Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:5]2[O:9][CH2:8][C:7]([CH3:11])([CH3:10])[C:6]=2[CH:12]=1.[Li]C(C)(C)C.[CH3:22][N:23]([CH3:26])[C:24]#[N:25].[ClH:27]>CCOCC.C(Cl)(Cl)Cl.CCO.CO>[ClH:27].[C:13]([C:4]1[C:5]2[O:9][CH2:8][C:7]([CH3:11])([CH3:10])[C:6]=2[CH:12]=[C:2]([C:24](=[NH:25])[N:23]([CH3:26])[CH3:22])[CH:3]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)c1cc(Br)cc2c1OCC2(C)C
Reactant: CN(C)C#N
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CN(C)C(=N)c1cc(C(C)(C)C)c2c(c1)C(C)(C)CO2
Temperature: 0 °C
Reaction time: 1 h
Yield: 19.7 %

Procedure:
To a solution of 5-bromo-7-tert-butyl-2,3-dihydro-3,3-dimethylbenzofuran (500 mg, 1.8 mmol) in Et2O (0.6 mL), and hexanes (5.5 mL) at -78° C. is added t-BuLi (1.5M in hexanes, 2.9 eq, 5.3 mmol, 3.3 mL) at such a rate that the reaction temperature does not exceed -60° C. This solution is stirred for 1 h and then slowly cannulated into a -78° C. solution of dimethylcyanamide (1.0 eq, 1.8 mmol, 0.15 mL) in Et2O (5 mL). The reaction is kept at -78° C. for 0.5 h and then is allowed to warm to 0° C. After 1.5 h, TLC (10% MeOH in CHCl3) indicates the reaction to be complete. The reaction is quenched with H2O (10 mL) and 1N HCl (10 mL) and then extracted with Et2O (2×10 mL). The aqueous layer is brought to pH 9 with 1N NaOH and extracted with Et2O (3×15 mL), which is dried (MgSO4) and evaporated to a yellow oil (410 mg). This oil is purified by preparative TLC (15% MeOH in CHCl3) to give a yellow oil, which is stirred in EtOH (5 mL) and 1N HCl (10 mL) for 5 min. The EtOH is evaporated and the resulting solution extracted with CH2Cl2 (3×10 mL). The dried organic layers are evaporated to a yellow oil, which is triturated with Et2O to give the title compound as a white powder (110 mg, 19.7%), mp>160° C. (dec).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:11]([N:18]1[CH2:23][CH2:22][N:21]([N:24]2[CH2:29][CH2:28][CH2:27][NH:26][C:25]2=[O:30])[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH3:31]I>C1COCC1>[CH2:11]([N:18]1[CH2:23][CH2:22][N:21]([N:24]2[CH2:29][CH2:28][CH2:27][N:26]([CH3:31])[C:25]2=[O:30])[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CI
Reactant: O=C1NCCCN1N1CCN(Cc2ccccc2)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCCN(N2CCN(Cc3ccccc3)CC2)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Lithium bis(trimethylsilyl)amide (1M THF solution; 1.5 mL) was added to a solution of 1-(4-benzylpiperazin-1-yl)tetrahydropyrimidin-2(1H)-one (0.27 g) obtained in Example 25a} in THF (10 mL) at 0° C., and the mixture was stirred at room temperature for one hour. Methyl iodide (0.09 mL) was added thereto, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with an aqueous sodium bicarbonate solution, and extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (0.30 g, quantitative) as a brown oil.
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C:13]#[C:12]2)=[CH:6][CH:5]=1.[Li+].[OH-]>O1CCOCC1.O>[CH:11]1([CH2:10][C:7]2[CH:6]=[CH:5][C:4]([C:3]([OH:19])=[O:2])=[CH:9][CH:8]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C:13]#[C:12]1
Reactant: COC(=O)c1ccc(CC2C#CCCCCC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1ccc(CC2C#CCCCCC2)cc1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a solution of cyclooctyne 8a (283 mg, 1.11 mmol) in dioxane (12 mL) and H2O (3 mL) was added finely crushed LiOH (530 mg, 22.1 mmol). The suspension was heated to 50° C. and stirred for 3 h. The dioxane was removed on a rotary evaporator. The residue was diluted with EtOAc (50 mL), washed with 1 N HCl (3×50 mL), H2O (3×50 mL), and brine (2×50 mL), and dried over MgSO4 to yield a white solid (254 mg, 95%, Rf=0.25 in 27:3:1 hexane/EtOAc/AcOH), mp 112.0-113.9° C. (dec). IR: 3071, 2922, 2846, 1680 cm−1. 1H NMR (CD3CN, 400 MHz): δ 1.35-1.48 (m, 2H), 1.56-1.66 (m, 1H), 1.66-1.95 (m, 4H), 2.01-2.17 (m, 3H), 2.70 (d, 1H, J=5.2 Hz), 2.71 (d, 1H, J=1.2 Hz), 2.76 (m, 1H), 7.33 (d, 2H, J=8.4 Hz), 7.91 (d, 2H, J=8.4 Hz), 9.40 (br s, 1H). 13C NMR (CD3CN, 100 MHz): δ 21.2, 29.2, 30.8, 35.6, 37.3, 40.8, 42.5, 95.7, 97.1, 128.9, 130.1, 130.5, 147.4, 167.8. EI-HRMS: Calcd. for C16H18O2M+: 242.1307. found: 242.1307. Anal. Calcd. for C16H18O2: C, 79.31; H, 7.49. Found: C, 79.07; H, 7.26.
Reaction SMILES: [CH2:1]([C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][CH3:5])[OH:2].[C:10]([O:16]C(C)(C)C)(=[O:15])[CH2:11][C:12]([CH3:14])=[O:13]>C1(C)C=CC=CC=1>[C:10]([OH:16])(=[O:15])[CH2:11][C:12]([CH3:14])=[O:13].[C:10]([OH:16])(=[O:15])[CH2:11][C:12]([CH3:14])=[O:13].[C:10]([OH:16])(=[O:15])[CH2:11][C:12]([CH3:14])=[O:13].[CH2:1]([C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][CH3:5])[OH:2]
Reactant: CC(=O)CC(=O)OC(C)(C)C
Agent: CCC(CO)(CO)CO
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)O
Temperature: 111 °C

