Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17](=[O:21])(=[O:20])[NH:18][CH3:19])=[CH:13][C:12]=2[CH3:22])=[O:9])[CH:3]=1.C(NC(C)C)(C)C.[CH:30]1([CH2:33][NH:34][CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)[CH2:32][CH2:31]1>C(O)C>[CH:35]1([N:34]([CH2:33][CH:30]2[CH2:31][CH2:32]2)[C:2]2[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([S:17]([NH:18][CH3:19])(=[O:21])=[O:20])=[CH:13][C:12]=3[CH3:22])=[O:9])[CH:3]=2)[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]1
Reactant: C1CCC(NCC2CC2)CC1
Reactant: CNS(=O)(=O)c1ccc(NC(=O)c2cc(Cl)ncn2)c(C)c1
Solvent: CCO
Solvent: CC(C)NC(C)C
Product: CNS(=O)(=O)c1ccc(NC(=O)c2cc(N(CC3CC3)C3CCCCC3)ncn2)c(C)c1
Temperature: 160 °C
Yield: 69.7 %

Procedure:
A solution of 6-chloro-N-(2-methyl-4-(N-methylsulfamoyl)phenyl)pyrimidine-4-carboxamide (Intermediate 37, 80 mg; 0.235 mmol) and diisopropylamine (82 mL; 0.47 mmol) in ethanol (2.5 ml) was treated with N-(cyclopropylmethyl)cyclohexanamine (49.1 mg; 0.29 mmol). The mixture was heated to 160° C. in a microwave for 1 hour and then filtered. The solid was washed with a 1:1 mixture of water:ethanol and allowed to dry to give the title compound as a white solid (75 mg, 70%).
Reaction SMILES: Br[C:2]1[C:3]([F:17])=[C:4]2[O:8][C:7]([CH:9]3[CH2:11][CH2:10]3)=[N:6][C:5]2=[C:12]([C:15]#[N:16])[C:13]=1[CH3:14].C([Sn](CCCC)(CCCC)[C:23]1[CH:28]=[N:27][CH:26]=[CH:25][N:24]=1)CCC>C1(C)C=CC=CC=1.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.C(C1(C)C(O)=C(C(C)(C)C)C=CC1)(C)(C)C>[CH:9]1([C:7]2[O:8][C:4]3[C:5](=[C:12]([C:15]#[N:16])[C:13]([CH3:14])=[C:2]([C:23]4[CH:28]=[N:27][CH:26]=[CH:25][N:24]=4)[C:3]=3[F:17])[N:6]=2)[CH2:11][CH2:10]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Reactant: Cc1c(Br)c(F)c2oc(C3CC3)nc2c1C#N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)C1=C(O)C(C)(C(C)(C)C)CC=C1
Solvent: Cc1ccccc1
Product: Cc1c(-c2cnccn2)c(F)c2oc(C3CC3)nc2c1C#N
Yield: 79 %

Procedure:
6-Bromo-2-cyclopropyl-7-fluoro-5-methyl-1,3-benzoxazole-4-carbonitrile (I-77) (200 mg, 0.68 mmol) was dissolved in toluene (4 ml), then 2-tributylstannylpyrazine (300 mg, 0.81 mmol) and 2,6-di-tert-butylcresol (2 mg) and bis(triphenylphosphine)palladium(II) dichloride (24 mg, 0.03 mmol) were added, followed by heating under reflux for 15 hours under nitrogen atmosphere. The reaction liquid was cooled, the insoluble matter was separated by filtration through Celite, the solvent was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography, followed by removing tin-derived side products with n-hexane and by elution with a mixed solvent of n-hexane/ethyl acetate (3:1, v/v) to obtain 2-cyclopropyl-7-fluoro-5-methyl-6-(pyrazin-2-yl)-1,3-benzoxazole-4-carbonitrile (158 mg, 79%) as a yellow white solid. This was dissolved in dimethyl sulfoxide (3.2 ml), triethylamine (189 μl, 1.34 mmol) and (3S)-3-(dimethylamino)pyrrolidine (102 μl, 0.81 mmol) were added, followed by stirring at 90° C. under nitrogen atmosphere for 14 hours. After cooling to room temperature, ethyl acetate was added, followed by fractionation with water. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated away, the resulting residue was subjected to silica gel column chromatography and eluted with a mixed solvent of chloroform/methanol (20:1, v/v) to obtain the entitled compound (121 mg, 58%) as a pale brown solid.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][C:8]([CH3:20])([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:9](O)=[O:10]>CCOCC>[CH3:7][C:8]([CH3:20])([CH2:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH2:9][OH:10]
Reactant: CC(C)(CCc1ccccc1)C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(C)(CO)CCc1ccccc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 94.1 %

