Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.[C:23]1([O:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]Cl)[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][O:33][C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25][CH:24]=3)[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: ClCCCCCOc1cccc2ccccc12
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCOc2cccc3ccccc23)CC1
Yield: 91.1 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (1.5 g) as starting compound and 5-(1-naphthyloxy)-pentyl chloride (1.2 g) were reacted and treated in the same manner as in Example 168 to give 1.88 g of 4-amino-5-chloro-N-((1-(5-(1-naphthyloxy)pentyl)piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:41][C:42]([OH:45])([CH3:44])[CH3:43])[C:7]2[C:16]3[CH:15]=[CH:14][C:13]([C:17](O)=[O:18])=[CH:12][C:11]=3[N:10]=[C:9]([NH:20][C:21]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:8]=2[N:40]=1)[CH3:2].CN([C:49]([O:53][N:54]1N=NC2C=CC=C[C:55]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.CNOC>CN(C=O)C>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:41][C:42]([OH:45])([CH3:43])[CH3:44])[C:7]2[C:16]3[CH:15]=[CH:14][C:13]([C:17]([N:54]([O:53][CH3:49])[CH3:55])=[O:18])=[CH:12][C:11]=3[N:10]=[C:9]([NH:20][C:21]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:8]=2[N:40]=1)[CH3:2]
Reactant: CCOCc1nc2c(NC(c3ccccc3)(c3ccccc3)c3ccccc3)nc3cc(C(=O)O)ccc3c2n1CC(C)(C)O
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CNOC
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOCc1nc2c(NC(c3ccccc3)(c3ccccc3)c3ccccc3)nc3cc(C(=O)N(C)OC)ccc3c2n1CC(C)(C)O
Yield: 111.1 %

Procedure:
To a solution of 2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-4-(tritylamino)-1H-imidazo[4,5-c]quinoline-7-carboxylic acid (484 mg, 741 μmol) in DMF (5.19 mL) in an inert atmosphere was added TBTU (357 mg, 1.11 mmol), DIEA (388 μL, 2.22 mmol) and N,O-dimethylhydroxylamine hydrochloride (108 mg, 1.11 mmol) with stirring. The reaction mixture was stirred for 1 h at room temperature and afterwards the mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate (40 mL, 2×20 mL) and water (40 mL). The organic phases were washed with water (2×20 mL), combined, dried over MgSO4, concentrated in vacuo and purified by flash chromatography (silica gel, 50% to 100% ethyl acetate in heptane) to give the title compound (0.53 g, quant.) as white foam; LC-MS (UV peak area, ESI) 92%, 644.4 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].CC(C)([O-])C.[K+].Cl[C:17]1[CH:22]=[CH:21][N:20]=[C:19](C(N)=O)[CH:18]=1.[OH-].[Na+]>CS(C)=O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[CH:4][C:3]=1[F:9]
Reactant: NC(=O)c1cc(Cl)ccn1
Reactant: Nc1ccc(O)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CS(C)=O
Product: Nc1ccc(Oc2ccncc2)cc1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90.2 %

Procedure:
4-Amino-3-fluorophenol (5.7 g) was dissolved in dimethyl sulfoxide (57 ml) under a nitrogen stream, potassium tert-butoxide (5.6 g) was added at room temperature, and the reaction mixture was stirred for 15 minutes. 4-Chloropyridine-2-carboxamide (5.0 g) was added to the reaction mixture, followed by stirring in an oil bath at 80° C. (external temperature) under a nitrogen stream for 50 minutes. The reaction mixture was allowed to cool down to room temperature. A 1N aqueous solution of sodium hydroxide (85.5 ml) was added to the reaction mixture, followed by stirring. The precipitated solid was collected by filtration and washed with water. The residue was dried under aeration and then dried by hot air at 100° C. to give the title compound (5.88 g, 74.3%) as pale brown powder.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[N:7]=[CH:6][N:5]=1.I[CH2:19][CH3:20].[Cl-].[NH4+]>O1CCCC1>[Cl:3][C:4]1[CH:9]=[C:8]([N:10]([CH2:19][CH3:20])[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[N:7]=[CH:6][N:5]=1
Reactant: CCI
Reactant: Fc1cccc(Nc2cc(Cl)ncn2)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCN(c1cccc(F)c1)c1cc(Cl)ncn1
Temperature: 25 °C
Yield: 76.4 %

