Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][C:5]([C:7]1[CH:8]=[CH:9][C:10]2[O:14][C:13]([CH3:16])([CH3:15])[S:12][C:11]=2[CH:17]=1)=[O:6])=[N+]=[N-].[CH:18]([O-])=[O:19].[Na+].C(OC(=O)C)=O>C(O)=O>[CH:18]([NH:1][CH2:4][C:5]([C:7]1[CH:8]=[CH:9][C:10]2[O:14][C:13]([CH3:16])([CH3:15])[S:12][C:11]=2[CH:17]=1)=[O:6])=[O:19]
Reactant: O=C[O-]
Reactant: CC1(C)Oc2ccc(C(=O)CN=[N+]=[N-])cc2S1
Agent: CC(=O)OC=O
Agent: [Na+]
Solvent: O=CO
Product: CC1(C)Oc2ccc(C(=O)CNC=O)cc2S1
Yield: 59.5 %

Procedure:
10 g of 5-azidoacetyl-2,2-dimethyl-1,3-benzoxathiole (VIII) was added portionwise to a cooled solution of 20 g stannous chloride and 7 g sodium formate in the mixture of 16 ml of acetic-formic anhydride and 9 ml of formic acid. After 14 hours at room temperature the mixture was quenched with ice and dilute hydrochloric acid and extracted with ethyl acetate. The extract was dried over MgSO4, evaporated, and the residue purified by chromatography through a column of silica gel eluted with ethyl acetate-hexane (1:1) to yield 6 g of 5-formamidoacetyl-2,2-dimethyl-1,3-benzoxathiole (IX) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:9])[NH:4][N:5]=[C:6]([Cl:8])[CH:7]=1.[C:10](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C)C=O>[Br:1][C:2]1[C:3](=[O:9])[N:4]([CH3:10])[N:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=c1[nH]nc(Cl)cc1Br
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1nc(Cl)cc(Br)c1=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 97.5 %

Procedure:
4-Bromo-6-chloro-2H-pyridazin-3-one (5.02 g, 23.97 mmol) was dissolved in 40 ml dimethylformamide. Cesium carbonate (9.37 g, 28.76 mmol) was added. After 5 min, iodomethane (5.103 g, 35.95 mmol) was added dropwise over 20 min. The reaction mixture was stirred 3 hours at room temperature. The precipitate was filtered off and concentrated and the resulting residue was treated with 20 ml dichloromethane. The insoluble material was filtered off again and washed with dichloromethane. The filtrate was concentrated in vacuo to yield 4-Bromo-6-chloro-2-methyl-2H-pyridazine-3-one (5.223 g, 23.37 mmol). MS (ESI) 224.9 (M+H)+
Reaction SMILES: CN(CCN(C)C)C.[F:9][C:10]1[CH:11]=[C:12]([Mg]Br)[CH:13]=[C:14]([F:16])[CH:15]=1.CN1[C@@H](C)[C@@H](C2C=CC=CC=2)N([C:32](=[O:41])/[CH:33]=[CH:34]/[CH:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)C1=O.[O-]S(C(F)(F)F)(=O)=O.C([B+]CCCC)CCC.[Cl-].[NH4+]>C1COCC1.ClCCl.[Cu](I)I.C(OCC)(=O)C>[F:9][C:10]1[CH:11]=[C:12]([C@@H:34]([CH:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[CH2:33][CH:32]=[O:41])[CH:13]=[C:14]([F:16])[CH:15]=1
Reactant: Fc1cc(F)cc([Mg]Br)c1
Reactant: C[C@H]1[C@@H](c2ccccc2)N(C(=O)/C=C/C2CCOCC2)C(=O)N1C
Agent: I[Cu]I
Agent: CCCC[B+]CCCC
Agent: CN(C)CCN(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=CC[C@@H](c1cc(F)cc(F)c1)C1CCOCC1
Temperature: -70 °C
Reaction time: 0.33 h