Procedure:
At 0° C., under nitrogen atmosphere, to a stirring mixture of LiAlH4 (0.49 g, 12.8 mmol) in dry Et2O (25 mL), 2,2-dimethyl-4-phenyl-butanoic acid (0.62 g, 3.22 mmol) dissolved in Et2O (10 mL) was added dropwise. The mixture was left at rt for 4 h, then quenched at 0° C. by slowly adding H2O (0.5 mL) followed by 3M KOH solution (0.5 mL) and H2O (1.64 mL). The mixture was stirred for 1 h at 0° C., then the crude was filtered and the organic phase dried over Na2SO4. The organic solution was concentrated to dryness affording the title compound (0.540 g, 94%) as pale yellow transparent oil. 1H NMR (CDCl3): δ 0.96 (s, 6H), 1.55-1.64 (m, 2H), 2.58-2.65 (m, 2H) 3.41 (s, 2H), 7.17-7.33 (m, 5H).
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[C:11]([C:22]2[CH:27]=[C:26]([F:28])[C:25]([Cl:29])=[CH:24][C:23]=2[F:30])([C:20]#[N:21])[CH:10]([CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])[NH:9]1)=[O:7])(C)(C)C.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>ClCCl>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[Cl:29][C:25]1[C:26]([F:28])=[CH:27][C:22]([C:11]2([C:20]#[N:21])[CH:10]([CH2:31][C:32]([CH3:34])([CH3:35])[CH3:33])[NH:9][CH:8]([C:6]([OH:7])=[O:5])[CH:12]2[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)=[C:23]([F:30])[CH:24]=1
Reactant: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2)C1(C#N)c1cc(F)c(Cl)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1cc(F)c(Cl)cc1F

Procedure:
In a manner similar to the method described in Example 25a, rac-(2R,3R,4R,5S)-4-(4-chloro-2,5-difluoro-phenyl)-3-(3-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 109b (1.5 g, 2.8 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3R,4R,5S)-4-(4-chloro-2,5-difluoro-phenyl)-3-(3-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a off white solid (1.5 g, 91%).
Reaction SMILES: [F:1][CH:2]([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][C:12]2[CH:13]=[C:14]([CH:18]3[CH2:21][C:20](=[O:22])[CH2:19]3)[CH:15]=[CH:16][CH:17]=2)=[CH:6][CH:5]=1.[BH4-].[Na+].O>CO>[F:1][CH:2]([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][C:12]2[CH:13]=[C:14]([CH:18]3[CH2:21][CH:20]([OH:22])[CH2:19]3)[CH:15]=[CH:16][CH:17]=2)=[CH:6][CH:5]=1
Reactant: O=C1CC(c2cccc(C#Cc3ccc(OC(F)F)cc3)c2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OC1CC(c2cccc(C#Cc3ccc(OC(F)F)cc3)c2)C1
Reaction time: 0.33 h

