Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][Si](C)(C)C)=[CH:5][C:4]=1[F:15])[CH3:2].[OH2:16]>O1CCCC1.S(=O)(=O)(O)O.Cl[Hg]Cl>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:16])[CH3:10])=[CH:5][C:4]=1[F:15])[CH3:2]
Reactant: O
Reactant: CCc1ccc(C#C[Si](C)(C)C)cc1F
Agent: Cl[Hg]Cl
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: CCc1ccc(C(C)=O)cc1F
Reaction time: 6 h

Procedure:
To a stirred mixture of (4-ethyl-3-fluoro-phenylethynyl)-trimethyl-silane (1.43 g, 6.5 mmol), HgCl2 (250 mg, 0.92 mmol) in aqueous tetrahydrofuran (tetrahydrofuran, 10 mL, H2O, 3 mL), concentrated sulfuric acid (98%, 0.70 mL) was added and the mixture stirred for 6 hours. The mixture was poured into water (50 mL) and extracted with ether (3×20 mL). Removal of solvent gave a solid that was chromatographed (20% thyl acetate/hexanes) to give the desired product. 560 mg, 52%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[C:9](Br)[CH:8]=[N:7][C:6]=1[NH:12][CH3:13])[CH3:2].[CH2:15]([Zn]CC)[CH3:16]>O1CCOCC1>[CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[C:9]([CH2:15][CH3:16])[CH:8]=[N:7][C:6]=1[NH:12][CH3:13])[CH3:2]
Reactant: CC[Zn]CC
Reactant: CCOC(=O)c1cc(Br)cnc1NC
Solvent: C1COCCO1
Product: CCOC(=O)c1cc(CC)cnc1NC
Yield: 15 %

Procedure:
A solution of 5-bromo-2-methylamino-nicotinic acid ethyl ester (400 mg, 1.54 mmol), diethylzinc solution (1 M in hexane, 3.1 mL, 3.1 mmol), and dichloro[1,1′-bis(diphenylphosphine)ferrocene]palladium(II) (34 mg, 46 μmol) in 1,4-dioxane was heated at reflux for 2 h, then partitioned between ethyl acetate and sat. aq. ammonium chloride solution. The organic layer was washed with brine, dried (MgSO4), and evaporated. Chromatography (SiO2, heptane-ethyl acetate gradient) afforded the title compound (48 mg, 15%). Colourless liquid, MS (ISP): 209.3 (M+H)+.
Reaction SMILES: [CH2:1]([N:5]1[CH:10]=[CH:9][C:8](O)=[C:7]([C:12]#[N:13])[C:6]1=[O:14])[CH2:2][CH2:3][CH3:4].P(Br)(Br)([Br:17])=O>CN(C=O)C>[Br:17][C:8]1[CH:9]=[CH:10][N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6](=[O:14])[C:7]=1[C:12]#[N:13]
Reactant: CCCCn1ccc(O)c(C#N)c1=O
Reactant: O=P(Br)(Br)Br
Solvent: CN(C)C=O
Product: CCCCn1ccc(Br)c(C#N)c1=O
Temperature: 110 °C
Yield: 70.9 %

Procedure:
To a solution of intermediate 4 (39 g, 203 mmol) in DMF (600 ml) was added phosphoric tribromide (116 g, 406 mmol) and the mixture was heated at 110° C. for 1.5 hours. After cooling in an ice bath the solution was partitioned between water and EtOAc. After three extractions with EtOAc the combined organic fractions were washed with brine, dried over Na2SO4 and the solvent evaporated in vacuo. The crude product was purified by column chromatography (silica gel; DCM as eluent). The desired fractions were collected and evaporated in vacuo to yield intermediate 6 (36.7 g, 72%).
Reaction SMILES: C(O)C.Cl.[CH:5]1([C:8]2[CH:9]=[C:10]([C:48]([O:50]CC)=[O:49])[C:11](=[O:47])[N:12]3[C:17]=2[C:16]([CH3:18])=[C:15]([C:19]2[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=2)[CH2:24][N:23](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:22]4)[CH:14]=[CH:13]3)[CH2:7][CH2:6]1>C1COCC1>[CH:5]1([C:8]2[CH:9]=[C:10]([C:48]([OH:50])=[O:49])[C:11](=[O:47])[N:12]3[C:17]=2[C:16]([CH3:18])=[C:15]([C:19]2[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=2)[CH2:24][NH:23][CH2:22]4)[CH:14]=[CH:13]3)[CH2:6][CH2:7]1
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc4c(c3)CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)C4)ccn2c1=O
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(-c2ccc3c(c2)CNC3)ccn2c(=O)c(C(=O)O)cc(C3CC3)c12
Temperature: 50 °C
Reaction time: 2 h
Yield: 76.3 %

