Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:5]2[C:6]([OH:10])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.Br[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.O.ClCCl>[Cl:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[CH2:13][O:10][C:6]1[C:5]2[N:4]([N:3]=[C:2]([NH2:1])[N:11]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: Nc1nc2c(O)cccn2n1
Reactant: Clc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Solvent: ClCCl
Product: Nc1nc2c(OCc3cccc(Cl)c3)cccn2n1
Temperature: 80 °C

Procedure:
260 c) 2-Amino-[1,2,4]triazolo[1,5-a]pyridin-8-ol (0.200 g, 1.33 mmol) was suspended in acetone (1.9 mL). 1-(bromomethyl)-3-chloro-benzene (0.184 mL, 1.40 mmol) and potassium carbonate (193 mg, 1.40 mmol) were added and the reaction mixture was heated to 80° C. for 1 hour. Reaction mixture was cooled to room temperature, diluted with water, extracted with dichloromethane, dried over magnesium sulfate, filtered, and concentrated. Resulting oil was taken up in dichloromethane and purified via chromatography (silica gel 0-100% ethyl acetate in hexanes). 8-(3-Chloro-benzyloxy)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine was isolated as an oil which solidified on standing. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.17 (d, J=6.6 Hz, 1H), 7.56 (s, 1H), 7.44-7.42 (m, 3H), 6.99 (d, J=7.9 Hz, 1H), 6.79-6.75 (m, 1H), 5.94 (bs, 2H), 5.30 (s, 2H). MS=275 (MH)+. 260 d) [8-(3-Chloro-benzyloxy)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine was prepared from 8-(3-chloro-benzyloxy)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (95.0 mg, 0.346 mmol) and 1-(4-bromo-phenyl)-4-methyl-piperazine (102 mg, 0.399 mmol in a manner analogous to Example 2d. Product was isolated as a pale orange solid (0.073 g, 47%). MP=135-138° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.33 (s, 1H), 8.37 (d, J=6.7 Hz, 1H), 7.58 (s, 1H), 7.51-7.44 (m, 5H), 7.09 (d, J=7.9 Hz, 1H), 6.91-6.86 (m, 3H), 5.35 (s, 2H), 3.04-3.01 (m, 4H), 2.46-2.44 (m, 4H), 2.22 (s, 3H). MS=449 (MH)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:13][O:14][C:15]([CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1)=[O:16].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1COCC1>>[CH3:13][O:14][C:15]([C:17]1([C:2]2[C:11]3[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH2:22]1)=[O:16]
Reactant: Fc1ccc2c(Cl)ncnc2c1
Reactant: COC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C1(c2ncnc3cc(F)ccc23)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.04 h