Procedure:
3-[3-(4-Difluoromethoxy-phenylethynyl)-phenyl]-cyclobutanone (0.834 g, 2.67 mmol) was dissolved in methanol (100 ml) and chilled in an ice bath. After 20 minutes sodium borohydride (0.159 gm, 4.02 mmol) was added and stirring was continued for another 20 minutes. Water (2 ml) was added and stirring was continued for another 20 minutes The reaction was concentrated by rotary evaporation and partitioned between water and dichloromethane. The organic layer was dried with magnesium sulfate and concentrated to an oil 845 mg (quant); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.65-1.92 (m, 2H) 2.47-2.64 (m, 2H) 2.68-2.91 (m, 1H) 3.87-4.09 (m, 1H) 5.03 (d, J=7.4 Hz, 1H) 7.03 (d, J=2.6 Hz, 1H) 7.18 (d, J=8.8 Hz, 2H) 7.21-7.25 (m, 1H) 7.27-7.32 (m, 2H) 7.38 (s, 1H) 7.58 (d, J=8.8 Hz, 2H).
Reaction SMILES: C(OC([N:11]1[CH2:22][CH2:21][CH2:20][C@H:12]1[C:13]([NH:15][CH2:16][C:17]([NH2:19])=[O:18])=[O:14])=O)C1C=CC=CC=1.[H][H]>[Pd].CO>[NH:11]1[CH2:22][CH2:21][CH2:20][C@H:12]1[C:13]([NH:15][CH2:16][C:17]([NH2:19])=[O:18])=[O:14]
Reactant: NC(=O)CNC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: NC(=O)CNC(=O)[C@@H]1CCCN1

Procedure:
A mixture consisting of 33.5 g. of N-benzyloxycarbonyl-L-prolylglycinamide (this compound has been reported in Synthetic Peptides, Vol. 1, G. R. Pettit, Van Nostrand Reinhold Company, New York, 1970, page 151), 1 g. of 20% palladium-on-carbon, and 500 ml. of methanol is hydrogenated at 50 lbs./in.2 hydrogen pressure and room temperature for one hour. The mixture is filtered to remove the catalyst, and the filtrate is evaporated to dryness to give a solid residue of L-prolylglycinamide; m.p. 124°-127° C., following crystallization from acetonitrile-toluene; [α]D25 -48.5° (2% in water).
Reaction SMILES: [CH:1]12[CH2:8][CH:5]([NH:6][NH:7]1)[CH:4]([OH:9])[CH2:3][CH:2]2[OH:10].O>C(O)C.[Ni]>[CH2:8]1[C@H:5]([NH2:6])[C@@H:4]([OH:9])[CH2:3][C@@H:2]([OH:10])[C@@H:1]1[NH2:7]
Reactant: OC1CC(O)C2CC1NN2
Agent: [Ni]
Solvent: CCO
Solvent: O
Product: N[C@@H]1C[C@H](N)[C@@H](O)C[C@H]1O
Reaction time: 15 h
Yield: 88.8 %

Procedure:
6,7-Diaza-bicyclo[3.2.1]octane-2,4-diol (0.20 g) was dissolved in 20 ml. of a mixture of water and ethanol (1:1 by volume) to which was then added 0.2 g of Ranney nickel. The admixture was shaken for 15 hours under an atmosphere of hydrogen at a pressure of 3.4 kg/cm2 for the hydrogenation. The reaction mixture was filtered to remove the catalyst, and the filtrate was concentrated under reduced pressure, giving a crystalline residue. This solid was dispersed in ethanol, removed by filtraton and then dried to afford 0.18 g of 2,5-dideoxystreptamine. Yield 91%. mp. 198°C. This substance was taken up into water, and to the resulting aqueous solution was added a slight excess of 1N hydrochloric acid. The mixture was concentrated by evaporation of the solvent, giving colorless platelets. Recrystallization of this product from water-ethanol gave 2,5-dideoxystreptamine dihydrochloride as colorless platelets of mp. 290°-295°C.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C:5](=[O:7])[N:4]([CH2:8][C:9]([OH:11])=[O:10])[C:3]1=[O:12].[C:13]([C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1)#[N:14].C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>C(O)(=O)C>[C:13]([C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[C:6]2[N:2]([CH3:1])[C:3](=[O:12])[N:4]([CH2:8][C:9]([OH:11])=[O:10])[C:5]2=[O:7])=[CH:17][CH:16]=1)#[N:14]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: CN1CC(=O)N(CC(=O)O)C1=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CN1C(=O)N(CC(=O)O)C(=O)C1=Cc1ccc(C#N)cc1