Procedure:
To a suspension of copper iodide (931 mg) in anhydrous THF (60 ml) under argon was added TMEDA (0.81 ml) and the resulting mixture was stirred for 20 minutes. The reaction mixture was cooled to −70° C. and 3,5-difluorophenyl magnesium bromide (9.8 ml of 0.5M solution in THF) was added dropwise and the mixture was stirred for a further 1 hour. A preformed solution of (4R,5S)-1,5-dimethyl-4-phenyl-3-[(2E)-3-(tetrahydro-2H-pyran-4-yl)prop-2-enoyl]imidazolin-2-one (800 mg) and dibutylboron triflate (2.93 ml of 1M solution in dichloromethane) in dichloromethane (2 ml) was added dropwise to the mixture. The reaction mixture was stirred for 1 hour at −70° C. and allowed to warm to room temperature, then saturated ammonium chloride (100 ml) and ethyl acetate (200 ml) was added. Air was blown through the mixture for 1 hour. The ethyl acetate was collected and the aqueous layer was extracted with ethyl acetate (2×100 ml). The combined ethyl acetate layers were washed with water, saturated EDTA, dried and evaporated to dryness. The residue was purified by chromatography on silica eluting with a solvent gradient of isohexane to 75% ethyl acetate/isohexane to give the title compound as a solid. Yield 887 mg. M+H 443. NMR CDCl3 0.8 (d, 3H), 1.2-1.5 (m, 3H), 1.7 (m, 2H), 2.85 (s, 3H), 3.0 (m, 1H), 3.15-3.4 (m, 3H), 3.8-4.0 (m, 4H), 5.2 (d, 1H), 6.6-6.7 (m, 3H), 6.85 (m, 2H), 7.2 (m, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][S:10]([C:13]1[N:17]=[C:16]([CH3:18])[N:15]([C:19]2[N:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[N:14]=1)(=[O:12])=[O:11].C(=O)([O-])[O-].[K+].[K+].[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CC(C)=O>[C:31]([N:9]([C:3]1[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=1[F:8])[S:10]([C:13]1[N:17]=[C:16]([CH3:18])[N:15]([C:19]2[N:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[N:14]=1)(=[O:11])=[O:12])(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1nc(S(=O)(=O)Nc2c(F)cccc2F)nn1-c1ncccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1nc(S(=O)(=O)N(C(=O)c2ccccc2)c2c(F)cccc2F)nn1-c1ncccn1
Reaction time: 18 h
Yield: 54 %

Procedure:
A suspension of N-(2,6-difluorophenyl)-5-methyl-1-(2-pyrimidinyl)-1,2,4-triazole-3-sulphonamide (1.5 g) (Compound A54) and anhydrous potassium carbonate (0.59 g) in dry acetone (50 ml) was heated under reflux for 30 minutes. A solution of benzoyl chloride (0.6 g) in acetone (50 ml) was added, and the mixture was refluxed for a further 2 hours. The mixture was then allowed to stand at 25° C. for 18 hours, after which it was warmed, filtered and evaporated. The solid produced was recrystallised from acetonitrile to give 1.05 g of the desired product, mp 218°-221° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C@H:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=2[N+:21]([O-])=O)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].CO>[C:1]([O:5][C:6](=[O:24])[NH:7][C@H:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=2[NH2:21])[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: Cc1ccc(N[C@H]2CC[C@H](NC(=O)OC(C)(C)C)C2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(N[C@H]2CC[C@H](NC(=O)OC(C)(C)C)C2)c(N)c1
Yield: 100 %

