Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:20])[CH2:9][CH2:10][C:11](=[O:19])[CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:4][CH:3]=1.[O:21]1[CH2:25][CH2:24][NH:23][C:22]1=[O:26].N1CCC[C@H]1C(O)=O.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.[Cu]I>[O:19]=[C:11]([CH2:10][CH2:9][C:8](=[O:20])[C:5]1[CH:6]=[CH:7][C:2]([N:23]2[CH2:24][CH2:25][O:21][C:22]2=[O:26])=[CH:3][CH:4]=1)[CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)CCC(=O)CCC(=O)c1ccc(Br)cc1
Reactant: O=C1NCCO1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CCOC(=O)CCC(=O)CCC(=O)c1ccc(N2CCOC2=O)cc1
Yield: 10 %

Procedure:
To a mixture of ethyl 7-(4-bromophenyl)-4,7-dioxoheptanoate ((36A, where Ar1-Br=4-bromophenyl, also see compound 5B, Scheme 5) (1.50 g, 4.4 mmol) and oxazolidin-2-one (575 mg, 6.6 mmol) in dioxane (5 mL) were added L-proline (50 mg, 0.44 mmol), CuI (42 mg, 0.22 mmol) and K2CO3 (1.22 g, 8.8 mmol). The resultant mixture was stirred under N2 at 110° C. for 48 h and then evaporated. The residue was diluted with EA/water (40 mL/40 mL). The mixture was filtered and the resultant aqueous layer was extracted with EA (30 mL×5). The combined organic layers were washed with brine, dried over NaSO4, concentrated and purified by silica gel column chromatography (pure DCM to DCM:MeOH=30:1) to afford titled compound as a white solid (158 mg, yield 10%).
Reaction SMILES: [C:1]1([CH:7]2[O:12][CH2:11][CH:10]([C:13]([OH:15])=O)[CH2:9][O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ON1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1.C(N(CC)C(C)C)(C)C.Cl.Cl.[N:50]1([C:56]2[CH:61]=[CH:60][C:59]([N:62]3[CH2:66][C@H:65]([CH2:67][O:68][C:69]4[CH:73]=[CH:72][O:71][N:70]=4)[O:64][C:63]3=[O:74])=[CH:58][C:57]=2[F:75])[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1>ClCCl>[C:1]1([CH:7]2[O:8][CH2:9][CH:10]([C:13]([N:53]3[CH2:52][CH2:51][N:50]([C:56]4[CH:61]=[CH:60][C:59]([N:62]5[CH2:66][C@H:65]([CH2:67][O:68][C:69]6[CH:73]=[CH:72][O:71][N:70]=6)[O:64][C:63]5=[O:74])=[CH:58][C:57]=4[F:75])[CH2:55][CH2:54]3)=[O:15])[CH2:11][O:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)C1COC(c2ccccc2)OC1
Reactant: O=C1O[C@@H](COc2ccon2)CN1c1ccc(N2CCNCC2)c(F)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(C1COC(c2ccccc2)OC1)N1CCN(c2ccc(N3C[C@H](COc4ccon4)OC3=O)cc2F)CC1
Reaction time: 1 h
Yield: 70 %

Procedure:
To a stirred solution of 2-phenyl-1,3-dioxan-5-ylcarboxylic acid (478 mg, 2.3 mmol) and N-hydroxysuccinimide (291 mg, 2.5 mmol) in anhydrous dichloromethane (25 ml) at 0° was added dicyclohexylcarbodiimide (522 mg, 2.5 mmol). After sitting 1 hour at 0°, N,N-diisopropylethylamine (623 mg, 4.8 mmol) was added, followed by 3-(4-(piperazin-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one dihydrochloride (1 g, 2.3 mmol) in portions over 5 minutes. The temperature was allowed to rise to ambient, and stirring continued for 3 hours. Solid was filtered off, washed with dichloromethane (2×20 ml), and the combined organics evaporated to dryness. The residue was purified by chromatography on a 20 g silica Mega Bond Elut® column, eluting with a gradient increasing in polarity from 0 to 10% MeOH in dichloromethane. Relevant fractions were combined and evaporated to give the required product (890 mg) as a mixture of cis and trans isomers.
Reaction SMILES: CN(C)C=O.[CH3:6][O:7][C:8](=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([SH:15])[CH:10]=1.CC(C)([O-])C.[K+].Br[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][N:25]=1>O>[CH3:6][O:7][C:8](=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([S:15][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][N:25]=2)[CH:10]=1
Reactant: COC(=O)c1cccc(S)c1
Reactant: Clc1ccc(Br)nc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(Sc2ccc(Cl)cn2)c1
Yield: 79.7 %