Procedure:
2.6 g (15 mmol) of (1-methyl-2,4-dioxoimidazolidin-3-yl)-acetic acid, 2.9 g (22 mmol) of 4-cyanobenzaldehyde, 1.8 g (22 mmol) of sodium acetate and 2.1 ml (22 mmol) of acetic anhydride are heated under reflux in 25 ml of acetic acid for 6 hours. After cooling, the mixture is poured onto ice and extracted with ethyl acetate. The ethyl acetate phase is extracted with sodium bicarbonate solution and the aqueous phase is acidified. The product which has precipitated is filtered off with suction and dried.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[O:18][C:19]([C:22]3[CH:23]=[C:24]4[C:29](=[CH:30][CH:31]=3)[CH:28]=[C:27]([OH:32])[CH:26]=[CH:25]4)=[CH:20][N:21]=2)=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:34][C:35]#[N:36].C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[O:18][C:19]([C:22]3[CH:23]=[C:24]4[C:29](=[CH:30][CH:31]=3)[CH:28]=[C:27]([O:32][CH2:34][C:35]#[N:36])[CH:26]=[CH:25]4)=[CH:20][N:21]=2)=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc2cc(-c3cnc(-c4cn(Cc5ccccc5)c5ccccc45)o3)ccc2c1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: N#CCOc1ccc2cc(-c3cnc(-c4cn(Cc5ccccc5)c5ccccc45)o3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.8 %

Procedure:
A mixture of 6-[2-(1-benzyl-1H-indol-3-yl)-1,3-oxazol-5-yl]-2-naphthol (137 mg, 0.329 mmol), prepared in step 4 of Example 5, bromoacetonitrile (28 μL, 0.402 mmol) and cesium carbonate (213 mg, 0.402 mmol) in 20 mL of acetone was stirred under nitrogen at room temperature for 20 h (overnight). The acetone was removed under reduced pressure and the residue partitioned between methylene chloride and water. The organic layer was separated and the aqueous layer extracted two times with methylene chloride. The combined extracts were dried (MgSO4), filtered and the solvent removed under reduced pressure to give ({6-[2-(1-benzyl-1H-indol-3-yl)-1,3-oxazol-5-yl]-2-naphthyl}oxy)acetonitrile (142 mg, 95%) as a tan solid, mp 205-208° C. Elemental Analysis for C30H21N3O2+0.38 mole of CH2Cl2 Calc'd: C, 74.86; H, 4.50; N, 8.62. Found: C, 73.58; H, 4.74; N, 8.32.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]1[CH2:16][CH2:15][CH:14]([NH2:22])[CH2:13][C:12]2=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].[C:31]1([CH2:37][CH2:38]Br)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(#N)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]1[CH2:16][CH2:15][CH:14]([NH:22][CH2:38][CH2:37][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:13][C:12]2=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC1CCc2[nH]c3ccc(OCc4ccccc4)cc3c2C1
Reactant: BrCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: c1ccc(CCNC2CCc3[nH]c4ccc(OCc5ccccc5)cc4c3C2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 79.1 %