Procedure:
8.3 ml of ethanol, 2.8 ml of THF and 1.5 ml of 1N hydrochloric acid were added to 275.4 mg of ethyl 1-cyclopropyl-9-methyl-8-(2-tritylisoindoline-5-yl)-4-oxo-4H-quinolizine-3-carboxylate (I) and the resulting mixture was stirred at 50° C. for 2 hours. The solvent was distilled off under reduced pressure and water was added to the resulting residue and the resulting residue was washed with ethyl acetate, and thereafter, the resulting water layer was concentrated under reduced pressure. 30 ml of water, 10 ml of ethanol and 5 ml of 1N sodium hydroxide were added to the resulting residue and the resulting mixture was stirred at 50° C. for 3.5 hours. The reaction solution was concentrated under reduced pressure, and thereafter, dissolved in 4 ml of water and neutralized with 1N hydrochloric acid. The precipitated crystal was separated by filtering to obtain 120.0 mg of 1-cyclopropyl-9-methyl-8-(isoindoline-5-yl)-4-oxo-4H-quinolizine-3-carboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH3:17])[CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=[N:4][C:3]=1[C:18]([NH2:20])=[O:19].[Br:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](OC)=O)=[CH:24][CH:23]=1>>[Br:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]2[NH:20][C:18](=[O:19])[C:3]3[N:4]=[N:5][N:6]([CH:7]([CH3:17])[CH2:8][CH2:9][CH2:10][C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:2]=3[N:1]=2)=[CH:24][CH:23]=1
Reactant: COC(=O)Cc1ccc(Br)cc1
Reactant: CC(CCCc1ccccc1)n1nnc(C(N)=O)c1N
Product: CC(CCCc1ccccc1)n1nnc2c(=O)[nH]c(Cc3ccc(Br)cc3)nc21

Procedure:
Analogously to the procedure of Example 1, the title compound is prepared from 1.0 g (3.8 mmol) of 5-amino-1-(1-methyl-4-phenyl-butyl)-1H-[1,2,3]triazole-4-carboxamide and 2.61 g (11.4 mmol) of methyl 4-bromophenylacetate.
Reaction SMILES: [CH3:1][C:2]([CH3:28])([CH3:27])[C@H:3]([NH:7][C:8]([C:10]1[N:11]=[C:12]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:13]2[CH2:19][CH2:18][CH2:17][N:16]([CH3:20])[CH2:15][C:14]=12)=[O:9])[C:4](O)=[O:5].[CH:29]([NH2:32])([CH3:31])[CH3:30].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH:29]([NH:32][C:4](=[O:5])[C@@H:3]([NH:7][C:8]([C:10]1[N:11]=[C:12]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:13]2[CH2:19][CH2:18][CH2:17][N:16]([CH3:20])[CH2:15][C:14]=12)=[O:9])[C:2]([CH3:27])([CH3:28])[CH3:1])([CH3:31])[CH3:30]
Reactant: CN1CCCn2c(-c3ccccc3)nc(C(=O)N[C@H](C(=O)O)C(C)(C)C)c2C1
Reactant: CC(C)N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: CC(C)NC(=O)[C@@H](NC(=O)c1nc(-c2ccccc2)n2c1CN(C)CCC2)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
To a solution of Compound 471 (30 mg, 0.078 mmol) and isopropylamine (33 μL, 0.39 mmol) in DMF was added TBTU (38 mg, 0.15 mmol). After stirring at room temperature overnight, the crude reaction mixture was purified by a prep LC-MS with 5% to 95% MeCN/water in 15 min to give pure Compound 472 at 66% yield. 1H-NMR (400 MHz, CDCl3) δ: 1.04 (s, 9H), 1.11-1.28 (m, 6H), 1.95 9(br, 2H) 2.59 (s, 3H), 3.25 (br, 2H), 4.01-4.16 (m, 1H), 4.23 (d, J=9.3 Hz, 1H), 5.80 (br, 1H), 7.47-7.55 (m, 5H), 7.95 (d, J=9.3 Hz, 1H). LCMS (+ESI) m/z 426.0 [M+H]+.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]1[CH3:15])C.[H-].C([Al+]CC(C)C)C(C)C>C(COC)OC.ClCCl.C1CCCCC1>[CH3:15][C:7]1[N:6]([CH2:5][CH:4]=[O:3])[C:14]2[C:9]([CH:8]=1)=[CH:10][CH:11]=[CH:12][CH:13]=2
Reactant: CCOC(=O)Cn1c(C)cc2ccccc21
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCCCC1
Solvent: COCCOC
Solvent: ClCCl
Product: Cc1cc2ccccc2n1CC=O
Temperature: -70 °C
Reaction time: 4 h
Yield: 68.6 %