Procedure:
The trans-[3-(4-methyl-2-nitro-phenylamino)-cyclopentyl]-carbamic acid tert-butyl ester (320 mg, 0.95 mmol) and palladium on charcoal (10% Pd on carbon, 35 mg) in methanol (15 mL) were shaken at 52 psi of hydrogen pressure for 2.5 hours. The mixture was filtered through Celite®. Solvents were evaporated to yield trans-[3-(2-amino-4-methyl-phenylamino)-cyclopentyl]-carbamic acid tert-butyl ester as a pale brown oil (290 mg). This material (290 mg, 0.95 mmol) was dissolved in a solution (5 mL) of acetic acid and trimethyl orthoacetate (4:1 v/v). The mixture was stirred at 70° C. for 60 minutes and solvents were evaporated. The residue was extracted with ethyl acetate (25 mL) and saturated aqueous sodium bicarbonate (20 mL). The aqueous phase was again extracted with a portion of ethyl acetate and each organic phase was washed with brine. The extracts were combined, dried over sodium sulfate, filtered and evaporated to give trans-[3-(2,5-dimethyl-benzoimidazol-1-yl)-cyclopentyl]-carbamic acid tert-butyl ester as a light brown foam (320 mg). 1H-NMR is consistent with the assigned structure. LC-MS showed a single peak, C19H27N3O2 (m/e) calcd 329.2103, obsd 330.2 (M+H).
Reaction SMILES: [CH:1]1([CH:4]2[O:15][C:8]3[N:9]=[C:10]([Cl:14])[N:11]=[C:12](Cl)[C:7]=3[O:6][CH2:5]2)[CH2:3][CH2:2]1.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C(N(CC)CC)C>>[Cl:14][C:10]1[N:11]=[C:12]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:7]2[O:6][CH2:5][CH:4]([CH:1]3[CH2:3][CH2:2]3)[O:15][C:8]=2[N:9]=1
Reactant: Clc1nc(Cl)c2c(n1)OC(C1CC1)CO2
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Product: Clc1nc2c(c(N3CCOCC3)n1)OCC(C1CC1)O2
Temperature: 140 °C
Yield: 82.3 %

Procedure:
A mixture of 7-cyclopropyl-2,4-dichloro-6,7-dihydro-[1,4]dioxino[2,3-d]pyrimidine (93 mg, 0.40 mmol), morpholine (150 μL, 1.71 mmol) and triethylamine (80 μL, 0.57 mmol) in IMS (3 mL) was heated at 140° C. for 35 minutes using microwave irradiation before being concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, 0-20% ethyl acetate in cyclohexane) affording 2-Chloro-7-cyclopropyl-4-morpholin-4-yl-6,7-dihydro-[1,4]dioxino[2,3-d]pyrimidine as a white solid (98 mg, 87%). LCMS: RT=3.02 min, [M+H]+=284/286.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](OS(C(F)(F)F)(=O)=O)=[N:8][C:9]2[C:14]([C:15]=1[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])=[CH:13][C:12]([Cl:24])=[CH:11][CH:10]=2)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH3:39][NH:40][CH3:41]>C1COCC1.O>[CH2:1]([O:3][C:4]([C:6]1[C:7]([N:40]([CH3:41])[CH3:39])=[N:8][C:9]2[C:14]([C:15]=1[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])=[CH:13][C:12]([Cl:24])=[CH:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: CNC
Reactant: CCOC(=O)c1c(OS(=O)(=O)C(F)(F)F)nc2ccc(Cl)cc2c1Cc1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1c(N(C)C)nc2ccc(Cl)cc2c1Cc1ccccc1Cl
Temperature: 70 °C
Reaction time: 3 h
Yield: 68.2 %

Procedure:
To a solution of 6-chloro-4-(2-chloro-benzyl)-2-trifluoromethanesulfonyloxy-quinoline-3-carboxylic acid ethyl ester (100 mg, 0.2 mmol) in THF (2 ml) was added potassium carbonate (109 mg, 0.79 mmol) and dimethylamine (2M solution in THF; 0.5 ml, 0.98 mmol) at 25° C. and the resulting reaction mixture was stirred at 70° C. for 3 h. The mixture was diluted with water (5 ml), and extracted with EtOAc (3×15 ml) and the organic phases were combined and washed with brine (15 ml), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography (3% EtOAc/hexane) to give 6-chloro-4-(2-chloro-benzyl)-2-dimethylamino-quinoline-3-carboxylic acid ethyl ester (55 mg, 69%) as pale yellow solid. LC-MS (ESI): 403 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.Cl.[C:11]1(NN)[CH:16]=CC=[CH:13][CH:12]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:16]=[CH:11][C:12]([CH3:13])=[N:9]2)=[CH:4][CH:3]=1
Reactant: NNc1ccc(Cl)cc1
Reactant: NNc1ccccc1
Agent: Cl
Product: Cc1ccn(-c2ccc(Cl)cc2)n1

