C.CS(Cl)(=O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][N:11]([S:14](/[CH:17]=[CH:18]/[CH2:19][CH2:20][C:21]3[CH:22]=[N:23][CH:24]=[C:25]([Cl:27])[CH:26]=3)(=[O:15])=[O:16])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: O=S(=O)(CC(O)CCc1cncc(Cl)c1)N1CCN(c2ccc(Cl)cc2)CC1
Agent: CN(C)C
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(/C=C/CCc1cncc(Cl)c1)N1CCN(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 1-{[4-(4-chlorophenyl)piperazin-1-yl]sulfonyl}-4-(5-chloropyridin-3-yl)butan-2-ol (111 mg, 0.25 mmol) in dry CH2Cl2 (2.5 mL) at RT was added under an atmosphere of argon, trimethylamine hydrochloride (2 mg, 0.02 mmol), triethylamine (52 μl, 0.25 mmol), then methanesulfonyl chloride (21 μl, 0.25 mmol). The reaction was stirred for 30 mins at RT, then quenched by addition of saturated aqueous sodium bicarbonate solution (5 mL). The layers were separated and the aqueous phase extracted with ethyl acetate (3×6 mL). The combined organic extracts were then dried, (MgSO4), filtered and concentrated in vacuo. The residue was then dissolved in CH2Cl2 (2.5 mL) and treated with triethylamine (100 μl, 1.36 mmol). After 30 minutes, the reaction was quenched by addition of saturated aqueous sodium bicarbonate solution (5 mL). The layers were separated and the aqueous phase extracted with ethyl acetate (3×6 mL). The combined organic extracts were then dried, (MgSO4), filtered and concentrated in vacuo. The crude material was used in the next step.
Reaction SMILES: C1(C)C=CC=CC=1.[NH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1.[O:13]1[C:17]2([CH2:22][CH2:21][CH:20]([CH:23]3[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]3)[CH2:19][CH2:18]2)[O:16][CH2:15][CH2:14]1>O>[O:13]1[C:17]2([CH2:18][CH2:19][CH:20]([CH:23]3[CH2:28][CH2:27][C:26]([N:8]4[CH2:12][CH2:11][CH2:10][CH2:9]4)=[CH:25][CH2:24]3)[CH2:21][CH2:22]2)[O:16][CH2:15][CH2:14]1
Reactant: O=C1CCC(C2CCC3(CC2)OCCO3)CC1
Reactant: C1CCNC1
Solvent: Cc1ccccc1
Solvent: O
Product: C1=C(N2CCCC2)CCC(C2CCC3(CC2)OCCO3)C1
Temperature: 25 °C

Procedure:
Toluene (200 ml) and pyrrolidine (90 ml) were added to 4-(1,4-dioxaspiro[4.5]decan-8-yl)cyclohexanone (100 g) in a reaction vessel equipped with a Dean-Stark apparatus under an atmosphere of nitrogen. The mixture was refluxed for 3 hours while the water formed was removed by a Dean-Stark apparatus. After the reaction mixture had been cooled to a room temperature, it was washed with brine, and dried over anhydrous magnesium sulfate. The toluene was distilled off to give 1-(4-(1,4-dioxaspiro[4.5]decan-8-yl)cyclohex-1-enyl)pyrrolidine (105.8 g).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[CH:6]=[CH:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1.[O:14]=[C:15]([OH:27])[C@@H:16]([C@H:18]([C@H:20]([C@@H:22]([C:24]([OH:26])=[O:25])[OH:23])[OH:21])[OH:19])[OH:17]>C(O)C.O>[O:14]=[C:15]([OH:27])[C@@H:16]([C@H:18]([C@H:20]([C@@H:22]([C:24]([OH:26])=[O:25])[OH:23])[OH:21])[OH:19])[OH:17].[NH:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1/[CH:6]=[CH:7]/[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1.[NH:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1/[CH:6]=[CH:7]/[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1
Reactant: C(=C[C@@H]1CCCN1)c1cccnc1
Agent: O=C(O)[C@@H](O)[C@H](O)[C@H](O)[C@@H](O)C(=O)O
Solvent: CCO
Solvent: O
Product: C(=C/[C@@H]1CCCN1)\c1cccnc1
Temperature: 70 °C

