Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([F:17])[CH:16]=1)[CH2:5][NH:6][C:7](=[O:13])[CH:8]([CH3:12])[C:9]([OH:11])=O.Cl.[C:19]([O:23][C:24](=[O:37])[C@H:25]([CH2:27][C:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[NH:30][CH:29]=1)[NH2:26])([CH3:22])([CH3:21])[CH3:20].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.O>[C:19]([O:23][C:24](=[O:37])[CH:25]([NH:26][C:9](=[O:11])[CH:8]([C:7](=[O:13])[NH:6][CH2:5][C:4]1[CH:14]=[C:15]([F:17])[CH:16]=[C:2]([F:1])[CH:3]=1)[CH3:12])[CH2:27][C:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[NH:30][CH:29]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: CC(C(=O)O)C(=O)NCc1cc(F)cc(F)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC(C(=O)NCc1cc(F)cc(F)c1)C(=O)NC(Cc1c[nH]c2ccccc12)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
N-(3,5-Difluoro-benzyl)-2-methyl-malonamic acid (3.00 g, 12.3 mmol), L-tryptophan-tert-butylester hydrochloride (3.66 g, 12.3 mmol), TBTU (O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-tetrafluoroborate, 3.96 g, 12.3 mmol) and triethylamin (3.74 g, 3.70 mmol) were dissolved in DMF (15 ml) and stirred for 5 h at r.t. The reaction mixture was poured into water and the product mixture was extracted with ethyl acetate. The organic layers were dried (Na2SO4). After evaporation of the solvent, the title compound, MS: m/e=486.4 (M+H+), (6.45 g, quant.) was obtained by chromatographic purification of the residue (silica gel, MeOH, CH2Cl2).
Reaction SMILES: [C:1]([O:11]CC)(=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O-])=O.[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[SH:21]>O>[S:21]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:7]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([OH:11])=[O:10]
Reactant: CCOC(=O)CCCCCC(=O)[O-]
Reactant: Nc1ccccc1S
Solvent: O
Product: O=C(O)CCCCCc1nc2ccccc2s1
Temperature: 130 °C
Reaction time: 2 h

Procedure:
A mixture of monoethyl heptanedioate (9.41 g), o-aminothiophenol (5.35 ml) and polyphosphoric acid (150 g) was heated to 130° C. with stirring and the reaction was conducted at the same temperature for 2 hours. After cooling to 40° C., pure water (300 ml) was added and the mixture was stirred at 50° C. for 30 minutes. After cooling to room temperature, the reaction mixture was extracted with ethyl acetate (500 ml). The organic layer was extracted with 1N NaOH, acidified with concentrated HCl, and reextracted with ethyl acetate. The extract was dried and concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate) to provide the title compound (4.6 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])(C)(C)C.[CH2:20]([Sn:24](Cl)([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH3:23].[Cl-].[NH4+]>C1COCC1>[C:1]([O:5][C:6](=[O:14])[NH:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[Sn:24]([CH2:25][CH2:26][CH2:27][CH3:28])([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:20][CH2:21][CH2:22][CH3:23])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: CC(C)(C)OC(=O)Nc1ccncc1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cnccc1NC(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 3 h
Yield: 49 %

Procedure:
Pyridin-4-yl-carbamic acid tert-butyl ester (1.74 g, 8.95 mmol) (prepared as described in Venuti et al, J. Med. Chem. 1988, 31(11), 2136-45) dissolved in THF (150 mL) was cooled to −78° C. and a solution of 1.7M tert-butyllithium in hexanes (11.6 mL, 19.70 mmol) was added dropwise. After the addition, the stirring was continued for 1 h to −78° C. and the solution was then allowed to warm to −20° C. and stirred for an additional 3 h. The reaction was cooled again to −78° C. and tributyltin chloride (2.91 mL, 10.74 mmol) was added dropwise and the reaction was allowed to reach room temperature overnight. A saturated ammonium chloride solution was added and the product extracted with dichloromethane. The combined organics were dried over magnesium sulfate, the solvent was evaporated and residue purified by flash chromatography eluting with 20% ethyl acetate in hexanes to yield 2.12 g of (3-tributylstannyl-pyridin-4-yl)-carbamic acid tert-butyl ester.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2([OH:12])[CH2:11][O:10][CH2:9]2)=[CH:6][N:5]=[C:4]([C:13]#[N:14])[CH:3]=1.[F:15][C:16]([F:20])([F:19])[CH2:17][OH:18].CC(C)([O-])C.[K+]>CN(C=O)C>[OH:12][C:8]1([C:7]2[C:2]([O:18][CH2:17][C:16]([F:20])([F:19])[F:15])=[CH:3][C:4]([C:13]#[N:14])=[N:5][CH:6]=2)[CH2:11][O:10][CH2:9]1
Reactant: OCC(F)(F)F
Reactant: N#Cc1cc(Cl)c(C2(O)COC2)cn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cc(OCC(F)(F)F)c(C2(O)COC2)cn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 92.1 %

