Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[ClH:3].[N:4]12[CH2:11][CH2:10][CH:7]([CH2:8][CH2:9]1)[C@@H:6]([NH:12][C:13]([C:15]1[O:16][C:17]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[O:30][CH3:31])=[CH:22][CH:21]=[CH:20][C:18]=3[CH:19]=1)=[O:14])[CH2:5]2.I[CH3:33].O>CN(C=O)C>[Cl-:3].[CH3:31][O:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:23]1[C:17]2[O:16][C:15]([C:13]([NH:12][C@@H:6]3[CH:7]4[CH2:8][CH2:9][N+:4]([CH3:33])([CH2:11][CH2:10]4)[CH2:5]3)=[O:14])=[CH:19][C:18]=2[CH:20]=[CH:21][CH:22]=1
Reactant: Cl
Reactant: CI
Reactant: COc1ccccc1-c1cccc2cc(C(=O)N[C@H]3CN4CCC3CC4)oc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccccc1-c1cccc2cc(C(=O)N[C@H]3C[N+]4(C)CCC3CC4)oc12
Product: [Cl-]
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
60.5 mg (1.51 mmol) of sodium hydride (60% suspension in mineral oil) are added to a solution, cooled to −20° C., of 250 mg (0.61 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-(2-methoxyphenyl)-1-benzofuran-2-carboxamide hydrochloride (Example 102) in 2.5 ml of DMF. After 30 min at room temperature and renewed cooling to −20° C., 33.9 μl (0.54 mmol) of iodomethane are added. After 18 h at room temperature, the reaction is stopped by adding water. The reaction mixture is purified by preparative HPLC. The product fractions are concentrated, codistilled with 1N hydrochloric acid, again concentrated and dried under high vacuum. 206 mg (79.7% of theory) of the title compound are obtained.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[C:17](=[S:21])[S:18][S:19][CH:20]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[S-:22][S-].[Na+].[Na+].O>CN(C)C=O>[SH:22][C:20]1[S:19][S:18][C:17](=[S:21])[C:16]=1[C:7]1[CH:6]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[C:10]([OH:11])=[C:9]([C:12]([CH3:14])([CH3:15])[CH3:13])[CH:8]=1
Reactant: [S-][S-]
Reactant: CC(C)(C)c1cc(-c2cssc2=S)cc(C(C)(C)C)c1O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1cc(-c2c(S)ssc2=S)cc(C(C)(C)C)c1O
Temperature: 100 °C

Procedure:
33.8 parts of 4-(3,5-di-t-butyl-4-hydroxyphenyl)-1,2-dithiole-3-thione and 40 parts of a 2.5 molar solution of sodium disulphide were dissolved in 40 parts of dimethylformamide and warmed at 100°C for 15 minutes. 500 parts of water were then added, the mixture extracted several times with ether to remove any starting material, and then 60 parts of 3N hydrochloric acid solution were added slowly with stirring. The solid was filtered giving 27 parts of 5-mercapto-4-(3,5-di-t-butyl-4-hydroxyphenyl)-1,2-dithiole-3-thione m.p. 182°C which gave the following elemental analysis:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.CO[CH:13](OC)[N:14](C)C>>[O:10]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=2)=[CH:9][CH:13]=[N:14]1
Reactant: CC(=O)c1ccc(O)cc1
Reactant: COC(OC)N(C)C
Product: Oc1ccc(-c2ccno2)cc1

Procedure:
1-(4-hydroxyphenyl)ethanone (5 g, 36.7 mmol) was heated in dimethylformamide dimethyl acetal (6.56 g, 55 mmol) at 100° C. overnight. The solution turned dark red. Volatile solvent was removed under high vacuum. The crude 3-(dimethylamino)-1-(4-hydroxyphenyl)prop-2-en-1-one was dissolved in ethanol, followed by addition of hydroxylamine hydrochloride salt. The mixture was heated under reflux for 3 hours. The solvent was removed under vacuum. The residue was purified twice by column chromatography through 120 g biotage silica gel cartridges eluting with 10-40% EtOAc/hexanes (gradient) and 20% ethyl acetate/hexanes (isocratic) to give the product as white solid. LRMS calc: 161.1; obs: 162.2 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH:10]([CH3:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][N:21]=[CH:20]2.C(O)(=O)C.C(=O)([O-])O.[Na+]>CO.C(O)(=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:16][C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][N:21]=[CH:20]3)[CH:10]([CH3:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1CN(Cc2ccccc2)CCC1=O
Reactant: Nc1ccc2[nH]ncc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC1CN(Cc2ccccc2)CCC1Nc1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 39.6 %

