Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]([C:7]1[N:27]=[CH:26][C:10]2[NH:11][C:12]3[C:17]([C:9]=2[C:8]=1[CH2:28][O:29][CH3:30])=[CH:16][C:15]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:14][CH:13]=3)=[O:6])[CH3:3].[H-].[Na+].[CH3:33][N:34]([CH2:43][CH2:44][CH2:45][CH2:46][C:47](=[O:50])[CH2:48]Br)[CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.Cl>O1CCCC1.O>[CH3:3][CH:2]([O:4][C:5]([C:7]1[N:27]=[CH:26][C:10]2[N:11]([CH2:48][C:47](=[O:50])[CH2:46][CH2:45][CH2:44][CH2:43][N:34]([CH3:33])[CH2:35][CH2:36][C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:12]3[C:17]([C:9]=2[C:8]=1[CH2:28][O:29][CH3:30])=[CH:16][C:15]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:14][CH:13]=3)=[O:6])[CH3:1]
Reactant: CN(CCCCC(=O)CBr)CCc1ccccc1
Reactant: COCc1c(C(=O)OC(C)C)ncc2[nH]c3ccc(OCc4ccccc4)cc3c12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCc1c(C(=O)OC(C)C)ncc2c1c1cc(OCc3ccccc3)ccc1n2CC(=O)CCCCN(C)CCc1ccccc1
Temperature: 25 °C
Yield: 99.2 %

Procedure:
2.63 g of 6-benzyloxy-4-methoxymethyl-9H-pyrido[3,4-b]indole-3-carboxylic acid-(1-methyl-ethyl)-ester (6.5 mmol) is taken up in 50 ml of dry tetrahydrofuran and mixed for deprotonation with 235 mg of 80% sodium hydride suspension in oil (7.1 mmol). It is allowed to stir for 20 more minutes at room temperature, then 2.22 g of 6-[N-methyl-N-(2-phenylethyl)-amino]-2-oxohexylbromide (7.1 mmol)--dissolved in 10 ml of tetrahydrofuran--is added. It is stirred for 12 hours at room temperature, mixed with 5 ml of 2N aqueous hydrochloric acid and diluted with water. It is then extracted with dichloromethane, the solvent is drawn off in a vacuum, and the crude product that is obtained is chromatographed on silica gel using hexane-ethyl acetate. 4.1 g of 6-benzyloxy-4-methoxymethyl-9{6-[N-methyl-N-(2-phenylethyl)-amino]-2-oxohexyl}9H-pyrido[3,4-b]indole-3-carboxylic acid-(1-methylethyl)-ester is obtained as a brownish oil.
Reaction SMILES: [SiH](CC)(CC)CC.[CH3:8][CH:9]([CH:14](O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21])[C:10]([O:12][CH3:13])=[O:11].B(F)(F)F.CCOCC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:8][CH:9]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21])[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)C(C)C(O)c1ccccc1C
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)C(C)Cc1ccccc1C
Reaction time: 20 h

Procedure:
132 ml (826 mmol) of HSiEt3 were added to 86 g (413 mmol) of β-hydroxy ester f1 in 800 ml of CH2Cl2. 102 ml (826 mmol) of BF3 -ether were added in portions at -5°--10° C. in the course of 5-10 minutes. After 20 hours at room temperature, the mixture was worked up. After hydrolysis with 220 ml of NaHCO3 (pH 3), the mixture was extracted with ether, and the organic phase was separated off, washed with NaCl solution, dried and distilled (120° C./1 mmHg).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[N:5]=[C:6]([NH:11][C:12]3[C:13]([Cl:27])=[CH:14][C:15]([F:26])=[C:16]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:17]=3)[N:7]=[CH:8][C:9]=2[N:10]=1.[C:28](Cl)(=[O:30])[CH3:29].C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[C:21]([O:20][C:19](=[O:25])[NH:18][C:16]1[CH:17]=[C:12]([NH:11][C:6]2[N:7]=[CH:8][C:9]3[N:10]=[C:2]([NH:1][C:28](=[O:30])[CH3:29])[S:3][C:4]=3[N:5]=2)[C:13]([Cl:27])=[CH:14][C:15]=1[F:26])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)Nc1cc(Nc2ncc3nc(N)sc3n2)c(Cl)cc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(=O)Nc1nc2cnc(Nc3cc(NC(=O)OC(C)(C)C)c(F)cc3Cl)nc2s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl {5-[(2-amino[1,3]thiazolo[5,4-d]pyrimidin-5-yl)amino]-4-chloro-2-fluorophenyl}carbamate (470 mg, 1.14 mmol) in pyridine (10 mL) was added acetyl chloride (204 μL, 2.86 mmol), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (50 mL), and the mixture was extracted with ethyl acetate/tetrahydrofuran mixture (1:1, 50 mL, 20 mL). The combined organic layer was washed with saturated brine (10 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give tert-butyl(5-{[2-(acetylamino)[1,3]thiazolo[5,4-d]pyrimidin-5-yl]amino}-4-chloro-2-fluorophenyl)carbamate as a brown amorphous solid. The obtained compound was used for the next reaction without further purification.
Reaction SMILES: [OH:1][NH:2][C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].C(N(CC)CC)C.[C:17](Cl)(=[O:19])[CH3:18]>ClCCl>[C:17]([O:1][NH:2][C:3]([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])=[O:9])(=[O:19])[CH3:18]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)NO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)ONC(=O)OC(C)(C)C
Temperature: 0 °C