Procedure:
A solution of (2-methyl-indol-1-yl)-acetic acid ethyl ester (400 mL, 1.97 mmol) in dimethoxyethane-dichloromethane (1:1, 30 mL) was cooled to −70° C. and treated with a solution of diisobutyl aluminum hydride in cyclohexane (3.9 mL, 1.0 M). The reaction was stirred at −70° C. for 4 h, quenched with an aqueous solution of hydrochloric acid (80 mL, 1 N) and extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered and concentrated, and the residue was purified to give (2-methyl-indol-1-yl)-acetaldehyde (234 mg, 75% yield). LCMS (m/z): 206.1 (M+1).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][C:11]([NH:13][CH:14]([B:27]3[O:35][CH:34]4[C:29]([CH3:39])([CH:30]5[CH2:36][CH:32]([CH2:33]4)[C:31]5([CH3:38])[CH3:37])[O:28]3)[CH2:15][C:16]3[C:17]([O:25][CH3:26])=[C:18]([CH:22]=[CH:23][CH:24]=3)[C:19]([OH:21])=[O:20])=[O:12])=[CH:7][CH:8]=2)[CH2:3][NH:2]1.[CH2:40]=O>[Pd].CO>[CH3:26][O:25][C:17]1[C:16]([CH2:15][CH:14]([NH:13][C:11](=[O:12])[CH2:10][C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[CH2:1][N:2]([CH3:40])[CH2:3]3)[B:27]2[O:35][CH:34]3[C:29]([CH3:39])([CH:30]4[CH2:36][CH:32]([CH2:33]3)[C:31]4([CH3:38])[CH3:37])[O:28]2)=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([OH:21])=[O:20]
Reactant: COc1c(CC(NC(=O)Cc2ccc3c(c2)CNC3)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)O
Reactant: C=O
Agent: [Pd]
Solvent: CO
Product: COc1c(CC(NC(=O)Cc2ccc3c(c2)CN(C)C3)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)O
Reaction time: 18 h

Procedure:
A solution of 3-[2-(2-2,3-Dihydro-1H-isoindol-5-yl-acetylamino)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethyl]-2-methoxy-benzoic acid (0.110 g, 0.207 mmol), formaldehyde (37% in H2O, 0.06 mL, 0.740 mmol), and methanol (2.5 mL) was purged with argon. Palladium on carbon (10%, 0.049 g) was added, the flask evacuated, and the reaction placed under hydrogen for 18 hr. The reaction mixture was filtered through a Celite-plugged filter frit, washed with CH3OH and CH2Cl2, and concentrated. The crude product was carried forward without purification. ESI-MS m/z 547 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C:6]([CH3:18])=[C:5]([C:19]([OH:21])=O)[CH:4]([C:22]2[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][CH:23]=2)[C:3]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31].CN(C)C=O.[NH2:40][CH2:41][CH2:42][OH:43]>>[NH2:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:17])[F:16])[CH:9]=2)[C:6]([CH3:18])=[C:5]([C:19]([NH:40][CH2:41][CH2:42][OH:43])=[O:21])[CH:4]([C:22]2[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][CH:23]=2)[C:3]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: CCOC(=O)C1=C(N)N(c2cccc(C(F)(F)F)c2)C(C)=C(C(=O)O)C1c1ccc(C#N)cc1
Reactant: NCCO
Solvent: CN(C)C=O
Product: CCOC(=O)C1=C(N)N(c2cccc(C(F)(F)F)c2)C(C)=C(C(=O)NCCO)C1c1ccc(C#N)cc1
Reaction time: 0.25 h

