Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[O:15][CH2:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)[C:6]1=[O:27])[CH2:2][CH2:3][CH3:4].[BH4-].[Na+].O>CO>[CH2:1]([C:5]1([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[O:15][CH2:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)[CH:6]1[OH:27])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1(CCCC)CCc2c(OCc3ccc4ccccc4n3)cccc2C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCCC1(CCCC)CCc2c(OCc3ccc4ccccc4n3)cccc2C1O

Procedure:
To a solution of 2,2-dibutyl-3,4-dihydro-5-(2-quinolylmethoxy)-1(2H)-naphthalenone (500 Mg) in methanol (20 ml) was added sodium borohydride (68 mg) with stirring in an ice bath. The mixture was stirred for half an hour in an ice bath and then sodium borohydride (136 mg) was added thereto at the same temperature. The solution was stirred for 1.5 hours at ambient temperature, followed by the addition of sodium borohydride (68 mg). The mixture was stirred at ambient temperature for half an hour and then poured into water with stirring in an ice bath. The separated solid was collected by filtration, washed with water (50 ml), dried, and recrystallized from methanol to yield 2,2-dibutyl-5-(2-quinolylmethoxy)-1,2,3,4-tetrahydro-1-naphthol (388 mg). mp: 122°-123° C.
Reaction SMILES: B(Br)(Br)Br.[F:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([C:16]([O:18]C)=[O:17])=[CH:13][CH:14]=2)[C:9]([C:20]2[C:25]([O:26]C)=[CH:24][CH:23]=[CH:22][C:21]=2[F:28])=[N:8][CH:7]=1.ClCCl>O>[F:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([C:16]([OH:18])=[O:17])=[CH:13][CH:14]=2)[C:9]([C:20]2[C:25]([OH:26])=[CH:24][CH:23]=[CH:22][C:21]=2[F:28])=[N:8][CH:7]=1
Reactant: COC(=O)c1ccc2c(F)cnc(-c3c(F)cccc3OC)c2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: O=C(O)c1ccc2c(F)cnc(-c3c(O)cccc3F)c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.2 %

Procedure:
Boron tribromide (1M dichloromethane solution, 2.5 mL) was added to a mixture of methyl 4-fluoro-1-(2-fluoro-6-methoxyphenyl)isoquinoline-7-carboxylate (270 mg) and dichloromethane (3 mL) under ice-cooling, and stirred at room temperature for 16 hours. The reaction mixture was diluted with water, and the precipitate was collected by filtration to obtain 4-fluoro-1-(2-fluoro-6-hydroxyphenyl)isoquinoline-7-carboxylic acid (240 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[N:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[CH:17][CH:16]=2)[CH:7]=1.Cl.[N:29]1[CH:34]=[CH:33][CH:32]=[C:31]([S:35](Cl)(=[O:37])=[O:36])[CH:30]=1>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([S:35]([C:31]2[CH:30]=[N:29][CH:34]=[CH:33][CH:32]=2)(=[O:37])=[O:36])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[N:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[CH:17][CH:16]=2)[CH:7]=1
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: COC(=O)CCc1cccc(CNCc2ccc(-c3ncccn3)cc2)c1
Agent: Cl
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cccc(CN(Cc2ccc(-c3ncccn3)cc2)S(=O)(=O)c2cccnc2)c1

Procedure:
The title compound of Step A was prepared following the method described in Step B of Example 1 from 3-{3-[(4-pyrimidin-2-yl-benzylamino)-methyl]-phenyl}-propionic acid methyl ester, prepared in Step A of Example 11z, and pyridine-3-sulfonyl chloride hydrochloride salt, of Preparation 2, using triethylamine in place of N,N-diisopropylethylamine. 1H NMR (400 MHz, CDCl3) δ 9.03 (d, 1H), 8.77 (m, 3H), 8.29 (d, 2H), 8.03 (m, 1H), 7.40 (m, 1H), 7.15 (m, 4H), 7.04 (d, 1H), 6.90 (d, 1H), 6.84 (s, 1H), 4.41 (s, 2H), 4.34 (s, 2H), 3.62 (s, 3H), 2.80 (t, 2H), 2.49 (t, 2H); MS 487 (M−1).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]([P:24]([O:29][CH2:30][CH3:31])(=[O:28])[O:25][CH2:26][CH3:27])[P:16]([O:21][CH2:22][CH3:23])(=[O:20])[O:17][CH2:18][CH3:19].C(N(CC)CC)C>ClCCl>[C:1]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]([P:24]([O:29][CH2:30][CH3:31])(=[O:28])[O:25][CH2:26][CH3:27])[P:16]([O:21][CH2:22][CH3:23])(=[O:20])[O:17][CH2:18][CH3:19])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOP(=O)(OCC)C(CCCCN)P(=O)(OCC)OCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOP(=O)(OCC)C(CCCCNC(=O)c1ccccc1)P(=O)(OCC)OCC
Temperature: 25 °C
Yield: 30.7 %