Procedure:
To a dimethylformamide (7.0 mL) solution of 3-mercapto-benzoic acid methyl ester (600 mg, 3.5 mmol) was added potassium t-butoxide (500 mg, 4.0 mmol). Upon stirring the reaction at room temperature for 15 min, 2-bromo-5-chloro-pyridine (700 mg, 3.5 mmol) was added. The reaction was stirred at room temperature for 15 h. Crude reaction mass was added to water, aqueous layer was acidified to pH 4.0 and product was extracted with ethyl acetate to give 3-(5-chloro-pyridin-2-ylsulfanyl)-benzoic acid methyl ester (780 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[S:13](N)([NH2:16])(=[O:15])=[O:14]>O1CCOCC1>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:8][CH2:9][N:10]([S:13]([NH2:16])(=[O:15])=[O:14])[CH2:11][CH2:12]2)=[CH:3][CH:2]=1
Reactant: c1cc(N2CCNCC2)ccn1
Reactant: NS(N)(=O)=O
Solvent: C1COCCO1
Product: NS(=O)(=O)N1CCN(c2ccncc2)CC1

Procedure:
To a solution of 1-pyridin-4-ylpiperazine (1.23 g) in dioxane (10 ml) was added sulfamide (0.746 g) and the reaction mixture was then heated at reflux in dioxane for 72 h. The reaction mixture was purified by loading onto SCX and eluting with (200 ml) MeOH/NH3. The eluent was then reduced in vacuo to yield 4-pyridin-4-ylpiperazine-1-sulfonamide as a white solid. A mixture of 4-pyridin-4-ylpiperazine-1-sulfonamide (0.260 g), tris(dibenzylideneacetone)dipalladium (0) (50 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (XPHOS) (50 mg), cesium carbonate (0.438 g) and 2-[[6-chloro-2-[[(2,3-difluorophenyl)methyl]thio]-4-pyrimidinyl]oxy]-(2R)-propanoic acid ethyl ester ((the product of example 5 step i), 0.350 g) in dioxane (10 ml) was heated at reflux in a microwave at 100 C, 300 W, open vessel with cooling for 30 mins. The reaction mixture was then reduced in vacuo and the residue was partitioned between EtOAc (150 ml) and H2O (100 ml). The organics were separated and the aqueous layer was re-extracted with EtOAc (2×150 ml). Organics were combined, dried (MgSO4) and reduced in vacuo to give the subtitle compound as a yellow solid. Yield: 0.720 g
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:17][CH2:16][CH2:15]2)[C:11]([C:18]([F:21])([F:20])[F:19])=[CH:10][C:9]=1[NH2:22])([CH3:4])([CH3:3])[CH3:2].C([O:28][C:29](=O)[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][N:36]=[C:35]([C:39]#[N:40])[CH:34]=1)=[O:32])(C)(C)C>>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:17][CH2:16][CH2:15]2)[C:11]([C:18]([F:20])([F:21])[F:19])=[CH:10][C:9]=1[NH:22][C:29](=[O:28])[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][N:36]=[C:35]([C:39]#[N:40])[CH:34]=1)=[O:32])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCC2)c(C(F)(F)F)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1ccnc(C#N)c1
Product: CC(C)(C)OC(=O)Nc1cc(N2CCC2)c(C(F)(F)F)cc1NC(=O)CC(=O)c1ccnc(C#N)c1