Procedure:
To a solution of 0.32 gm (1.1 mMol) 6-benzyloxy-3-amino-1,2,3,4-tetrahydro-9H-carbazole in 8 mL acetonitrile were added 0.30 gm (1.68 mMol) potassium carbonate, 0.25 gm (1.68 mMol) sodium iodide and 0.23 mL (1.68 mMol) 2-phenyl-1-ethyl bromide. The resulting mixture was stirred 4 hours at room temperature followed by 5 hours at reflux. The reaction mixture was cooled to room temperature and then partitioned between dichloromethane and water. The aqueous phase was extracted well with dichloromethane. All of the organic phases were combined, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with 7% methanol in dichloromethane. Fractions shown to contain product were concentrated under reduced pressure to give 0.345 gm (79%) of the desired compound. A portion was converted to the corresponding hydrochloride salt, m.p.=242-244° C. (ethanol/diethyl ether).
Reaction SMILES: C(O)(=[O:3])C.S(=O)(=O)(O)O.O.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([CH3:29])[C:19]([NH:21][C:22]([C:27]#N)([CH3:26])[CH:23]([CH3:25])[CH3:24])=[O:20])=[CH:14][CH:13]=1>C(OCC)(=O)C>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([C:19]2[O:20][C:26](=[O:3])[C:22]([CH:23]([CH3:25])[CH3:24])([CH3:27])[N:21]=2)[CH3:29])=[CH:14][CH:13]=1
Reactant: CC(C(=O)NC(C)(C#N)C(C)C)c1ccc(Cl)cc1
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C1=NC(C)(C(C)C)C(=O)O1)c1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
40 ml of glacial acetic acid, 1.96 g (0.019 mole) of concentrated sulfuric acid and 0.36 g (0.02 mole) of water were added to 5.56 g (0.02 mole) of 2-(4-chlorophenyl)-N-(1-cyano-1,2-dimethylpropyl)propanamide. The mixture was stirred at 60° C. for 2 hours to give rise to a reaction. After the completion of the reaction, the reaction mixture was cooled. Thereto were added 400 ml of water and 400 ml of ethyl acetate for layer separation. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, and concentrated to obtain 5.58 g of 2-[1-(4-chlorophenyl)ethyl]-4-isopropyl-4-methyl-1,3-oxazol-5-one (yield=100%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH3:11])=[C:4]([N+:12]([O-])=O)[CH:3]=1.[Cl-].[NH4+]>C(O)C.O.[Zn]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH3:11])=[C:4]([CH:3]=1)[NH2:12]
Reactant: CCCSc1ccc(F)cc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCO
Solvent: O
Product: CCCSc1ccc(F)cc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.7 %

Procedure:
4-Fluoro-2-nitro-1-propylsulfanylbenzene (6.7 g, 31.1 mmol) was dissolved in a mixed solvent of ethanol (40 ml) and water (4 ml). Ammonium chloride (17 g, 0.32 mol) was added to the resulting mixture, and zinc powder (20 g, 0.31 mol) were added little by little. The resulting mixture was then stirred at room temperature for 1 hour. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure to thereby obtain 5.8 g of oily brown 5-fluoro-2-propylsulfanylaniline (yield: 93%).
Reaction SMILES: [OH:1][C:2]12[CH2:9][CH2:8][C:5]([C:10]([O:12][CH3:13])=[O:11])([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.[CH2:14]([Li])CCC.IC>C1COCC1>[CH3:14][O:1][C:2]12[CH2:3][CH2:4][C:5]([C:10]([O:12][CH3:13])=[O:11])([CH2:8][CH2:9]1)[CH2:6][CH2:7]2
Reactant: [Li]CCCC
Reactant: COC(=O)C12CCC(O)(CC1)CC2
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C12CCC(OC)(CC1)CC2
Temperature: 60 °C
Reaction time: 3 h
Yield: 68.3 %

Procedure:
To a solution of methyl 4-hydroxybicyclo[2.2.2]octane-1-carboxylate (8.9 g, 48 mmol) in anhydrous THF (150 mL) at −78° C. was added n-butyl lithium (23 mL, 57.5 mmol, 2.5 M solution in hexane) over 30 min, followed by the slow addition of iodomethane (14 g, 98 mmol). The mixture was stirred at 60° C. for 3 h and quenched by addition of saturated aqueous ammonium chloride solution (50 mL). The resulting solution was concentrated and the residue was extracted with ethyl acetate (150 mL×2). The organic layers were combined and washed with brine, dried over magnesium sulfate and then concentrated. The residue was purified by silica gel column chromatography (10% ethyl acetate in petroleum ether) to give the title product (6.5 g, 67%). 1H NMR (400 MHz, CDCl3) δ ppm 3.64 (s, 3H), 3.18 (s, 3H), 1.95-1.89 (m, 6H), 1.70-1.65 (m. 6H).
Reaction SMILES: I[C:2]1[C:6]([CH2:7][N:8]([CH3:19])[CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:5][N:4]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)[N:3]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH3:34][N:35]1[C:43]2[C:38](=[CH:39][CH:40]=[C:41](B(O)O)[CH:42]=2)[CH:37]=[N:36]1.C(Cl)Cl>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CC#N.O>[CH3:19][N:8]([CH2:7][C:6]1[C:2]([C:41]2[CH:42]=[C:43]3[C:38]([CH:37]=[N:36][N:35]3[CH3:34])=[CH:39][CH:40]=2)=[N:3][N:4]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)[CH:5]=1)[CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15]
Reactant: Cn1ncc2ccc(B(O)O)cc21
Reactant: CN(CCNC(=O)OC(C)(C)C)Cc1cn(C2CCCCO2)nc1I
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: CC#N
Solvent: ClCCl
Solvent: COCCOC
Product: CN(CCNC(=O)OC(C)(C)C)Cc1cn(C2CCCCO2)nc1-c1ccc2cnn(C)c2c1
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 24.8 %