Procedure:
To a solution of 23.57 mg (0.05 mmol) of the compound of Example 60 in 100 μl dimethylformamide 16.22 mg (0.10 mmol) 1-(1H-imidazol-1-ylcarbonyl)-1H-imidazole and 12.22 mg (0.20 mmol) 2-aminoethanol are added. After stirring for 15 minutes, the reaction mixture is allowed to stand at room temperature for two days. The reaction mixture is purified by preparative HPLC (column: Agilent Zorbax Extend C18 20 mm×50 mm, 5 μm; solvent A: acetonitrile, solvent B: water+0.1% triethylamine; gradient: 0 min 10% A, 2 min 10% A, 6 min 90% A, 7 min 90% A, 7.1 min 10% A, 8 min 10% A; wavelength: 220 nm; injection volume: ca 500 μl; number of injections: 1). The product containing fractions are combined and concentrated in vacuo.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[C:13]([F:14])=[CH:12][C:11]([F:15])=[CH:10][C:9]=2[F:16])=[C:6](Cl)[N:5]2[N:18]=[CH:19][N:20]=[C:4]2[N:3]=1.Cl.[F:22][C:23]([F:28])([F:27])[C@@H:24]([NH2:26])[CH3:25].C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([C:8]2[C:13]([F:14])=[CH:12][C:11]([F:15])=[CH:10][C:9]=2[F:16])=[C:6]([NH:26][C@@H:24]([CH3:25])[C:23]([F:28])([F:27])[F:22])[N:5]2[N:18]=[CH:19][N:20]=[C:4]2[N:3]=1
Reactant: Fc1cc(F)c(-c2c(Cl)nc3ncnn3c2Cl)c(F)c1
Reactant: C[C@H](N)C(F)(F)F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@H](Nc1c(-c2c(F)cc(F)cc2F)c(Cl)nc2ncnn12)C(F)(F)F
Temperature: 25 °C
Reaction time: 13 h
Yield: 95.7 %

Procedure:
A mixture of 5,7-dichloro-6-(2,4,6-trifluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidine (3.0 g, 9.4 mmol), (1S)-2,2,2-trifluoro-1-methylethylamine hydrogen chloride (4.2 g, 28.2 mmol), and N,N-diisopropylethylamine (4.9 mL, 28.2 mmol) in 100 mL of N,N-dimethylformamide is stirred at room temperature under nitrogen atmosphere for 13 h. The reaction mixture is diluted with ethyl acetate. The organic layer is washed with 1 N hydrochloric acid (2×) and saturated sodium chloride (2×), dried over magnesium sulfate, and concentrated to a residue. The residue is chromatographed over silica gel, eluting with 20% ethyl acetate in hexanes. Concentration provides 5-chloro-6-(2,4,6-trifluorophenyl)-N-[(1S)-2,2,2-trifluoro-1-methylethyl][1,2,4]triazolo[1,5-a]pyrimidin-7-amine as a light yellow solid (3.56 g). MS: m/z 396.0 (M+H).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]1[CH:9]=[C:8]2[C:10]([CH3:16])=[CH:11][C:12]([CH3:15])([CH3:14])[NH:13][C:7]2=[CH:6][CH:5]=1.[C:17](Cl)([Cl:19])=[O:18]>C(OC(=O)C)C>[Cl:19][C:17]([N:13]1[C:7]2[C:8](=[CH:9][C:4]([O:3][CH2:2][CH3:1])=[CH:5][CH:6]=2)[C:10]([CH3:16])=[CH:11][C:12]1([CH3:15])[CH3:14])=[O:18]
Reactant: O=C(Cl)Cl
Reactant: CCOc1ccc2c(c1)C(C)=CC(C)(C)N2
Solvent: CCOC(C)=O
Product: CCOc1ccc2c(c1)C(C)=CC(C)(C)N2C(=O)Cl