Procedure:
A solution of benzoyl chloride (0.73 g, 5.0 mmol) in dichloromethane was added slowly to a solution of tetraethyl 5-aminopentane-1,1-bisphosphonate (1.50 g, 4.5 mmol) from Example 11, part A, and triethylamine (0.76 mL, 5.5 mmol) in dichloromethane at 0° C. After warming to room temperature for 30 minutes, the reaction was quenched by addition of 1N HCl (30 mL). The product was extracted into dichloromethane (2×20 mL) and the combined organic layers were washed with saturated NaHCO3 (2×15 mL), dried (Na2SO4), and concentrated in vacuo. Flash chromatography on silica gel eluting with 15% i-propanol in ethylacetate in EtOAc gave the title compound (0.64 g) as an oil.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:10]2[N:11]([CH3:27])[CH:12]=[C:13]([C:16]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)=[O:17])[C:14](=[O:15])[C:9]=2[S:8][C:7]=1[CH2:28][N:29]([CH2:31][C@@H:32]([OH:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=1)[CH3:30])C=C>CO.[Pd]>[Cl:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][NH:18][C:16]([C:13]2[C:14](=[O:15])[C:9]3[S:8][C:7]([CH2:28][N:29]([CH2:31][C@@H:32]([OH:39])[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=4)[CH3:30])=[C:6]([CH2:5][OH:4])[C:10]=3[N:11]([CH3:27])[CH:12]=2)=[O:17])=[CH:25][CH:24]=1
Reactant: C=CCOCc1c(CN(C)C[C@@H](O)c2ccccn2)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Agent: [Pd]
Solvent: CO
Product: CN(Cc1sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c2c1CO)C[C@@H](O)c1ccccn1
Temperature: 100 °C
Yield: 29 %

Procedure:
A mixture of 104 mg of 3-[(allyloxy)methyl]-N-(4-chlorobenzyl)-2-{[[(2R)-2-hydroxy-2-pyridin-2-ylethyl](methyl)amino]methyl}-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide and 75 mg of 5% Pd/C in 5 mL of MeOH is stirred and heated at 100° C. in a sealed tube for 3 days, then cooled and filtered through Celite. The filtrate is concentrated under reduced pressure, and the residue flash chromatographed on silica gel using 5% MeOH in CH2Cl2 to afford 28 mg of the title compound as a pale yellow glass. Recrystallization from EtOAc-hexane provides 18 mg of white solid.
Reaction SMILES: [Cr:1]([O-:5])([O-:4])(=[O:3])=[O:2].[Na+:6].[Na+].[Cr:8]([O-])([O-:11])(=[O:10])=[O:9]>O>[Cr:1]([O:5][Cr:8]([O-:11])(=[O:10])=[O:9])([O-:4])(=[O:3])=[O:2].[Na+:6].[Na+:6]
Reactant: O=[Cr](=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]

Procedure:
A sodium monochromate solution containing from 300 to 500 g/l Na2CO4 is obtained by leaching the furnace clinker leaving the roasting furnace with water or a chromate containing aqueous solution, adjusting the pH value of the mash from 7 to 9.5 and removing the insoluble constituents by filtration. The pH value is generally adjusted with sulfuric acid and/or with sodium dichromate solution. To produce sodium dichromate, the monochromate ions of the solution are converted into dichromate ions either by acidification with sulfuric acid, by acidification with carbon dioxide under pressure or by electrolytic acidification. Where sulfuric acid is used for acidification, sodium sulfate is formed and precipitates when the solution is concentrated to approximately 70% by weight Na2Cr2O7.2H2O. The chromate-containing sodium sulfate obtained has to be worked up.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)[CH:8]=[CH:9][CH:10]=[O:11].[CH3:13][C:14]1[O:15][CH:16]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH:18]=1>C(#N)C>[CH3:13][C:14]1[O:15][C:16]([CH:8]=[CH:9][CH:10]=[O:11])=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH:18]=1
Reactant: CN(C)C=CC=O
Reactant: Cc1cc(-c2ccc(F)cc2)co1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: Cc1cc(-c2ccc(F)cc2)c(C=CC=O)o1
Temperature: -23 °C
Reaction time: 0.25 h
Yield: 96.8 %