Procedure:
The starting material is prepared as follows: tert-Butyl N-hydroxycarbamate (3.89 g, 29.2 mmol) is dissolved in 25 ml of dichloromethane and cooled to 0° C. To this is added triethylamine (3.25 g, 32.1 mmol) and acetyl chloride (2.29 g, 29.2 mmol) dropwise. The mixture is extracted with ether and the extracts are washed with aqueous 2N HCl, water, 10% sodium bicarbonate, water, dried (MgSO4) and evaporated. The resulting colorless oil is purified by silica gel chromatography (10% ethyl acetate/hexane) to give O-acetyl-N-tert-butoxycarbonylhydroxylamine as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:10]2[CH:29]=[CH:28][CH:27]=[CH:26][C:11]=2[C:12]2[CH:13]([CH2:24][Cl:25])[CH2:14][N:15]([C:18](=[O:23])[C:19](F)(F)F)[C:16]=2[CH:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[CH3:36][O:37][C:38]1[CH:48]=[CH:47][C:41](/[CH:42]=C/C(Cl)=O)=[CH:40][CH:39]=1>CN1CCCC1=O.O.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([NH:8][C:9]1[C:10]2[CH:29]=[CH:28][CH:27]=[CH:26][C:11]=2[C:12]2[CH:13]([CH2:24][Cl:25])[CH2:14][N:15]([C:18](=[O:23])/[CH:19]=[CH:42]/[C:41]3[CH:47]=[CH:48][C:38]([O:37][CH3:36])=[CH:39][CH:40]=3)[C:16]=2[CH:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(/C=C/C(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)Nc1cc2c(c3ccccc13)C(CCl)CN2C(=O)C(F)(F)F
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1ccc(/C=C/C(=O)N2CC(CCl)c3c2cc(NC(=O)OC(C)(C)C)c2ccccc32)cc1
Temperature: 20 °C
Reaction time: 0.75 h
Yield: 48.5 %