Procedure:
This compound was prepared by the same methodology described for EXAMPLE 1 with 4-chlorophenyl hydrazine.HCl substituted for phenyl hydrazine. There was obtained 1-(4′-chlorophenyl)-3-methyl-1H-pyrazole-5-[(2′-aminosulfonyl-[1,1′]-biphen-4-yl)carboxyamide; HRMS (M+H)+: calc. 467.094465; found 467.093532.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[C@@H:5]([NH:18][S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:21])=[O:20])[CH2:6][NH:7][C:8](=[O:17])[C:9]1[CH:14]=[CH:13][C:12]([C:15]#[CH:16])=[CH:11][CH:10]=1)[CH3:2].[NH2:29][C:30]1[N:31]=[C:32](Br)[C:33]2[C:38]([CH:39]=1)=[CH:37][CH:36]=[CH:35][CH:34]=2.C(N(CC)CC)C>C(#N)C.CCOC(C)=O.[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>[CH2:1]([O:3][C:4](=[O:28])[C@@H:5]([NH:18][S:19]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)(=[O:20])=[O:21])[CH2:6][NH:7][C:8](=[O:17])[C:9]1[CH:10]=[CH:11][C:12]([C:15]#[C:16][C:32]2[C:33]3[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:39]=[C:30]([NH2:29])[N:31]=2)=[CH:13][CH:14]=1)[CH3:2]
Reactant: Nc1cc2ccccc2c(Br)n1
Reactant: C#Cc1ccc(C(=O)NC[C@H](NS(=O)(=O)c2ccccc2)C(=O)OCC)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)[C@H](CNC(=O)c1ccc(C#Cc2nc(N)cc3ccccc23)cc1)NS(=O)(=O)c1ccccc1
Temperature: 100 °C

Procedure:
Ethyl ester 35-3 (0.50 g, 1.25 mmol), 3-amino-1-bromoisoquinoline (0.279 g, 1.25 mmol), triethylamine (0.697 mL, 5.00 mmol), CuI (10 mg, 0.053 mmol), and (Ph3P)2PdCl2 (20 mg, 0.028 mmol) were combined in 5 mL acetonitrile in a sealed pressure tube under Ar and heated to 100° C. overnight. The dark solution was cooled and diluted with EtOAc, then washed with water (2×) and brine, dried (MgSO4), filtered, and concentrated. Flash chromatography (silica, 75% EtOAc/Hexane) gave 35-4 as a greenish foam.
Reaction SMILES: [CH3:1][C:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[CH:3][CH2:4][OH:5].[C:12](OC(=O)C)(=[O:14])[CH3:13].C(O)(=O)C.C1(C)C=CC=CC=1>C1(C)C=CC=CC=1.C(O)(=O)C>[C:12]([O:5][CH2:4][CH:3]=[C:2]([CH3:1])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCCC(C)=CCO
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCCCCCC(C)=CCOC(C)=O

