Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4](Cl)[N:3]=1.C(N(CC)C(C)C)(C)C.[CH:21]1([NH2:25])[CH2:24][CH2:23][CH2:22]1>C(O)CCC>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([NH:25][CH:21]2[CH2:24][CH2:23][CH2:22]2)[N:3]=1
Reactant: Clc1nc(Cl)c2nc[nH]c2n1
Reactant: NC1CCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Clc1nc(NC2CCC2)c2nc[nH]c2n1
Temperature: 75 °C
Yield: 86.8 %

Procedure:
A 12 L, 4-neck, round-bottomed flask fitted with a mechanical stirrer, digital thermometer, heating and cooling capabilities, condenser, addition funnel, and nitrogen inlet and outlet, was flushed with nitrogen and charged with 492.9 g (2.61 moles) of 2,6-dichloro-9H-purine, 497.7 mL (2.87 moles) of N,N-diisopropylethylamine, and 3.65 L of anhydrous 1-butanol. The mixture was stirred and heated to 75° C. and 244.9 mL (2.87 moles) of cyclobutylamine in 1.25 L of anhydrous 1-butanol, was added during about 1 hour at a temperature of 75° C.-77° C. The reaction temperature and stirring was maintained for 4.5 hours. The mixture was cooled to 5° C. over a period of 1 hour. The product was filtered and the filter cake was washed three times with a total of 0.9 L of 1-butanol. The filter cake was collected and dried at 75° C./20 mm Hg for 24 hours to give 506.6 g of light yellow crystalline solid. Theoretical yield was 583.3 g. Actual yield was 86.9%.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)/[C:10](=[CH:18]/[C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=2[O:26][C:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])([CH3:29])[CH3:28])/[C:9]1=[O:35])=O)(C)(C)C.[F:36][C:37]1[CH:38]=[CH:39][C:40]([CH3:52])=[C:41]([CH:43]=[N:44][C:45]([O:47][Si](C)(C)C)=[CH2:46])[CH:42]=1>C1(C)C=CC=CC=1>[Cl:17][C:14]1[CH:15]=[C:16]2[NH:8][C:9](=[O:35])[C:10]3([CH:18]([C:19]4[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=4[O:26][C:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])([CH3:28])[CH3:29])[CH2:46][C:45](=[O:47])[NH:44][CH:43]3[C:41]3[CH:42]=[C:37]([F:36])[CH:38]=[CH:39][C:40]=3[CH3:52])[C:11]2=[CH:12][CH:13]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(F)cc1/C=C1\C(=O)N(C(=O)OC(C)(C)C)c2cc(Cl)ccc21
Reactant: C=C(N=Cc1cc(F)ccc1C)O[Si](C)(C)C
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)(C)Oc1ccc(F)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12
Yield: 13.7 %

Procedure:
In a manner similar to the method described in Example 1e, E/Z-6-Chloro-3-[2-(1-ethoxycarbonyl-1-methyl-ethoxy)-5-fluoro-benzylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (5 g, 10 mmol) was reacted with 1-(5-fluoro-2-methyl-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (40 mmol) in toluene to give the title compound as a white solid (800 mg).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:17]=[CH:16][C:6]2[N:7]([CH:12]3[CH2:15][CH2:14][CH2:13]3)[C:8](=[O:11])[N:9]([CH3:10])[C:5]=2[CH:4]=1.[C-:18]#[N:19].[Na+]>CS(C)=O.O>[CH:12]1([N:7]2[C:6]3[CH:16]=[CH:17][C:3]([CH2:2][C:18]#[N:19])=[CH:4][C:5]=3[N:9]([CH3:10])[C:8]2=[O:11])[CH2:15][CH2:14][CH2:13]1
Reactant: [C-]#N
Reactant: Cn1c(=O)n(C2CCC2)c2ccc(CCl)cc21
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cn1c(=O)n(C2CCC2)c2ccc(CC#N)cc21
Temperature: 90 °C
Yield: 100.3 %