Procedure:
A stirred solution of the above 5-(tert-butyloxycarbonylamino)-1-(chloromethyl)-3-trifluoroacetyl-1,2-dihydro-3H-benz[e]indole (100 mg, 0.23 mmol) in N-methylpyrrolidone (2.5 mL) was treated dropwise at 20° C. with a solution of Cs2CO3 (650 mg) in water (1.5 mL). the mixture was stirred for a further 45 min at 20° C. then diluted with water (20 mL) and extracted with benzene (2×15 mL). The combined organic extracts were washed with water (2×), dried (Na2SO4) and concentrated under reduced pressure below 30° C. The residue was dissolved in pyridine (2 mL), cooled to -5° C. and treated with (E)-4-methoxycinnamoyl chloride (46 mg, 0.23 mmol) followed by DMAP (15 mg). The mixture was stirred for a further 30 min at 20° C., then diluted with KHCO3 solution. The precipitated solid was collected, washed with water, dried and chromatographed on silica gel. Elution with CH2Cl2 /EtOAc gave the crude product which was recrystallised from CH2Cl2 /petroleum either to give 5-(tert-butyloxycarbonylamino)-1-(chloromethyl)-3-[(E)-4-methoxycinnamoyl]-1,2-dihydro-3H-benz[e]indole (55 mg, 48%), mp 185-185.5° C. 1H NMR [(CD3)2SO] δ 9.28 (br s, 1 H, NH), 8.64 (br s, 1 H, H-4), 8.01 (d, J=8.1 Hz, 1 H, H-6), 7.92 (d, J=8.3 Hz, 1 H, H-9), 7.78 (d, J=8.6 Hz, 2 H, H-2',6'), 7.66 (d, J=15.3 Hz, 1 H, PhCH=CH), 7.54 (t, J=7.6 Hz, 1 H, H-8), 7.42 (t, J=7.7 Hz, 1 H, H-7), 7.10 (d, J=15.2 Hz, 1 H, PhCH=CH), 7.01 (d, J=8.7 Hz, 2 H, H-3',5'), 4.60-4.44 (m, 2 H, H-2), 4.41-4.28 (m, 1 H, H-1), 4.02 (dd, J=11.1, 3.0 Hz, 1 H, CHHCl), 3.92 (dd, J=11.1, 7.2 Hz, 1 H, CHHCl), 3.82 (s, 3 H, OCH3), 1.51 (s, 9 H, C(CH3)3).
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][N:21]3[CH:24]=[CH:25][CH:26]=[C:20]3[CH:19]=2)=[CH:8]1)(C)(C)C.Br[CH2:28][C:29]([NH:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][N:33]=1)=[O:30]>>[F:38][C:35]1[CH:36]=[CH:37][C:32]([NH:31][C:29](=[O:30])[CH2:28][O:17][C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][N:21]4[CH:24]=[CH:25][CH:26]=[C:20]4[CH:19]=2)=[CH:8][C:7]3=[N:6][OH:5])=[N:33][CH:34]=1
Reactant: O=C(CBr)Nc1ccc(F)cn1
Reactant: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2ccc(O)cc12
Product: O=C(COc1ccc2oc(-c3cc4cccn4cn3)cc(=NO)c2c1)Nc1ccc(F)cn1

Procedure:
N-(5-Fluoro-pyridin-2-yl)-2-{4-hydroxyimino-2-pyrrolo[1,2-c]pyrimidin-3-yl-4H-chromen-6-yloxy}-acetamide was prepared in 2% overall yield using the method described in example 147, starting from 6-hydroxy-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one O-tert-butyl-oxime (example 81A) and 2-Bromo-N-(5-fluoro-pyridin-2-yl)-acetamide (Bioorg. Med. Chem. 11 (2003) 2769-2782).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([Br:17])[C:14]=1[O:15][CH3:16])[CH2:5][C@:6]([CH3:11])([C:8]([OH:10])=[O:9])[NH2:7].F[C:19](F)(F)C(O)=O.Br.C=O>>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([Br:17])[C:14]=1[O:15][CH3:16])[CH2:19][NH:7][C@@:6]([CH3:11])([C:8]([OH:10])=[O:9])[CH2:5]2
Reactant: COc1c(Br)cc(C[C@@](C)(N)C(=O)O)cc1Br
Reactant: O=C(O)C(F)(F)F
Agent: Br
Agent: C=O
Product: COc1c(Br)cc2c(c1Br)CN[C@@](C)(C(=O)O)C2
Temperature: 75 °C
Reaction time: 17 h

Procedure:
Compound 2.5 (4.8 mmol) was added to trifluoroacetic acid (5 mL). HBr (33% in acetic acid, 0.9 mL, 4.8 mmol) was added dropwise to the reaction mixture under nitrogen atmosphere. Upon the addition of the acid, formaldehyde (8.64 mmol, 260 mg, 0.7 mL) was added dropwise and the mixture stirred at 70-80° C. for 17 h. The reaction mixture was cooled, dried and concentrated. APCI MS 378 (M+1). The product was used in the next step.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].CC1(C)C(C)(C)OB([C:22]2[CH:23]=[C:24]([C:28]([O:30][CH3:31])=[O:29])[CH:25]=[N:26][CH:27]=2)O1>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.O.C(OCC)(=O)C.COCCOC>[N:3]1[CH:4]=[CH:5][CH:6]=[N:7][C:2]=1[C:22]1[CH:23]=[C:24]([C:28]([O:30][CH3:31])=[O:29])[CH:25]=[N:26][CH:27]=1
Reactant: Brc1ncccn1
Reactant: COC(=O)c1cncc(B2OC(C)(C)C(C)(C)O2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1cncc(-c2ncccn2)c1
Temperature: 25 °C
Yield: 36.7 %