Procedure:
A mixture of 4-chloro-7-fluoro-quinazoline (2.87 g, 15.4 mmol) (WO 9609294 A1) and piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester (4.15 g, 17.1 mmol), as prepared in Example 1b, was placed in a −78° C. bath for 5 min under argon before adding a 1.08 M LiHMDS/THF solution (17.8 mL, 19.2 mmol) rapidly by syringe along the sides of the flask (to allow cooling and dispersion of the hindered base before reaction with the ester). Following completion of LiHMDS/THF addition, the reaction was manually swirled in the −78° C. bath for 2-3 min before removing the cold bath and allowing the mixture to stir with gradual warming to rt. After 2.5 h stirring at rt, the dark brown homogeneous solution was quenched with 1.0 M NaH2PO4 (38 mL) and extracted with DCM (1×150 mL and 1×25 mL). The organic layers were combined, dried (Na2SO4), and concentrated under reduced pressure, and subject to high vacuum at 90° C. with toluene chasers (3×10 mL) to provide the crude title compound as an opaque thick yellow oil that was used in the next step without further purification (6.83 g, “114%” crude yield). 1H-NMR (300 MHz, CDCl3) δ 9.26 (s, 1H), 8.11 (dd, 1H), 7.70 (dd, 1H), 7.36 (ddd, 1H), 3.74-3.64 (m, 2H), 3.62-3.51 (m, 2H), 3.61 (s, 3H), 2.47-2.38 (br m, 4H), 1.46 (s, 9H). LC/MS (ESI): calcd mass 389.2, found 390.1 (MH)+.
Reaction SMILES: [CH:1]1([NH:7][CH2:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[Cl:21][CH2:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[CH:1]1([N:7]([CH2:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[S:23]([CH2:22][Cl:21])(=[O:25])=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=S(=O)(Cl)CCl
Reactant: c1cncc(CNC2CCCCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=S(=O)(CCl)N(Cc1cccnc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A 2.85 g. portion of 3-(cyclohexylaminomethyl)pyridine was dissolved in 20 ml. of dichloromethane, and 2.7 g. of potassium carbonate was added, followed by 3.5 g. of chloromethanesulfonyl chloride. The mixture was stirred at ambient temperature for 2 days, another 2 g. of chloromethanesulfonyl chloride was added, and the mixture was stirred for 3 days more. It was then diluted with 20 ml. of water, and the organic phase was separated, dried over magnesium sulfate and evaporated to an oil. The oil was dissolved in dichloromethane and chromatographed over silica gel, eluting with 9:1 dichloromethane:ethyl acetate. The product-containing fractions were combined and evaporated to obtain 1.4 g. of product, initially an oil, which crystallized spontaneously. M.P. 67°-72°.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:12]2[N:11]([CH3:13])[C:10]3[CH2:14][CH2:15][NH:16][C:17](=[O:18])[C:9]=3[C:8]=2[CH:7]=[CH:6][CH:5]=1.Cl[CH2:20][C:21]1[O:25][CH:24]=[N:23][C:22]=1[CH3:26].O>COCCOC>[F:3][C:4]1[C:12]2[N:11]([CH3:13])[C:10]3[CH2:14][CH2:15][N:16]([CH2:20][C:21]4[O:25][CH:24]=[N:23][C:22]=4[CH3:26])[C:17](=[O:18])[C:9]=3[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: Cn1c2c(c3cccc(F)c31)C(=O)NCC2
Reactant: Cc1ncoc1CCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1ncoc1CN1CCc2c(c3cccc(F)c3n2C)C1=O
Reaction time: 6 h
Yield: 76.6 %

Procedure:
Sodium hydride (73% dispersion in oil; 167 mg) was added to a stirred suspension of 6-fluoro-2,3,4,5-tetrahydro-5-methyl-1H-pyrido[4,3-b]indol-1-one (500 mg) in dry DME (150 ml), and the suspension was stirred at 60° under nitrogen for 6 h. 5-Chloromethyl-4-methyloxazole (440 mg) was then added and the mixture was stirred overnight at 60°. A further quantity of sodium hydride (73% dispersion in oil; 84 mg) was added and the mixture was stirred for 3 h, and then cooled (0°). Water (200 ml) was added, and the mixture was extracted with dichloromethane (3×200 ml). The combined organic extracts were concentrated in vacuo and the residue was purified by FCC eluting with System A (100:8:1) to give the title compound (550 mg) as a solid, m.p. 158°-161°.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:13])C(O)=O)=[CH:5][CH:4]=1)#[N:2].CN1CC[O:18][CH2:17]C1.ClC(OCC(C)C)=O.[C:29]1([S:35]([NH:38][C:39]2[CH:40]=[C:41]3[C:46](=[CH:47][CH:48]=2)[NH:45][CH2:44][CH2:43][CH2:42]3)(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O1CCCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:13][C:17]([N:45]2[C:46]3[C:41](=[CH:40][C:39]([NH:38][S:35]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)(=[O:37])=[O:36])=[CH:48][CH:47]=3)[CH2:42][CH2:43][CH2:44]2)=[O:18])=[CH:7][CH:8]=1)#[N:2]
Reactant: CC(C(=O)O)c1ccc(C#N)cc1
Reactant: CN1CCOCC1
Reactant: O=S(=O)(Nc1ccc2c(c1)CCCN2)c1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Product: N#Cc1ccc(CCC(=O)N2CCCc3cc(NS(=O)(=O)c4ccccc4)ccc32)cc1
Temperature: -35 °C
Reaction time: 2 h

