Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].[CH2:2]([Zn+])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1COCC1.[O:15]1[C:19]2[CH:20]=[CH:21][C:22]([C:24]3([C:27]([NH:29][C:30]4[CH:35]=[N:34][CH:33]=[C:32](Cl)[N:31]=4)=[O:28])[CH2:26][CH2:25]3)=[CH:23][C:18]=2[O:17][CH2:16]1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[O:15]1[C:19]2[CH:20]=[CH:21][C:22]([C:24]3([C:27]([NH:29][C:30]4[CH:35]=[N:34][CH:33]=[C:32]([CH2:2][C:3]5[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=5)[N:31]=4)=[O:28])[CH2:26][CH2:25]3)=[CH:23][C:18]=2[O:17][CH2:16]1
Reactant: O=C(Nc1cncc(Cl)n1)C1(c2ccc3c(c2)OCO3)CC1
Reactant: [Zn+]Cc1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Br-]
Solvent: C1CCOC1
Product: O=C(Nc1cncc(Cc2ccccc2)n1)C1(c2ccc3c(c2)OCO3)CC1
Reaction time: 0.33 h
Yield: 5.4 %

Procedure:
To a 0.5 M solution of benzylzinc(II) bromide in THF (0.8 mL, 0.4 mmol) was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (8 mg, 0.01 mmol) and the reaction was stirred under nitrogen for 20 minutes. 1-(Benzo[d][1,3]dioxol-5-yl)-N-(6-chloropyrazin-2-yl)cyclopropanecarboxamide (32 mg, 0.1 mmol) was added and the reaction was irradiated in a microwave reactor for 10 minutes at 150° C. The reaction was quenched with a saturated ammonium chloride solution (2 mL) and a saturated ethylenediamine tetraacetic acid disodium salt solution (2 mL). The mixture was stirred for 30 minutes before it was extracted with dichloromethane (3×4 mL). The organics were dried over Na2SO4 and evaporated. The crude product was dissolved in DMSO (1 mL) and purified by reverse-phase preparative liquid chromatography utilizing a gradient of 0-99% acetonitrile in water containing 0.05% trifluoracetic acid to yield the pure product (2.0 mg, 0.0054 mmol, 5.4%). ESI-MS m/z calc. 373.14. Found 374.1 (M+1)+; retention time 3.32 minutes.
Reaction SMILES: [CH2:1]([Li])[CH2:2]CC.C[Si](C#C)(C)C.[CH:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]#[C:21][C:22]1([O:30][Si](C)(C)C)[CH:27]2[CH2:28][CH2:29][N:24]([CH2:25][CH2:26]2)[CH2:23]1)=[O:13]>CCCCCC.O1CCCC1.C(OCC)(=O)C>[OH:13][CH:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]#[C:21][C:22]1([OH:30])[CH:27]2[CH2:28][CH2:29][N:24]([CH2:25][CH2:26]2)[CH2:23]1)[C:1]#[CH:2]
Reactant: [Li]CCCC
Reactant: C[Si](C)(C)OC1(C#Cc2ccccc2C=O)CN2CCC1CC2
Agent: C#C[Si](C)(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C#CC(O)c1ccccc1C#CC1(O)CN2CCC1CC2
Temperature: -70 °C
Reaction time: 1 h