Procedure:
A solution of 1.1 mL (11.9 mmol) of phosphorus oxychloride in 15 mL of acetonitrile was allowed to react with 1.2 mL (11.9 mmol) of 3-dimethylaminoacrolein at -23° C. After 0.25 hour at -23° C., 1.4 g (7.9 mmol) of 2-methyl-4-(4'-fluorophenyl)furan in 10 mL of acetonitrile was added dropwise. The reaction mixture was stirred at -23° C. for 0.15 hour then at 24° C. for 2 hours. The reaction was quenched upon treatment with 20 mL of 1M NaOH and extracted three times with CHCl3. The CHCl3 layers were combined, dried (MgSO4) and concentrated under reduced pressure. Column chromatography (3:1 hexanes-diethyl ether) of the residue on silica gel produced 1.76 g (97%) of 3-(5-methyl-3-p-fluorophenyl-furan-2-yl)acrylaldehyde as a solid (m.p. 89°-90° C.), homogeneous by TLC and spectroscopic criteria; Rf 0.58 (1:1 hexanes-diethyl ether); IR (KBr) 1655, 1600, 1205, 1118, 1095 cm-1 ; 1HNMR (300 MHz, CDCl3) 9.60 (d, 1H, J=10.5 Hz), 7.41 (m, 2H), 7.27 (d, 1H, J=15 Hz), 7.18 (t, 2H, J=9.0 Hz), 6.64 (dd, 1H, J=10.5 Hz, 15 Hz), 6.32 (s, 1H), 2.42 (s, 3H).
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[Br:14][C:15]([F:23])([F:22])[C:16]([F:21])([F:20])[CH2:17][CH2:18]I.Cl>CN(C)C=O>[CH2:12]([O:11][C:3](=[O:10])[CH:4]([CH2:18][CH2:17][C:16]([F:21])([F:20])[C:15]([Br:14])([F:23])[F:22])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:13]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: FC(F)(Br)C(F)(F)CCI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CCC(F)(F)C(F)(F)Br)C(=O)OCC
Reaction time: 1 h
Yield: 73.7 %

Procedure:
In nitrogen atmosphere, 1900 mL of dimethylformamide was prepared with the addition of 320 g (7.17 mol) of sodium hydride (60% mineral oil-containing product), followed by putting it in an iced bath with the addition of 1208 g (7.17 mol) of diethyl malonate. After 1 hour of stirring, 2400 g (7.17 mol) of 1-bromo-1,1,2,2-tetrafluoro-4-iodobutane was added to this solution while regulating the reaction solution so as to be not higher than 100° C. After 1 hour of stirring, 1000 mL of 1N hydrochloric acid was added thereto, followed by extracting it with diisopropyl ether. Then, an organic layer was concentrated, followed by distillation under reduced pressure (115-116° C./0.53 kPa), thereby obtaining 1940 g of the objective 2-(4-bromo-3,3,4,4-tetrafluorobutyl)-malonic acid diethyl ester (74% yield, 89% GC purity) in the form of a light yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([F:27])[CH:5]=[C:6]2[C:11]=1[N:10]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[C:14]([O:19][CH3:20])[CH:13]=1)[CH:9]=[C:8]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:7]2=[O:26].S(=O)(=O)(O)O.[N+:34]([O-])([O-:36])=[O:35].[K+]>>[Cl:1][C:2]1[C:3]([F:28])=[C:4]([F:27])[CH:5]=[C:6]2[C:11]=1[N:10]([C:12]1[CH:13]=[C:14]([O:19][CH3:20])[C:15]([F:18])=[CH:16][C:17]=1[N+:34]([O-:36])=[O:35])[CH:9]=[C:8]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:7]2=[O:26]
Reactant: O=[N+]([O-])[O-]
Reactant: CCOC(=O)c1cn(-c2ccc(F)c(OC)c2)c2c(Cl)c(F)c(F)cc2c1=O
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCOC(=O)c1cn(-c2cc(OC)c(F)cc2[N+](=O)[O-])c2c(Cl)c(F)c(F)cc2c1=O
Temperature: 0 °C
Yield: 57.3 %