Procedure:
1-Benzyl-3-methyl-4-piperidone (152.7 mg), 5-aminoindazole (100 mg), and acetic acid (0.02 ml) were dissolved in methanol (10 ml). Acetic acid (five drops) was added to the solution, and a borane-pyridine complex (0.06 ml) was then added dropwise to the solution at room temperature. The reaction mixture was stirred at room temperature for 18 hr. After the completion of the reaction, a saturated aqueous sodium hydrogencarbonate solution (1 ml) was added thereto, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated brine and was dried over sodium sulfate. The solvent was then removed by distillation under the reduced pressure. The residue was purified by column chromatography [silica gel, chloroform/methanol] to give the title compound (95.3 mg, yield 65%).
Reaction SMILES: CI.[C:3](=O)([O-])[O-].[K+].[K+].[NH2:9][C:10]1[C:15]([OH:16])=[CH:14][CH:13]=[CH:12][C:11]=1[C:17](=[O:19])[CH3:18]>CN(C=O)C>[NH2:9][C:10]1[C:15]([O:16][CH3:3])=[CH:14][CH:13]=[CH:12][C:11]=1[C:17](=[O:19])[CH3:18]
Reactant: CC(=O)c1cccc(O)c1N
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cccc(C(C)=O)c1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.9 %

Procedure:
Under an atmosphere of nitrogen, methyl iodide (1.35 g, 10 mmol) and potassium carbonate (4.39 g, 320 mmol) were added to a solution of 2′-amino-3′-hydroxyacetophenone (960 mg, 6 mmol, TCI Europe) in DMF (6 ml). The reaction mixture was stirred for 1 h at r.t., during which time the color of the mixture changed from light brown to dark green. The mixture was then worked up by extraction with H2O/ethyl acetate, drying of the organic phase (Na2SO4), and evaporation of solvent. The title compound (960 mg, 92%) was isolated from the residue by column chromatography (silica gel, heptan/ethyl acetate=100/0-70/30).
Reaction SMILES: C(O)(=O)C.[F:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:16][CH2:15][O:14][C:13]2=[O:17])=[CH:8][CH:7]=1.[NH2:18][NH2:19].N>CO.C(OCC)(=O)C>[F:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH2:16][CH2:15][OH:14])[C:13]([NH:18][NH2:19])=[O:17])=[CH:8][CH:7]=1
Reactant: NN
Reactant: O=C1OCCC1c1ccc(F)cc1
Agent: N
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CC(=O)O
Product: NNC(=O)C(CCO)c1ccc(F)cc1
Temperature: 25 °C
Yield: 31.8 %

Procedure:
Acetic acid (1 mL) was added to a solution of 3-(4-fluorophenyl)dihydrofuran-2-one (393 mg) and hydrazine (699 mg) in methanol (10 mL), and the reaction solution was heated to reflux for two hours. The reaction solution was left to cool to room temperature. Then, ethyl acetate and concentrated aqueous ammonia were added to the reaction solution, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. Chloroforum was added to the residue, and the precipitated solid was collected by filtration to obtain 147 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([CH3:18])=[CH:15][CH:16]=3)[N:11]=[C:10]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[OH:25])[N:9]=2)[CH2:4]1.CN(C=O)C.C(N(CC)CC)C.Cl[C:39]([O:41][CH2:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:40]>C(Cl)Cl>[OH:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:10]1[N:9]=[C:8]([N:5]2[CH2:6][CH2:7][C@@H:3]([CH2:2][NH:1][C:39](=[O:40])[O:41][CH2:42][C:43]([CH3:46])([CH3:45])[CH3:44])[CH2:4]2)[C:17]2[C:12](=[CH:13][C:14]([CH3:18])=[CH:15][CH:16]=2)[N:11]=1
Reactant: Cc1ccc2c(N3CC[C@@H](CN)C3)nc(-c3ccccc3O)nc2c1
Reactant: CC(C)(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc2c(N3CC[C@@H](CNC(=O)OCC(C)(C)C)C3)nc(-c3ccccc3O)nc2c1
Temperature: 25 °C
Yield: 82.5 %