Procedure:
Butyl Lithium in hexane (1.6M, 3.4 ml) was added slowly to a stirred solution of trimethylsilylacetylene (1.0 g) in tetrahydrofuran (20 ml) at -70° C. under an atmosphere of argon. The reaction mixture was stirred at -70° C. for a further 60 minutes. A solution of 3-[2-(2-formylphenyl)ethynyl]-3-trimethylsilyloxyquinuclidine (1.3 g) in tetrahydrofuran (10 ml) was added slowly to the reaction mixture whilst maintaining the temperature at -70° C. The reaction mixture was allowed to warm to ambient temperature and then stirred for 20 hours. The reaction mixture was evaporated, potassium carbonate (4 g) and methanol (50 ml) added and the mixture was stirred vigorously at ambient temperature for 60 minutes. The inorganic salts were removed by filtration and the filtrate was evaporated to give a residue which was dissolved in ethyl acetate (150 ml). The solution was extracted with 2M hydrochloric acid (2×100 ml). The aqueous extracts were combined, washed with ether (2×200 ml) and then basified to pH 9 by addition of 5N sodium hydroxide solution. The aqueous mixture was extracted with ethyl acetate (2×100 ml), the ethyl acetate extracts combined, washed with water (100 ml), brine (100 ml), dried (MgSO4) and evaporated. The residue was purified by column chromatography on alumina (Alumina N 32-63) using a gradient of 2:98 to 5:95 (v/v) methanol in ethyl acetate as eluent to give a solid which was recrystallised from a mixture of tetrahydrofuran/hexane to give 3-[2-{2-(1-hydroxy-1-ethynylmethyl)phenyl}ethynyl]quinuclidin-3-ol (110 mg), m.p. 217° C.; microanalysis; found: C, 74.6; H, 7.2; N, 4.6%, C18H19NO2.0.5 H2O requires: C, 74.5; H, 6.9; N, 4.8%; NMR: 1.2-1.4 (1H, m), 1.45-1.7 (1H, m), 1.8-2.05 (3H, m), 2.55-2.8 (4H, m), 2.85 (1H, d), 3.15 (1H, d), 3.38 (1H, dd), 5.58 (1H, s), 5.6-5.7 (1H, m), 6.08 (1H, d), 7.25-7.46 (3H, m), 7.65 (1H, d), m/z 282 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:36])[CH2:28]CC2C=CC=CC=2)=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([O:12][CH2:28][C:27]([C:24]2[CH:25]=[CH:26][C:21]([O:20][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:22][CH:23]=2)=[O:36])=[O:11])=[CH:7][CH:8]=1
Reactant: COc1ccc(CC(=O)O)cc1
Reactant: O=C(CCc1ccccc1)c1ccc(OCc2ccccc2)cc1
Solvent: CC#N
Product: COc1ccc(CC(=O)OCC(=O)c2ccc(OCc3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 128.1 %

Procedure:
To a stirred solution of 2-(4-methoxyphenyl)acetic acid (3 g, 0.01 mol) in acetonitrile (60 mL) were added TEA (16.5 mL, 0.129 mol) and 1-(4-(benzyloxy)phenyl)-3-phenylpropan-1-one (6.6 g, 0.02 mol). The reaction mixture was stirred at RT for 16 h, concentrated in vacuo and the resulting residue was extracted with EtOAc (2×100 mL). The combined organic layers were washed with water, dried over Na2SO4 and concentrated in vacuo to afford 2-(4-(benzyloxy)phenyl)-2-oxoethyl 2-(4-methoxyphenyl)acetate (5 g, 71%) as a brown solid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[C:14]([B:23]2[O:27][C:26](C)(C)[C:25](C)(C)[O:24]2)=[C:15]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])C=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:32](C)([O-:34])=[O:33].[OH-].[Na+].C1COCC1>O>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[C:14]2[B:23]([OH:27])[O:24][CH:25]([CH2:26][N+:32]([O-:34])=[O:33])[C:15]=2[CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[N+](=O)[O-]
Reactant: COc1ccc(C=O)c(B2OC(C)(C)C(C)(C)O2)c1OCCCOCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2c(c1OCCCOCc1ccccc1)B(O)OC2C[N+](=O)[O-]