Procedure:
Ethyl 8-chloro-6,7-difluoro-1-(4-fluoro-3-methoxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (830 mg) was added to concentrated sulfuric acid (4 ml), and anhydrous potassium nitrate (250 mg) was added portionwise to the mixture while stirring under ice cooling. The resultant mixture was stirred for 15 minutes under ice cooling and for 50 minutes at room temperature. The reaction mixture was poured into ice water (50 ml) and then extracted with chloroform (50 ml). After a chloroform layer was washed with distilled water (20 ml), dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. Deposits were dispersed in ethanol, collected by filtration and washed with ethanol and diisopropyl ether in that order to obtain the title compound (528 mg) as a colorless powder.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:5]2[O:10]C[N:8]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:7][C:6]=2[CH:15]=1.[N:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)(C)C.O>[C:11]([NH:8][CH2:7][C:6]1[CH:15]=[C:2]([C:25]2[CH:26]=[CH:27][N:22]=[CH:23][CH:24]=2)[CH:3]=[C:4]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:5]=1[OH:10])([CH3:14])([CH3:12])[CH3:13]
Reactant: OB(O)c1ccncc1
Reactant: CC(C)(C)N1COc2c(cc(Br)cc2-c2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Product: CC(C)(C)NCc1cc(-c2ccncc2)cc(-c2ccccc2)c1O
Temperature: 55 °C
Yield: 32.4 %

Procedure:
A mixture of 6-bromo-3-(tert-butyl)-8-phenyl-3,4-dihydro-2H-benzo[e][1,3]oxazine (from Example 42, Step 2) (0.404 g, 1.17 mmol), pyridin-4-ylboronic acid (0.288 g, 2.0 equiv), and potassium carbonate (0.647 g, 4 equiv) in isopropanol (30 mL) and water (6 mL) was purged with nitrogen for 20 minutes. Tetrakis(triphenylphosphine)Pd (0) (88 mg, 6.5 mol %) was added and the resulting mixture was heated at 55° C. for 4 hours. The cooled reaction mixture was concentrated and the resulting residue was purified by column chromatograph to give 3-((tert-butylamino)methyl)-5-(pyridine-4-yl)-[1,1′-biphenyl]-2-ol (0.126 g).
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[N:24]=[C:23]([C:25](O)=[O:26])[CH:22]=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.[CH:36]1([NH2:39])[CH2:38][CH2:37]1>>[CH:36]1([NH:39][C:25]([C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([C:16]3[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]4[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:34])[CH3:35])([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[O:9][C:8]4=[O:10])[CH3:12])=[CH:18][CH:17]=3)[N:24]=2)=[O:26])[CH2:38][CH2:37]1
Reactant: NC1CC1
Reactant: C[C@@H](c1ccc(-c2cccc(C(=O)O)n2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2cccc(C(=O)NC3CC3)n2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (6-(4-{(S)-1-[(S)-6-(2-hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[1,3]oxazinan-3-yl]-ethyl}-phenyl)-pyridine-2-carboxylic acid and cyclopropylamine following a procedure analogous to that described in Example 203. Mass spectrum (ESI+): m/z=514 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:7][CH2:6][CH2:5][CH:4]([CH:8]([O:10][C:11]([CH3:15])([CH3:14])[CH2:12][OH:13])[CH3:9])[CH2:3]1.[CH3:17][O:18][C:19](=O)[CH2:20][O:21]C.C[O-].[Na+]>CO>[CH3:16][C:2]1([CH3:1])[CH2:7][CH2:6][CH2:5][CH:4]([CH:8]([O:10][C:11]([CH3:15])([CH3:14])[CH2:12][O:13][C:20](=[O:21])[CH2:19][O:18][CH3:17])[CH3:9])[CH2:3]1
Reactant: COCC(=O)OC
Reactant: CC(OC(C)(C)CO)C1CCCC(C)(C)C1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COCC(=O)OCC(C)(C)OC(C)C1CCCC(C)(C)C1