Procedure:
To a solution of 5-Chloromethyl-1-cyclobutyl-3-methyl-1,3-dihydro-benzoimidazol-2-one (11.92 g, 47.5 mmol) in methyl sulfoxide (50 mL) was added sodium cyanide (6.6 g). The reaction was heated to 90° C. for 2 hours then was cooled, diluted with water and extracted into ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated to give (1-Cyclobutyl-3-methyl-2-oxo-2,3-dihydro-1H-benzoimidazol-5-yl)-acetonitrile (11.5 g).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([CH:50]=[CH:51][CH:52]=1)[CH2:13][N:14]1[CH:18]=[C:17]([C:19]2[C:27]3[C:22](=[N:23][CH:24]=[C:25]([C:28]4[CH:29]=[N:30][C:31]([N:34]5[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]5)=[CH:32][CH:33]=4)[CH:26]=3)[N:21]([S:40]([C:43]3[CH:49]=[CH:48][C:46]([CH3:47])=[CH:45][CH:44]=3)(=[O:42])=[O:41])[CH:20]=2)[CH:16]=[N:15]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:53][C@H:54]1[CH2:56][O:55]1.CCN(C(C)C)C(C)C>C(O)C>[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([CH:50]=[CH:51][CH:52]=1)[CH2:13][N:14]1[CH:18]=[C:17]([C:19]2[C:27]3[C:22](=[N:23][CH:24]=[C:25]([C:28]4[CH:33]=[CH:32][C:31]([N:34]5[CH2:35][CH2:36][N:37]([CH2:53][C@@H:54]([OH:55])[CH3:56])[CH2:38][CH2:39]5)=[N:30][CH:29]=4)[CH:26]=3)[N:21]([S:40]([C:43]3[CH:44]=[CH:45][C:46]([CH3:47])=[CH:48][CH:49]=3)(=[O:41])=[O:42])[CH:20]=2)[CH:16]=[N:15]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(OCc5ccccc5)c4)c3)c3cc(-c4ccc(N5CCNCC5)nc4)cnc32)cc1
Reactant: C[C@H]1CO1
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(OCc5ccccc5)c4)c3)c3cc(-c4ccc(N5CCN(C[C@H](C)O)CC5)nc4)cnc32)cc1

Procedure:
Using similar reaction conditions as described in step-i of example-82A, 3-(1-(3-(benzyloxy)benzyl)-1H-pyrazol-4-yl)-5-(6-(piperazin-1-yl)pyridin-3-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine hydrochloride (200 mg. 0.273 mmol) was alkylated using (S)-2-methyloxirane (48 mg, 0.819 mmol), DIPEA (211 mg, 1.638 mmol) and ethanol (20 mL) to get 200 mg (crude) of the titled compound. MS: m/z=754.3 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([OH:13])=O)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:15]([O:22][C:23](=[O:29])[C@@H:24]1[CH2:28][CH2:27][CH2:26][NH:25]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C>O1CCCC1.C(OCC)(=O)C>[CH2:15]([O:22][C:23](=[O:29])[C@@H:24]1[CH2:28][CH2:27][CH2:26][N:25]1[C:11](=[O:13])[C@H:9]([CH3:10])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: -15 °C
Reaction time: 3 h
Yield: 88.6 %

Procedure:
N-t-butyloxycarbonyl-L-alanine (3.8 g, 20 m mole), L-proline benzyl ester hydrochloride (5 g, 20.6 m mole) and 1-hydroxy benzotriazole, which is hereinafter referred to as HOBt (2.7 g, 20 m mole) were suspended in tetrahydrofuran, which is hereinafter referred to as THF (50 ml). N,N'-dimethylaminopropylethylcarbodiimide, which is hereinafter referred to as WSC (3.8 ml) in THF (10 ml) solution was added dropwisely to the above suspended solution while cooling at -15° C. and stirring. The reaction was carried for 3 hours at a temperature of less than 0° C. and thereafter at room temperature overnight. The thus obtained solution was distilled under reduced pressure leaving a residue. The residue was dissolved in ethyl acetate and washed with 1N hydrochloric acid, water, 5% aqueous sodium bicarbonate and water in order, and dried over anhydrous sodium sulfate. The thus obtained solution was distilled under reduced pressure leaving a residue. The residue was recrystallized in ether-n-hexan to give N-t-butyloxycarbonyl-L-alanyl-L-proline benzyl ester (6.7 g, yield: 89%) having melting point of 71° to 72° C. This product gave one spot by thin layer chromatography (developing solvent; chloroform:methanol:acetic acid=95:5:3, colour forming method; spraying with 0.1% ninhydrin and heating).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][OH:8])[CH:5]=[CH:4][CH:3]=[N:2]1.C([Li])CCC.[I:14]I>O1CCCC1>[I:14][C:5]1[N:1]([CH2:6][CH2:7][OH:8])[N:2]=[CH:3][CH:4]=1
Reactant: OCCn1cccn1
Reactant: II
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OCCn1nccc1I
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 37.7 %