Procedure:
To a solution of 4-chloro-5-(3-hydroxyoxetan-3-yl)pyridine-2-carbonitrile (example 123b, 1 g, 4.75 mmol) in dry DMF (20 ml) under an argon atmosphere cooled down to 0° C. was added 2,2,2-trifluoroethanol (570 mg, 412 μl, 5.7 mmol) followed by addition of potassium tert-butoxide (639 mg, 5.7 mmol). The reaction was stirred at 0° C. for 10 minutes and then stirred at 80° C. for 2 hours. DMF was removed in vacuo and the residue was dissolved in ethylacetate. The organic phase was extracted with a 2M aqueous solution of sodium carbonate. The organic phase was collected and the aqueous phase back-extracted with ethylacetate. The combined organic phases were dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a heptane/ethyl acetate gradient to yield the title compound (1.2 gr, 92%); MS (ESI, m/z): 275.4 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:10][CH2:9][CH2:8][C:7](=[O:11])[C:6]=2[CH:12]=1.N(CC)CC.[CH3:18][Si:19]([C:22]#[CH:23])([CH3:21])[CH3:20]>C1COCC1.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>[CH3:18][Si:19]([CH3:21])([CH3:20])[C:22]#[C:23][C:2]1[CH:3]=[CH:4][C:5]2[S:10][CH2:9][CH2:8][C:7](=[O:11])[C:6]=2[CH:12]=1
Reactant: O=C1CCSc2ccc(Br)cc21
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CCNCC
Product: C[Si](C)(C)C#Cc1ccc2c(c1)C(=O)CCS2
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 1.00 g (4.11 mmol) 2,3-dihydro-6-bromo-(4H)-1-benzothiopyran-4-one and 78.3 mg (0.41 mmol) Cul in 15.0 ml THF and 6.0 ml Et2NH was sparged with argon for 5 minutes. To this solution was added 2.0 ml (1.39 g, 14.2 mmol) of (trimethylsilyl)acetylene followed by 288.5 mg (0.41 mmol) of bis(triphenylphosphine)palladium(II) chloride. The resulting dark solution was stirred at room temperature for 3 days and then filtered through a pad of Celite, which was washed with EtOAc. The filtrate was washed with H2O and saturated aqueous NaCl before being dried over MgSO4. The title compound was isolated as an orange oil by column chromatography (4% EtOAc-hexanes). 1H NMR (CDCl3): δ 8.13 (1H, d, J=1.9 Hz), 7.36 (1H, dd, J=2.1, 8.2 Hz), 7.14 (1H, d, J=8.2 Hz), 3.19 (2H, d, J=6.3 Hz), 2.91 (2H, d, J=6.3 Hz), 0.21 (9H, s).
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5](=[O:7])[NH:4][C:3]=1[C:8]([O:10]CC)=[O:9]>[OH-].[Na+]>[CH3:1][C:2]1[NH:6][C:5](=[O:7])[NH:4][C:3]=1[C:8]([OH:10])=[O:9]
Reactant: CCOC(=O)c1[nH]c(=O)[nH]c1C
Agent: [Na+]
Agent: [OH-]
Product: Cc1[nH]c(=O)[nH]c1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.8 %