Procedure:
A 1 liter, 4-neck round-bottom flask fitted with mechanical stirrer, pressure equalizing addition funnel (nitrogen inlet), thermocouple connected to a controller and mantle for heating, a 5-plate Oldershaw column and vacuum type distilling head with finger type condenser and stopcock to control the reflux ratio was charged with 201 g (1.50 mol) trimethylolpropane, 100 g (0.63 mol) tert.-butyl acetoacetate and 282 g of toluene. An additional 626.5 g (3.96 mol) of tert.-butyl acetoacetate was charged to the addition funnel. A slow nitrogen flow was maintained through the addition funnel and reactor and the mixture was heated to about 111° C. Reflux began when the flask contents reached about 111° C. and the reflux ratio/take-off was adjusted to keep the head temperature between 82-84° C. The additional tert.-butyl acetoacetate was gradually added over about 4 hr as 442 ml of distillate was collected. The pot temperature increased gradually to 117° C. during the addition. Distillation continued: the pot temperature gradually increased to 132° C. and the head temperature increased to 109° C. over an additional 2.3 hr. Total distillate collected was 472 g determined to be 70.59% tert.-butanol or 100.1% of theory.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[C:21]([C:25]([NH:27][C@H:28]4[C@H:32]([OH:33])[CH2:31][NH:30][CH2:29]4)=[O:26])=[C:22]([CH3:24])[NH:23][C:16]=23)[CH2:4][CH2:3]1.[CH3:34][O:35][CH2:36][C:37](Cl)=[O:38]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[C:21]([C:25]([NH:27][C@H:28]4[C@H:32]([OH:33])[CH2:31][N:30]([C:37](=[O:38])[CH2:36][O:35][CH3:34])[CH2:29]4)=[O:26])=[C:22]([CH3:24])[NH:23][C:16]=23)[CH2:4][CH2:3]1
Reactant: COCC(=O)Cl
Reactant: COc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@@H]4CNC[C@H]4O)c(C)[nH]c23)c1
Agent: Cl
Product: COCC(=O)N1C[C@@H](O)[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(OC)ccc4OCC4CC4)ccnc23)C1