Procedure:
To a cold (0° C.) solution of 2-pyrazol-1-yl-ethanol (0.5 g, 4.46 mmol) in tetrahydrofuran (15 mL), under an atmosphere of nitrogen, was added N,N,N′,N′-tetramethyl-ethylenenediamine (1.34 ml, 8.92 mmol, 2.0 eq.) followed by n-butyllithium (2.5M in hexane, 4.0 ml, 10 mmol, 2.2 eq.) at such a rate as to maintain the temperature below 5° C. The resulting yellow solution was stirred at 0° C. for 0.5 hr before adding a solution of iodine (1.36 g, 5.35 mmol, 1.2 eq.) in tetrahydrofuran (10 mL). The resulting mixture was stirred for 20 min before concentrating the mixture by evaporation under reduced pressure. The residue was partition between ethyl acetate (50 mL) and aqueous citric acid (1M, 100 ml). The organic phase was washed with 10% aqueous sodium thiosulphate solution, saturated brine (20 mL) and dried over sodium sulphate. The resulting mixture was filtered and the filtrate concentrated under reduced pressure to give a brown oil. The crude oil was purified by chromatography on silica gel (60 g) eluting with a gradient of ethyl acetate in heptane (50:50) to give the title compound as a white solid (0.4 g, 38%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:28](O)=[O:29])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)[CH:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][C:37]=1[N:38]1[CH2:43][C@H:42]([CH3:44])[C@H:41]([NH:45][C:46](=[O:49])[O:47][CH3:48])[C@H:40]([NH:50][C:51](=[O:57])[O:52][C:53]([CH3:56])([CH3:55])[CH3:54])[CH2:39]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:28]([NH:31][C:32]2[CH:33]=[N:34][CH:35]=[CH:36][C:37]=2[N:38]2[CH2:43][C@H:42]([CH3:44])[C@H:41]([NH:45][C:46](=[O:49])[O:47][CH3:48])[C@H:40]([NH:50][C:51](=[O:57])[O:52][C:53]([CH3:56])([CH3:55])[CH3:54])[CH2:39]2)=[O:29])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)[CH:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1cc2ccc(N3CCOCC3)cc2nc1C(=O)O)OCc1ccccc1
Reactant: COC(=O)N[C@H]1[C@@H](C)CN(c2ccncc2N)C[C@H]1NC(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)N[C@H]1[C@@H](C)CN(c2ccncc2NC(=O)c2nc3cc(N4CCOCC4)ccc3cc2NC(=O)OCc2ccccc2)C[C@H]1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
To a mixture of 3-{[(benzyloxy)carbonyl]amino}-7-morpholin-4-ylquinoline-2-carboxylic acid (31 mg, 0.075 mmol), tert-butyl methyl [(3R,4S,5S)-1-(3-aminopyridin-4-yl)-5-methylpiperidine-3,4-diyl]biscarbamate (30 mg, 0.079 mmol) and HATU (92 mg, 0.24 mmol) in DMF (1.0 mL), DIPEA (90 μL, 0.52 mmol) was added. The reaction mixture was stirred at room temperature overnight. The mixture was then purified by preparative LCMS (pH=10 method; XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and water with 0.1% NH4OH) to give the sub-title compound as a yellow solid (30 mg, 51%). LCMS calc. for C40H49N8O8 (M+H)+: m/z=769.4. Found: 769.4.
Reaction SMILES: [NH2:1][C:2]1[N:6]2[C:7]([O:13][CH3:14])=[N:8][CH:9]=[C:10]([O:11][CH3:12])[C:5]2=[N:4][N:3]=1.C[O-].[Na+]>CO.O>[NH2:1][C:2]1[N:6]=[C:5]2[N:4]([C:7]([O:13][CH3:14])=[N:8][CH:9]=[C:10]2[O:11][CH3:12])[N:3]=1
Reactant: COc1cnc(OC)n2c(N)nnc12
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cnc(OC)n2nc(N)nc12
Yield: 92.9 %