Procedure:
In 6.7 ml of tetrahydrofuran was suspended 0.16 g of sodium hydride (60% in oil), to which 0.8 ml of a tetrahydrofuran solution containing 0.5 g of 4-chloro-6-(3-fluorophenylamino)pyrimidine was slowly added dropwise with stirring at room temperature. The mixture was stirred at room temperature for 20 minutes, to which 0.8 ml of a tetrahydrofuran solution containing 0.42 g of iodoethane was slowly added at 0° C., followed by further stirring for 8 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution and extracted three times with t-butyl methyl ether. The organic layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.43 g of 4-chloro-6-(N-ethyl-N-(3-fluorophenyl)amino)pyrimidine.
Reaction SMILES: COC1C=C([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH:29]=[C:28]([CH3:30])[N:27]=[CH:26]3)=[C:21]([O:31][CH3:32])[CH:20]=2)=S)C=CC=1N1C=C(C)N=C1.[Cl:33][C:34]1[CH:43]=[CH:42][C:37]([C:38]([NH:40]N)=[O:39])=[CH:36][CH:35]=1>CO.[Hg]=O>[Cl:33][C:34]1[CH:43]=[CH:42][C:37]([C:38]2[O:39][C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH:29]=[C:28]([CH3:30])[N:27]=[CH:26]4)=[C:21]([O:31][CH3:32])[CH:20]=3)=[N:15][N:40]=2)=[CH:36][CH:35]=1
Reactant: NNC(=O)c1ccc(Cl)cc1
Reactant: COc1cc(NC(=S)Nc2ccc(-n3cnc(C)c3)c(OC)c2)ccc1-n1cnc(C)c1
Agent: O=[Hg]
Solvent: CO
Product: COc1cc(Nc2nnc(-c3ccc(Cl)cc3)o2)ccc1-n1cnc(C)c1
Yield: 8.1 %

Procedure:
A solution of mercury-(II)-oxide (97 mg, 0.45 mmol) in 5 ml of methanol was treated with 1,3-bis-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea (200 mg, 0.45 mmol) and 4-chloro-benzhydrazide (76 mg, 0.45 mmol). The resulting mixture was refluxed for 3 hours, concentrated and triturated with ethyl acetate. Filtering of the suspension and chromatography on silica gel using ethyl acetate as eluent gave the title compound as a brownish solid (14 mg, 8%).
Reaction SMILES: C([S-])C.[Na+].[NH2:5][C:6]1[C:22]([Cl:23])=[CH:21][C:9]([C:10]([NH:12][CH:13]2[CH:18]3[CH2:19][CH2:20][N:15]([CH2:16][CH2:17]3)[CH2:14]2)=[O:11])=[C:8]([O:24]C)[CH:7]=1.Cl>CN(C=O)C>[NH2:5][C:6]1[C:22]([Cl:23])=[CH:21][C:9]([C:10]([NH:12][CH:13]2[CH:18]3[CH2:17][CH2:16][N:15]([CH2:20][CH2:19]3)[CH2:14]2)=[O:11])=[C:8]([OH:24])[CH:7]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NC1CN2CCC1CC2
Agent: CC[S-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1cc(O)c(C(=O)NC2CN3CCC2CC3)cc1Cl