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-N-[(3R*,4R*)-4-hydroxypyrrolidin-3-yl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f17) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]1([C:7]2[NH:16][C:15](=[O:17])[C:14]3[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH:19]([CH3:29])[C:20]([N:22]([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])=[O:21].CC1C(=O)NC(C2C=CC=CC=2)=NC=1C.BrCC(N(CCC)CCC)=O>>[C:1]1([C:7]2[N:16]=[C:15]([O:17][CH:19]([CH3:29])[C:20]([N:22]([CH2:23][CH2:24][CH3:25])[CH2:26][CH2:27][CH3:28])=[O:21])[C:14]3[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=3[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=c1[nH]c(-c2ccccc2)nc2c1CCCC2
Reactant: CCCN(CCC)C(=O)C(C)Br
Agent: CCCN(CCC)C(=O)CBr
Agent: Cc1nc(-c2ccccc2)[nH]c(=O)c1C
Product: CCCN(CCC)C(=O)C(C)Oc1nc(-c2ccccc2)nc2c1CCCC2

Procedure:
The same procedures as Example 136 are repeated except that 5,6,7,8-tetrahydro-2-phenyl-4-(3H)-quinazolinone and 2-bromo-N,N-dipropylpropanamide are used instead of 5,6-dimethyl-2-phenyl-4-(3H)-pyrimidinone and 2-bromo-N,N-dipropylacetamide, respectively. The product thus obtained is recrystallized from n-hexane to give the desired compound, m.p. 73-74° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:35][CH3:36])[C:4](=[O:34])[CH:5]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=1)[C:6]([NH:8][S:9]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1)(=[O:11])=[O:10])=[O:7])[CH3:2].C(N[C:40]1[CH:45]=CC=[CH:42][CH:41]=1)C>>[CH2:35]([N:3]([C:1]1[CH:42]=[CH:41][CH:40]=[CH:45][CH:2]=1)[C:4](=[O:34])[CH:5]([CH2:22][C:23]1[CH:24]=[CH:25][C:26]([O:29][C:30]([F:31])([F:32])[F:33])=[CH:27][CH:28]=1)[C:6]([NH:8][S:9]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1)(=[O:10])=[O:11])=[O:7])[CH3:36]
Reactant: CCNc1ccccc1
Reactant: CCN(CC)C(=O)C(Cc1ccc(OC(F)(F)F)cc1)C(=O)NS(=O)(=O)c1ccc2ccccc2c1
Product: CCN(C(=O)C(Cc1ccc(OC(F)(F)F)cc1)C(=O)NS(=O)(=O)c1ccc2ccccc2c1)c1ccccc1
Yield: 40.3 %

Procedure:
In the same manner as in Example 1 (4), a crude product was obtained using the compound (1.18 g) obtained in Example 117 (4) and N-ethylaniline (305 mg). This was purified by silica gel column chromatography to give the title compound (519 mg) as a white powder.
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([O:12][CH3:13])=[CH:7][CH:8]=2)[CH2:3]1.C(N(CC)CC)C.Br[CH2:22][C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:24].[ClH:31]>O1CCCC1.C(O)(C)C>[ClH:31].[CH3:13][O:12][C:6]1[CH:5]=[C:4]2[C:9]([CH2:10][CH2:11][CH:2]([NH:1][CH2:22][CH:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[OH:24])[CH2:3]2)=[CH:8][CH:7]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: COc1ccc2c(c1)CC(N)CC2
Agent: Cl
Solvent: CC(C)O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)CC(NCC(O)c1ccccc1)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 30 %