Procedure:
To a stirred solution of (2S)-3-(2-pyrrolidin-2-ylvinyl)pyridine (120 mg, 0.689 mmol) in ethanol (2 mL), galactaric acid (72.4 mg, 0.344 mmol) was added. The mixture was heated at 70° C., sonicated and then water (1-2 drops) was added; this process was repeated until most of the solid dissolved. The remaining insoluble material was removed by filtration. To the filtrate anhydrous diethyl ether was added dropwise until it became cloudy. After 16 h at 4° C. a precipitate was formed; this was filtered and vacuum dried to give 120 mg (61.9% yield) of product as a light brown solid.
Reaction SMILES: Cl[C:2]1[N:23]=[CH:22][CH:21]=[CH:20][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[S:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:12]=1)=[O:5].[NH2:24][CH2:25][CH:26]1[CH2:28][CH2:27]1.FC(F)(F)C(O)=O>CS(C)=O>[CH:26]1([CH2:25][NH:24][C:2]2[N:23]=[CH:22][CH:21]=[CH:20][C:3]=2[C:4]([NH:6][CH2:7][C:8]2[S:9][C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)=[O:5])[CH2:28][CH2:27]1
Reactant: NCC1CC1
Reactant: O=C(NCc1ccc(Oc2ccccc2)s1)c1cccnc1Cl
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCc1ccc(Oc2ccccc2)s1)c1cccnc1NCC1CC1
Temperature: 120 °C
Reaction time: 14 h
Yield: 17 %

Procedure:
To a solution of 2-chloro-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide described in Preparation Example A+-7 (64 mg, 0.186 mmol) in dimethylsulfoxide (1 mL) was added (aminomethyl)cyclopropane (48 μl, 0.56 mmol), and the solution was stirred for 14 hours at 120° C. The reaction mixture was purified by reverse phase high performance liquid chromatography (acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid) was used), and the title compound (15.6 mg, 0.0316 mmol, 17%) was obtained as a trifluoroacetic acid salt.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:24]=[C:25]([NH:29][C:30](=[O:32])[CH3:31])[CH:26]=[CH:27][CH:28]=2)[CH2:19][CH2:18]1>>[C:30]([NH:29][C:25]1[CH:24]=[C:23]([CH:20]2[CH2:21][CH2:22][N:17]([CH2:16][CH2:15][CH2:14][NH:13][C:9](=[O:11])[CH:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[CH3:12])[CH2:18][CH2:19]2)[CH:28]=[CH:27][CH:26]=1)(=[O:32])[CH3:31]
Reactant: CC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: CC(C(=O)O)c1ccc(Cl)cc1
Product: CC(=O)Nc1cccc(C2CCN(CCCNC(=O)C(C)c3ccc(Cl)cc3)CC2)c1

Procedure:
Example 95 was prepared from 2-(4-chlorophenyl) propanoic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}acetamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 7.48 (s, 1H), 7.36 (s, 1H), 7.31–7.25 (m, 6H), 6.98–6.93 (m, 2H), 3.51–3.48 (m, 1H), 3.35–3.31 (m, 2H), 3.03 (d, 1H, J=11.6 Hz), 2.93 (d, 1H, J=11.2 Hz), 2.50 (m, 1H), 2.42–2.38 (m, 2H), 2.19 (s, 3H), 2.05–1.96 (m, 2H), 1.90–1.80 (m, 2H), 1.70–1.59 (m, 4H), 1.51 (d, 3H, J=7.2 Hz); ESMS m/e: 442.2 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10](#[N:14])[CH2:11][C:12]#[N:13]>C(O)(C)C.N1CCCCC1>[C:12]([C:11]([C:10]#[N:14])=[CH:6][C:5]1[CH:8]=[CH:9][C:2]([OH:1])=[CH:3][CH:4]=1)#[N:13]
Reactant: O=Cc1ccc(O)cc1
Reactant: N#CCC#N
Solvent: CC(C)O
Solvent: C1CCNCC1
Product: N#CC(C#N)=Cc1ccc(O)cc1
Temperature: 25 °C
Yield: 69.8 %

Procedure:
3.7 g of p-hydroxybenzaldehyde and 2.3 g of malononitrile were dissolved in 10 ml of isopropanol followed by adding 1 drop of piperidine and reacted at 80° C. for 1 hour. Crystals were precipitated after cooling to the room temperature, collected by filtration and recrystallized from isopropanol to obtain 3.6 g of 4-(2,2'-dicyanovinyl)phenol as yellow crystals. Melting point=188-189.5° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[Br:14])[CH:10]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])[CH2:9][CH2:8]2)(=[O:3])[CH3:2].FC(F)(F)C(O)=O.[N+:27]([O-])([OH:29])=[O:28]>>[C:1]([NH:4][C:5]1[C:6]([N+:27]([O-:29])=[O:28])=[C:7]2[C:11](=[CH:12][C:13]=1[Br:14])[CH:10]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])[CH2:9][CH2:8]2)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc2c(cc1Br)C(CCC(=O)O)CC2
Reactant: O=[N+]([O-])O
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1c(Br)cc2c(c1[N+](=O)[O-])CCC2CCC(=O)O
Reaction time: 2 h

Procedure:
A mixture of 5-acetamido-6-bromo-2-carboxyethylindane (7 g, 20 mmol) and trifluoroacetic acid (150 mL) was cooled in an ice bath and treated with fuming nitric acid (10 mL). After 2 h at 0° C., the solvent was removed and the residue solidified upon addition of water. The solid was collected by filtration, washed with ether and dried. Crystallization from hot toluene gave the pure product (7 g).