Procedure:
2-Bromopyrimidine (73 mg), sodium carbonate (81 mg), water (0.3 mL), and bis(triphenylphosphine)palladium(II) dichloride (5.3 mg) were added to an ethylene glycol dimethyl ether (1 mL) solution of methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-carboxylate (0.10 g), followed by heating to reflux under a nitrogen atmosphere for 1 hour and 30 minutes. After cooling the reaction mixture to room temperature, ethyl acetate and water were added thereto, and the insoluble substance was removed by filtration. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent: 90-50% hexane/ethyl acetate] to obtain 30 mg of methyl 5-(pyrimidin-2-yl)pyridine-3-carboxylate as a yellow solid.
Reaction SMILES: C(N(CC)CC)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.[CH2:23]([NH:27][C:28]([CH:30]1[CH2:38][C:37]2[C:32](=[CH:33][CH:34]=[C:35]([O:39][CH3:40])[CH:36]=2)[NH:31]1)=[O:29])[CH2:24][CH2:25][CH3:26].[CH2:41]([O:48][C:49]([NH:51][C@H:52]([C:54](O)=[O:55])[CH3:53])=[O:50])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>ClCCl>[CH2:23]([NH:27][C:28]([CH:30]1[CH2:38][C:37]2[C:32](=[CH:33][CH:34]=[C:35]([O:39][CH3:40])[CH:36]=2)[N:31]1[C:54](=[O:55])[C@H:52]([CH3:53])[NH:51][C:49]([O:48][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:50])=[O:29])[CH2:24][CH2:25][CH3:26]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CCCCNC(=O)C1Cc2cc(OC)ccc2N1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCNC(=O)C1Cc2cc(OC)ccc2N1C(=O)[C@H](C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
Triethylamine (1.12 ml, 8 mmol) and bis(2-oxo-3-oxazolidinyl)phosphinyl chloride (0.815 g, 3.2 mmol) were added to a cooled (0° C.) solution of 5-methoxyindoline-2(R/S)-carboxylic acid butylamide (0.500 g, 2.01 mmol) and N-benzyloxycarbonyl-L-alanine (0.4956 g, 2.22 mmol) dissolved in dichloromethane (25 ml), under nitrogen. The mixture was stirred at room temperature for 22 hours. It was then washed with 10% citric acid (3×30 ml), 5% NaHCO3 (3×30 ml) and water (30 ml). The organic phase was dried and concentrated and the residue was purified by chromatography on a column of silica gel, using a 1/1 petroleum ether/ethyl acetate mixture as eluent. A white solid was obtained.
Reaction SMILES: [F:1][C:2]([F:18])([C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)[CH2:3][NH:4][C@H:5]1[CH2:9][CH2:8][C@H:7]([NH2:10])[CH2:6]1.Cl[C:20]1[C:21]2[C:22](=[N:26][N:27]([CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][O:30]3)[CH:28]=2)[N:23]=[CH:24][N:25]=1.C(N(C(C)C)CC)(C)C>C(O)CCC>[F:1][C:2]([F:18])([C:11]1[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=1)[CH2:3][NH:4][C@H:5]1[CH2:9][CH2:8][C@H:7]([NH:10][C:20]2[C:21]3[C:22](=[N:26][N:27]([CH:29]4[CH2:34][CH2:33][CH2:32][CH2:31][O:30]4)[CH:28]=3)[N:23]=[CH:24][N:25]=2)[CH2:6]1
Reactant: Cc1ccc(C(F)(F)CN[C@H]2CC[C@H](N)C2)cc1
Reactant: Clc1ncnc2nn(C3CCCCO3)cc12
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(F)(F)CN[C@H]2CC[C@H](Nc3ncnc4nn(C5CCCCO5)cc34)C2)cc1
Temperature: 150 °C
Yield: 87.4 %