Procedure:
A solution of ethyl 5-methyl-2-oxo-2,3-dihydro-1H-imidazole-4-carboxylate (1.00 g, 5.88 mmol) in 3N NaOH (5.88 mL) was heated to 65° C. for 2 h then cooled to RT. The mixture was filtered then added dropwise to a stirred solution of concentrated H2SO4 (1.10 mL) in water (7.35 mL). The mixture was stirred for 2 h then filtered. The solid was washed with water (2×10 mL) then dried under vacuum to give 0.65 g (78%) of the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.21 (d, 1H), 10.52 (br. s., 1H), 9.77-10.21 (m, 1H), 1.95-2.35 (m, 3H).
Reaction SMILES: [N:1]1([C:20]([O:22][CH2:23][CH:24]=[CH2:25])=[O:21])[CH2:5][CH2:4][CH:3]([C:6]([O:8]C(C)(C)C)=[O:7])[N:2]1C(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O.O>ClCCl>[CH2:23]([O:22][C:20]([N:1]1[CH2:5][CH2:4][CH:3]([C:6]([OH:8])=[O:7])[NH:2]1)=[O:21])[CH:24]=[CH2:25]
Reactant: C=CCOC(=O)N1CCC(C(=O)OC(C)(C)C)N1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: C=CCOC(=O)N1CCC(C(=O)O)N1
Temperature: 25 °C
Reaction time: 72 h
Yield: 100 %

Procedure:
2,3-Bis(1,1-dimethylethyl) 1-(2-propen-1-yl) 1,2,3-pyrazolidinetricarboxylate (1.2 g, 3.37 mmol) was dissolved in dichloromethane (DCM) (6.63 ml) under N2 at ambient temperature. TFA (15.56 ml, 202 mmol) and water (1.820 ml, 101 mmol) were added in one portion. The reaction was stirred at ambient temperature for 3 days. The solvent was removed under reduced pressure to give crude 1-[(2-propen-1-yloxy)carbonyl]-3-pyrazolidinecarboxylic acid (0.674 g, 3.37 mmol, 100% crude yield). MS (ES+) m/z 201.0 (MH+).
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][C:8](=[O:16])[CH:7]([NH:17][C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[N:6]=1)([CH3:4])[CH3:3].[H-].[Na+].[CH3:30][CH:31]([CH3:34])[CH2:32]I>CN(C)C=O>[CH3:4][C:2]([C:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]([CH2:30][CH:31]([CH3:34])[CH3:32])[C:8](=[O:16])[CH:7]([NH:17][C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[N:6]=1)([CH3:1])[CH3:3]
Reactant: CC(C)(C)C1=NC(NC(=O)OCc2ccccc2)C(=O)Nc2ccccc21
Reactant: CC(C)CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)CN1C(=O)C(NC(=O)OCc2ccccc2)N=C(C(C)(C)C)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.2 %

Procedure:
A solution of 1,3-dihydro-5-(1,1-dimethylethyl)-3(R,S) -[(benzyloxycarbonyl)-amino]-2H-1,4-benzodiazepin-2-one (500 mg, 1.4 mmol) in dimethylformamide (10 ml) under an atmosphere of nitrogen, was treated with sodium hydride (54 mg of a 57% dispersion in mineral oil, 1.4 mol) in one portion at 0° C. After 1 h, 2-methylpropyl iodide (0.17 ml, 1.45 mmol) was added and the resulting mixture stirred at room temperature for 16 h. The solvent was then evaporated and the crude residue partitioned between water (15 ml) and dichloromethane (2×20 ml). The combined organic phases were washed with brine (2×20 ml), dried (MgSO4) and evaporated. The residue was chromatographed on silica using 2:1 petrol:ethyl acetate as eluent, to afford the title compound as a colourless solid (320 mg, 56%). 1H NMR (250 MHz, D6 -DMSO) δ 0.63 (3H, d, J=7 Hz), 0.77 (3H, d, J=7 Hz), 1.26 (9H, s), 1.49 (1H, m), 3.56 (1H, dd, J=4 Hz, 14 Hz), 4.10 (1H, dd, J=4 Hz, 14 Hz), 4.88 (1H, m), 5.02 (2H, m), 7.20-7.40 (5H, m), 7.58 (1H, t, J=8 Hz), 7.66 (1H, d, J=9 Hz), 7.77 (1H, d, J=8 Hz), 8.18 (1H, d, J=9 Hz).
Reaction SMILES: [F:1][CH:2]1C(=O)[CH2:6][CH2:5][N:4]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=2[F:18])[CH2:3]1.[CH3:19][O:20][CH:21](OC)[O:22][CH3:23].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:19][O:20][C:21]1([O:22][CH3:23])[CH2:6][CH2:5][N:4]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=2[F:18])[CH2:3][CH:2]1[F:1]
Reactant: O=C1CCN(c2ccc([N+](=O)[O-])cc2F)CC1F
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: COC1(OC)CCN(c2ccc([N+](=O)[O-])cc2F)CC1F
Temperature: 45 °C
Yield: 78 %