Procedure:
4.6 g 3-(4-cyano-phenylpropionic acid are dissolved with 2.8 g of N-methyl-morpholine in 120 ml of tetrahydrofuran and cooled to −35° C. To this solution are added 3.6 ml of isobutyl chloroformate, stirring is continued for half an hour and then at −40° C. 7.2 g of 6-phenylsulphonamido-1,2,3,4-tetrahydro-quinoline are added (see Example IV). After 2 hours the solution is slowly allowed to come back to ambient temperature and stirring is continued overnight. Then it is concentrated by evaporation and the residue is taken up in ethyl acetate and water. The organic phase is again washed with water, dried and concentrated by evaporation. The oil remaining is chromatographed over a silica gel column with ethyl acetate/petroleum ether (7:3).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:13]2[N:14]=[CH:15][N:16]([C:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:17]=2)([OH:12])[CH:9]([CH3:11])[CH3:10])=[CH:4][CH:3]=1.[C:37]([NH:40][C:41]1[CH:42]=[C:43](B(O)O)[CH:44]=[CH:45][CH:46]=1)(=[O:39])[CH3:38]>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>[OH:12][C:8]([C:5]1[CH:6]=[CH:7][C:2]([C:45]2[CH:44]=[CH:43][CH:42]=[C:41]([NH:40][C:37](=[O:39])[CH3:38])[CH:46]=2)=[CH:3][CH:4]=1)([C:13]1[N:14]=[CH:15][N:16]([C:18]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=1)[CH:9]([CH3:11])[CH3:10]
Reactant: CC(=O)Nc1cccc(B(O)O)c1
Reactant: CC(C)C(O)(c1ccc(Br)cc1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CC(=O)Nc1cccc(-c2ccc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)cc2)c1
Yield: 96.1 %

Procedure:
By the reaction in the same manner as in Example 4-(ii) using 1-(4-bromophenyl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol (1.04 g), 3-(acetylamino)phenylboronic acid (571 mg) and tetrakis(triphenylphosphine)palladium(0) (301 mg), the title compound (1.10 g) was obtained as a pale-yellow amorphous powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[C:5]([NH:7][C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=O)=[O:6].[CH2:22]([NH2:30])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(C(C)C)CC)(C)C.CCN=C=NCCCN(C)C.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[C:5]([NH:7][C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([NH:30][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:12])=[O:6]
Reactant: NCCc1ccccc1
Reactant: COc1ccc(C(=O)Nc2ccccc2C(=O)O)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Nc2ccccc2C(=O)NCCc2ccccc2)cc1Cl
Reaction time: 0.5 h
Yield: 71.8 %

Procedure:
A solution of 42B (50 mg, 0.16 mmol) in DMF (5 mL) was treated with phenethylamine (150 μL, 1.6 mmol), diisopropylethylamine (42 mL, 0.32 mmol), and EDCI (31 mg, 0.32 mmol) at room temperature. After 2 hours Bop reagent (100 mg, 0.22 mmol) was added. After 30 minutes, the reaction was concentrated and purified by chromatography (SiO2, 30% EtOAc in hexanes) to afford 42C (47 mg, 70%). HPLC retention time: 2.79 minutes (YMC S-5 Combiscreen 4.6×50 mm, 10% to 90% MeOH/H2O w/0.2% H3PO4, 4 minute gradient).
Reaction SMILES: C([N:8]1[CH2:17][CH:16]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C:15]2[C:10](=[CH:11][C:12]([O:26][CH3:27])=[CH:13][CH:14]=2)[CH2:9]1)C1C=CC=CC=1.CO.CCOC(C)=O>CCO.[Pd]>[CH3:27][O:26][C:12]1[CH:11]=[C:10]2[C:15]([CH:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[CH2:17][NH:8][CH2:9]2)=[CH:14][CH:13]=1
Reactant: COc1ccc(C2CN(Cc3ccccc3)Cc3cc(OC)ccc32)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCO
Product: COc1ccc(C2CNCc3cc(OC)ccc32)cc1
Reaction time: 12 h
Yield: 75.3 %