Procedure:
3-Amino-5,8-dimethoxy[1,2,4]triazolo[4,3-c]-pyrimidine (9.762 g, 0.050 mole) was loaded into a 500 mL three necked flask equipped with an overhead stirrer, condenser, addition funnel, and thermocouple temperature probe. Methanol (70 mL) was added and the mixture was stirred to form a slurry. Sodium methoxide (16.716 g of a 25% solution in methanol) was added dropwise over 28 min, after which the mixture was stirred at room temperature for 3 h. The reaction mixture was then diluted with water (135 mL) and stirred for an additional 1.5 h. The product solids were recovered by filtration through Whatman #54 paper using a Buchner funnel and aspirator vacuum. After washing with water, the solids were dried in vacuo at room temperature to give 9.064 g of 2-amino-5,8-dimethoxy[1,2,4]triazolo[1,5-c]pyrimidine (yield=92.8%): 1H NMR (300 MHz, DMSO-d6) 3.88 (s, 3H), 4.04 (s, 3H), 6.38 (br s, 2H), 7.48 (s, 1H); MS(GC, 70eV) 195 (M+, 85%), 194 (100%)
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:14][C:13]([SH:15])=[N:12][N:11]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1.[CH3:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:14][C:13]([S:15][CH2:16][C:17]4[CH:24]=[CH:23][C:20]([CH3:21])=[CH:19][CH:18]=4)=[N:12][N:11]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: Cc1ccc(CBr)cc1
Reactant: Sc1nnc(-c2ccc3c(c2)CCO3)o1
Product: Cc1ccc(CSc2nnc(-c3ccc4c(c3)CCO4)o2)cc1
Yield: 75 %

Procedure:
In the same manner as in Example 1 and using 5-(2,3-dihydro-1-benzofuran-5-yl)-1,3,4-oxadiazole-2-thiol instead of 5-(benzothiazol-6-yl)-1,3,4-oxadiazole-2-thiol and 4-methylbenzyl bromide instead of 3-(trifluoromethyl)benzyl chloride, the title compound (yield 75%) was obtained as colorless crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH2:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=1>CN(C)C=O>[N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:12][C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=2)[N:5]=1)([O-:3])=[O:2]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: O=[N+]([O-])c1cc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Cn2ccc([N+](=O)[O-])n2)cc1
Yield: 90.4 %

Procedure:
To a solution of 3-nitro-1H-pyrazole (prepared in example 3, 200 mg, 1.77 mmol) in anhydrous N,N-dimethylformamide (2 mL), a 60% dispersion of sodium hydride in mineral oil (92 mg, 2.30 mmol) was added while stirring under nitrogen. After the effervescence ceased and the mixture was stirred for additional 30 min, 4-bromomethyl-benzonitrile (345 mg, 2.30 mmol) was added. The mixture was continued to stir under nitrogen for an additional 2 h. The solvent was removed in vacuo and purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 40 g; 2% methanol/methylene chloride to 5% methanol/methylene chloride) afforded 4-(3-nitro-pyrazol-1-ylmethyl)-benzonitrile (365 mg, 90%) as a white solid. The crude material was used in the following step without any further purification.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:6]=[C:7]([CH:18]=[CH:19][C:20]=1[N:21]1[CH2:25][CH2:24][CH2:23][C:22]1=O)[O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=[O:13])(=[O:4])=[O:3].C1CCN2C(=NCCC2)CC1.Cl>C1COCC1>[O:3]=[S:2]1(=[O:4])[C:5]2[CH:6]=[C:7]([O:8][C:9]3[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=3)[C:12]([OH:14])=[O:13])[CH:18]=[CH:19][C:20]=2[N:21]2[CH2:25][CH2:24][CH2:23][C:22]2=[N:1]1
Reactant: NS(=O)(=O)c1cc(Oc2cccc(C(=O)O)c2)ccc1N1CCCC1=O
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: O=C(O)c1cccc(Oc2ccc3c(c2)S(=O)(=O)N=C2CCCN23)c1

Procedure:
A suspension of the product obtained in Step B (850 mg, 2.26 mmol) in 25 ml of THF in the presence of 675 μl (4.52 mmol) of DBU is refluxed for 1 hour. It is allowed to return to ambient temperature and is acidified with 1N HCl, and the white precipitate corresponding to the title product is filtered off. Elemental micro-analysis:
Reaction SMILES: Br[C:2]1[C:3]([CH2:9][CH3:10])=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:11][N:12](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:8][C:5]1[CH:4]=[C:3]([CH2:9][CH3:10])[C:2]([C:11]#[N:12])=[CH:7][N:6]=1
Reactant: CCc1cc(N)ncc1Br
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CCc1cc(N)ncc1C#N