Procedure:
57 g (0.25 mol) of 2-[1-(3,3-dimethyl-cyclohexyl)-ethoxy]-2-methyl-propan-1-ol, 41.6 g (0.4 mol) of methoxyacetic acid methyl ester and 0.3 g of sodium methylate in 50 g methanol were placed in a 250-ml stirred vessel and were boiled under reflux. During this, methanol was distilled off via a still head. Then 100 ml water and 100 ml toluene were added to the reaction solution at room temperature, the aqueous phase was separated, the organic phase was washed with water until neutral and concentrated by evaporation. The raw product (81 g) was fractionated on a 30-cm Vigreux column in vacuum.
Reaction SMILES: [I-].[CH:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([CH3:4])[CH3:3].C([Li])CCC.[Br:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH:33]=O>C1COCC1>[CH:33]([C:32]1[CH:31]=[C:30]([Br:29])[CH:37]=[CH:36][CH:35]=1)=[C:2]([CH3:4])[CH3:3]
Reactant: O=Cc1cccc(Br)c1
Reactant: CC(C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)=Cc1cccc(Br)c1
Temperature: -23 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
To a suspension of iso-propyltriphenylphosphonium iodide in dry THF (150 mL) under nitrogen at −23° C. was added 2.5 M n-butyl lithium in hexanes (13.4 mL, 33.6 mmol). The resulting solution was stirred 0.5 hours at −23° C., the cooling bath was removed, and the reaction was stirred 0.5 hours at ambient temperature to give a dark red homogeneous solution which was cooled to −23° C. To the solution was added neat 3-bromobenzaldehyde (3.73 mL, 32 mmol). The cooling bath was removed, the reaction was stirred at ambient temperature for 1 hour, quenched by adding excess saturated ammonium chloride, and partitioned between ether and brine. The organic layer was washed with saturated aqueous Na2S2O5, brine, dried (Na2SO4), filtered, and concentrated under vacuum. Purification on silica gel with hexanes gave the title compound (5.34 g, 79%) as a colorless oil.
Reaction SMILES: O.[NH2:2][NH2:3].[Cl:4][C:5]1[CH:10]=[C:9](Cl)[N:8]=[CH:7][N:6]=1>C(O)C>[Cl:4][C:5]1[CH:10]=[C:9]([NH:2][NH2:3])[N:8]=[CH:7][N:6]=1
Reactant: NN
Reactant: Clc1cc(Cl)ncn1
Solvent: O
Solvent: CCO
Product: NNc1cc(Cl)ncn1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
At RT, 11.8 ml (12.1 g, 241.6 mmol) of hydrazine hydrate are added dropwise with stirring to a solution of 20.0 g (134.3 mmol) of 4,6-dichloropyrimidine in 300 ml of ethanol. If the solution becomes turbid during the metered addition of the hydrazine hydrate, further ethanol (about 400 ml) is added. The reaction solution is stirred at RT for 12 h. For work-up, the precipitated solid is filtered off, the filter residue is washed twice with in each case 150 ml of water and twice with in each case 100 ml of diethyl ether and the product is dried under reduced pressure. The concentrated mother liquor gives a further crystalline product fraction. Yield: 16.8 g (87% of theory)
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([CH2:11][CH2:12][O:13][CH3:14])[CH:8]=[C:7]([O:15][CH2:16][O:17][CH3:18])[CH:6]=1.[Br:19]N1C(=O)CCC1=O.O>CN(C)C=O>[CH3:18][O:17][CH2:16][O:15][C:7]1[C:8]([Br:19])=[C:9]([CH2:11][CH2:12][O:13][CH3:14])[CH:10]=[C:5]([O:4][CH2:3][O:2][CH3:1])[CH:6]=1
Reactant: COCCc1cc(OCOC)cc(OCOC)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: COCCc1cc(OCOC)cc(OCOC)c1Br
Temperature: 4 °C
Reaction time: 1 h
Yield: 87.2 %

Procedure:
1,3-Bis(methoxymethoxy)-5-(2-methoxyethyl)benzene (5.00 g, 19.5 mmol) obtained in Example 1, Step 3 was dissolved in N,N-dimethylformamide (40 mL). After the solution was cooled to 4° C., N-bromosuccinimide (3.47 g, 19.5 mmol) was added thereto, followed by stirring for 1 hour. To the reaction mixture was added water (0.10 L), and the mixture was extracted with a mixed solvent of hexane and ethyl acetate (hexane/ethyl acetate=1/1, 0.30 L). The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/9-1/2) to obtain 3,5-bis(methoxymethoxy)-2-bromo-1-(2-methoxyethyl)benzene (5.7 g, 87%).
Reaction SMILES: [OH:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]([OH:12])=[CH:4][CH:3]=1.[CH3:13][O:14]C(Cl)Cl.Cl>ClCCl>[OH:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]([OH:12])=[CH:4][C:3]=1[CH:13]=[O:14]
Reactant: Oc1ccc(O)c2c1CCCC2
Reactant: COC(Cl)Cl
Agent: Cl
Solvent: ClCCl
Product: O=Cc1cc(O)c2c(c1O)CCCC2
Yield: 60 %