Procedure:
A mixture of (1S,3S)-N-[2,2-difluoro-2-(4-methylphenyl)ethyl]cyclopentane-1,3-diamine (627 mg, 2.46 mmol), 4-chloro-2-(tetrahydro-2H-pyran-2-yl)-2H-pyrazolo[3,4-d]pyrimidine (588 mg, 2.46 mmol), n-butanol (1.6 mL) and diisopropylethylamine (1.6 mL) was heated in microwave for 15 min at 150° C. The reaction mixture was concentrated in vacuo to a viscous brown oil, which was purified by silica gel chromatography (CH2Cl2/MeOH gradient) to give the title compound (0.982 g) as a cream colored foam: MS=457.4 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[C:15]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:16]([CH:21]=O)=[CH:17][CH:18]=[CH:19][CH:20]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C1(C2C=CC=CC=2)C=CC=CC=1CN1CCN(C2C=CC=CC=2)CC1>>[C:15]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][N:12]1[CH2:13][CH2:14][N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH2:10][CH2:11]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: O=Cc1ccccc1-c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: c1ccc(-c2ccccc2CN2CCN(c3ccccc3)CC2)cc1
Product: COc1ccccc1N1CCN(Cc2ccccc2-c2ccccc2)CC1

Procedure:
74 mg of the target compound (0.21 mmol, 37.5%) was obtained using 1-(2-methoxyphenyl)piperazine (211 mg, 1.10 mmol), biphenyl-2-carbaldehyde (100 mg, 0.55 mmol) and NaBH(OAc)3 (355 mg, 1.65 mmol) according to the synthesis method of Compound 1.
Reaction SMILES: O.O.O.O.O.O.O.O.[OH-].[Sr+2:10].[OH-].[NH2:12][C@H:13]([C:15]([OH:17])=[O:16])[CH3:14]>O>[NH2:12][C@H:13]([C:15]([O-:17])=[O:16])[CH3:14].[Sr+2:10].[NH2:12][C@H:13]([C:15]([O-:17])=[O:16])[CH3:14]
Reactant: C[C@H](N)C(=O)O
Agent: [OH-]
Agent: [Sr+2]
Solvent: O
Product: C[C@H](N)C(=O)[O-]

Procedure:
Strontium hydroxide octahydrate (1.0 g, 3.79 mmol) and L-alanine (0.67 g, 7.52 mmol) in water (30 ml) were stirred for 4 hours at room temperature. The mixture was filtered and the filtrate was evaporated to dryness and dried in vaccuo at ambient temperature. Yield 0.81 g (63%).
Reaction SMILES: [CH2:1]([N:5]([CH2:21][CH2:22][CH2:23][CH3:24])[C:6]([NH:8][C:9](=O)[C:10]1[CH:15]=[CH:14][C:13]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:12][CH:11]=1)=[S:7])[CH2:2][CH2:3][CH3:4].[OH-].[Na+].Cl[CH2:28]C(O)=O>O>[CH2:1]([N:5]([CH2:21][CH2:22][CH2:23][CH3:24])[C:6]1[S:7][CH:28]=[C:9]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:12][CH:11]=2)[N:8]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(O)CCl
Reactant: CCCCN(CCCC)C(=S)NC(=O)c1ccc(C(C)(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCN(CCCC)c1nc(-c2ccc(C(C)(C)C)cc2)cs1
Yield: 49.7 %

Procedure:
To a mixture of 174.15 g (0.50 mol) of N,N-di-n-butyl-N′-(4-t-butylbenzoyl)thiourea (compound 1-2), 44.0 g (1.10 mol) of sodium hydroxide and 500 ml of water was added 56.70 g (0.60 mol) of chloroacetic acid. The mixture was stirred and heated on a steam bath for 22 hrs and cooled. The water phase was decanted from the solid phase, and the solid was washed with water and methanol. Recrystallization of the solid from methanol gave 85.6 g (49.7% yield) of product; mp: 48.5-49.5° C. The NMR spectrum was consistent with the proposed structure. Anal. Calcd. for C21H32N2S: C, 73.20; H, 9.36; N, 8.13; S, 9.30. Found: C, 73.04; H, 9.29; N, 8.02; S, 9.19.
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13](=[O:28])[C:14]2[CH:19]=[CH:18][C:17]([O:20]CC3C=CC=CC=3)=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].C1CCCCC=1>[OH-].[OH-].[Pd+2].C(O)C>[CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13](=[O:28])[C:14]2[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1ccc(OC(=O)c2ccc(OCc3ccccc3)cc2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: C1=CCCCC1
Product: CCCCCc1ccc(OC(=O)c2ccc(O)cc2)cc1
Yield: 93.2 %