Procedure:
A mixture of 2-(4-((S)-3-(aminomethyl)pyrrolidin-1-yl)-7-methylquinazolin-2-yl)phenol (200 mg, 0.6 mmol), DMF (6.0 mL), and DMF (1 mL) was stirred under an N2 atmosphere. Triethylamine (0.166 mL, 1.2 mmol) was added, and the reaction was cooled in an ice bath. To this was added 1 M neopentyl chloroformate solution (89 μL in 600 μL THF, 0.6 mmol). After allowing the reaction mixture to warm to room temperature over a period of 30 minutes, CH2Cl2 was added to the reaction mixture, and it was washed once with water before it was dried over Na2SO4, filtered, and concentrated. Purification via silica gel chromatography using 0-20% EtOAc in CH2Cl2/hexanes (1:1) gave neopentyl ((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)methylcarbamate (222 mg, 94%). LC/MS: m/z 449 (M+H)+ at 2.73 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). 1H NMR (400 MHz, acetic acid-d4) δ 8.42 (dd, J=8.1, 1.8 Hz, 1H), 8.20 (d, J=8.7 Hz, 1H), 7.57 (s, 1H), 7.40-7.29 (m, 3H), 6.92-6.89 (m, 2H), 4.11-3.92 (m, 3H), 3.78-3.61 (m, 3H), 3.33-3.28 (m, 1H), 3.23-3.10 (m, 2H), 2.49 (s, 3H), 2.16-2.08 (m, 1H), 1.83-1.75 (m, 1H), 0.89 (s, 9H) ppm.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2.[Li][C:11](C)([CH3:13])[CH3:12].IC(C)C>C1COCC1>[CH:11]([C:5]1[S:1][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=1)([CH3:13])[CH3:12]
Reactant: [Li]C(C)(C)C
Reactant: c1ccc2sccc2c1
Solvent: CC(C)I
Solvent: C1CCOC1
Product: CC(C)c1cc2ccccc2s1
Temperature: 25 °C
Reaction time: 24 h
Yield: 85 %

Procedure:
2-i-Propylbenzo[b]thiophene was prepared by the method of Example 40A with benzo[b]thiophene (7.5 mmoles, 1.0 g), t-BuLi (1.7 M, 11.2 mmoles, 6.6 ml), 2-iodopropane (11.2 mmoles, 1.12 ml) and THF (20 ml) with stirring at ambient temperature for 24 hrs. It was isolated as a yellow oil (1.11 g; 85% yield).
Reaction SMILES: CC1C=CC(C)N1C(C1C=[CH:12][C:13]([N:16]2[CH2:21][CH2:20][CH:19]([NH:22][C:23](=[O:37])[C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=4)=[N:26][CH:25]=3)[CH2:18][CH2:17]2)=[N:14]C=1)=O.[N:38]1[CH:43]=[CH:42]C=C(N2CCC(N)CC2)N=1>>[F:36][C:32]1[CH:31]=[C:30]([C:27]2[CH:28]=[CH:29][C:24]([C:23]([NH:22][CH:19]3[CH2:18][CH2:17][N:16]([C:13]4[N:14]=[N:38][CH:43]=[CH:42][CH:12]=4)[CH2:21][CH2:20]3)=[O:37])=[CH:25][N:26]=2)[CH:35]=[CH:34][CH:33]=1
Reactant: NC1CCN(c2cccnn2)CC1
Reactant: CC1C=CC(C)N1C(=O)c1ccc(N2CCC(NC(=O)c3ccc(-c4cccc(F)c4)nc3)CC2)nc1
Product: O=C(NC1CCN(c2cccnn2)CC1)c1ccc(-c2cccc(F)c2)nc1