Procedure:
The title compound was prepared from (2-amino-5-azetidin-1-yl-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example J17) and 3-(2-cyano-pyridin-4-yl)-3-oxo-propionic acid tert.-butyl ester (Example K3) according to the general procedure M. Obtained as a light yellow solid (131 mg).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:4]=[CH:5][NH:6][C:7]=1[C:8]([NH2:10])=[O:9].CN(C)[CH:13]=[CH:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1)=O.C([O-])(=O)C.[Na+]>C(O)(=O)C>[F:24][C:23]([F:25])([F:26])[C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:15]2[N:4]3[CH:5]=[N:6][C:7]([C:8]([NH2:10])=[O:9])=[C:3]3[N:2]=[CH:13][CH:14]=2)[CH:18]=1
Reactant: CN(C)C=CC(=O)c1cccc(C(F)(F)F)c1
Reactant: NC(=O)c1[nH]cnc1N
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: NC(=O)c1ncn2c(-c3cccc(C(F)(F)F)c3)ccnc12

Procedure:
A mixture of 1.62 g. of 4-amino-5-imidazolecarboxamide hydrochloride, 2.43 g. of 3-dimethylamino-3'-trifluoromethylacrylophenone and 0.82 g. of sodium acetate in 25 ml. of glacial acetic acid is refluxed for 15 hours and then evaporated to dryness. The residue is treated as described in Example 1, giving the desired product, m.p. 239°-240° C.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:18][CH:17]=2)[C:7](=[O:14])[C:8]([CH:12]=[O:13])=[C:9]([CH3:11])[N:10]=1)[CH2:2][CH2:3][CH3:4].[C:30]1([Mg]Br)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:20][CH:21]=2)[C:7](=[O:14])[C:8]([CH:12]([OH:13])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:9]([CH3:11])[N:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)c(C=O)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: Br[Mg]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCc1nc(C)c(C(O)c2ccccc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 0 °C
Yield: 46 %

Procedure:
To a solution of 4′-[(2-butyl-5-formyl-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (0.66 g) in tetrahydrofuran (10 mL) was added phenylmagnesium bromide (1.0 mL, 1 M tetrahydrofuran solution) at −78° C., and the mixture was allowed to warm to 0° C. over 3 hr. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow oil (0.36 g, 46%).
Reaction SMILES: ClC1C=C2C(=CC=1)[NH:7]C(C=O)=C2.C(C=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=O.[Cl:35][C:36]1[CH:37]=[C:38]2[C:42](=[CH:43][CH:44]=1)[NH:41][C:40](/[CH:45]=[CH:46]/[CH:47]=[O:48])=[CH:39]2>>[Cl:35][C:36]1[CH:37]=[C:38]2[C:42](=[CH:43][CH:44]=1)[NH:41][C:40](/[CH:45]=[CH:46]/[CH:47]=[O:48])=[CH:39]2.[CH2:36]1[CH2:44][CH2:43][N:7]2[C:42](=[N:41][CH2:40][CH2:45][CH2:46]2)[CH2:38][CH2:37]1
Reactant: O=Cc1cc2cc(Cl)ccc2[nH]1
Agent: O=C/C=C/c1cc2cc(Cl)ccc2[nH]1
Agent: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: C1CCC2=NCCCN2CC1

Procedure:
5-Chloroindole-2-carboxaldehyde was prepared starting from ethyl 5-chloroindole-2-carboxylate (7.4 g, 33 mmol) according to the procedure of Preparation 1, obtaining 2 g of a yellow solid, m.p.=208-209° C. The aldehyde (1.2 g, 6.7 mmol) was transformed in (E)-3-(5-chloro-2-indolyl)-2-propenaldehyde through the reaction with (formylmethylene)triphenylphosphorane (2 g, 6.7 mmol) following the procedure described in Preparation 2, obtaining 0.5 g of yellow powder, m.p.=207-209° C. (E)-3-(5-Chloro-2-indolyl)-2-propenaldehyde (0.5 g, 2.4 mmol) and DBU (0.75 ml, 5 mmol) were treated with methyl 2-methoxy-2-(triphenylphosphonium)acetate bromide (2.16 g, 5 mmol) according to the procedure of Example 1A to afford 250 mg (47%) of the title compound, m.p.=166-168° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([N:12]([CH3:14])[CH3:13])=[CH:9][CH:10]=2)[C:5]([O:15][CH3:16])=[CH:4][N:3]=1.[F-:17].C[N+](C)(C)C>CS(C)=O.C(OC(=O)C)C>[F:17][C:2]1[C:11]2[C:6](=[CH:7][C:8]([N:12]([CH3:14])[CH3:13])=[CH:9][CH:10]=2)[C:5]([O:15][CH3:16])=[CH:4][N:3]=1
Reactant: COc1cnc(Cl)c2ccc(N(C)C)cc12
Reactant: [F-]
Agent: C[N+](C)(C)C
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COc1cnc(F)c2ccc(N(C)C)cc12
Temperature: 110 °C
Yield: 55.9 %