Procedure:
A solution of ethoxyquin (30 g) in ethylacetate (300 ml) was added dropwise at room temperature to a stirred saturated solution of phosgene in ethylacetate (100 ml). Phosgene was rapidly and continuously bubbled into the stirred solution during the period of addition (2 hours). After the addition of the ethoxyquin solution was finished, phosgene bubbling was stopped and the solvent was gradually distilled (atmospheric pressure). At the end of the distillation, CCl4 (50 ml) was added and distillation continued under a slow stream of N2 (to eliminate traces of phosgene), another portion of CCl4 (50 ml) was added. Undesired ethoxyquin hydrochloride was filtered off (9.26 g), and the filtrate was evaporated to dryness under reduced pressure, yielding 1-Chlorocarbonyl-6-ethoxy-1,2-dihydro-2,2,4-trimethylquinoline as yellow, viscous syrup, which crystallised on standing (31.67 g). Recrystallisation from acetone. m.p.: 75.5°-76.5°.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH2:10][C:11]([O:13]C)=[O:12])[CH:7]=[CH:8][CH:9]=1)[CH3:2].[OH-].[Na+].Cl>C(O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH2:10][C:11]([OH:13])=[O:12])[CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCOc1cccc(CC(=O)OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1cccc(CC(=O)O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Methyl 3-ethoxyphenylacetate (7.5 g, 38.6 mmol) was dissolved in ethanol (15 mL) and 1N NaOH (40 mL) was added. The mixture was stirred at room temperature for 30 minutes then acidified by addition of 1N hydrochloric acid (45 mL). A white precipitate formed which was filtered, washed with 1N HCl, water and dried. 3-Ethoxyphenylacetic acid (6.4 g, 92%). 1H NMR (500 MHz, CDCl3) δ 7.20 (1H, dd), 6.8 (3H, m), 4.0 (2H, q), 3.6 (2H, s), 1.4 (3H, t).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[CH:25][N:24]=[C:23](Cl)[N:22]=3)[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:28][CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH:28][CH2:29][CH2:30][C:31]4[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=4)[N:22]=3)[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cccc(-c3ccnc(Cl)n3)c2)CC1
Reactant: NCCc1ccc(O)cc1
Product: CC(C)(C)OC(=O)N1CCC(Nc2cccc(-c3ccnc(NCCc4ccc(O)cc4)n3)c2)CC1

Procedure:
Intermediate 7 was coupled with tyramine following procedure F. LC-MS showed the product had the expected M+H+ of 490. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 8.28 (d, 1H) 7.25 (m, 3H) 7.05 (m, 2H) 6.92 (d, 1H) 6.7 (m, 3H) 5.45 (m, 1H) 4.0 (m, 2H) 3.7 (m, 4H) 3.49 (m, 1H) 2.85 (m, 4H) 2.45 (t, 2H) 1.5 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][O-].[K+].S(=O)(=O)(O)O>C(O)C>[Br:1][C:2]1[C:3]2[N:4]([C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][N:9]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCOC(=O)C(Cl)=C[O-]
Reactant: Nc1ncc(Cl)cc1Br
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)c1cnc2c(Br)cc(Cl)cn12
Yield: 57.4 %