Procedure:
6-(3-fluorophenyl)-N-(1-pyridazin-3-ylpiperidin-4-yl)nicotinamide was prepared analogous to N-(1-{5-[(2,5-dimethyl-2,5-dihydro-1H-pyrrol-1-yl)carbonyl]pyridin-2-yl}piperidin-4-yl)-6-(3-fluorophenyl)nicotinamide, except 1-(pyridazin-3-yl)piperidin-4-amine was used as R—NH2. M+H=378.3 observed, 378.17 expected.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl[C:11]1[CH:12]=[CH:13][C:14]2[N:15]([C:17]([C:20]([F:23])([F:22])[F:21])=[N:18][N:19]=2)[N:16]=1.[C:24]([N:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][CH2:35][O:36][C:37]2[CH:42]=[CH:41][C:40]([CH:43]3[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]3)=[CH:39][CH:38]=2)[CH2:29][CH2:28]1)(=[O:26])[CH3:25]>CN(C=O)C>[C:24]([N:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][CH2:35][O:36][C:37]2[CH:38]=[CH:39][C:40]([CH:43]3[CH2:48][CH2:47][N:46]([C:11]4[CH:12]=[CH:13][C:14]5[N:15]([C:17]([C:20]([F:23])([F:22])[F:21])=[N:18][N:19]=5)[N:16]=4)[CH2:45][CH2:44]3)=[CH:41][CH:42]=2)[CH2:29][CH2:28]1)(=[O:26])[CH3:25]
Reactant: CC(=O)N1CCN(CCCOc2ccc(C3CCNCC3)cc2)CC1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(CCCOc2ccc(C3CCN(c4ccc5nnc(C(F)(F)F)n5n4)CC3)cc2)CC1
Temperature: 80 °C
Reaction time: 1 h
Yield: 95.4 %

Procedure:
DIPEA (5.21 mL, 29.93 mmol) was added to 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (obtained as described in Monatsh. Chem. 1972, 103, 1591) (6.06 g, 27.21 mmol) and 4-[4-[3-(4-acetylpiperazin-1-yl)propoxy]phenyl]piperidine (9.40 g, 27.21 mmol) in DMF (200 mL). The resulting solution was stirred at 80° C. for 1 hour. The reaction mixture was cooled to room temperature then evaporated to dryness. Water (600 mL) was then added and the mixture extracted with DCM (2×600 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM. Pure fractions were evaporated to dryness to afford 6-[4-[4-[3-(4-acetylpiperazin-1-yl)propoxy]phenyl]piperidin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (13.80 g, 95%) as an orange solid.
Reaction SMILES: C(O[C:5]1[C:6](=[O:20])[C:7](=[O:19])[C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)(C)C.[NH2:21][CH:22]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH3:23]>>[F:18][C:15]([F:16])([F:17])[C:12]1[CH:11]=[CH:10][C:9]([C:8]2[C:7](=[O:19])[C:6](=[O:20])[C:5]=2[NH:21][CH:22]([CH3:23])[C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:14][CH:13]=1
Reactant: CC(N)C(C)(C)C
Reactant: CC(C)Oc1c(-c2ccc(C(F)(F)F)cc2)c(=O)c1=O
Product: CC(Nc1c(-c2ccc(C(F)(F)F)cc2)c(=O)c1=O)C(C)(C)C