Procedure:
A suspension of 10% Pd/C (3.80 g) and 2-benzyl-7-methoxy-4-(4-methoxy-phenyl)-1,2,3,4-tetrahydroisoquinoline (3.87 g, 10.8 mmol, see Example 80) in EtOH (160 ml) was hydrogenated at 50 p.s.i. for 12 hours. The catalyst was removed via filtration through diatomaceous earth and the filtrate was concentrated in vacuo. Purification via flash chromatography (Biotage , SiO2, 9:1 EtOAc:MeOH then 1:1 EtOAc:MeOH) gave the title product (2.19 g, 8.13 mmol, 76% yield).
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C@@H:12]2[CH2:14][C@H:13]2[CH2:15]OS(C)(=O)=O)=[O:11])[CH2:5][CH2:4]1)[CH3:2].Cl.[Cl:22][C:23]1[CH:24]=[C:25]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:26]=[CH:27][C:28]=1[Cl:29].Cl.ClC1C=C(N2CCNCC2)C=CC=1>>[CH2:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C@@H:12]2[CH2:14][C@H:13]2[CH2:15][N:33]2[CH2:32][CH2:31][N:30]([C:25]3[CH:26]=[CH:27][C:28]([Cl:29])=[C:23]([Cl:22])[CH:24]=3)[CH2:35][CH2:34]2)=[O:11])[CH2:5][CH2:4]1)[CH3:2]
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Reactant: CC[C@H]1CC[C@H](NC(=O)[C@@H]2C[C@H]2COS(C)(=O)=O)CC1
Agent: Cl
Agent: Clc1cccc(N2CCNCC2)c1
Product: CC[C@H]1CC[C@H](NC(=O)[C@@H]2C[C@H]2CN2CCN(c3ccc(Cl)c(Cl)c3)CC2)CC1

Procedure:
Follow the procedure of Example 11e, and substitute methane sulfonic acid 2-(trans-4-ethyl-cyclohexylcarbamoyl)-trans-cyclopropylmethyl ester (Example 13d) for 2-(trans-4-methyl-cyclohexylcarbamoyl)-trans-cyclopropylmethyl ester and 4-(3,4-dichlorophenyl)-piperazine hydrochloride for 1-(3-chloro-phenyl)-piperazine hydrochloride therein to obtain the title compound LC/MS, m/z=438 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[F:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]([CH2:25][CH3:26])[NH:20][CH2:19][CH2:18]2>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:20]3[CH2:19][CH2:18][C:17]4[C:22](=[CH:23][CH:24]=[C:15]([F:14])[CH:16]=4)[CH:21]3[CH2:25][CH3:26])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CCC1NCCc2cc(F)ccc21
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CCC1c2ccc(F)cc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-fluoro-1-ethyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [C:1]([N:5]([CH2:13][CH2:14][S:15][CH2:16][C:17]#[C:18][C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)[C:6](=[O:12])[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].Cl>O1CCOCC1.O>[C:1]([N:5]([CH2:13][CH2:14][S:15][CH2:16][C:17]#[C:18][C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)[C:6](=[O:12])[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(=O)N(CCSCC#Cc1cccs1)C(C)(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)N(CCSCC#Cc1cccs1)C(=O)C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.3 %

Procedure:
A solution of 520 mg of 9f in 12 ml of dioxane and a solution of 330 mg of KOH in 2 ml of water were mixed and stirred for 4 h at ambient temperature. The reaction mixture was diluted with 20 ml of water and acidified with cold 0.5 HCl to pH3. The product was extracted into ethyl acetate. The extract was washed once with water, dried and concentrated to provide 480 mg of acid 9g as a colorless oil, which was used without further purification in the next step.
Reaction SMILES: [CH:1]([N:4](CC)[CH:5](C)C)(C)C.[C:10]([O:14][C:15]([NH:17][C@@H:18]([CH:22]([CH3:24])[CH3:23])[C:19](O)=[O:20])=[O:16])([CH3:13])([CH3:12])[CH3:11].Cl.CN(C)CCCN=C=NCC.CNC>C1COCC1.C(Cl)Cl>[CH3:1][N:4]([CH3:5])[C:19]([C@@H:18]([NH:17][C:15](=[O:16])[O:14][C:10]([CH3:13])([CH3:12])[CH3:11])[CH:22]([CH3:24])[CH3:23])=[O:20]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCN(C(C)C)C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: CNC
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.6 %