Procedure:
A mixture of 5-bromo-4-ethylpyridin-2-amine (intermediate 99, 110 mg, 0.55 mmol), zinc cyanide (71 mg, 0.60 mmol) and Pd(PPh3)4 (63 mg, 0.06 mmol) in DMF (1 ml) was flushed with argon and heated in a septum sealed vial at 85° C. for 18 h. The cooled reaction mixture was evaporated, preabsorbed onto isolate and purified by normal phase chromatography with a 12 g RediSep® column: eluting with a gradient from DCM to 20% MeOH in DCM. Product containing fractions were combined and evaporated to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ 8.24 (s, 1H), 6.92 (s, br, 2H), 6.37 (s, 1H), 2.57 (q, 2H), 1.17 (t, 3H).
Reaction SMILES: [H-].[Na+].[C:3]([O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][C:38]1[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:46][CH2:47][O:48][CH2:49][CH2:50][O:51][CH2:52][CH2:53][O:54][CH2:55][CH2:56][O:57][CH2:58][CH2:59][O:60][CH2:61][C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1>C1COCC1>[CH2:61]([O:60][CH2:59][CH2:58][O:57][CH2:56][CH2:55][O:54][CH2:53][CH2:52][O:51][CH2:50][CH2:49][O:48][CH2:47][CH2:46][O:44][C:41]1[CH:42]=[CH:43][C:38]([O:37][CH2:36][CH2:35][O:34][CH2:33][CH2:32][O:31][CH2:30][CH2:29][O:28][CH2:27][CH2:26][O:25][CH2:24][CH2:23][O:22][C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[CH:39][CH:40]=1)[C:62]1[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=1
Reactant: Oc1ccc(OCCOCCOCCOCCOCCOC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: BrCCOCCOCCOCCOCCOCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: c1ccc(COCCOCCOCCOCCOCCOc2ccc(OCCOCCOCCOCCOCCOC(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 84.1 %

Procedure:
To an ice-cooled suspension of sodium hydride (800 mg, 20 mmol; 60% in mineral oil) in THF (15 ml), a solution of Compound 22 (1.2 g, 2.1 mmol) in THF (20 ml) was gradually added; this was followed by stirring for 20 minutes. A solution of Compound 20 (1.7 g, 4.3 mmol) in THF (12 ml) was added thereto, and this was followed by stirring for 20 minutes. After the ice bath was removed, stirring was further conducted at room temperature for 2 hours. Water was carefully added to stop the reaction, and this was followed by concentration under reduced pressure. Extraction from methylene chloride was conducted, and the combined organic phases were washed with saturated brine and dried with anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue obtained was purified by silica gel column chromatography (Yamazen YFLC Gel, eluent (n-hexane:ethyl acetate 2:1-1:1)) to yield Compound 23 (light-yellow oil 1.56 g, 84%).
Reaction SMILES: [CH3:1][C:2]([CH3:20])([CH2:18][CH3:19])[CH2:3][CH2:4][C@H:5]([NH:9][C:10]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[O:11])[C:6]([OH:8])=O.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[NH2:35][C:36]1([C:47]#[N:48])[CH2:41][CH2:40][N:39]([CH2:42][CH2:43][CH2:44][O:45][CH3:46])[CH2:38][CH2:37]1>ClCCl>[C:47]([C:36]1([NH:35][C:6]([C@@H:5]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[O:11])[CH2:4][CH2:3][C:2]([CH3:1])([CH3:20])[CH2:18][CH3:19])=[O:8])[CH2:41][CH2:40][N:39]([CH2:42][CH2:43][CH2:44][O:45][CH3:46])[CH2:38][CH2:37]1)#[N:48]
Reactant: COCCCN1CCC(N)(C#N)CC1
Reactant: CCC(C)(C)CC[C@H](NC(=O)N1CCOCC1)C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: CCC(C)(C)CC[C@H](NC(=O)N1CCOCC1)C(=O)NC1(C#N)CCN(CCCOC)CC1
Yield: 15.5 %