Procedure:
Synthesized according to the methods of general procedure 8 in U.S. Pat. Pub. No. 20090227541 (U.S. patent application Ser. No. 12/142,692) using the following reactants and amounts: 3-(3-benzyloxy-propoxy)-4-methoxy-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde (3.36 g, 7.88 mmol), nitromethane (1.28 mL, 23.66 mmol), NaOH (0.22 g, 5.52 mmol), THF (6 mL), water (18 mL). Purification: flash column chromatography (30% EtOAc/hexanes): yield 1.2 g (41%). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.36 (s, 1H), 7.40-7.22 (m, 5H), 7.22-7.04 (m, 2H), 5.68 (dd, J=9.4, 2.7 Hz, 1H), 5.29 (dd, J=13.4, 2.5 Hz, 1H), 4.52 (dd, J=13.3, 9.4 Hz, 1H), 4.45 (s, 2H), 4.25 (t, J=6.2 Hz, 2H), 3.75 (s, 3H), 3.61 (t, J=6.2 Hz, 2H), 1.92 (quin, J=6.5 Hz, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2=[N:15][NH:16][C:17](=O)[CH:18]=[C:11]2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O=P(Cl)(Cl)[Cl:22]>>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[N:15]=[N:16][C:17]([Cl:22])=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CCc2cc(=O)[nH]nc2CC1
Product: CC(C)(C)OC(=O)N1CCc2cc(Cl)nnc2CC1

Procedure:
11 g 3-oxo-2,3,5,6,8,9-hexahydro-1,2,7-triaza-benzocycloheptene-7-carboxylic acid tert-butyl ester in 90 ml phosphor oxychloride was refluxed overnight. The phosphor oxychloride was quenched with 8.7 g sodium carbonate to pH 8 and 100 mL water was added to the reaction mixture. Di-tert.butyl-dicarbonate was added to the reaction mixture and stirred over night. The solution was extracted with 50% ethyl acetate in hexane. The extracted organic layer was dried, concentrated under reduced pressure and purified by column chromatography to afford 8.0 g of the desired product. (M+H)+=284
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([Cl:9])[N:3]=1.[C:10]1([NH:16][NH2:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O.O.O.C([O-])(=O)C.[Na+]>O.C(O)C>[C:10]1([N:16]([C:6]2[CH:5]=[C:4]([Cl:9])[N:3]=[C:2]([Cl:1])[N:7]=2)[NH2:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: NNc1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: NN(c1ccccc1)c1cc(Cl)nc(Cl)n1
Reaction time: 72 h

Procedure:
A mixture of 2,4,6-trichloropyrimidine (50ml.) and phenylhydrazine (45ml.) was added to a solution of sodium acetate trihydrate (100g.) in water (270ml.) and ethanol (720ml.). The resulting mixture was kept at room temperature for 3 days. The resulting crystalline precipitate was collected by filtration, washed with ethanol (100ml.) and dried at 60° C. to give N-phenyl-N-(2,6-dichloropyrimidin-4-yl)hydrazine, m.p. 114°-116° C.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:29])[NH:5][C:6]1[CH:27]=[CH:26][C:9]([O:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:24][CH3:25])=[C:18]([C:21]([OH:23])=O)[CH:19]=3)[N:14]=[CH:13][CH:12]=2)=[CH:8][C:7]=1[F:28])[CH3:2].[F:30][C@H:31]1[CH2:33][C@H:32]1[NH2:34].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(N(CC)CC)C>[F:30][C@H:31]1[CH2:33][C@H:32]1[NH:34][C:21]([C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][C:17]=1[O:24][CH3:25])[N:14]=[CH:13][CH:12]=[C:11]2[O:10][C:9]1[CH:26]=[CH:27][C:6]([NH:5][C:4]([NH:3][CH2:1][CH3:2])=[O:29])=[C:7]([F:28])[CH:8]=1)=[O:23]
Reactant: N[C@@H]1C[C@@H]1F
Reactant: CCNC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(C(=O)O)cc23)cc1F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Product: CCNC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(C(=O)N[C@@H]4C[C@@H]4F)cc23)cc1F