Procedure:
A mixture of tert-butyl N-[2-([[3-iodo-1-(oxan-2-yl)-1H-pyrazol-4-yl]methyl](methyl)amino)ethyl]carbamate (200 mg, 0.43 mmol, 1.00 equiv), K3PO4 (273 mg, 1.29 mmol, 3.00 equiv), (1-methyl-1H-indazol-6-yl)boronic acid (113 mg, 0.64 mmol, 1.50 equiv) and Pd(dppf)Cl2.CH2Cl2 (70 mg, 0.10 mmol, 0.20 equiv) in ethylene glycol dimethyl ether (20 mL) was stirred under nitrogen at 95° C. overnight. The resulting mixture was cooled to room temperature then concentrated under vacuum. The crude product was purified by Pre-HPLC with the following conditions (1#-Pre-HPLC-005 (Waters)): Column, XBridge Shield RP18 OBD Column, 5 m, 19×150 mm; mobile phase, water with 10 mmol NH4HCO3 and CH3CN (18% CH3CN up to 58% in 10 min, up to 95% in 1 min, down to 18% in 2 min); Detector, UV 254/220 nm to yield 50 mg (25%) of tert-butyl 2-(methyl((3-(1-methyl-1H-indazol-6-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)methyl)amino)ethylcarbamate as a colorless oil. LCMS (method A, ESI): RT=1.16 min, m/z=469.0 [M+H]+.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][NH2:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:12]1[C:21]2[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=2)[N:15]=[CH:14][CH:13]=1.Cl.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>C(#N)C>[Cl:22][C:18]1[CH:17]=[C:16]2[C:21]([C:12]([NH:10][CH2:9][CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:13][CH:14]=[N:15]2)=[CH:20][CH:19]=1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Reactant: NCCCN1CCCCC1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CC#N
Product: Clc1ccc2c(NCCCN3CCCCC3)ccnc2c1

Procedure:
2.73 g from 2.83 g of 3-(piperidin-1-yl)-propylamine and 3.94 g of 4,7-dichloroquinoline (reaction duration, 16 hours at 140° C.); the base (yellowish crystals from acetonitrile, m.p.: 113°-116° C.) was converted with isopropanolic hydrochloric acid into the dihydrochloride which when recrystallized from acetonitrile/ethanol, yielded colourless crystals, m.p.: 137°-141° C.
Reaction SMILES: [CH2:1]([O:3][C:4](Cl)=[O:5])[CH3:2].[NH2:7][CH2:8][CH2:9][CH2:10][C:11]1[NH:15][C:14]2[CH:16]=[CH:17][C:18]([C:20]3[CH:21]([CH3:27])[CH2:22][C:23](=[O:26])[NH:24][N:25]=3)=[CH:19][C:13]=2[N:12]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.O>[CH2:1]([O:3][C:4]([NH:7][CH2:8][CH2:9][CH2:10][C:11]1[NH:15][C:14]2[CH:16]=[CH:17][C:18]([C:20]3[CH:21]([CH3:27])[CH2:22][C:23](=[O:26])[NH:24][N:25]=3)=[CH:19][C:13]=2[N:12]=1)=[O:5])[CH3:2]
Reactant: CC1CC(=O)NN=C1c1ccc2[nH]c(CCCN)nc2c1
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)NCCCc1nc2cc(C3=NNC(=O)CC3C)ccc2[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 52 %