Procedure:
To a solution of sodium ethanethiolate in DMF is added 4-amino-N-(1-azabicyclo[2.2.2]oct-3-yl)-5-chloro-2-methoxybenzamide and the mixture heated under reflux to 1 h. After cooling, the mixture is neutralized with hydrochloric acid, concentrated in vacuo and the residue purified by chromatography to give the title compound.
Reaction SMILES: [Si]([O:8][C:9]1[C:10]([F:22])=[C:11](B(O)O)[CH:12]=[CH:13][C:14]=1[CH:15]1[CH2:18][CH2:17][CH2:16]1)(C(C)(C)C)(C)C.[NH2:23][C:24]1[CH:29]=[N:28][C:27](Br)=[CH:26][N:25]=1.C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>O.CN(C=O)C.C1(C)C=CC=CC=1>[NH2:23][C:24]1[N:25]=[CH:26][C:27]([C:11]2[C:10]([F:22])=[C:9]([OH:8])[C:14]([CH:15]3[CH2:16][CH2:17][CH2:18]3)=[CH:13][CH:12]=2)=[N:28][CH:29]=1
Reactant: Nc1cnc(Br)cn1
Reactant: CC(C)(C)[Si](C)(C)Oc1c(C2CCC2)ccc(B(O)O)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Nc1cnc(-c2ccc(C3CCC3)c(O)c2F)cn1
Temperature: 80 °C
Reaction time: 2 h
Yield: 87.3 %

Procedure:
A 50 mL three-neck flask, equipped with a stir bar, nitrogen inlet and temperature probe, was charged with (3-((tert-butyldimethylsilyl)oxy)-4-cyclobutyl-2-fluorophenyl)boronic acid (1.7 g, 5.3 mmol), toluene (4.7 mL), DMF (2.8 mL) and water (4.7 mL). The solvent mixture was sparged for 30 minutes and then treated with 2-amino-5-bromopyrazine (923 mg, 5.3 mmol), potassium carbonate (2.19 g, 15.8 mmol) and dichloro[1,1′-bis(diphenyl-phosphino)ferrocene]palladium(II).CH2Cl2 (137 mg, 0.17 mmol). The reaction mixture was heated at 80° Celsius for 24 hours. The reaction mixture was then cooled to room temperature, diluted with water (8 mL) and the stirred for two hours. The precipitate was collected by filtration and dried in a vacuum oven at 60° Celsius overnight to give 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol (1.2 g, 87%). MS (ESI+) Calcd. for C14H14FN3O, 260.3; m/z found 260.1 [M+H]+. 1H NMR (400 MHz, DMSO), δ 8.24 (m, 1H), 7.98 (d, J=1.5 Hz, 1H), 7.09 (m, 1H), 7.00 (d, J=8.2 Hz, 1H), 6.57 (s, 2H), 3.81-3.72 (m, 1H), 2.34-2.14 (m, 2H), 2.14-1.69 (m, 4H).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:17][CH2:16][C:7]2[NH:8][C:9]3[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][C:14]=3[C:6]=2[CH2:5]1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2([CH3:29])[CH2:28][O:27]2)=[CH:22][CH:21]=1>CN(C=O)C>[CH3:3][N:4]1[CH2:17][CH2:16][C:7]2[N:8]([CH2:29][C:26]([C:23]3[CH:22]=[CH:21][C:20]([O:19][CH3:18])=[CH:25][CH:24]=3)([OH:27])[CH3:28])[C:9]3[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][C:14]=3[C:6]=2[CH2:5]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: COc1ccc(C2(C)CO2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C(C)(O)Cn2c3c(c4cc(C)ccc42)CN(C)CC3)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A flask was charged with sodium hydride 60% (0.803 mg, 20.12 mmol) in DMF and stirred at RT for 10 min. 2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (1.28 g, 6.4 mmol) was added and the mixture stirred at RT for 1 h. 2-(4-Methoxyphenyl)-2-methyloxirane (1.5 g, 9.14 mmol) was added and the mixture stirred at RT overnight. Ice water was added and the mixture extracted with ethyl acetate (3×). The combined organic layers were washed with water (4×) and concentrated, followed by purification of the product on silica gel (#100-200 mesh) using 0-5% MeOH:DCM as eluent.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([C:16]2[NH:20][N:19]=[C:18]([C:21]([NH:23][CH2:24][C:25]([OH:27])=O)=[O:22])[CH:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[CH3:51][O:52][C:53](=[O:68])[C:54]1[CH:59]=[CH:58][C:57]([CH3:60])=[C:56]([O:61][CH:62]2[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]2)[CH:55]=1>CN(C=O)C.O>[CH3:51][O:52][C:53](=[O:68])[C:54]1[CH:59]=[CH:58][C:57]([CH3:60])=[C:56]([O:61][CH:62]2[CH2:67][CH2:66][N:65]([C:25](=[O:27])[CH2:24][NH:23][C:21]([C:18]3[CH:17]=[C:16]([C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=4)[NH:20][N:19]=3)=[O:22])[CH2:64][CH2:63]2)[CH:55]=1
Reactant: COC(=O)c1ccc(C)c(OC2CCNCC2)c1
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C)c(OC2CCN(C(=O)CNC(=O)c3cc(-c4ccccc4)[nH]n3)CC2)c1
Reaction time: 8 h
Yield: 68.55 %