Procedure:
A solution of (S)-5,5-Dimethyl-2-[(morpholine-4-carbonyl)-amino]-heptanoic acid (4.70 g, 16.4 mmol) in dichloromethane (75 mL), cooled in an ice water bath, was treated with HOBT (2.45 g, 18.13 mmol), then EDC (3.47 g, 18.1 mmol). The reaction mixture was stirred with cooling for 35 min, then the ice bath was removed and a solution of 4-amino-(3-methoxy-propyl)-piperidine-4-carbonitrile (3.61 g, 18.3 mmol) in dichloromethane (25 mL) was added. The reaction mixture was stirred overnight, then concentrated on a rotary evaporator. The resulting residue was taken up in ethyl acetate (300 mL) and washed with saturated sodium bicarbonate solution (2×300 mL). The organic phase was then dried (magnesium sulfate) and concentrated to provide 8.1 grams of crude material. This material was further purified on a shimadzu reverse phase hplc using a gradient of acetonitrile in water (40 to 65% over 35 min flow rate 45 mL/min) to provide 1.18 g (25.8%) of the desired product as a white crunchy foam; m/z calculated for C24H43N5O4 465.6, found 466.6 (M+H)+
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH2:8][CH2:9][C:10]4[C@:15]3([CH3:16])[CH2:14][CH2:13][C:12](=[O:20])C=4)[C@@H:6]1[CH2:5][CH2:4][C:3]2=[O:21].[Cl-].[CH3:23][NH3+:24].C(O)(=O)C>C(OCC)(=O)C>[CH3:23][N:24]1[C:12](=[O:20])[CH2:13][CH2:14][C@@:15]2([CH3:16])[C:10]1=[CH:9][CH2:8][C@@H:7]1[C@@H:17]2[CH2:18][CH2:19][C@@:2]2([CH3:1])[C@H:6]1[CH2:5][CH2:4][C:3]2=[O:21]
Reactant: C[NH3+]
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: [Cl-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CN1C(=O)CC[C@@]2(C)C1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Androst-4-ene-3,17-dione is oxidized into 5-oxo-4-nor-3,5-seco-androstane-5,17-dione as in Example 16A (seco-acid). The seco-acid (9.000 g, 31.423 mmol) is slurried with methylammonium chloride (19.5000 g, 288.80 mmol) into acetic acid (75 mL) and heated to reflux under an inert atmosphere. After 3 days, the reaction mixture is allowed to cool to room temperature and diluted with ethyl acetate (EtOAc, 500 mL). The organic solution is washed with water (3×200 mL), saturated aqueous NaHCO3 (2×200 mL) and brine (200 mL), then dried over magnesium sulfate (MgSO4), filtered, concentrated and purified by flash chromatography (1:1:2 EtOAc/CH2Cl2) to afford 4-methyl-4-aza-androst-5-ene-3,17-dione (aza-dione).
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C@@H:10]([C:13]([C:26]#[N:27])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9]1)C1C=CC=CC=1.S(=O)(=O)(O)O.[H][H]>[C].[Pd].C(O)C>[C:26]([C:13]([C@@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)#[N:27]
Reactant: N#CC(c1ccccc1)(c1ccccc1)[C@@H]1CCN(Cc2ccccc2)C1
Reactant: [H][H]
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CCO
Product: N#CC(c1ccccc1)(c1ccccc1)[C@@H]1CCNC1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A mixed solution obtained by mixing 3.9 g of 79% pure (S)-1-benzyl-3-(1-cyano-1,1-diphenylmethyl)-pyrrolidine with 3.1 ml of ethanol and adding dropwise 446 mg of 97% sulfuric acid thereto with cooling on an ice-water bath was charged, together with 158 mg of moist 5% palladium-carbon (water content 52% by weight), into an autoclave, hydrogen was introduced thereinto and the autoclave was heated to raise the temperature to 60 and the pressure to 203 kPa, and the reaction was allowed to proceed for 3.5 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and depressurized. The reaction mixture was taken out, the catalyst was filtered off, the filtrate obtained was concentrated under reduced pressure, toluene and water were added to the thus-obtained oily concentrate, and the pH was adjusted to 13 by adding dropwise 30% aqueous sodium hydroxide with stirring on an ice-water bath. The toluene layer was recovered, the aqueous layer was further extracted with toluene, and the toluene layers were combined, washed with a saturated aqueous solution of sodium chloride, dried with anhydrous sodium sulfate and, after filtration, concentrated under reduced pressure, to give an oil. This was purified by silica gel column chromatography using, as an eluant, dichloromethane containing methanol (0% to 10%). Main fractions containing the product were combined and concentrated under vacuum to give (S)-3-(1-cyano-1,1-diphenylmethyl)-pyrrolidine in a yield of 84 mole percent.