Procedure:
The mixture of 4-(3-fluoro-4-oxo-piperidin-1-yl)-3-fluoronitrobenzene (65 mmol), trimethylorthoformate (130 mmol), p-toluene-sulphonic acid monohydrate (67 mmol) in methanol was heated at 45° C. for 24 hours. Solvent was removed and residual mass was taken into ethyl acetate and saturated sodium bicarbonate solution mixture. The organic layer was dried and removal of the solvent afforded title compound as a solid in 78% yield.
Reaction SMILES: [F:1][C:2]1([F:23])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[CH:12][C:11]=2[N+:20]([O-])=O)[CH2:4][CH2:3]1>CCOC(C)=O.[Pd]>[NH2:20][C:11]1[CH:12]=[C:13]([NH:16][C:17](=[O:19])[CH3:18])[CH:14]=[CH:15][C:10]=1[NH:9][CH2:8][CH:5]1[CH2:6][CH2:7][C:2]([F:23])([F:1])[CH2:3][CH2:4]1
Reactant: CC(=O)Nc1ccc(NCC2CCC(F)(F)CC2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc(NCC2CCC(F)(F)CC2)c(N)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
N-(4-{[(4,4-Difluorocyclohexyl)methyl]amino}-3-nitrophenyl)acetamide (1.48 g, 4.52 mmol) was dissolved in 50 mL of EtOAc containing a catalytic amount of 10% Pd/C. The solution was shaken in a Parr hydrogenation apparatus under H2 atmosphere (45 psi) at rt for 24 h. The solution was filtered through Celite and the solvent was evaporated. Yield: 1.32 g (98%). 1H NMR (400 MHz, CHLOROFORM-D) δ 1.31-1.43 (m, 2 H), 1.64-1.73 (m, 2 H), 1.74-1.82 (m, 1 H), 1.89-1.93 (m, 1 H), 1.93-1.96 (m, 1 H), 2.08-2.17 (m, 5 H), 3.00 (d, J=6.64 Hz, 2 H), 3.27-3.46 (m, 2 H), 6.55 (d, J=8.40 Hz, 1 H), 6.70 (dd, J=8.40, 2.34 Hz, 1 H), 7.01 (s, 1 H), 7.13 (d, J=2.34 Hz, 1 H).
Reaction SMILES: [CH:1]1([O:7][N:8]2[C:13]([CH3:15])([CH3:14])[CH2:12][C:11](=O)[CH2:10][C:9]2([CH3:18])[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:19]([NH2:23])[CH2:20][CH2:21][CH3:22]>>[CH:1]1([O:7][N:8]2[C:13]([CH3:15])([CH3:14])[CH2:12][CH:11]([NH:23][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:10][C:9]2([CH3:18])[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCCCN
Reactant: CC1(C)CC(=O)CC(C)(C)N1OC1CCCCC1
Product: CCCCNC1CC(C)(C)N(OC2CCCCC2)C(C)(C)C1

Procedure:
The title compound, a colorless oil, is prepared from 1-cyclohexyloxy-2,2,6,6-tetramethylpiperidin-4-one and butylamine according to the procedure given in Example 38.
Reaction SMILES: [C:1]1([C:7](Cl)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:21]([O:28][C@H:29]([CH2:34][CH2:35][CH2:36][O:37][Si:38]([C:51]([CH3:54])([CH3:53])[CH3:52])([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C@H:30]([OH:33])[CH2:31][OH:32])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1.O>[CH2:21]([O:28][C@H:29]([CH2:34][CH2:35][CH2:36][O:37][Si:38]([C:51]([CH3:54])([CH3:53])[CH3:52])([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C@H:30]([OH:33])[CH2:31][O:32][C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)[Si](OCCC[C@@H](OCc1ccccc1)[C@H](O)CO)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](OCCC[C@@H](OCc1ccccc1)[C@H](O)COC(c1ccccc1)(c1ccccc1)c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.7 %