Procedure:
To a mixture of 1.77 g of 2-amino-7-methoxy-1,2,3,4-tetrahydronaphthalene and 1.1 g of triethylamine in 25 ml of tetrahydrofurane, there is added slowly 1.94 g of bromoacetophenone in 50 ml of tetrahdryofurane. The reaction mixture is left under stirring at room temperature for 2 hours, then is filtered andevaporated. The residue thus obtained is dissolved in isopropyl alcohol and acidified with a solution of hydrogen chloride in isopropyl alcohol, then it is precipitated with an etheral solution, filtered and dried. To the solution of the residue in 70 ml of methanol, cooled to 4° C., there is added slowly 1.5 g of sodium borohydride. The reaction mixture is stirred at room temperature for an hour, poured into water and acidified with acetic acid. The solution is made alkaline with sodium bicarbonate and the organic phase is extracted with methylene chloride, dried and evaporated to dryness. The oil thus obtained is purified by flash-chromatography using a mixture ethyl acetate/methanol 8/2. After recrystallization from isopropyl alcohol, the 2-[(7-methoxy-1,2,3,4-tetrahydronaphth-2-yl)amino]-1-phenylethanol hydrochloride is obtained. Yield: 30% of the theoretical value.
Reaction SMILES: [H-].[Na+].[CH:3]([S:5]([CH3:8])(=[O:7])=[O:6])=[CH2:4].[CH2:9]([O:11][CH2:12][C:13]1[N:14]([CH2:26][C:27]2([OH:33])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[C:15]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:18]=[CH:17][C:16]=2[N:25]=1)[CH3:10].O>O1CCCC1>[CH2:9]([O:11][CH2:12][C:13]1[N:14]([CH2:26][C:27]2([O:33][CH2:4][CH2:3][S:5]([CH3:8])(=[O:7])=[O:6])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[C:15]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:18]=[CH:17][C:16]=2[N:25]=1)[CH3:10]
Reactant: CCOCc1nc2cnc3ccccc3c2n1CC1(O)CCCCC1
Reactant: C=CS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOCc1nc2cnc3ccccc3c2n1CC1(OCCS(C)(=O)=O)CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.3 %

Procedure:
Sodium hydride (60% dispersion in oil, 25 mg, 0.62 mmol) followed by methyl vinyl sulfone (1.30 g, 12.4 mmol) were added to a stirred solution of 1-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclohexanol (2.1 g, 6.2 mmol) in tetrahydrofuran (25 mL). The reaction mixture was heated at reflux for 2 hours and additional methyl vinyl sulfone (1 equivalent) and sodium hydride (60% dispersion in oil, spatula tip full) were added. The mixture was allowed to stir overnight at room temperature. Water (50 mL) was added and a precipitate formed that was removed by filtration. The filtrate was extracted with dichloromethane (2×50 mL). The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford an oil that was purified by flash chromatography (silica gel, eluted with 5% methanol in dichloromethane) to provide 0.45 g of 2-(ethoxymethyl)-1-({1-[2-(methylsulfonyl)ethoxy]cyclohexyl}methyl)-1H-imidazo[4,5-c]quinoline as a colorless oil.
Reaction SMILES: [N+:1]([O-:4])([OH:3])=[O:2].[NH2:5][C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=1[CH3:15].[N:16]#[C:17][NH2:18]>C(O)C.O>[N+:1]([O-:4])([OH:3])=[O:2].[CH3:15][C:7]1[CH:8]=[CH:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][C:6]=1[NH:5][C:17]([NH2:18])=[NH:16]
Reactant: Cc1ccc([N+](=O)[O-])cc1N
Reactant: N#CN
Solvent: CCO
Solvent: O
Solvent: O=[N+]([O-])O
Product: Cc1ccc([N+](=O)[O-])cc1NC(=N)N