Procedure:
To a solution of 1-chloro-4-methoxy-N,N-dimethylisoquinolin-6-amine (250 mg, 1.056 mmol) in DMSO (5 mL) was added tetramethylammonium fluoride (295 mg, 3.17 mmol) and the solution was heated to 110° C. for 1 h. The reaction was diluted with Ethylacteate and washed with water, and brine. The organic phase was collected, dried over sodium sulfate, and concentrated under vacuum to give the crude product which was purified by silica gel chromatography using 80% DCM/hexanes. The product fractions were collected and the solvent removed under vacuum to give 1-fluoro-4-methoxy-N,N-dimethylisoquinolin-6-amine (130 mg, 56% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.00 (d, J=9.3 Hz, 1H), 7.37 (d, J=1.3 Hz, 1H), 7.28-7.24 (m, 1H), 7.17 (s, 1H), 4.04 (s, 3H), 3.20 (s, 6H); MS m/z 221.0 (M++1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][N:8]([C:14](=[O:19])[CH:15]([CH3:18])[CH2:16]Br)[CH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[S:21](C#N)[C:22]#[N:23].[K]>O.C(O)C>[C:1]([O:5][C:6](=[O:20])[CH2:7][N:8]([C:14](=[O:19])[CH:15]([CH3:18])[CH2:16][S:21][C:22]#[N:23])[CH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(CBr)C(=O)N(CC(=O)OC(C)(C)C)C1CCCC1
Reactant: N#CSC#N
Agent: [K]
Solvent: CCO
Solvent: O
Product: CC(CSC#N)C(=O)N(CC(=O)OC(C)(C)C)C1CCCC1

Procedure:
A mixture of 2 g of N(3-bromo-2-methyl-propanoyl)-N-cyclopentyl glycine-t-butyl ester, 0.7 g potassium thiocyanide in 5 ml water and 40 ml ethanol was stirred and refluxed for 16 hours. After removal of the solvent, it was diluted with water and extracted with ethyl acetate. The organic layer was dried over MgSO4 and evaporated to dryness. The oily residue was purified by HPLC using 20% EtOAc-hexane as eluent giving pure N(3-thiocyano-2-methyl propanoyl)-N-cyclopentyl glycine-t-butyl ester.
Reaction SMILES: [NH2:1][C:2]1[C:9]([I:10])=[CH:8][C:5]([C:6]#[N:7])=[C:4](Cl)[CH:3]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>>[NH2:1][C:2]1[C:9]([I:10])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:3]=1
Reactant: C1COCCN1
Reactant: N#Cc1cc(I)c(N)cc1Cl
Product: N#Cc1cc(I)c(N)cc1N1CCOCC1
Temperature: 200 °C
Reaction time: 1 h