Procedure:
In a manner similar to Example 9, Step 2, 3-isopropoxy-4-(4-trifluoromethyl-phenyl)-cyclobut-3-ene-1,2-dione (0.40 g, 1.408 mmol) and 2-amino-3,3-dimethylbutane (0.28 mL, 2.11 mmol) were converted to the title compound. Recrystallization from hot ethyl acetate afforded 0.18 g (39%) of compound as a white solid: m.p. 191-193° C.; 1H NMR (DMSO-d6) δ8.97(br d,1H), 8.22(ABq,2H), 7.88(ABq,2H), 4.30(m,1H), 1.26(d,3H), 0.92(s,9H); IR (KBr) 3450, 3180, 2970, 1775, 1740, 1600, 1420, 1370, 1170, 1110, 1060, 850 cm−1; MS (m/z) 325 [M+].
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][CH:5]1[CH2:10][CH:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][CH2:7][NH:6]1.CCN(C(C)C)C(C)C.Cl[C:29]([O:31][CH3:32])=[O:30]>C(Cl)Cl>[F:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][CH:5]1[CH2:10][CH:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][CH2:7][N:6]1[C:29]([O:31][CH3:32])=[O:30]
Reactant: COC(=O)Cl
Reactant: COC(=O)C1CCNC(Cc2ccccc2F)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1CCN(C(=O)OC)C(Cc2ccccc2F)C1
Reaction time: 1.5 h
Yield: 111.6 %

Procedure:
To a solution of methyl 2-(2-fluorobenzyl)piperidine-4-carboxylate (4.49 g, 17.85 mmol) and DIPEA (9.35 mL, 53.55 mmol) in DCM (100 mL) was added methyl chloroformate (1.798 mL, 23.21 mmol) in DCM (50 mL). The reaction mixture was stirred for 1.5 h. The organic phase was washed with satd NaHCO3. The phases were separated and the organic phase dried using a phase separator to yield crude dimethyl 2-(2-fluorobenzyl)piperidine-1,4-dicarboxylate (6.16 g, 112%). MS m/z 310 (M+H)+
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].[BH4-].[Na+].O.C(OCC)C>C(O)C.O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[CH2:14][CH2:13][C@H:12]([OH:15])[CH2:11][CH2:10]2)=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1ccc(C2CCC(=O)CC2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Solvent: O
Product: N#Cc1ccc([C@H]2CC[C@H](O)CC2)cc1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
51.0 g of 4-(p-cyanophenyl)cyclohexanone were almost completely dissolved in 1.5 l of ethanol/water (vol. 4:1) and then treated within 10 minutes with 9.68 g of sodium borohydride. The mixture was stirred for a further 30 minutes and then left to stand overnight. The reaction mixture was subsequently treated cautiously with 350 ml of dilute, ice-cold hydrochloric acid (1 part of concentrated hydrochloric acid to 4 parts of water), then treated with 2 l of water and 1 l of diethyl ether and shaken. The aqueous phase was separated and extracted four times with 0.5 l of diethyl ether each time. The combined organic phases were washed with 100 ml of saturated sodium hydrogen carbonate solution and with 100 ml of saturated sodium chloride solution, dried over sodium sulphate and concentrated. The crude product, which still contained water, was dried further by dissolution in toluene and acetone and concentration. The beige, solid residue (48.9 g) was dissolved in 300 ml of hot toluene and a fine, insoluble residue was filtered off while the mixture was hot. The filtrate was cooled to -20° C. and the crystallizate obtained was filtered off under suction, washed with 50 ml of toluene/hexane (vol. 9:1) and dried. There were thus obtained 31.72 g (61.6%) of pure, light beige trans-4-(p-cyanophenyl)cyclohexanol of m.p. 119.5°-122.4° C. A further 3.21 g (6.2%) of trans-4-(p-cyanophenyl)cyclohexanol of m.p. 116.5°-122.1° C. were obtained from the mother liquor by crystallization from 60 ml of toluene at -20° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH:15](CC2CC2)[C:16]2[S:20][C:19]([CH3:21])=[N:18][C:17]=2[CH3:22])[CH2:10][CH2:9]1)=O)(C)(C)C.[C:27]1(OC)[CH:32]=[CH:31][CH:30]=CC=1.FC(F)(F)C(O)=O>ClCCl>[CH:32]1([CH2:27][N:14]([CH2:15][C:16]2[S:20][C:19]([CH3:21])=[N:18][C:17]=2[CH3:22])[CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH2:30][CH2:31]1
Reactant: Cc1nc(C)c(C(CC2CC2)NC2CCN(C(=O)OC(C)(C)C)CC2)s1
Reactant: COc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(C)c(CN(CC2CC2)C2CCNCC2)s1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 86.4 %