Procedure:
9.1 ml (0.13 mol) of 65% nitric acid are added dropwise in the course of 5 minutes to a yellow suspension of 20.0 g (0.13 mol) of 2-amino-4-nitrotoluene in 50 ml of absolute ethanol. When the exothermic reaction has subsided, 8.32 g (0.198 mol) of cyanamide dissolved in 8.3 ml of water are added. The brown reaction mixture is boiled at reflux for 25 hours, cooled to 0.degree. and filtered. Washing with 4.times. 100 mi of ethanol/diethyl ether (1:1) and drying yield 2-methyl-5-nitrophenyl-guanidine nitrate; m.p. 219° C.-226° C.
Reaction SMILES: [CH:1]1([C:7]([C:9]2[O:10][C:11]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH:21]4[CH2:25][CH2:24][CH2:23][O:22]4)=[CH:15][C:12]=3[C:13]=2[CH3:14])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+].O>CO.O1CCCC1>[CH:1]1([CH:7]([C:9]2[O:10][C:11]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH:21]4[CH2:25][CH2:24][CH2:23][O:22]4)=[CH:15][C:12]=3[C:13]=2[CH3:14])[OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1c(C(=O)C2CCCCC2)oc2ccc(OCC3CCCO3)cc12
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1c(C(O)C2CCCCC2)oc2ccc(OCC3CCCO3)cc12
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 89.9 %

Procedure:
Cyclohexyl[3-methyl-5-(tetrahydrofuran-2-ylmethoxy)-1-benzofuran-2-yl]methanone (260 mg) synthesized above was dissolved in methanol (0.5 mL)-tetrahydrofuran (2.5 mL), and sodium tetrahydroborate (90%) (64 mg) was added to the solution at 0° C. The reaction mixture was stirred at 0° C. for 2.5 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated to give the title compound (235 mg, 90%) as a colorless oil.
Reaction SMILES: [C:1]([CH2:4][N:5]1[CH2:10][CH2:9][N:8](C(OCC2C=CC=CC=2)=O)[CH2:7][CH2:6]1)(=[O:3])[CH3:2]>[Pd].C(O)C>[C:1]([CH2:4][N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)CN1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(=O)CN1CCNCC1
Reaction time: 1.5 h
Yield: 78.8 %

Procedure:
10% Palladium-on-charcoal catalyst (0.3 g) was added to a solution of benzyl 4-(acetylmethyl)-1-piperazinecarboxylate (3.7 g) in ethanol (45 ml). The reaction mixture was stirred under hydrogen at 3 atmospheres pressure for 1.5 hours. The catalyst was removed by filtration and the solvent removed from the filtrate by evaporation. The residue was purified by flash chromatography using dichloromethane/methanol saturated with ammonia (3.5 M) (97/3). Evaporation of the solvent gave 1-(acetylmethyl)piperazine (1.5 g, 80%) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([NH:9][CH3:10])=[C:4]([NH2:11])[CH:3]=1.[C:12](Cl)(=[O:15])[CH2:13][CH3:14].O>N1C=CC=CC=1>[Br:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([NH:9][CH3:10])=[C:4]([NH:11][C:12](=[O:15])[CH2:13][CH3:14])[CH:3]=1
Reactant: CNc1c(N)cc(Br)nc1Cl
Reactant: CCC(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CCC(=O)Nc1cc(Br)nc(Cl)c1NC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
6-bromo-2-chloro-N3-methylpyridine-3,4-diamine 2.59 (410 mg, 2.74 mmol) was dissolved in pyridine (10 mL). Mixture was cooled down to 0° C. and then propanoyl chloride (207 mg) was added portion wise. Mixture was stirred at 0° C. for 1 h. Reaction mixture was poured into water and extracted with ethyl acetate. Organic phase was dried over Mg2SO4, filtered, and concentrated under reduced pressure. Resulting residues were purified by silica gel chromatography (5% MeOH in DCM) to provide N-(6-bromo-2-chloro-3-(methylamino)pyridin-4-yl)propionamide (2.78). LC/MS found for C9H11BrClN3O as (M+H)+ 291.9.
Reaction SMILES: [K+].[CH3:2][O:3][C:4]([C:6]1[N:11]=[C:10]([C:12]([O-:14])=O)[CH:9]=[CH:8][CH:7]=1)=[O:5].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:37][CH2:38][C:39]1[C:44]([CH2:45][CH3:46])=[N:43][C:42]2[N:47]([CH2:50][CH3:51])[N:48]=[CH:49][C:41]=2[C:40]=1[NH:52][CH:53]1[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1>CN(C)C=O>[CH2:50]([N:47]1[C:42]2=[N:43][C:44]([CH2:45][CH3:46])=[C:39]([CH2:38][NH:37][C:12]([C:10]3[N:11]=[C:6]([C:4]([O:3][CH3:2])=[O:5])[CH:7]=[CH:8][CH:9]=3)=[O:14])[C:40]([NH:52][CH:53]3[CH2:54][CH2:55][O:56][CH2:57][CH2:58]3)=[C:41]2[CH:49]=[N:48]1)[CH3:51]
Reactant: COC(=O)c1cccc(C(=O)[O-])n1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)OC)n1