Procedure:
4-Amino-2-chloro-5-iodobenzonitrile (0.60 g, 2.1 mmol) and morpholine (2.0 mL, 23 mmol) were added to a microwave vial and heated in the microwave to 200° C. After 60 minutes, the residue was concd then purified on silica gel (0-40% EtOAc in hexanes) to yield a white solid as 4-amino-5-iodo-2-morpholinobenzonitrile. Mass Spectrum (pos.) m/e: 330.0 (M+H)+. 4-amino-2-morpholinobenzonitrile was also isolated. 1H NMR (500 MHz, CDCl3) δ ppm 7.35 (1H, d, J=8.3 Hz), 6.28 (1H, dd, J=8.4, 2.1 Hz), 6.20 (1H, d, J=2.0 Hz), 4.14 (2H, br. s.), 3.95 (4H, m), 3.24 (4H, m). Mass Spectrum (pos.) m/e: 204.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:12]=[C:13]([C:18]([O:20][CH3:21])=[O:19])[C:14](=[O:17])[NH:15][N:16]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Br[CH2:23][CH:24]([CH3:26])[CH3:25]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:12]=[C:13]([C:18]([O:20][CH3:21])=[O:19])[C:14](=[O:17])[N:15]([CH2:23][CH:24]([CH3:26])[CH3:25])[N:16]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CC(C)CBr
Reactant: COC(=O)c1cc(-c2ccc(OC)c(OC)c2)n[nH]c1=O
Product: COC(=O)c1cc(-c2ccc(OC)c(OC)c2)nn(CC(C)C)c1=O
Yield: 86.6 %

Procedure:
Using 6-(3,4-dimethoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and 1-bromo-2-methylpropane as starting materials, the procedures of Example 1 were repeated likewise, whereby the title compound was obtained in a yield of 86.6%.
Reaction SMILES: [F:1][C:2]([F:8])([CH:5]([F:7])[F:6])[CH2:3][OH:4].[H-].[Na+].Cl[C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][N:13]=1>C1COCC1>[Cl:18][C:17]1[C:12]([O:4][CH2:3][C:2]([F:8])([F:1])[CH:5]([F:7])[F:6])=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: OCC(F)(F)C(F)F
Reactant: Clc1cccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: FC(F)C(F)(F)COc1ncccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.2 %

Procedure:
2,2,3,3-Tetrafluoropropan-1-ol (60.0 g, 0.45 mol) was added to a slurry of NaH (60% dispersion in oil, 15.20 g, 0.63 mol) in anhydrous THF (450 mL) at 0° C. and the reaction mixture allowed to warm up to room temperature, then stirred for 1 hour. 2,3-dichloropyridine (45.0 g, 0.30 mol) was added and the reaction heated to a gentle reflux for 16 hours. The reaction mixture was cooled to room temperature and the solvent removed in vacuo. The residue was partitioned between EtOAc (300 mL) and brine (200 mL). The organic layer was dried over magnesium sulfate, filtered and evaporated to afford the title compound as a yellow oil (71 g, 96%):
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]1[C:12]([N+:13]([O-])=O)=[C:11]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:10]=[C:9]([CH3:23])[C:8]=1[CH3:24].[Br-].[Br-].C([N+]1C=CC(C2C=C[N+](CCCCCCCC)=CC=2)=CC=1)CCCCCCC.C(=O)([O-])[O-].[K+].[K+].S(S([O-])=O)([O-])=O.[Na+].[Na+]>O.ClCCl>[Cl:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]1[C:8]([CH3:24])=[C:9]([CH3:23])[N:10]=[C:11]([O:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:12]=1[NH2:13]
Reactant: Cc1nc(Oc2ccccc2)c([N+](=O)[O-])c(NCCCCl)c1C
Agent: CCCCCCCC[n+]1ccc(-c2cc[n+](CCCCCCCC)cc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Product: Cc1nc(Oc2ccccc2)c(N)c(NCCCCl)c1C
Temperature: 25 °C