Procedure:
18.33 g of triphenylmethyl chloride were added to a solution of 26.22 g of (2R, 3R)-3-benzyloxy-6-(t-butyldiphenylsilyloxy)hexane-1,2-diol (prepared as described in Preparation 17) and 18.40 ml of triethylamine in 500 ml of toluene. The resulting mixture was heated under reflux for 3 hours. At the end of this time, it was cooled and then diluted with water. It was then extracted three times with ethyl acetate. The combined extracts were washed, in turn, with water, with a saturated aqueous solution of sodium bicarbonate and with a saturated aqueous solution of sodium chloride, after which they were dried over anhydrous magnesium sulfate, and the solvent was stripped off by evaporation under reduced pressure. The resulting oily residue was dissolved in 270 ml of tetrahydrofuran, and then 90 ml of a saturated aqueous solution of sodium bicarbonate were added, and the resulting mixture was stirred at room temperature for 1 hour. After this work-up, 40 g of the oily product were subjected to column chromatography through 500 g of silica gel, 37.01 g of the title compound were obtained, as a colorless oil, from those fractions eluted with mixtures of hexane and ethyl acetate ranging from 95:5 to 9:1 by volume.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([C:16]2[CH:21]=[N:20][C:19](Br)=[CH:18][N:17]=2)=[N:13][C:12]=1[CH3:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[C:30]1([CH2:36]/[CH:37]=[CH:38]/B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.O>COC.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]>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([C:16]2[CH:21]=[N:20][C:19](/[CH:38]=[CH:37]/[CH2:36][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:18][N:17]=2)=[N:13][C:12]=1[CH3:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)/C=C/Cc1ccccc1
Reactant: Cc1nc(-c2cnc(Br)cn2)sc1C(=O)NCc1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: COC
Solvent: O
Product: Cc1nc(-c2cnc(/C=C/Cc3ccccc3)cn2)sc1C(=O)NCc1ccccc1
Reaction time: 3 h
Yield: 46.9 %

Procedure:
Part A. To a solution of 2-(5-bromo-pyrazin-2-yl)-4-methyl-thiazole-5-carboxylic acid benzylamide (40 mg, 0.10 mmol, 1.0 equiv) in dimethyl ether (1 mL) was added Na2CO3 (21 mg, 0.20 mmol, 2.0 equiv), trans-3-phenylpropen-1-yl boronic acid (41 mg, 0.25 mmol, 2.5 equiv), PdCl2(dppf) (3.6 mg, 5 mol %) and water (0.1 mL) in a sealed tube. The reaction was immersed in an oil bath preheated to 100° C. After stirring for 3 hr, the reaction was cooled and the solvent was removed in vacuo. The crude product was purified by column chromatography [SiO2, methanol/dichloromethane, 0:100 to 10:90, v/v] to give 4-methyl-2-[5-((E)-3-phenyl-propenyl)-pyrazin-2-yl]-thiazole-5-carboxylic acid benzylamide (20 mg, 46%)
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]3[N:20]=[N:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[C:5]([CH3:27])[O:4][N:3]=1.[CH3:28][C:29](N=C(N(C)C)N(C)C)([CH3:31])[CH3:30].BrCC(C)C>C(#N)C.CO>[CH3:1][C:2]1[C:6]([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]([S:15]([N:18]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:19]3[N:20]=[N:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)(=[O:17])=[O:16])=[CH:13][CH:14]=2)=[C:5]([CH3:27])[O:4][N:3]=1
Reactant: CN(C)C(=NC(C)(C)C)N(C)C
Reactant: COc1ccc(NS(=O)(=O)c2ccc(OCc3c(C)noc3C)cc2)nn1
Solvent: CO
Solvent: CC#N
Solvent: CC(C)CBr
Product: COc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(OCc3c(C)noc3C)cc2)nn1
Temperature: 20 °C
Reaction time: 1 h
Yield: 5.5 %

Procedure:
To a solution of 4-{[(3,5-dimethyl-4-isoxazolyl)methyl]oxy}-N-[6-(methyloxy)-3-pyridazinyl]benzenesulfonamide (16 mg, 0.041 mmol) in acetonitrile (1 mL) stirred at room temperature was added N″-(1,1-dimethylethyl)-N,N,N′,N′-tetramethylguanidine (7.02 mg, 0.041 mmol). The reaction mixture was stirred at 20° C. for 1 hour, then 1-bromo-2-methylpropane (8.91 μL, 0.082 mmol) was added. The reaction was heated by microwaves to 150° C. for 15 minutes. After cooling, the reaction mixture was diluted with methanol and passed through an aminopropyl (NH2) solid phase extraction (SPE) cartridge followed by a sulphonic acid (SCX) SPE cartridge, eluting with methanol. The appropriate fractions were combined and evaporated under a stream of nitrogen to give the crude product. The crude was purified by mass directed autoprep (formic acid modifier), to provide the title compound (1.0 mg). LCMS (2 min, formic) Rt 1.27 min, m/z (ES+) 447 (M+H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH2:7]([C:10]1[N:11]([CH2:23][CH2:24][CH2:25][CH2:26][C:27]([OH:29])=O)[C:12]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]=[CH:14][C:13]=2[N:22]=1)[CH2:8][CH3:9].Cl.[CH3:31][NH:32][O:33][CH3:34].CN(C)C=O>ClCCl>[CH3:34][O:33][N:32]([CH3:31])[C:27](=[O:29])[CH2:26][CH2:25][CH2:24][CH2:23][N:11]1[C:12]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]=[CH:14][C:13]=2[N:22]=[C:10]1[CH2:7][CH2:8][CH3:9]
Reactant: CNOC
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCCC(=O)O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCc1nc2cnc3ccccc3c2n1CCCCC(=O)N(C)OC
Reaction time: 1 h
Yield: 92.9 %