Procedure:
To 100 mL of dehydrated ethanol, 15.6 g (41.5 mmol) of 4-benzyloxy-benzoic acid 4-pentyl-phenyl ester, 25 mL of cyclohexene, and 0.78 g of palladium hydroxide/carbon were added. Then, the mixture was refluxed for 10 hours under argon. The resulting reaction mixture was filtered, and the filtered liquid was concentrated. The residue was recrystallized from toluene. As a result, 11.0 g of a white solid was obtained.
Reaction SMILES: CN([CH:4]=[O:5])C.[N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13]2[C:14]([NH2:19])=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:7]=1>O>[N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N:12]2[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[NH:19][C:4]2=[O:5])[CH:7]=1
Reactant: Nc1ccccc1Nc1cccnc1
Reactant: CN(C)C=O
Solvent: O
Product: O=c1[nH]c2ccccc2n1-c1cccnc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
N,N′-Carbonyldiimidazole(0.57 g) was added to a DMF solution (5 ml) of N-pyridine-3-ylbenzene-1,2-diamine(0.5 g). The mixture was stirred at room temperature for 1.5 hours. Water was added to the reaction mixture and the precipitated insoluble matter was separated, washed with water, and dried to give the title compound(0.5 g) as a pale whitish purple powder.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([CH2:13][O:14][C:15]3[CH:24]=[C:23]4[C:18]([CH2:19][CH2:20][NH:21][CH2:22]4)=[CH:17][CH:16]=3)[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.[ClH:34].[N:35]1([C:40](N)=[NH:41])C=CC=N1.C(OCC)C>CN(C)C=O>[ClH:34].[ClH:34].[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:8][CH2:9][CH:10]([CH2:13][O:14][C:15]3[CH:24]=[C:23]4[C:18]([CH2:19][CH2:20][N:21]([C:40]([NH2:41])=[NH:35])[CH2:22]4)=[CH:17][CH:16]=3)[CH2:11][CH2:12]2)=[CH:3][CH:2]=1
Reactant: N=C(N)n1cccn1
Reactant: c1cc(N2CCC(COc3ccc4c(c3)CNCC4)CC2)ccn1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: N=C(N)N1CCc2ccc(OCC3CCN(c4ccncc4)CC3)cc2C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 127.9 %

Procedure:
To a solution of 7-[1-(pyridin-4-yl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline (50 mg) in dimethylformamide (0.5 ml) were added diisopropylethylamine (0.027 ml) and 1H-pyrazole-1-carboxamidine hydrochloride (23 mg), and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, diethyl ether was added and insoluble material was collected by filtration. The obtained solid was washed with diethyl ether. A part (45 mg) of the obtained solid was treated with hydrogen chloride-methanol and dried under reduced pressure to give the title compound (44 mg).
Reaction SMILES: C([O:3][C:4]([C:6]1([CH:19]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[CH2:20][NH2:21])[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1)=O)C>C1(C)C=CC=CC=1>[C:15]([O:14][C:12]([N:8]1[CH2:9][CH2:10][CH2:11][C:6]2([C:4](=[O:3])[NH:21][CH2:20][CH:19]2[C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[CH2:7]1)=[O:13])([CH3:16])([CH3:17])[CH3:18]
Reactant: CCOC(=O)C1(C(CN)c2cccnc2)CCCN(C(=O)OC(C)(C)C)C1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCCC2(C1)C(=O)NCC2c1cccnc1