Procedure:
4-{[Cyclopropylmethyl-(2,4-dimethyl-thiazol-5-ylmethyl)]-amino}-piperidine-1-carboxylic acid tert-butyl ester (1.96 g, 5.18 mmol) is added to a stirred solution of dichloromethane (5 ml) and anisole (9.0 ml, 82.8 mmol). The reaction is cooled to 0° C. Trifluoroacetic acid (6.0 ml, 72.9 mmol) is then added. The reaction is stirred for 20 minutes at 0° C. and then for 5 h at room temperature. The reaction is loaded onto a pre-washed SCX-2 (10 g) column and washed with methanol (200 ml). The product is then eluted off with 2M ammonia in methanol (100 ml) and concentrated on a rotary evaporator to yield (1.25 g, 87%) of N-(cyclopropylmethyl)-N-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]piperidin-4-amine: mass spectrum (ion spray): m/z=280.2 (M+1); 1H NMR (CDCl3): δ=3.75 (2H, s), 3.19-3.11 (2H, m), 2.81-2.73 (1H, m), 2.65-2.52 (5H, m), 2.42 (2H, d), 2.32 (3H, s), 1.76 (3H, brd), 1.50-1.38 (2H, m), 0.89-0.80 (1H, m), 0.52-0.44 (2H, m), 0.11-0.05 (2H, m).
Reaction SMILES: [CH3:1][C:2]1[CH:26]=[CH:25][C:5]2[NH:6][C:7]3[CH:24]=[CH:23][CH:22]=[CH:21][C:8]=3[N:9]=[C:10]([N:11]3[CH2:16][CH2:15][NH:14][C@@H:13]([CH2:17][CH2:18][O:19][CH3:20])[CH2:12]3)[C:4]=2[CH:3]=1.C=O.[C:29](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:1][C:2]1[CH:26]=[CH:25][C:5]2[NH:6][C:7]3[CH:24]=[CH:23][CH:22]=[CH:21][C:8]=3[N:9]=[C:10]([N:11]3[CH2:16][CH2:15][N:14]([CH3:29])[C@@H:13]([CH2:17][CH2:18][O:19][CH3:20])[CH2:12]3)[C:4]=2[CH:3]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: COCC[C@H]1CN(C2=Nc3ccccc3Nc3ccc(C)cc32)CCN1
Agent: C=O
Agent: [Na+]
Solvent: ClCCCl
Product: COCC[C@H]1CN(C2=Nc3ccccc3Nc3ccc(C)cc32)CCN1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.1 %

Procedure:
Combine (S)-2-methyl-11-[3-(2-methoxy-ethyl)-piperazin-1-yl]-5H-dibenzo[b,e][1,4]diazepine (300.0 mg, 0.86 mmol), formaldehyde (76.4 μL, 0.94 mmol, 37% in water), and 1,2-dichloroethane (28.0 ml) and stir the mixture at ambient temperature for 5 minutes and add sodium triacetoxyborohydride (272.1 mg, 1.28 mmol). After stirring for 30 minutes at ambient temperature, quench the reaction with saturated sodium bicarbonate. Remove the organic portion, extract the aqueous with dichloromethane and combine, wash (brine), dry (sodium sulfate), and reduce the extracts to residue. Purify the residue on silica gel using dichloromethane/methanol (90:10) to give 260.4 mg (89%) of a yellow foam: mp=60° C., dec; mass spectrum (ion spray): m/z=365.2 (M+1).
Reaction SMILES: [C:1]1([NH:7][C:8]([NH2:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11](Cl)(=[O:15])[C:12](Cl)=[O:13]>O1CCCC1>[C:1]1([N:7]2[C:12](=[O:13])[C:11](=[O:15])[NH:10][C:8]2=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC(=O)Nc1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: O=C1NC(=O)N(c2ccccc2)C1=O
Temperature: 50 °C
Reaction time: 1 h