Procedure:
A mixture of 3-bromo-5-chloropyridin-2-amine (1.0 g), potassium 2-chloro-3-ethoxy-3-oxoprop-1-en-1-olate (2.27 g), sulfuric acid (0.334 mL) and ethanol (20 mL) was heated with reflux overnight. The solvent was evaporated under reduced pressure, the residue was neutralized with saturated aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and the obtained solid was recrystallized from ethyl acetate/hexane to give the title compound (0.84 g).
Reaction SMILES: [ClH:1].C([O:9][C@@H:10]1[C@H:14]([O:15]CC2C=CC=CC=2)[CH2:13][N:12]([CH2:23][CH:24]2[CH2:26][CH2:25]2)[C@:11]1([CH3:35])OCC1C=CC=CC=1)C1C=CC=CC=1.Cl.C([OH:39])C>[Pd]>[ClH:1].[CH:24]1([CH2:23][N:12]2[CH2:13][C@@H:14]([OH:15])[C@H:10]([OH:9])[C@H:11]2[CH2:35][OH:39])[CH2:25][CH2:26]1
Reactant: C[C@@]1(OCc2ccccc2)[C@H](OCc2ccccc2)[C@H](OCc2ccccc2)CN1CC1CC1
Reactant: CCO
Agent: [Pd]
Agent: Cl
Product: OC[C@@H]1[C@@H](O)[C@H](O)CN1CC1CC1
Reaction time: 24 h
Yield: 100 %

Procedure:
To a solution of (2R,3R,4R)-3,4-dibenzyloxy-2-benzyloxy-methyl-1-cyclopropylmethylpyrrolidine, hydrochloride (Compound 8) (0.14 g, 0.28 mmol) in 96% ethanol (15 ml) was added 10% Pd/C (50 mg) and 1 M hydrochloric acid (0.1 ml). The reaction mixture was hydrogenated in Parr apparatus at 40 psi for 24 hours. The mixture was filtered and concentrated in vacuo giving (2R,3R,4R)-1-cyclopropylmethyl-3,4-dihydroxy-2-hydroxymethylpyrrolidine, hydrochloride as a yellow oil (0.063 g, yield: 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7])=[CH:4][CH:3]=1.S(Cl)([Cl:19])(=O)=O>C(Cl)(Cl)Cl>[Cl:19][C:4]1[CH:3]=[C:2]([Cl:1])[CH:15]=[CH:14][C:5]=1[C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOC(=O)CC(=O)c1ccc(Cl)cc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CC(=O)c1ccc(Cl)cc1Cl
Yield: 107.2 %

Procedure:
To a cold (5° C.) vigorously stirred mixture of 121.87 g (0.936 mole) of ethyl acetoacetate, 314 ml. of benzene and 626 ml. of water was added 41.25 ml. of 33% sodium hydroxide. To the above mixture was added simultaneously, in two dropping funnels, 177.0 g (1.01 mole) of p-chlorobenzoyl chloride and 188.8 ml. of 33% sodium hydroxide in 2 hours. The reaction mixture became pasty. The reaction mixture was heated at 35° C. for 1 hour, cooled and filtered to give 170.0 g of sodium salt of ethyl 2-benzoylacetoacetate. Part (150 g) of this salt was added to a mixture of 39.0 g (0.729 mole) of ammonium chloride and 78 ml. of concentrated ammonium hydroxide in 780 ml. of water. The mixture was stirred at 40°-50° C. for 3 hours and cooled in an ice bath. The precipitate was filtered to give 115.5 g of yellow solid which was Kugelrohr distilled to give 76.0 g (38% based on ethyl acetoacetate) of crude ethyl p-chlorobenzoylacetate. A mixture of 40.0 g (0.175 mole) of crude ethyl p-chlorobenzoylacetate, 24.2 g (0.18 mole) of sulfuryl chloride and some chloroform was held at reflux for 6 hours, cooled and concentrated to give 49.0 g of crude ethyl 2-chloro-p-chlorobenzoylacetate. A mixture of 46.0 g (0.174 mole) of crude ethyl 2-chloro-p-chlorobenzoylacetate, 13.25 g (0.174 mole) of thiourea, and 174 ml. of ethanol was held at reflux for 2 hours and cooled. The precipitate was filtered and neutralized with saturated sodium bicarbonate. The insoluble material was filtered to give 37.0 g (80%) of ethyl 2-amino-4-p-chlorophenyl-5-thiazolecarboxylate, m.p. 198°-200° C.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([NH:9][CH2:10][CH2:11][C:12]#[N:13])[CH:6]=[CH:7][CH:8]=1.N.[H][H]>[Ni].CO>[F:1][C:2]([F:14])([F:15])[C:3]1[CH:4]=[C:5]([NH:9][CH2:10][CH2:11][CH2:12][NH2:13])[CH:6]=[CH:7][CH:8]=1
Reactant: N#CCCNc1cccc(C(F)(F)F)c1
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CO
Product: NCCCNc1cccc(C(F)(F)F)c1
Yield: 100 %