Procedure:
A solution of 3-(2-Amino-1-pyridin-3-yl-ethyl)-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (2.5 g, 6.6 mmol) in toluene (21 ml) was heated at reflux overnight. The resulting mixture was concentrated in vacuo and the residue was purified by chromatography on silica eluting with 0-10% MeOH in DCM to afford the individual diastereomers as white solids:
Reaction SMILES: CC(C)(C)[C@H](NC(N1C2CCNCC=2C(C2C=CC(F)=CC=2)=N1)=O)C(NC)=O.C=O.[CH3:31][C:32]([CH3:61])([CH3:60])[C@H:33]([NH:38][C:39]([N:41]1[C:49]2[CH2:48][CH2:47][N:46]([CH3:50])[CH2:45][C:44]=2[C:43]([C:51]2[CH:56]=[C:55](F)[C:54]([F:58])=[CH:53][C:52]=2F)=[N:42]1)=[O:40])[C:34]([NH:36][CH3:37])=[O:35]>>[CH3:31][C:32]([CH3:61])([CH3:60])[C@H:33]([NH:38][C:39]([N:41]1[C:49]2[CH2:48][CH2:47][N:46]([CH3:50])[CH2:45][C:44]=2[C:43]([C:51]2[CH:52]=[CH:53][C:54]([F:58])=[CH:55][CH:56]=2)=[N:42]1)=[O:40])[C:34]([NH:36][CH3:37])=[O:35]
Reactant: CNC(=O)[C@@H](NC(=O)n1nc(-c2cc(F)c(F)cc2F)c2c1CCN(C)C2)C(C)(C)C
Agent: C=O
Agent: CNC(=O)[C@@H](NC(=O)n1nc(-c2ccc(F)cc2)c2c1CCNC2)C(C)(C)C
Product: CNC(=O)[C@@H](NC(=O)n1nc(-c2ccc(F)cc2)c2c1CCN(C)C2)C(C)(C)C

Procedure:
Compound 54 was prepared by reductive amination of compound 53 with formaldehyde following the procedure as described for the synthesis of compound 37. 1H NMR (CDCl3) δ 7.94 (d, J=9.5 Hz, 1H), 7.65-7.68 (m, 2H), 7.11-7.27 (m, 2H), 6.15 (br, 1H), 4.16 (d, J=9.5 Hz, 1H), 3.63 (s, 2H), 3.17-3.22 (m, 2H), 2.83 (d, J=4.8 Hz, 3H), 2.78 (br, 1H), 2.55 (s, 3H), 1.06 (s, 9H). LCMS (+ESI) m/z=402.3 [M+H]+.
Reaction SMILES: [O:1]=[C:2]([O-:11])[C@H:3]([C@H:5]([C@@H:7]([CH2:9][OH:10])O)[OH:6])[OH:4].[K+].Cl>>[C:2]1(=[O:1])[O:11][C@H:7]([CH2:9][OH:10])[C@H:5]([OH:6])[C@@H:3]1[OH:4]
Reactant: O=C([O-])[C@@H](O)[C@@H](O)[C@H](O)CO
Agent: Cl
Agent: [K+]
Product: O=C1O[C@H](CO)[C@H](O)[C@@H]1O

Procedure:
reacting the potassium D-lyxonate in alcoholic solution with gaseous HCl to provide furanose ring closure and form the D-lyxono-1,4lactone,
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Cl[C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=2)[N:13]=[CH:12][N:11]=1>>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(Br)c1
Reactant: O=[N+]([O-])c1ccc2ncnc(Cl)c2c1
Product: O=[N+]([O-])c1ccc2ncnc(Nc3cccc(Br)c3)c2c1

Procedure:
In one particular, 3-bromoaniline is reacted with 4-chloro-6-nitroquinazoline to produce 4-[(3-bromophenyl)amino]-6-nitroquinazoline, which is reduced thereafter, by means of an ethanolic solution of hydrazine hydrate and Raney®Nickel, to the corresponding 6-aminoquinazoline. The 4-[(3-bromophenyl)amino]-6-aminoquinazoline is then reacted with bistributyltin in the presence of tetrakis(triphenylphosphine)palladium in THF solution and the obtained stanylated product is reacted thereafter with iodine 124, as described hereinabove. The obtained iodine-124 labeled 4-[(3-iodophenyl)amino]-6-aminoquinazoline is then reacted with an acryloyl chloride to produce an iodine-124 labeled N-{4-[(3-iodophenyl)amino]quinazoline-6-yl}acrylamide.