Procedure:
To a suspension of 6-[(methyloxy)carbonyl]-2-pyridinecarboxylate potassium salt (39.5 g, 180 mmol) in a 500 mL 3-neck flask was added N,N-dimethylformamide (DMF) (1,700 mL) followed by TBTU (60.4 g, 188 mmol) [still a suspension]. After 2 min the 5-(aminomethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine (55.6 g, 164 mmol) was added as a solid and after 15 min nearly all the material had gone into solution. After 2.5 h the slightly cloudy mixture was evaporated off to remove as much DMF as possible using high vacuum and this gave a beige oily solid which was partitioned between saturated sodium bicarbonate and ethyl acetate. Solid started to come out of solution from the organics so they it was filtered off dried under high vacuum. This gave 29.56 g (39%) of the above named compound as a white solid. Lab HPLC of this material showed 95.8% of desired product (ret time 1.87 min) contaminated with 3.4% of HOBt. (ret time 1.16 min). LC-MS m/z 467 (M+H)+, 0.78 min (ret time).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:20][C:21]([NH:23][N:24]([C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=2)[C:25]2[C:30]([N:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:37])=[O:22])=[CH:4][C:5]([O:18][CH3:19])=[C:6]([CH:17]=1)[C:7]([O:9]N1C(=O)CCC1=O)=O.[CH3:46][N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1>ClCCl>[CH3:45][O:44][C:41]1[CH:42]=[CH:43][C:38]([N:24]([C:25]2[C:30]([N:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:37])[NH:23][C:21](=[O:22])[CH2:20][C:3]2[CH:4]=[C:5]([O:18][CH3:19])[C:6]([C:7]([N:50]3[CH2:51][CH2:52][N:47]([CH3:46])[CH2:48][CH2:49]3)=[O:9])=[CH:17][C:2]=2[Br:1])=[CH:39][CH:40]=1
Reactant: CN1CCNCC1
Reactant: COc1ccc(N(NC(=O)Cc2cc(OC)c(C(=O)ON3C(=O)CCC3=O)cc2Br)c2c(C)cccc2N2CCCCC2)cc1
Solvent: ClCCl
Product: COc1ccc(N(NC(=O)Cc2cc(OC)c(C(=O)N3CCN(C)CC3)cc2Br)c2c(C)cccc2N2CCCCC2)cc1
Reaction time: 2 h
Yield: 54 %