Procedure:
To a solution of 1,4-dihydroxy-5,6,7,8-tetrahydronaphthalene (164 mg, 1 mmol) in dichloromethane (5 ml) is added titantetrachloride (569 mg, 3 mmol). Then 1,1-dichlorodimethyl ether (173 mg, 1.5 mmol) is added dropwise under vigorous stirring and the reaction mixture stirred for another 3 h at room temperature. Finally hydrochloric acid 5% (1 ml) is added under ice-cooling. The organic phase is separated and the residual aqueous phase repeatedly extracted with ether. The combined organic phases are washed with saturated saline solution, dried over sodium sulfate and evaporated under vacuum. The residue is crystallized from benzene or alternatively submitted to flash chromatography on silica gel with benzene/ethylacetate 85:15 to afford pure 1,4-dihydroxy-5,6,7,8-tetrahydronaphthalene-2-carboxaldehyde in about 60% yield (108 mg).
Reaction SMILES: [N:1]([C@H:4]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5]1)=[N+]=[N-].[H][H]>CO>[NH2:1][C@H:4]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5]1
Reactant: [N-]=[N+]=N[C@H]1CCN(C(=O)OCc2ccccc2)C1
Reactant: [H][H]
Solvent: CO
Product: N[C@H]1CCN(C(=O)OCc2ccccc2)C1
Yield: 99.9 %

Procedure:
A solution of 14.7 g (60 mmol) of (S)-3-azido-1-pyrrolidinecarboxylic acid, phenylmethyl ester in 200 ml of methanol was treated with 1.0 g of Raneynickel and shaken in a hydrogen atmosphere at pressures of 49.5-51 psi and temperatures of 25.3°-29.4° for nine hours. The catalyst was removed by filtration and the solvent was removed in vacuo to give 13.2 g of the title compound.
Reaction SMILES: [NH2:1][C@@H:2]([CH:11]([CH3:13])[CH3:12])[C:3]([N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4].S=[C:15]1[CH2:19][S:18][C:17](=[O:20])[NH:16]1>C(O)C>[CH3:12][CH:11]([CH3:13])[C@H:2]([NH:1][C:15]1[CH2:19][S:18][C:17](=[O:20])[N:16]=1)[C:3]([N:5]1[CH2:6][CH2:7][O:8][CH2:9][CH2:10]1)=[O:4]
Reactant: O=C1NC(=S)CS1
Reactant: CC(C)[C@H](N)C(=O)N1CCOCC1
Solvent: CCO
Product: CC(C)[C@H](NC1=NC(=O)SC1)C(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.8 %

Procedure:
To a solution of (2S)-2-amino-3-methyl-1-(morpholin-4-yl)butan-1-one (850 mg) in ethanol (10 mL) was added 4-thioxothiazolidin-2-one (608 mg) at room temperature. The reaction mixture was stirred at room temperature overnight, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (583 mg).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][C:13](=[O:19])[CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C(O[CH:23]=[C:24]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:25]([O:27][CH2:28][CH3:29])=[O:26])C.O>CN(C)C=O>[CH2:15]([CH:14]([CH2:17][CH3:18])[C:13]([NH:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][N:3]=[C:2]2[NH:1][CH:23]=[C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:19])[CH3:16]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CCC(CC)C(=O)Nc1ccc2ncnc(N)c2c1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(=CNc1ncnc2ccc(NC(=O)C(CC)CC)cc12)C(=O)OCC
Temperature: 100 °C
Reaction time: 0.67 h
Yield: 73.7 %

Procedure:
A mixture of 4-amino-6-(2-ethylbutyramido)quinazoline (0.9 g) and diethyl ethoxymethylenepropanedioate (0.95 g) in N,N-dimethylformamide (4 ml) was stirred at 100° C. for 2 hours and 40 minutes. Water was added to the reaction mixture. The resulting crystals were collected, washed with water and dried. The crude crystals were chromatographed on silica gel with 20% ethyl acetate-chloroform and recrystallized from a mixture of ethyl acetate, chloroform and hexane to give crystaline diethyl [[6-(2-ethylbutyramido)-4-quinazolinylamino]methylene]propanedioate (1.1 g).