Procedure:
156 G. (1 mole) of 3-methyl-2-nonen-1-ol, 122 g. (1.2 moles) of acetic anhydride and 264 ml. of toluene were combined in a reaction flask and heated. The formed acetic acid-toluene azeotropic mixture consisting of 34 parts of acetic acid and 66 parts of toluene and boiling at 105° C. was removed by distillation through a 11/2 ft. Vigreux column. After termination of the reaction, the reaction mass was washed with 100 ml. of aqueous sodium carbonate solution, 100 ml. of aqueous sodium bicarbonate solution, and finally twice with 100 ml. of water. The desired ester, 3-methyl-2-nonen-1-yl-acetate, having a b.p. of 119°-121° C. at 10 mm. and an R.I. at 20°:1.445, was recovered by fractional distillation.
Reaction SMILES: [OH:1][C@H:2]([CH3:16])[CH2:3][NH:4][CH2:5][C@@H:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH3:7].C(N(C(C)C)CC)(C)C.Cl[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28].Cl>ClCCl>[C:11]([O:10][C:9]([NH:8][C@@H:6]([CH3:7])[CH2:5][N:4]([CH2:3][C@H:2]([OH:1])[CH3:16])[C:27](=[O:28])[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:15])([CH3:14])([CH3:13])[CH3:12]
Reactant: C[C@@H](O)CNC[C@H](C)NC(=O)OC(C)(C)C
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](O)CN(C[C@H](C)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.5 %

Procedure:
To a stirred solution of tert-butyl (S)-1-[(R)-2-hydroxypropylamino]propan-2-ylcarbamate (3.0 g, 12.93 mmol) and diisopropylethylamine (3.38 mL, 19.4 mmol) in anhydrous dichloromethane (100 mL) at 0° C. was added benzyl chloroformate (2.65 g, 15.5 mmol). After stirring at 0° C. for 1 hour, the cooling bath was removed and the reaction mixture was allowed to stir at room temperature for an additional 45 minutes. Reaction was complete as determined by TLC. The reaction mixture was added with 1N HCl and extracted with dichloromethane. Organic layer washed with water then brine and it was dried over MgSO4. Solvent evaporation afforded benzyl {(2S)-2-[(tert-butoxycarbonyl)amino]propyl}[(2R)-2-hydroxypropyl]carbamate in 84.5% yield (3.95 g) as colorless gummy oil.
Reaction SMILES: Cl.[CH3:2][N:3]([CH:5]([C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=1)[CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=[O:12])[CH3:4].N.[CH2:24]([Mg][Cl:32])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[Cl-].[NH4+]>O1CCCC1.O>[ClH:32].[CH2:24]([C:7]1([OH:12])[CH2:8][CH2:9][CH2:10][CH2:11][CH:6]1[CH:5]([N:3]([CH3:2])[CH3:4])[C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CN(C)C(c1ccc2ccccc2c1)C1CCCCC1=O
Reactant: Cl[Mg]Cc1ccccc1
Agent: Cl
Agent: N
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C(c1ccc2ccccc2c1)C1CCCCC1(O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 68.1 %

Procedure:
The base was freed from 3.0 g (9.44 mmole) of the hydrochloride of 2-(dimethylaminonaphthalene-2-ylmethyl)cyclohexanone obtained according to stage 1 with 30 ml of water and 5 ml of ammonia solution (25 vol. %), extracted three times with 30 ml of ether each time, and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation one a rotary evaporator without heating (500 to 10 mbar). 2.5 g (8.9 mmole) of this base were dissolved in 15 ml of tetrahydrofuran, added dropwise while cooling in an ice bath to 5.3 ml (10.7 mmole) of benzylmagnesium chloride (2 M solution in tetrahydro-furan), and the whole was stirred for 15 hours at RT. The reaction mixture was worked up by adding 20 ml of saturated ammonium chloride solution while cooling in an ice bath, and was extracted three times at RT with 20 ml. of other each time. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 3.17 g of crude base (99.2% of theory) were obtained, from which 2.4 g of 1-benzyl-2-(dimethylaminonaphthalene-2-yl-methyl)cyclohexanol, hydrochloride (68.1% of theory) were obtained according to the procedure described in Example 1 (3rd Stage) with chlorotrimethylsilane/water in 2-butanone. The hydrochloride decomposes on heating above 180° C.
Reaction SMILES: C(C1C(I)=[C:6]([O:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]([CH3:22])[CH3:21])=[C:16](CC=C)[C:15]=2I)[CH:7]=[CH:8]C=1C(C)C)C=C.N(CCCC)(CCCC)CCCC.C([O-])=O.[NH4+]>C([N+]1C=CN(C)C=1)CCC.F[B-](F)(F)F.Cl[Pd]Cl>[CH:20]([C:17]1[CH:18]=[CH:19][C:14]2[O:13][CH:6]=[C:7]([CH3:8])[C:15]=2[CH:16]=1)([CH3:21])[CH3:22]
Reactant: C=CCc1c(C(C)C)ccc(Oc2ccc(C(C)C)c(CC=C)c2I)c1I
Agent: Cl[Pd]Cl
Agent: CCCC[n+]1ccn(C)c1
Agent: F[B-](F)(F)F
Solvent: CCCCN(CCCC)CCCC
Product: Cc1coc2ccc(C(C)C)cc12
Temperature: 60 °C
Yield: 127.5 %