Procedure:
DIPEA (423 mg, 2.4 mmol) was added to a stirred solution of [(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetic acid (200 mg, 0.81 mmol) in DMF (3 mL) followed by HOBt (130 mg, 0.93 mmol) and EDCI.HCl (187 mg, 0.93 mmol). After 2 minutes 4-methyl-3-(piperidin-4-yloxy)-benzoic acid methyl ester hydrochloride (prepared according to the method used for the synthesis of Intermediate 15) (280 mg, 0.97 mmol) was added to the reaction mixture and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with cold water, extracted with ethyl acetate and dried over sodium sulfate. The organic layer was concentrated under reduced pressure to afford 266 mg (68.55% Yield) of 4-methyl-3-(1-{2-[(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetyl}-piperidin-4-yloxy)-benzoic acid methyl ester. LC/MS [M+H]+: 477.21, 96.63%. 1H NMR (300 MHz, DMSO-d6): δ13.8 (s, 1H), 8.1-8.0 (m, 1H), 7.8 (d, 2H), 7.54-7.28 (m, 6H), 7.1 (bs, 1H), 4.8 (m, 1H), 4.2 (d, 2H), 3.8 (s, 3H), 3.8-3.6 (m, 2H), 3.6-3.4 (m, 2H), 2.2 (s, 3H), 2.1-1.8 (m, 2H), 1.8-1.5 (m, 2H).
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:38]=[CH:39][C:40]2[N:41]([N:43]=[C:44]([CH3:46])[N:45]=2)[CH:42]=1>>[OH:1][C:2]([CH3:34])([CH3:35])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:37]3[CH:38]=[CH:39][C:40]4[N:41]([N:43]=[C:44]([CH3:46])[N:45]=4)[CH:42]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: Cc1nc2ccc(Br)cn2n1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: Cc1nc2ccc(-c3ccc([C@H](C)N4CC[C@](CC(C)(C)O)(c5ccccc5)OC4=O)cc3)cn2n1

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 6-bromo-2-methyl-[1,2,4]triazolo[1,5-a]pyridine following a procedure analogous to that described in Example 3. LC-MS Method 2 tR=1.27 min, 507, 485; 1H NMR (CD3OD) δ 0.97 (s, 3H), 1.29 (s, 3H), 1.58 (d, 3H), 2.18 (s, 2H), 2.27 (m, 1H), 2.51 (m, 2H), 2.63 (s, 3H), 3.10 (m, 1H), 5.62 (q, 1H), 7.13 (d, 2H), 7.30-7.40 (5H), 7.52 (d, 2H), 7.82 (d, 1H), 8.05 (d, 1H), 8.96 (s, 1H).
Reaction SMILES: CS[C:3]1[N:4]=[N:5][C:6]([C:21]#[N:22])=[C:7]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)[N:8]=1.[C:23]([NH:30][CH2:31][CH2:32][NH2:33])([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]>>[C:26]([O:25][C:23](=[O:24])[NH:30][CH2:31][CH2:32][NH:33][C:3]1[N:4]=[N:5][C:6]([C:21]#[N:22])=[C:7]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)[N:8]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: CSc1nnc(C#N)c(N2CCN(c3ccccc3)CC2)n1
Product: CC(C)(C)OC(=O)NCCNc1nnc(C#N)c(N2CCN(c3ccccc3)CC2)n1