Procedure:
A mixture of 13.6 parts of 3-[[3-(trifloromethyl)phenyl]amino]propanenitrile and 400 parts of methanol saturated with ammonia was hydrogenated at normal pressure and at a temperature below 20° C. with 3 parts of Raney Nickel catalyst. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 13 parts (100%) of N1 -[3-(trifluoromethyl)phenyl]-1,3-propanediamine as a residue (int. 106).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:6]([C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=1)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.[OH-].[Na+]>[N:1]1([CH2:6][C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNC1
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Product: COC(=O)c1ccc(CN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 49.8 %

Procedure:
Pyrrolidine (0.12 mL, 1.52 mmol), methyl 4-formylbenzoate (0.250 g, 1.52 mmol), NaBH(OAc)3 (0.52 g, 2.4 mmol) and 5 Å molecular sieves were dissolved in 1,2-dichloroethane (5 mL) under Ar atmosphere and stirred for 24 h at RT. Then, the reaction was diluted with 2 N NaOH (30 mL) and extracted with EtOAc (3×20 mL). The combined organic fractions were washed with brine (15 mL), dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified via automated column chromatography (50-100% EtOAc/hexane, 25 g cartridge) to yield the title compound as a clear oil (0.166 g, 50%). 1H NMR (400 MHz, CDCl3): δ 8.00 (d, J=8.0 Hz, 2H), 7.43 (d, J=8.0 Hz, 2H), 3.92 (s, 3H), 3.69 (s, 2H), 2.54 (br, 4H), 1.81 (t, J=3.2 Hz, 4H).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]([NH:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][CH:15]=[CH:14]3)[CH:5]=1.[CH2:20]([NH:22][C:23](=[O:31])OC1C=CC=CC=1)[CH3:21]>CN(C)C=O>[CH2:20]([NH:22][C:23]([N:16]1[C:17]2[C:13](=[CH:12][C:11]([NH:10][C:6]3[CH:5]=[C:4]([NH:3][C:23]([NH:22][CH2:20][CH3:21])=[O:31])[N:9]=[CH:8][N:7]=3)=[CH:19][CH:18]=2)[CH:14]=[CH:15]1)=[O:31])[CH3:21]
Reactant: Nc1cc(Nc2ccc3[nH]ccc3c2)ncn1
Reactant: CCNC(=O)Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1cc(Nc2ccc3c(ccn3C(=O)NCC)c2)ncn1
Reaction time: 0.5 h
Yield: 4.5 %

Procedure:
Sodium hydride (69 mg, 1.73 mmol) was suspended in N,N-dimethylformamide (3 ml); 6-amino-4-(1H-5-indolylamino)pyrimidine (311 mg, 1.38 mmol) was added thereto at room temperature under nitrogen stream; the reaction mixture was stirred for 30 minutes; phenyl N-ethylcarbamate (286 mg, 1.73 mmol) was added thereto; and the reaction mixture was stirred overnight. The reaction mixture was partitioned between a solvent mixture of ethyl acetate-tetrahydrofuran (1:1) and a saturated aqueous solution of sodium hydrogencarbonate; the organic layer was washed with water and brine, and dried over anhydrous sodium sulfate; the solvent was distilled off; the residue was purified by silica gel column chromatography (eluent; ethyl acetate:tetrahydrofuran=1:1); eluted fractions were concentrated; ethyl acetate was added to the residue to crystallize; and the crystals were filtered off, and dried under aeration to yield the title compound (14.3 mg, 0.039 mmol, 2.8%) as white crystals.