Procedure:
4-(4-(3-Ethylureido)-3-fluorophenoxy)-7-methoxyquinoline-6-carboxylic acid (20 mg) was treated with cis-2-fluorocyclopropylamine, triethylamine and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate in the same manner as Example 634, to obtain the title compound (9 mg) as a solid.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:29][C:30]1[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=1)[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][C@H:10]([N:13]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[C:23]([NH2:28])[CH:22]=1)(=[O:20])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:11][OH:12])=[O:4].[CH:40]1([C:43](Cl)=[O:44])[CH2:42][CH2:41]1>>[NH2:28][C:23]1[CH:22]=[C:21]([S:18]([N:13]([CH2:14][CH:15]([CH3:16])[CH3:17])[C@H:10]([CH2:11][OH:12])[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:3]([C@@H:2]([NH:1][C:43]([CH:40]2[CH2:42][CH2:41]2)=[O:44])[CH2:29][C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=2)=[O:4])(=[O:19])=[O:20])[CH:26]=[CH:25][C:24]=1[F:27]
Reactant: CC(C)CN([C@H](CO)CCCCNC(=O)[C@@H](N)Cc1ccc2ccccc2c1)S(=O)(=O)c1ccc(F)c(N)c1
Reactant: O=C(Cl)C1CC1
Product: CC(C)CN([C@H](CO)CCCCNC(=O)[C@H](Cc1ccc2ccccc2c1)NC(=O)C1CC1)S(=O)(=O)c1ccc(F)c(N)c1

Procedure:
The title compound was prepared from (2S,5S)-2-amino-N-{5-[(3-amino-4-fluoro-benzenesulfonyl)-isobutyl-amino]-6-hydroxy-hexyl}-3-naphthalen-2-yl-propionamide (example 81) as described in general procedure D using cyclopropanecarbonyl chloride. The final product was obtained in 48% yield.
Reaction SMILES: [CH:1]([C:3]1[C:7]([CH3:8])=[C:6]([CH3:9])[NH:5][C:4]=1[C:10]([O:12][CH3:13])=[O:11])=[O:2].[Cl:14][C:15]([CH2:17]Cl)=[CH2:16]>>[Cl:14][C:15](=[CH2:16])[CH2:17][N:5]1[C:6]([CH3:9])=[C:7]([CH3:8])[C:3]([CH:1]=[O:2])=[C:4]1[C:10]([O:12][CH3:13])=[O:11]
Reactant: C=C(Cl)CCl
Reactant: COC(=O)c1[nH]c(C)c(C)c1C=O
Product: C=C(Cl)Cn1c(C)c(C)c(C=O)c1C(=O)OC

Procedure:
The title compound was prepared as pale yellow crystals in 77.5% yeild in a similar procedure to that described in Referential Example 9 by using methyl 3-formyl-4,5-dimethylpyrrole-2-carboxylate and 2,3-dichloro-1-propene.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]2[O:9][CH2:8][CH:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23.[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>CS(C)=O>[Cl:1][C:2]1[C:3]([N:25]2[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]2)=[C:4]2[O:9][CH2:8][CH:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23
Reactant: CN1CCNCC1
Reactant: CC1COc2c(F)c(Cl)cc3c(=O)c(C(=O)O)cn1c23
Solvent: CS(C)=O
Product: CC1COc2c(N3CCN(C)CC3)c(Cl)cc3c(=O)c(C(=O)O)cn1c23
Yield: 34.4 %

Procedure:
150 mg (0.5 mmol) of 9-chloro-10-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid was suspended in 3 ml of dimethyl sulfoxide and 150 mg of N-methylpiperazine was added to the suspension. The mixture was then allowed to react at 120°-130° C. (bath temperature) for 6 hours. After cooling, the solvent was distilled off under reduced pressure and the residue was washed with diethyl ether to remove any insoluble substance. The resulting residue was purified by silica gel (7 g) column chromatography using methanol-chloroform (5:95 by volume) and then methanol-chloroform (10:90 by volume) as eluants, and the resulting product was recrystallized from ethanol to provide 65 mg (34.4% yield) of 9-chloro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid as pale yellow fine needles with m.p. 275°-276° C. (with decomposition).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:10]=1)[NH:7][CH:6]=[CH:5]2.CN1CCCC1=O.[CH3:22][S:23]([O-:25])=[O:24].[Na+]>[Cu](Cl)Cl.C(OCC)(=O)C>[CH3:22][S:23]([C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:10]=1)[NH:7][CH:6]=[CH:5]2)(=[O:25])=[O:24]
Reactant: COC(=O)c1cc(Br)cc2cc[nH]c12
Reactant: CS(=O)[O-]
Agent: Cl[Cu]Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: COC(=O)c1cc(S(C)(=O)=O)cc2cc[nH]c12
Temperature: 150 °C
Reaction time: 17 h
Yield: 30.4 %