Procedure:
N,N-Diisopropylethylamine (1.0 mL, 5.74 mmol) was added to a mixture of (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoic acid (0.217 g, 1.0 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.211 g, 1.1 mmol) and dimethylamine in THF (2M, 1.0 mL) in methylene chloride (10 mL). The mixture was stirred overnight at RT. The mixture was washed with water, saturated NaHCO3 solution, brine, dried over Na2SO4, filtered, and concentrated. The residue was chromatographed on silica gel to give the desired product (131 mg, 53.6%).
Reaction SMILES: [O:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([OH:10])=[N:2]1.[CH3:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18](Cl)=[O:19])[CH2:14][CH2:13]1.C(N(CC)CC)C>N1C=CC=CC=1>[CH3:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:10][C:3]2[C:4]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[O:1][N:2]=2)=[O:19])[CH2:14][CH2:13]1
Reactant: CC1CCN(C(=O)Cl)CC1
Reactant: Oc1noc2ncccc12
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CC1CCN(C(=O)Oc2noc3ncccc23)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
125 mg (0.918 mmol) of isoxazolo[5,4-b]pyridin-3-ol, 178 mg (1.1 mmol) of 4-methylpiperidine-1-carbonyl chloride and 255 μl (1.84 mmol) of triethylamine were dissolved in 10 ml of pyridine and stirred at room temperature for 4 h. A further 89 mg (0.55 mmol) of 4-methylpiperidine-1-carbonyl chloride and 128 μl (0.92 mmol) of triethylamine were added, and stirring was continued at room temperature for 6 h. The reaction mixture was concentrated, and the residue was dissolved in water and extracted with ethyl acetate. The organic phase was concentrated and purified by preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 101 mg (42%), M+H+: 262.1.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH:7]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][C:21]2=[O:26])[CH2:8]1.C(N(CC)CC)C.[C:34](OC(=O)C)(=[O:36])[CH3:35]>C(OCC)C>[C:34]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH:7]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][C:21]2=[O:26])[CH2:8]1)(=[O:36])[CH3:35]
Reactant: O=C1CCCCN1c1ccccc1CCN1CCC(C2CCCCN2)C1
Reactant: CC(=O)OC(C)=O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(=O)N1CCCCC1C1CCN(CCc2ccccc2N2CCCCC2=O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.1 %

Procedure:
To a solution of 1-(2-{2-[3-(piperidin-2-yl)pyrrolidin-1-yl]ethyl}phenyl)piperidin-2-one a12-1 (25 mg, 0.070 mmol, 1 eq) in diethylether (2 ml) at 0° C. are added triethylamine and acetic anhydride (7 μl, 0.077 mmol, 1.1 eq). The mixture is stirred for 1 hour at room temperature. The solvent is removed under vacuum. The residue obtained is purified by basic reverse phase chromatography (gradient: acetonitrile/H2O/ammonium formate from 5% to 95% of acetonitrile in 8 minutes) to afford 14.5 mg of 1-(2-{2-[3-(1-acetylpiperidin-2-yl)pyrrolidin-1-yl]ethyl}phenyl)piperidin-2-one 72 as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:13])[C:5]2[N:9]=[C:8]([CH3:10])[N:7]([CH3:11])[C:6]=2[CH:12]=1.[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O.[C:23]1(C)C=CC(S(O)(=O)=O)=C[CH:24]=1.C([Mg]Br)=C.[Cl-].[NH4+]>C1(C)C=CC=CC=1.O>[Br:1][C:2]1[CH:3]=[C:4]([NH:13][CH:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:23]=[CH2:24])[C:5]2[N:9]=[C:8]([CH3:10])[N:7]([CH3:11])[C:6]=2[CH:12]=1
Reactant: O=Cc1ccccc1
Reactant: Cc1nc2c(N)cc(Br)cc2n1C
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: C=C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: Cc1ccccc1
Product: C=CC(Nc1cc(Br)cc2c1nc(C)n2C)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 747.5 %