Procedure:
According to the method described by Xie et al. (Xie et al., (2004) Tetrahedron Lett. 45, 6235-6237) a mixture of allyl-2-iodo-4-isopropylphenyl ether (300 mg, 0.99 mmol), NBu3 (350 μL, 1.49 mmol), ammonium formate (65 mg, 1.03 mmol) and PdCl2 (10 mg, 0.06 mmol) in 1-butyl-3-methylimidazolium-tetrafluoroborate (1.5 mL) was heated at 60° C. for 2 days. A second portion of PdCl2 (24 mg) was added and the mixture was heated at 60° C. additional 5 h. The reaction mixture was extracted with Et2O. Evaporation of the solvent afforded 220 mg crude product, which was purified on silica giving the title compound in 30% yield (55 mg). 1H NMR (400 MHz, CDCl3) δ ppm 1.31 (d, J=6.90 Hz, 6 H) 2.24 (d, J=1.25 Hz, 3 H) 3.03 (spt, J=6.90 Hz, 1 H) 7.17 (dd, J=8.34, 1.94 Hz, 1 H) 7.34-7.39 (m, 3 H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[N:14][CH:15]=2)=[CH:5][CH:4]=1)#[N:2].[Br:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1>>[Br:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][N:9]([C:10]2[CH:15]=[N:14][CH:13]=[N:12][CH:11]=2)[C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)=[CH:19][CH:18]=1
Reactant: N#Cc1ccc(Nc2cncnc2)cc1
Reactant: BrCc1ccc(Br)cc1
Product: N#Cc1ccc(N(Cc2ccc(Br)cc2)c2cncnc2)cc1

Procedure:
Starting compounds: 5-[(4-cyanophenyl)amino]pyrimidine and 4-bromobenzyl bromide
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[CH:3]([CH:9]1[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]1)[O:4][Si](C)(C)C.[ClH:24].CCOCC>C(Cl)Cl.CO>[ClH:24].[F:23][C:2]([F:1])([F:22])[CH:3]([CH:9]1[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]1)[OH:4]
Reactant: CC(C)(C)OC(=O)N1CCC(C(O[Si](C)(C)C)C(F)(F)F)CC1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Solvent: ClCCl
Product: OC(C1CCNCC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 84 %

Procedure:
To a solution of tert-butyl 4-(2,2,2-trifluoro-1-(trimethylsilyloxy)ethyl)piperidine-1-carboxylate (1.6 g, 4.50 mmol) in DCM (9 mL) and MeOH (1 mL) was added 2 M HCl in ether (11.25 mL, 22.51 mmol). The reaction was stirred at RT for 16 hours. The precipitate that formed was collected by vacuum filtration, washed with diethyl ether, and dried in vacuo to generate 2,2,2-trifluoro-1-(piperidin-4-yl)ethanol hydrochloride as a white powder (0.83 g, 84% yield).
Reaction SMILES: CO[C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([NH:24][CH:25]([CH3:27])[CH3:26])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[N:6][CH:5]=1.[NH2:29][CH2:30][CH2:31][CH2:32][OH:33].O>CO>[OH:33][CH2:32][CH2:31][CH2:30][NH:29][C:3]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:13][CH2:14][N:15]([C:18]3[C:23]([NH:24][CH:25]([CH3:27])[CH3:26])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:16][CH2:17]2)=[O:11])=[N:6][CH:5]=1)=[O:28]
Reactant: COC(=O)c1ccc(C(=O)N2CCN(c3ncccc3NC(C)C)CC2)nc1
Reactant: NCCCO
Solvent: O
Solvent: CO
Product: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)NCCCO)cn2)CC1
Reaction time: 2 h
Yield: 78 %