Procedure:
Oxalyl chloride (2.62 mL, 30.1 mmol) was added to a solution of 5-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)pentanoic acid (5.21 g, 16.7 mmol) in dichloromethane (50 mL) at room temperature. The reaction was stirred for 1 hour, then the volatiles were removed under reduced pressure. Dichloromethane (50 mL) was added to the residue, followed by N,O-dimethylhydroxylamine hydrochloride (3.26 g, 33.5 mmol) and N,N-dimethylformamide (2 mL). The reaction mixture was stirred at room temperature overnight, then was concentrated under reduced pressure. The residue was diluted with dichloromethane and an ammonium hydroxide solution. The mixture was transferred to a separatory funnel and the layers were separated. The organic layer was washed with saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford 5.5 g of crude N-methoxy-N-methyl-5-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)pentanamide as a brown oil that was used without purification in the next step.
Reaction SMILES: [C@@H:1]12[C:10](=O)[O:9][C:7](=[O:8])[C@@H:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2.[BH4-].[Na+]>C1COCC1>[C@@H:2]12[C:7](=[O:8])[O:9][CH2:10][C@@H:1]1[CH2:6][CH2:5][CH2:4][CH2:3]2
Reactant: O=C1OC(=O)[C@@H]2CCCC[C@H]12
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1OC[C@@H]2CCCC[C@H]12

Procedure:
With stirring and ice-cooling, 80 ml of a solution of cis-cyclohexane-1,2-dicarboxylic anhydride (15.4 g, 100 mmol) in THF are added over a period of 10 min to a mixture of sodium borohydride (3.8 g, 100 mmol) in 20 ml of THF. The ice-bath is removed and the mixture is stirred for 2 h. 40 ml of 6 N hydrochloric acid are added carefully and the mixture is concentrated. 200 ml of water are added and the aqueous phase is extracted with ether. The organic phase is dried, filtered, concentrated and distilled under reduced pressure (123° C., 13 mm; 75° C., 0.5 mm).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]=[CH:13][N:14]=[C:15]([NH2:18])[C:16]=3[N:17]=2)[CH:5]=[CH:6][CH:7]=1.FC1C=C(B(O)O)C=C([CH:26]=[O:27])C=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:18][C:15]1[C:16]2[N:17]=[C:8]([C:4]3[CH:5]=[C:6]([CH:7]=[C:2]([F:1])[CH:3]=3)[CH:26]=[O:27])[CH:9]=[CH:10][C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: Nc1ncnc2ccc(-c3cccc(F)c3)nc12
Reactant: O=Cc1cc(F)cc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Nc1ncnc2ccc(-c3cc(F)cc(C=O)c3)nc12
Temperature: 100 °C
Yield: 89.5 %

Procedure:
A suspension of 6-chloropyrido[3,2-d]pyrimidin-4-amine (1) (3.61 g, 20 mmol), 3-fluoro-5-formylphenylboronic acid (CAS 328956-60-1) (4.03 g, 24 mmol, 1.2 eq), Pd(PPh3)4 (1.16 g, 1.0 mmol, 0.05 eq), and K2CO3 (5.53 g, 40 mmol, 2.0 eq) in a mixture of dioxane (100 mL) and H2O (10 mL) was heated at 100° C. for 3 h. After it was cooled to r.t., the reaction was extracted with EtOAc (100 mL) and water (60 mL). The organic layer were washed with water and concentrated. The yellow solid was recrystallized in MeCN to give the titled product (4.8 g, yield: 90%).