Procedure:
N-(3-chloropropyl)-2,3-dimethyl-5-nitro-6-phenoxypyridin-4-amine hydrochloride (12.62 g, 33.72 mmol), 1,1′-di-n-octyl-4,4′-bipyridinium dibromide (dioctyl viologen) (910 mg, 1.69 mmol), dichloromethane (227 mL), water (28 mL) and potassium carbonate (2.33 g, 16.9 mmol) were added sequentially to a 1 L round bottom flask. The reaction mixture was allowed to stir under nitrogen. A solution of of potassium carbonate (23.30 g, 168.6 mmol) and sodium dithionite (26.42 g, 174.1 mmol) in water (114 mL) was added to the reaction mixture. The reaction mixture was heated at reflux for about 2.5 hr and then allowed to cool to ambient temperature. The layers were separated. The aqueous layer was extracted with dichloromethane (100 mL). The combined organics were dried over sodium sulfate, filtered and then concentrated under reduced pressure to provide N4-(3-chloropropyl)-5,6-dimethyl-2-phenoxypyridine-3,4-diamine as a brown sludge. This material was used directly in the next step.
Reaction SMILES: COC1C=CC(C([NH:24][C:25]2[N:30]([CH3:31])[C:29](=[O:32])[C:28]([CH3:34])([CH3:33])[C@:27]([C:36]3[CH:41]=[C:40](Br)[CH:39]=[CH:38][C:37]=3[F:43])([CH3:35])[N:26]=2)(C2C=CC(OC)=CC=2)C2C=CC=CC=2)=CC=1.[CH3:44][O:45][C:46]1[N:51]=[CH:50][C:49]([NH2:52])=[CH:48][CH:47]=1>>[NH2:24][C:25]1[N:30]([CH3:31])[C:29](=[O:32])[C:28]([CH3:34])([CH3:33])[C@:27]([C:36]2[CH:41]=[C:40]([NH:52][C:49]3[CH:50]=[N:51][C:46]([O:45][CH3:44])=[CH:47][CH:48]=3)[CH:39]=[CH:38][C:37]=2[F:43])([CH3:35])[N:26]=1
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(Br)ccc3F)C(C)(C)C(=O)N2C)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: COc1ccc(N)cn1
Product: COc1ccc(Nc2ccc(F)c([C@@]3(C)N=C(N)N(C)C(=O)C3(C)C)c2)cn1

Procedure:
The coupling of (S)-2-{[bis-(4-methoxy-phenyl)-phenyl-methyl]-amino}-6-(5-bromo-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate K) and 6-methoxy-pyridin-3-ylamine according to procedure B followed by deprotection yielded the title compound as an pale brown foam. MS (ESI): m/z=386.2 [M+H]+.
Reaction SMILES: CN1CCOCC1.ON1C2C=CC=CC=2N=N1.[NH2:18][CH:19]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH:20]([OH:22])[CH3:21].[Cl:29][C:30]1[CH:47]=[CH:46][CH:45]=[CH:44][C:31]=1[C:32]([NH:34][C:35]1[CH:43]=[CH:42][C:38]([C:39](O)=[O:40])=[CH:37][CH:36]=1)=[O:33].Cl.CN(C)CCCN=C=NCC>CN(C=O)C.C(OCC)(=O)C.O>[Cl:29][C:30]1[CH:47]=[CH:46][CH:45]=[CH:44][C:31]=1[C:32]([NH:34][C:35]1[CH:43]=[CH:42][C:38]([C:39]([NH:18][CH:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:20]([OH:22])[CH3:21])=[O:40])=[CH:37][CH:36]=1)=[O:33]
Reactant: O=C(O)c1ccc(NC(=O)c2ccccc2Cl)cc1
Reactant: CC(O)C(N)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(O)C(NC(=O)c1ccc(NC(=O)c2ccccc2Cl)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
to a room temperature mixture of 1-methylmorpholine (602 mg, 5.95 mmol), 1-hydroxybenzotriazole (322 mg, 2.38 mmol), 1-amino-1-phenylpropan-2-ol (300 mg, 1.98 mmol) and 4-(2-chlorobenzamido)benzoic acid (656 mg, 2.38 mmol) dissolved in 10 mL DMF was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (456 mg, 2.38 mmol) all in one portion. The reaction was left to stir at ambient temperature for 20 hours then poured into 30 mL water. The aqueous mixture was extracted with 50 mL 30% dichloromethane in diethyl ether. The organic extract was washed with 3×25 mL water then 20 mL brine, stirred over magnesium sulfate, filtered and the filtrate concentrated under reduced pressure to afford a white solid. The solid was suspended in hot ethyl acetate, cooled to room temperature and filtered, drying over a stream of air (658 mg, 81%). ESI+ m/z=409.1 [MH]+.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1.[NH:18]1[CH2:21][CH:20]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:19]1>CN(C=O)C.O>[N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]=[CH:17][C:8]=1[N:18]1[CH2:21][CH:20]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])[CH2:19]1
Reactant: Clc1ccc2ccccc2n1
Reactant: CC(C)(C)OC(=O)NC1CNC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CN(c2ccc3ccccc3n2)C1
Temperature: 100 °C
Yield: 58 %