Procedure:
0.45 ml (4 7 mmol) of ethylchloroformate are added dropwise over a period of 10 minutes to a solution of 1 00 g (3.5 mmol) of 6-[2-(3-aminopropyl)-1H-benzimidazol-5-yl]-4,5-dihydro -5-methyl-3(2H)-pyridazinone and 1 25 g (9.0 mmol) of potassium carbonate in 10 ml of acetone and 10 ml of water with cooling in an ice bath. After 3 hours' stirring at room temperature, the reaction mixture is filtered and the filtrate is diluted with 20 ml of water and extracted three times with 20 ml portions of dichloromethane. The combined organic phases are dried and concentrated by evaporation under vacuum and the residue is chromatographed on silica gel with dichloromethane/methanol (9:1) as solvent. The polar main fraction (Rf 0 46) yields 0.65 g (52%) of the title compound in the form of a yellowish, amorphous solid after concentration by evaporation under vacuum.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:9][CH:10]=2)[CH:5]=[N:4][C:3]=1[C:19](OC)=[O:20].[NH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29].C[O-].[Na+].CO>>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:9][CH:10]=2)[CH:5]=[N:4][C:3]=1[C:19]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[O:20]
Reactant: COC(=O)c1ncc2cc(Nc3ccccc3)ccc2c1O
Reactant: NCCCCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)CCCCNC(=O)c1ncc2cc(Nc3ccccc3)ccc2c1O
Temperature: 25 °C

Procedure:
A mixture of methyl 4-hydroxy-7-(phenylamino)isoquinoline-3-carboxylate (30.0 mg, 0.09 mmol), 5-aminovaleric acid (216.3 mg, 1.9 mmol, Sigma-Aldrich) and NaOMe in MeOH (2.8 mL, 1.4 mmol, 0.5 M solution, Sigma-Aldrich) was heated to reflux for 20 hours before cooling to room temperature. The solvent was removed in vacuo and the residue was dissolved in H2O (10 mL) and EtOAc (10 mL). To the stirred mixture was added 1 N hydrochloric acid until pH was 1. The layers were separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over MgSO4, concentrated, and purified by flash chromatography (0-30% MeOH/CH2Cl2) to give the title compound in 27 mg. MS: (+) m/z 380.11 (M+1).
Reaction SMILES: [CH2:1]([N:4]1[C@H:13]2[C@@H:8]([CH2:9][C:10](=O)[C:11](=[CH:14]N(C)C)[CH2:12]2)[CH2:7][CH2:6][CH2:5]1)[CH2:2][CH3:3].[NH2:19][C:20]([NH2:22])=[S:21]>C(O)C>[SH:21][C:20]1[N:22]=[CH:14][C:11]2[CH2:12][C@H:13]3[C@@H:8]([CH2:7][CH2:6][CH2:5][N:4]3[CH2:1][CH2:2][CH3:3])[CH2:9][C:10]=2[N:19]=1
Reactant: NC(N)=S
Reactant: CCCN1CCC[C@@H]2CC(=O)C(=CN(C)C)C[C@H]21
Solvent: CCO
Product: CCCN1CCC[C@H]2Cc3nc(S)ncc3C[C@@H]21

Procedure:
One gram of trans-(±)-1-n-propyl-6-oxo-7-dimethylaminomethylenedecahydroquinoline was reacted with 0.33 g. of thiourea in 20 ml. of ethanol by refluxing overnight under a nitrogen atmosphere. The volatile constituents were removed in vacuo to yield trans-(±)-2-mercapto-6-n-propyl-5,5a,6,7,8,9,9a,10-octahydropyrimido[4,5-g]quinoline free base. The free base was converted to the dihydrochloride salt by standard procedures to yield 0.17 g. of dihydrochloride salt melting at 267°-277° C. after recrystallization from methanol.