Procedure:
272.3 g of N-phenylurea are dissolved in 1.5 liters of tetrahydrofuran. The solution is heated to 50°C and slowly treated with 171 ml of oxalyl chloride, in the course of which the reaction temperature should not exceed 65°C. Stirring is continued for 1 hour at room temperature and then for 4 hours under reflux. The reaction mixture is evaporated and the residue is recrystallised from isopropanol to give 1-phenyl-2,4,5-trioxo-imidazolidine (m.p. 214°-216°C).
Reaction SMILES: Br[CH:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[CH2:3]1.[CH3:15][C:16]([CH3:20])([CH3:19])[CH:17]=[O:18].[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>CN1CCCC1=O.C(Cl)Cl>[CH3:15][C:16]([CH3:20])([CH2:19][N:25]1[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]1)[C:17]([N:7]1[CH2:6][CH2:5][N:4]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[CH2:3][CH2:2]1)=[O:18]
Reactant: CN1CCNCC1
Reactant: Fc1ccc(N2CCNC(Br)C2)cc1
Reactant: CC(C)(C)C=O
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: CN1CCN(CC(C)(C)C(=O)N2CCN(c3ccc(F)cc3)CC2)CC1
Temperature: 200 °C
Reaction time: 0.33 h
Yield: 21.3 %

Procedure:
3-Bromo-1-(4-fluorophenyl)piperazine-2,2-dimethylpropan-1-one (2.00 g, 5.83 mmol) was dissolved in N-methylpyrrolidinone (10 mL). N-Methylpiperazine (1.30 mL, 11.7 mmol) was added. The reaction mixture was split into four batches and each was heated at 200° C. for 15 minutes in a Biotage Initiator microwave at high absorption. The reaction mixtures were combined and dissolved in DCM (100 mL), and washed with water (2×80 mL), dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by reverse phase column chromatography (gradient eluting with MeOH in water, with 1% formic acid in each solvent, 0-30%). The resulting residue was dissolved in DCM (100 mL) and stirred with solid Na2CO3 for 20 minutes, filtered and concentrated in vacuo, to give 1-[2,2-dimethyl-3-(4-methylpiperazin-1-yl)propanoyl]-4-(4-fluorophenyl)piperazine (451 mg, 21%) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[C:3]([NH2:17])=[N:4][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[N:6][CH:7]=1.[H-].[Na+].[CH2:20]([Si:22](Cl)([CH2:25][CH3:26])[CH2:23][CH3:24])[CH3:21].CCOCC>C1COCC1>[F:1][C:2]1[C:3]([NH:17][Si:22]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:20][CH3:21])=[N:4][C:5]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)=[N:6][CH:7]=1
Reactant: CC[Si](Cl)(CC)CC
Reactant: Nc1nc(OCc2ccc(F)cc2)ncc1F
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)Nc1nc(OCc2ccc(F)cc2)ncc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.8 %

Procedure:
To a magnetically stirred mixture of 5-fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-ylamine (0.25 g, 1.05 mmol) in dry THF (5 mL) at 0° C. was added NaH (0.042 g of 60 wt. % suspension in mineral oil, 1.05 mmol). When bubbling ceased, triethylsilyl chloride (0.158 g, 1.05 mmol) was added dropwise (neat) via syringe. After stirring overnight at ambient temperature, the reaction mixture was poured into ether and washed with a mixture of aqueous saturated sodium bicarbonate and brine solution. The organic layer was separated, dried over Na2SO4, filtered, and evaporated to give a white solid. This crude material was purified on silica by column chromatography (EtOAc/hexanes gradient) to give 0.121 g (33%) of [5-fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-yl]-triethylsilanylamine as a clear yellow oil: 1H NMR (300 MHz, CDCl3) δ 7.89 (d, J=2.5 Hz, 1H), 7.39 (m, 2H), 7.03 (t, J=8.6 Hz, 2H), 5.27 (s, 2H), 4.53 (s, 1H), 0.99 (m, 9H), 0.83 (m, 6H); HPLC-MS (ESI) m/z 352 (M+H)+.