Procedure:
A mixture of Cs2CO3 (3.2 g, 10.0 mmol), 2-chloro-quinoline (0.8 g, 5.0 mmol) and tert-butyl azetidin-3-ylcarbamate (0.8 g, 5.0 mmol) was dissolved in DMF (20 mL) and the resulting mixture was heated to 100° C. overnight. Then the mixture was diluted with water (20 mL) and extracted with EtOAc (2×50 mL). The combined organic extracts were combined and washed with water (20 mL) and brine (20 mL), dried over Na2SO4, and filtered. The filtrate was evaporated in vacuo and the residue was purified by flash column chromatography on silica gel (20% to 70% EtOAc in petroleum ether) to give tert-butyl (1-(quinolin-2-yl)azetidin-3-yl)carbamate (0.8 g, 2.9 mmol, 53% yield) as white solid. ESI-MS (M+1): 300 calc. for C17H21N3O2 299.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[C:8]([CH3:22])([CH3:21])[N:9]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:10](=[O:11])[C:5]2=[CH:4][CH:3]=1.[CH3:23][O-:24].[Na+]>CN(C=O)C>[CH3:23][O:24][C:2]1[N:7]=[C:6]2[C:8]([CH3:22])([CH3:21])[N:9]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:10](=[O:11])[C:5]2=[CH:4][CH:3]=1
Reactant: C[O-]
Reactant: COc1ccc(CN2C(=O)c3ccc(Cl)nc3C2(C)C)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CN2C(=O)c3ccc(OC)nc3C2(C)C)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.6 %

Procedure:
To solution of 2-chloro-6-(4-methoxy-benzyl)-7,7-dimethyl-6,7-dihydro-pyrrolo[3,4-b]pyridin-5-one (intermediate A-16 [F], 3.15 g, 10 mmol) in DMF (30 mL) was added sodium methanolate (0.813 g, 15 mmol) at room temperature. The reaction mixture was stirred at room temperature for 4 hours before it was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give title compound (2.8 g, 90%) as a solid. MS: 313.1 (M+H+).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:24]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]=[C:16]([NH2:25])[C:15]=2[N:14]=[C:13]1[CH2:26][CH2:27][CH2:28][CH3:29].[CH2:30]([N:34]=[C:35]=[O:36])[CH2:31][CH2:32][CH3:33].C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O.O>[NH2:25][C:16]1[C:15]2[N:14]=[C:13]([CH2:26][CH2:27][CH2:28][CH3:29])[N:12]([CH2:11][CH2:10][CH2:9][NH:8][C:35]([NH:34][CH2:30][CH2:31][CH2:32][CH3:33])=[O:36])[C:24]=2[C:23]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N:17]=1
Reactant: CCCCN=C=O
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCNC(=O)NCCCn1c(CCCC)nc2c(N)nc3ccccc3c21
Yield: 40 %

Procedure:
Triethylamine (765 mg, 7.56 mmol) was added to a solution of 1-(3-aminopropyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (1.5 g, 5.04 mmol) in 1-methyl-2-pyrrolidinone (100 mL). Butyl isocyanate (549 mg, 5.55 mmol) was added dropwise with stirring. The reaction mixture was allowed to stir overnight and then it was poured into water (500 mL). The pH was adjusted to 10 using solid potassium carbonate. The resulting precipitate was isolated by filtration, washed with water and then purified by column chromatography (silica gel eluting with 5% methanol in dichloromethane and then with 10% methanol in dichloromethane. The purified material was recrystallized from acetonitrile to provide 800 mg of N-[3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]-N′-butylurea as a white solid, m.p. 185.5-186.4° C. Analysis: Calculated for C22H32N6O: %C, 66.64; %H, 8.13; %N, 21.29; Found: %C, 66.38; %H, 8.19; %N, 21.10.