Procedure:
A mixture of methyl 5-bromo-1H-indole-7-carboxylate (300 mg), 1-methyl-2-pyrrolidinone (6 mL), sodium methanesulfinate (600 mg), and copper iodide (I) (1.10 g) was stirred at 150° C. for 17 hours under an argon atmosphere. The reaction mixture was left to be cooled to room temperature, ethyl acetate was added thereto, and then the insoluble materials were removed by filtration. To this filtrate was added water, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine in this order, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain methyl 5-(methanesulfonyl)-1H-indole-7-carboxylate (91 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:25][CH3:26])=[C:8]([NH:10][C:11](=[O:24])[CH2:12][C:13](=[O:23])[C:14]2([CH3:22])[CH2:19][O:18][C:17]([CH3:21])([CH3:20])[O:16][CH2:15]2)[CH:9]=1)([O-])=O>O1CCCC1.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:25][CH3:26])=[C:8]([NH:10][C:11](=[O:24])[CH2:12][C:13](=[O:23])[C:14]2([CH3:22])[CH2:19][O:18][C:17]([CH3:20])([CH3:21])[O:16][CH2:15]2)[CH:9]=1
Reactant: COc1ccc([N+](=O)[O-])cc1NC(=O)CC(=O)C1(C)COC(C)(C)OC1
Agent: [Pd]
Solvent: C1CCOC1
Product: COc1ccc(N)cc1NC(=O)CC(=O)C1(C)COC(C)(C)OC1

Procedure:
N-(5-Nitro-2-methoxyphenyl)-2,2,5-trimethyl-β-oxo-1,3-dioxane-5-propanamide (22parts) are dissolved in dry tetrahydrofuran (250 parts) and placed in a Parr bottle. The nitro compound is hydrogenated at low pressure and at ambient conditions in a Parr apparatus over Pd-C catalyst (2.5 parts) for 3.5 hr. Thin layer chromatography is used to monitor reaction completion which appears to be quantitative with no other products except the desired amine. The reaction product is carried to the next synthesis without purification other than filtration to remove spent catalyst.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([NH:11][C:12](=O)[C@@H:13]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[CH2:8][CH2:9][CH3:10].O.[OH-].[Na+]>C1COCC1>[C:24]([O:23][C:22]([NH:21][C@@H:13]([CH2:14][CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1)[CH2:12][NH:11][CH2:7][CH2:8][CH2:9][CH3:10])=[O:28])([CH3:25])([CH3:26])[CH3:27]
Reactant: CCCCNC(=O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCNC[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 84.8 %

Procedure:
A 1 M solution of LiAlH4 in THF (2.5 mL, 2.5 mmol) was added to a solution of (S)-tert-butyl 1-(butylamino)-3-cyclohexyl-1-oxopropan-2-ylcarbamate (384.7 mg, 1.18 mmol) in THF (10 mL) at 0° C. The reaction was permitted to warm to 25° C. and stirred for 12 h. The reaction was cooled to 0° C., and H2O (0.2 mL) and then 1 N NaOH (0.2 mL) were introduced with cautious dropwise addition maintaining the temperature below 10° C. The resulting gel was filtered through a pad of Celite and the solids were washed with Et2O (50 mL). The solvent was removed to yield crude (2S)-2-(tert-butoxycarbonylamino)-1-butylamino-3-cyclohexylpropane (312.8 mg, 85%) as a white solid. MS ESI +ve m/z 313 (M+1). The crude amine was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:15]([NH:17][CH3:18])=[O:16])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([NH2:14])[CH:9]=2)=[CH:6][N:7]=1.Cl[C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH:14][C:20](=[O:21])[O:22][CH2:23][CH3:24])[CH:11]=[CH:12][CH:13]=2)=[N:4][C:3]=1[C:15]([NH:17][CH3:18])=[O:16]
Reactant: CNC(=O)c1nc(-c2cccc(N)c2)cnc1N
Reactant: CCOC(=O)Cl
Product: CCOC(=O)Nc1cccc(-c2cnc(N)c(C(=O)NC)n2)c1
Yield: 55 %