Procedure:
6-[1-[3-(Isopropylamino)-2-pyridyl]piperazine-4-yl-carbonyl]nicotinic acid methyl ester (2.5 g) was dissolved in methanol (40 ml) and with the addition of 3-amino-1-propanol (0.95 g), the mixture was heated to reflux for 12 hours and cooled. The excess of water was added slowly at 25° C. for precipitation, the mixture was stirred for 2 hours and filtered. The filtered solid was recrystallized with isopropanol and ether, filtered and dried to give a desired compound of 2.17 g (yield: 78%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1.[CH3:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([NH2:24])[CH:19]=1>>[CH2:16]([O:17][C:18]1[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=1)[NH:24][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1)[CH3:15]
Reactant: Cc1cc(Cl)nc(-c2ccccn2)n1
Reactant: CCOc1cccc(N)c1
Product: CCOc1cccc(Nc2cc(C)nc(-c3ccccn3)n2)c1

Procedure:
The title compound was prepared from 4-chloro-6-methyl-2-(2-pyridinyl)pyrimidine (100 mg, 0.486 mmol) and m-phenetidine (65 μl, 0.486 mmol) similar to Example 11 and isolated as a light tan solid (1116 mg, 78%). 1H NMR (CDCl3): 8.86–8.83 (m, 1H), 8.50 (d, J=8.1 Hz, 1H), 7.89–7.83 (m, 1H), 7.42–7.38 (m, 1H), 7.35–7.30 (m, 1H), 7.09 (s, 1H), 6.96–6.84 (m, 2H), 6.76 (d, J=3.3 Hz, 1H), 6.71 (s, 1H), 4.09 (q, J=7.2 Hz, 2H), 2.53 (s, 3H), 1.47 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.C([Li])CCC.COCN[C:16](=[O:28])[CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24]>O1CCCC1>[CH3:26][C:23]([O:22][C:21](=[O:27])[NH:20][CH2:19][CH2:18][CH2:17][C:16]([C:3]1[N:2]([CH3:1])[CH:6]=[CH:5][N:4]=1)=[O:28])([CH3:24])[CH3:25]
Reactant: Cn1ccnc1
Reactant: COCNC(=O)CCCNC(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1ccnc1C(=O)CCCNC(=O)OC(C)(C)C
Temperature: -70 °C
Yield: 61 %

Procedure:
N-methylimidazole (0.83 g, 10.1 mmol) was dissolved in anhydrous tetrahydrofuran (30 ml) and the solution cooled to −70° C. n-Butyllithium (2.29M, 3.48 ml, 10.1 mmol) was added dropwise and the solution stirred for 0.5hat −70° C. 1,1-Dimethylethyl [4-(methoxymethylamino)-4-oxobutyl]-carbamate (1.24 g, 5.03 mmol) as a solution in tetrahydrofuran (50 ml) was added dropwise and the resultant solution stirred at −70° C. for 1 h. The cooling bath was removed and the reaction mixture allowed to warm to 0° C. The reaction was quenched with saturated aqueous ammonium chloride solution (30 ml) and extracted with ethyl acetate (3×70 ml). The combined extracts were washed with water (2×20 ml), dried (magnesium sulphate) and evaporated. The residue was eluted down a flash chromatography column eluting with hexane:ethyl acetate (3:1) to afford the sub-title compound as a pale straw-coloured oil (0.82 g, 61%);