Procedure:
To 92 mg of a solution of the compound obtained in stage 8 of Example 1 in 450 μL of dichloromethane, are added at room temperature 82 μL of N-methylpiperazine (5 equivalents). The reaction medium is stirred for 2 hours before being dry evaporated. The obtained white solid is taken up in 10 mL of ethyl acetate. The resulting organic phase is washed several times in water and then with a saturated NaCl solution, dried on sodium sulphate, dry evaporated. The raw product is chromatographed on silica gel (dichloromethane/methanol:98/2) in order to provide 53 mg of the expected compound as a white solid.
Reaction SMILES: [C:1]([C:5]1[C:10]([Cl:11])=[CH:9][C:8]([C:12]2[N:13]([C:31](Cl)=[O:32])[C@H:14]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[C@H:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[N:16]=2)=[C:7]([O:34][CH2:35][CH3:36])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:37]1[CH2:42][CH2:41][NH:40][CH2:39][C:38]1=[O:43]>>[C:1]([C:5]1[C:10]([Cl:11])=[CH:9][C:8]([C:12]2[N:13]([C:31]([N:40]3[CH2:41][CH2:42][NH:37][C:38](=[O:43])[CH2:39]3)=[O:32])[C@H:14]([C:24]3[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=3)[C@H:15]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)[N:16]=2)=[C:7]([O:34][CH2:35][CH3:36])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CNCCN1
Reactant: CCOc1cc(C(C)(C)C)c(Cl)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C)c(Cl)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCNC(=O)C1

Procedure:
4-[(4S,5R)-2-(4-tert-Butyl-5-chloro-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-2-one was prepared from (4S,5R)-2-(4-tert-butyl-5-chloro-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 12h) and 2-piperazinone (Avocado Organics) in an analogous manner as described in example 25. LR-MS: 629.3 [(M+H)+]
Reaction SMILES: [CH2:1]1[CH2:34][O:33][C:3]2([CH2:24][CH2:23][C@@:22]3([CH3:25])[C:5](=[CH:6][C:7](=[O:30])[C@@H:8]4[C@@H:21]3[CH2:20][CH2:19][C@@:13]3([C:14]([CH3:18])([CH3:17])[O:15][SiH3:16])[C@H:9]4[CH2:10][CH2:11][C@@H:12]3[C:26]([CH3:29])([CH3:28])[CH3:27])[C:4]2([CH3:32])[CH3:31])[O:2]1>O1CCOCC1.[Pd]>[CH2:34]1[CH2:1][O:2][C:3]2([CH2:24][CH2:23][C@@:22]3([CH3:25])[CH:5]([CH2:6][C:7](=[O:30])[C@@H:8]4[C@@H:21]3[CH2:20][CH2:19][C@@:13]3([C:14]([CH3:17])([CH3:18])[O:15][SiH3:16])[C@H:9]4[CH2:10][CH2:11][C@@H:12]3[C:26]([CH3:29])([CH3:28])[CH3:27])[C:4]2([CH3:32])[CH3:31])[O:33]1
Reactant: CC(C)(C)[C@H]1CC[C@H]2[C@@H]3C(=O)C=C4C(C)(C)C5(CC[C@]4(C)[C@H]3CC[C@]12C(C)(C)O[SiH3])OCCO5
Agent: [Pd]
Solvent: C1COCCO1
Product: CC(C)(C)[C@H]1CC[C@H]2[C@@H]3C(=O)CC4C(C)(C)C5(CC[C@]4(C)[C@H]3CC[C@]12C(C)(C)O[SiH3])OCCO5
Reaction time: 72 h
Yield: 62.3 %

Procedure:
To a solution of 3,3-(ethylenedioxy)-4,4-dimethyl-17β-tert-butyldimethyl-silyloxyandrost-5-en-7-one (3.9 g) in dioxane (270 ml), Pd/C 10% (390 mg) was added, and then the mixture was hydrogenated at RT for 72 h. The catalyst was filtered off, washed with EtOAc and the organic phase evaporated under reduced pressure. The crude reaction mixture was purified by flash chromatography (SiO2, n-hexane/EtOAc/toluene 90/5/5) to give 3,3-(ethylenedioxy)-4,4-dimethyl-17β-tert-butyldimethyl-silyloxyandrostan-7-one (2.44 g, 63% yield).