Procedure:
6.4 g (26.7 mmol) 6-bromo-1,2-dimethyl-1H-benzimidazol-4-ylamine, 8.5 g (80 mmol) benzaldehyde and 0.3 g p-toluenesulphonic acid monohydrate in 80 ml toluene were refluxed on a Dean-Stark-trap. After complete reaction, the mixture was evaporated to one third of its volume and diluted with 50 ml tetrahydrofuran. The mixture was cooled to 0° C. and 80 ml (80 mmol) vinylmagnesiumbromide (1M solution in tetrahydrofuran) were added during 45 min. After 30 min., the reaction mixture was hydrolyzed with saturated ammonium chloride solution, diluted with water and extracted with ethyl acetate. The organic phase was separated, washed with water, dried over anhydrous magnesium sulphate and evaporated. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=7:3). Crystallization from diisopropyl ether afforded 4.2 g (44%) of the title compound as a colourless solid. m.p. 137-139° C.
Reaction SMILES: FC1C=CC(CN2C(=O)C(COS(C)(=O)=O)=CC(C3C=CC4OCCC=4C=3)=N2)=CC=1.[O:31]1[C:35]2[CH:36]=[CH:37][C:38]([C:40]3[CH:41]=[C:42]([C:47]([O:49]C)=[O:48])[C:43](=[O:46])[NH:44][N:45]=3)=[CH:39][C:34]=2[CH2:33][CH2:32]1.[Cl:51][C:52]1[CH:59]=[CH:58][C:55]([CH2:56]Cl)=[CH:54][CH:53]=1>>[C:47]([C:42]1[C:43](=[O:46])[N:44]([CH2:56][C:55]2[CH:58]=[CH:59][C:52]([Cl:51])=[CH:53][CH:54]=2)[N:45]=[C:40]([C:38]2[CH:37]=[CH:36][C:35]3[O:31][CH2:32][CH2:33][C:34]=3[CH:39]=2)[CH:41]=1)([OH:49])=[O:48]
Reactant: COC(=O)c1cc(-c2ccc3c(c2)CCO3)n[nH]c1=O
Reactant: ClCc1ccc(Cl)cc1
Agent: CS(=O)(=O)OCc1cc(-c2ccc3c(c2)CCO3)nn(Cc2ccc(F)cc2)c1=O
Product: O=C(O)c1cc(-c2ccc3c(c2)CCO3)nn(Cc2ccc(Cl)cc2)c1=O
Yield: 89.3 %

Procedure:
The general procedure of Example 1 (3) was carried out by use of 6-(2,3-dihydro-1-benzofuran-5-yl)-4-methoxycarbonyl-2H-pyridazin-3-one and 4-chlorobenzyl chloride, to thereby yield the title compound as a yellow powder (yield: 89.3%).
Reaction SMILES: Br[CH:2]([CH2:28][CH2:29][CH3:30])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([S:20][C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1)[C:8]#[N:9].[CH3:31][O:32][C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][C:42]=1[O:43][CH3:44])[CH2:39][NH:38][CH2:37][CH2:36]2>>[CH3:19][O:18][C:12]1[CH:11]=[C:10]([C:7]([S:20][C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:28][CH2:29][CH2:30][N:38]2[CH2:37][CH2:36][C:35]3[C:40](=[CH:41][C:42]([O:43][CH3:44])=[C:33]([O:32][CH3:31])[CH:34]=3)[CH2:39]2)[C:8]#[N:9])[CH:15]=[CH:14][C:13]=1[O:16][CH3:17]
Reactant: COc1cc2c(cc1OC)CNCC2
Reactant: CCCC(Br)CCCCC(C#N)(Sc1ccc(C)cc1)c1ccc(OC)c(OC)c1
Product: COc1ccc(C(C#N)(CCCCCCCCN2CCc3cc(OC)c(OC)cc3C2)Sc2ccc(C)cc2)cc1OC
Yield: 41.1 %

Procedure:
The procedure of Example 3 is repeated using 0.836 g of α-(5-bromooctyl)-3,4-dimethoxy-α-[(4-methylphenyl)thio]benzeneacetonitrile and 0.675 g of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline. This affords 0.422 g of the desired product as a brown gum.