Procedure:
Ethyl (3-{5-amino-6-[(methylamino)carbonyl]pyrazin-2-yl}phenyl)carbamate was synthesized according to the procedure described in above from 3-amino-6-(3-aminophenyl)-N-methylpyrazine-2-carboxamide and ethyl chloroformate. Yield 55%: 1H NMR (400 MHz, d6-DMSO): 9.60 (br s, 1H), 8.68 (br s, 2H), 8.12 (br s, 1H), 7.80 (d, 1H), 7.52 (d, 1H), 7.39 (t, 1H), 4.06 (q, 2H), 2.85 (br s, 3H), 1.24 (t, 3H); MS (EI) for C15H17N5O3: 316 (MH+)
Reaction SMILES: [CH2:1]([C:3]1[C:4](NN)=[N:5][CH:6]=[N:7][C:8]=1[C:9]1[O:10][CH:11]=[CH:12][CH:13]=1)[CH3:2].C(#N)C.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.N1C=CC=CC=1>O>[CH2:1]([C:3]1[C:8]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)=[N:7][CH:6]=[N:5][CH:4]=1)[CH3:2]
Reactant: CCc1c(NN)ncnc1-c1ccco1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CC#N
Solvent: c1ccncc1
Solvent: O
Product: CCc1cncnc1-c1ccco1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.5 %

Procedure:
To a mixture of [5-ethyl-6-(furan-2-yl)-pyrimidin-4-yl]-hydrazine (2.85 g), acetonitrile (50 ml), and para-toluensulfonyl chloride (2.86 g), pyridine (2.37 g) was added under ice-cooling, and the reaction mixture was stirred at room temperature for 2 hours. To the reaction mixture, water (50 ml) was added, and the precipitated solids were collected by filtration. The solid was sequentially washed with water (20 ml) and acetonitrile (20 ml), and dried. To the resulting solid, sodium hydroxide (8.1 g), ethylene glycol (100 ml), and water (50 ml) were added, and stirred under reflux for 3 hours. After standing to cool the reaction mixture to room temperature, to the reaction mixture, water was added, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 2.03 g of 5-ethyl-4-furan-2-yl-pyrimidine.
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:18]=[N:17][C:16]2[C:11]1=[N:12][C:13]([N:20]1[CH:24]=[C:23]([C:25]([NH2:27])=[O:26])[CH:22]=[N:21]1)=[N:14][C:15]=2[NH2:19].CN(C(ON1N=N[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>ClCCl.CN(C1C=CN=CC=1)C>[OH:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:18]=[N:17][C:16]2[C:11]1=[N:12][C:13]([N:20]1[CH:24]=[C:23]([C:25]([NH:27][CH2:37][CH:42]3[CH2:38][CH2:39][CH2:40][CH2:41]3)=[O:26])[CH:22]=[N:21]1)=[N:14][C:15]=2[NH2:19]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: NC(=O)c1cnn(-c2nc(N)c3ncn([C@@H]4O[C@H](CO)[C@@H](O)[C@H]4O)c3n2)c1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: Nc1nc(-n2cc(C(=O)NCC3CCCC3)cn2)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The trisilyl derivative acid 20 (0.14 g, 0.2 mmol) was then dissolved in 5 mL dichloromethane. To the solution was added HBTU (0.19 g, 0.4 mmol), HOBt (0.076 g, 4 mmol), N-methylmorpholine (0.04 g, 0.4 mmol) and cat. DMAP. The mixture was allowed to stir at RT for 24 h. The mixture was then washed with 10% citric acid, saturated NaHCO3, brine and dried over MgSO4. The solvent was removed and the residue was treated with 5 mL 0.5N NH4F/MeOH. The solution was heated at reflux for 24 h. The solvent was evaporated and the residue was purified by preparative TLC to afford compound 21, MS 445.26 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][C:11]=3[N:12]=2)[CH2:4]1>C(O)(=O)C.O>[CH3:1][N:2]([CH3:20])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][C:11]=3[N:12]=2)[CH2:4]1
Reactant: CN(C)C1CCN(c2nc3cc([N+](=O)[O-])ccc3o2)C1
Solvent: CC(=O)O
Solvent: O
Product: CN(C)C1CCN(c2nc3cc(N)ccc3o2)C1
Yield: 86.2 %