Procedure:
In analogy to the procedure described in example 84c, 3-methylsulfanyl-5-(4-phenyl-piperazin-1-yl)-[1,2,4]triazine-6-carbonitrile was treated with N-Boc-ethylene-diamine in a sealed tube at 130° C. during 48 hours to yield {2-[6-cyano-5-(4-phenyl-piperazin-1-yl)-[1,2,4]triazin-3-ylamino]-ethyl}-carbamic acid tert-butyl ester as an amorphous, light yellow solid; MS: [M+H]+=425.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[C:10]=1[C:11](OC)=[O:12].[OH-].[Na+].CN.F[P-](F)(F)(F)(F)F.[N:33]1(OC(N(C)C)=[N+](C)C)[C:37]2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CO.O1CCCC1.O.C(OCC)(=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[C:10]=1[C:11]([NH:33][CH3:37])=[O:12]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: COC(=O)c1c(-c2ccc(C)cc2C)cccc1[N+](=O)[O-]
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1c(-c2ccc(C)cc2C)cccc1[N+](=O)[O-]
Temperature: 65 °C
Reaction time: 12 h
Yield: 29.8 %

Procedure:
To a mixture containing 0.32 g (1.12 mmol) of methyl 2-(2,4-dimethylphenyl)-6-nitrobenzoate in methanol (2.2 ml), tetrahydrofuran (3.5 ml) and water (3.5 ml) was added 0.18 g (4.5 mmol) of sodium hydroxide. The reaction was allowed to stir at 65° C. for 12 h. The solution was cooled, diluted with ethyl acetate (10 mL) and water (10 mL) and shaken vigorously. The aqueous layer was separated, acidified to pH=3 and extracted with ethyl acetate (3×). The combined ethyl acetate layers were washed with brine, dried (Na2SO4), filtered and concentrated. The residue was then dissolved in tetrahydrofuran (10 mL) and methylamine (0.14 g, 2.2 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU) (0.62 g, 1.66 mmol), and diisopropylethylamine (0.28 mL, 2.2 mmol) were added. The reaction was allowed to stir at room temperature for 12 h. The reaction was diluted with ethyl acetate and washed with saturated sodium bicarbonate. The organic phase was dried over magnesium sulfate. Filtration, removal of solvent and purification of the residue via biotage eluting with 30% ethyl acetate/hexanes gave 0.095 g (30%) of product.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=O.[C:6]1([C@H:12]([NH:14][CH2:15][CH2:16][CH:17]=[CH2:18])[CH3:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O.[OH-].[Na+]>O1CCCC1.[Cl-].[Na+].O>[C:6]1([C@H:12]([N:14]2[CH2:15][CH2:16][C@@H:17]3[CH2:18][C@H:2]2[C:1](=[O:4])[O:5]3)[CH3:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C=CCCN[C@H](C)c1ccccc1
Reactant: O=CC(=O)O
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](c1ccccc1)N1CC[C@@H]2C[C@H]1C(=O)O2
Temperature: 60 °C

Procedure:
Glyoxylic acid (7.43 mL) was added dropwise to a solution of (R)—N-(1-phenylethyl)but-3-en-1-amine (7.80 g) in tetrahydrofuran (30 mL) at 60° C. over a period of 1.5 h. The reaction was heated at 60° C. for a further 7 h. Water (30 mL) and brine (30 mL) were added and the pH adjusted with 2M NaOH solution to pH 9. The aqueous was extracted with ethyl acetate (3×50 mL), the organics combined, washed with saturated aqueous NaHCO3 solution, water, brine, dried (MgSO4), filtered and evaporated to afford an orange oil (9.5 g). Purification (SiO2 chromatography using elution gradient 25% ethyl acetate in isohexane) afforded the subtitle product (3.10 g) as an orange oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]3[N:19]=[C:18]([CH3:20])[NH:17][C:16](=[O:21])[C:15]=3[N+:22]([O-:24])=[O:23])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:25]([Si:29]([O:32][CH2:33][CH2:34][CH2:35][CH2:36]Cl)([CH3:31])[CH3:30])([CH3:28])([CH3:27])[CH3:26].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:25]([Si:29]([CH3:30])([CH3:31])[O:32][CH2:33][CH2:34][CH2:35][CH2:36][O:21][C:16]1[C:15]([N+:22]([O-:24])=[O:23])=[C:14]([N:11]2[CH2:10][CH2:9][CH:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:13][CH2:12]2)[N:19]=[C:18]([CH3:20])[N:17]=1)([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)[Si](C)(C)OCCCCCl
Reactant: Cc1nc(N2CCC(c3ccc(F)cc3)CC2)c([N+](=O)[O-])c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(OCCCCO[Si](C)(C)C(C)(C)C)c([N+](=O)[O-])c(N2CCC(c3ccc(F)cc3)CC2)n1

Procedure:
In analogy to the procedure described in example 8, the 6-[4-(4-fluoro-phenyl)-piperidin-1-yl]-2-methyl-5-nitro-3H-pyrimidin-4-one (example 7) was treated with tert.-butyl-(4-chlorobutoxy)dimethylsilane and potassium carbonate in N,N-dimethyl-formamide at 80° C. to yield the 4-[4-(tert-butyl-dimethyl-silanyloxy)-butoxy]-6-[4-(4-fluoro-phenyl)-piperidin-1-yl]-2-methyl-5-nitro-pyrimidine as a yellowish oil; MS: [M+H]+=519; and the 3-[4-(tert-butyl-dimethyl-silanyloxy)-butyl]-6-[4-(4-fluoro-phenyl)-piperidin-1-yl]-2-methyl-5-nitro-3H-pyrimidin-4 one as a yellowish oil; MS: [M+H]+=519.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][NH:9][C:10]2[C:15]([Cl:16])=[CH:14][N:13]=[C:12]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][C:26]([F:29])([F:28])[F:27])[N:11]=2)[CH2:4][CH2:3]1.Br[CH2:31][CH2:32][CH2:33]Br>CC(N(C)C)=O>[N:1]1([C@H:2]2[CH2:3][CH2:4][C@H:5]([CH2:8][NH:9][C:10]3[C:15]([Cl:16])=[CH:14][N:13]=[C:12]([NH:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][C:26]([F:27])([F:28])[F:29])[N:11]=3)[CH2:6][CH2:7]2)[CH2:33][CH2:32][CH2:31]1
Reactant: N[C@H]1CC[C@H](CNc2nc(NCc3ccccc3OC(F)(F)F)ncc2Cl)CC1
Reactant: BrCCCBr
Solvent: CC(=O)N(C)C
Product: FC(F)(F)Oc1ccccc1CNc1ncc(Cl)c(NC[C@H]2CC[C@H](N3CCC3)CC2)n1
Temperature: 100 °C