Procedure:
Combine dimethyl-[1-(5-nitro-benzooxazol-2-yl)-pyrrolidin-3-yl]-amine (1.00 g, 3.62 mmol) and Fe0 (1.98 g, 35.4 mmol) in acetic acid (20 mL) and stir at 40° C. for 2 h. Dilute with water (50 mL) and filter through Celite®. Wash with copious amounts of water and MeOH. Make the filtrate alkaline with 5 N NaOH and extract twice with CH2Cl2 (2×). Concentrate in vacuo to afford the title compound (769 mg, 86%). 1H NMR (400 MHz, CDCl3): δ 7.00 (d, 1H, J=8.4 Hz), 6.70 (d, 1H, J=2.2 Hz), 6.32 (dd, 1H, J=8.4, 2.6 Hz), 3.88 (dd, 1H, J=9.9, 7.1 Hz), 3.81 (m, 1H), 3.62-3.50 (m, 3H), 3.39 (dd, 1H, J=10.1, 8.8 Hz), 2.83 (m, 1H), 2.30 (s, 6H), 2.21 (m, 1H), 1.93 (m, 1H).
Reaction SMILES: [CH:1]1([N:7]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:8]([NH:10][C:11]2[S:12][C:13]([CH:16]=O)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(=O)C.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH:18]1([N:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:8]([NH:10][C:11]2[S:12][C:13]([CH2:16][N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[CH:14][N:15]=2)=[O:9])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: C1COCCN1
Reactant: O=Cc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(Nc1ncc(CN2CCOCC2)s1)N(C1CCCCC1)C1CCCCC1
Yield: 34.4 %

Procedure:
Prepared as described in general procedure (P) using 1,1-dicyclohexyl-3-(5-formyl-thiazol-2-yl)-urea (100 mg. 0.30 mmol), acetic acid (18 μL, 0.30 mmol), morpholine (78 μL, 0.90 mmol) and sodium triacetoxyborohydride (70 mg, 0.33 mmol) to afford 42 mg (34%) of the desired product after purification.
Reaction SMILES: [CH2:1]([S:5][C:6]1[C:11]([CH2:12]Cl)=[CH:10][CH:9]=[CH:8][N:7]=1)[CH2:2]CC.C([O:16][C:17](=[O:29])[CH2:18][CH2:19][C:20]1[CH:25]=[C:24]([F:26])[C:23]([OH:27])=[C:22]([F:28])[CH:21]=1)C>>[CH2:1]([S:5][C:6]1[C:11]([CH2:12][O:27][C:23]2[C:22]([F:28])=[CH:21][C:20]([CH2:19][CH2:18][C:17]([OH:29])=[O:16])=[CH:25][C:24]=2[F:26])=[CH:10][CH:9]=[CH:8][N:7]=1)[CH3:2]
Reactant: CCOC(=O)CCc1cc(F)c(O)c(F)c1
Reactant: CCCCSc1ncccc1CCl
Product: CCSc1ncccc1COc1c(F)cc(CCC(=O)O)cc1F
Yield: 76 %

Procedure:
3-Chloromethyl-2-ethylsulfanyl-pyridine (0.1 g, 0.53 mmol) obtained in Step C of Preparation Example 11 and 3-(3,5-difluoro-4-hydroxy-phenyl)-propionic acid ethyl ester (0.12 g, 0.53 mmol) obtained in Step D of Preparation Example 2 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (76% yield).