Procedure:
N4-[(trans-4-aminocyclohexyl)methyl]-5-chloro-N2-[2-(trifluoromethoxy)benzyl]pyrimidine-2,4-diamine (178 mg, 0.41 mmol) was dissolved in DMA (5 mL). To this solution was added 1,3-dibromopropane (208 μL, 2.01 mmol) and NaCO3 (217 mg, 2.01 mmol). The reaction was heated in the microwave at 100° C. for 5 min. The volatiles were removed and the reaction was diluted with EtOAc and poured into H2O. The aqueous phase was separated and extracted two more times with EtOAc. The organic layers were combined, dried (Na2SO4), decanted and concentrated. The crude product was purified on a 2000 micron SiO2 preparative TLC plate, eluting with 10:1 CH2Cl2:MeOH (1% NH4OH) to afford 102 mg (53%) of the title compound, m/z 470.5 [M+1]+.
Reaction SMILES: [C:1]1([N:7]2[CH2:11][CH2:10][CH2:9][C:8]2=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:13]Br.O.[OH-].[K+]>C(O)(=O)C>[Br:13][C:4]1[CH:3]=[CH:2][C:1]([N:7]2[CH2:11][CH2:10][CH2:9][C:8]2=[O:12])=[CH:6][CH:5]=1
Reactant: BrBr
Reactant: O=C1CCCN1c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: O=C1CCCN1c1ccc(Br)cc1
Reaction time: 0.5 h

Procedure:
8.06 g of N-phenylpyrrolidinone were dissolved in 33 ml glacial acetic acid; the mixture was cooled to 0°-5° C. and then a solution of 2.65 ml bromine in 12 ml of glacial acetic acid was added dropwise. Stirring was continued for 30 minutes at room temperature. Work-up was accomplished by pouring the mixture into 1 l of water and neutralizing the mixture with KOH. The solid was filtered and dissolved in ethylacetate and washed with a sodium thiosulphate solution until the brown colour disappeared; washing with brine and drying with MgSO4 provided 8.5 g of a white crystalline mass that could be recrystallized from ether; m.p. 102° C.
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]2[C@@:13]34[C@@H]5C[C@H]6C(CN5CC3)=CCO[C@H]3C[C:23](=O)[N:11]([C@H:12]4[C@@H:20]63)[C:6]2=[CH:7][C:8]=1OC.FC1C=CC2S(=[O:41])C3C=C(C(O)=O)C=CC=3C=CC=2C=1>>[CH3:20][C@H:12]([NH:11][CH3:23])[C@H:13]([OH:41])[C:5]1[CH:4]=[CH:3][CH:8]=[CH:7][CH:6]=1
Reactant: COc1cc2c(cc1OC)[C@@]13CCN4CC5=CCO[C@H]6CC(=O)N2[C@H]1[C@H]6[C@H]5C[C@H]43
Reactant: O=C(O)c1ccc2c(c1)S(=O)c1ccc(F)cc1C=C2
Product: CN[C@@H](C)[C@H](O)c1ccccc1

Procedure:
The brucine salt of (+) 7 or 8-fluorodibenzo[b,f]thiepin-3-carboxylic acid-5-oxide.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][N:12]=[CH:11]3)[CH2:3][CH2:2]1.Br[CH2:18][CH2:19][OH:20].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH:13]1[C:14]2[C:10](=[CH:9][C:8]([O:7][CH:4]3[CH2:3][CH2:2][N:1]([CH2:18][CH2:19][OH:20])[CH2:6][CH2:5]3)=[CH:16][CH:15]=2)[CH:11]=[N:12]1
Reactant: c1cc2[nH]ncc2cc1OC1CCNCC1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCN1CCC(Oc2ccc3[nH]ncc3c2)CC1
Reaction time: 17 h
Yield: 37.5 %

Procedure:
To a solution of the 5-(piperidin-4-yloxy)-1H-indazole (31 mg, 0.143 mmol) obtained in Example 42 in N,N-dimethylformamide (1 ml) were added 2-bromoethanol (0.0121 ml, 0.171 mmol) and potassium carbonate (49 mg, 0.357 mmol). After 17 hours, 2-bromoethanol (0.0121 ml, 0.171 mmol) was further added thereto. After another 24 hours, the reaction mixture was filtered by the use of Celite and the filtrate was concentrated under reduced pressure. The resulting residue was purified by a silica gel column chromatography (eluent: chloroform/methanol→chloroform/methanol/(1%-aqueous ammonia)) to obtain 2-[4-(1H-indazol-5-yloxy)piperidin-1-yl]ethanol (14 mg, 38%).