Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:11])[C:9]=1[OH:10])[CH:5]=[O:6].[H-].[Na+].Br[CH2:15][CH2:16][O:17][CH3:18]>CN(C=O)C>[CH3:18][O:17][CH2:16][CH2:15][O:10][C:9]1[C:8]([CH3:11])=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[CH3:1]
Reactant: COCCBr
Reactant: Cc1cc(C=O)cc(C)c1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOc1c(C)cc(C=O)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.6 %

Procedure:
To a solution of 3,5-dimethyl-4-hydroxy benzaldehyde (2.0 g, 13.33 mmol) in DMF was added NaH (640 mg, 16.0 mmol, 60% in oil) and the mixture was stirred for 1 h at room temperature. A solution of 1-bromo-2-methoxy ethane (1.85 g, 13.33 mmol) was added and the mixture was stirred for 72 h at room temperature. The reaction mixture was quenched by addition of saturated NH4Cl solution and diluted with water. The product was extracted with ethyl acetate. The combined organic layers were washed with water, brine and dried over Na2SO4. Upon removal of solvent, it gave 2.1 g of 4-(2-methoxy ethoxy)-3,5-dimethyl benzaldehyde (76 yield). To a solution of 2-amino-4,6-dimethoxybenzamide (200 mg, 1.02 mmol) and 4-(2-methoxy ethoxy)-3,5-dimethyl benzaldehyde (212 mg, 1.02 mmol) in N,N-dimethyl acetamide (10 mL), NaHSO3 (199 mg, 1.12 mmol) and p-TSA (22 mg, 0.102 mmol) were added and the reaction mixture was heated at 150° C. for 3 h. Cooled to room temperature and the solvent was evaporated under reduced pressure. The residue was diluted with water and the solid was collected to give the crude product. The crude product was purified by chromatography using 2% MeOH in CH2Cl2 to give 5,7-dimethoxy-2-(4-(2-methoxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one (170 mg, 43%). Selected data: MS (ES) m/z: 385.10; MP 201-202° C.
Reaction SMILES: [NH2:1][C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:15]1[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)=[O:21])[CH2:16]1>>[NH2:1][C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH:5]([N:15]2[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:32])[F:33])[CH:26]=3)=[O:21])[CH2:16]2)[CH2:4][CH2:3]1
Reactant: NC1(c2ccccc2)CCC(=O)CC1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: NC1(c2ccccc2)CCC(N2CC(NC(=O)CNC(=O)c3cccc(C(F)(F)F)c3)C2)CC1

Procedure:
The title compound was prepared as a white solid by reductive amination of 4-amino-4-phenyl-cyclohexanone (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in step B of Example 4) using the procedure described in Step C of Example 4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([OH:33])[C:9]1[N:24]([C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])[C:12]2[N:13]=[C:14]([NH:17][CH:18]([CH3:23])[C:19]([CH3:22])([OH:21])[CH3:20])[N:15]=[CH:16][C:11]=2[CH:10]=1.C(N(CC)CC)C.[C:41](Cl)(=[O:43])[CH3:42].C(OCC)(=O)C>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:33][C:41](=[O:43])[CH3:42])[C:9]1[N:24]([C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])[C:12]2[N:13]=[C:14]([NH:17][CH:18]([CH3:23])[C:19]([OH:21])([CH3:22])[CH3:20])[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: CC(Nc1ncc2cc(C(O)c3ccccc3Cl)n(-c3c(F)cccc3F)c2n1)C(C)(C)O
Reactant: CC(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CC(=O)OC(c1ccccc1Cl)c1cc2cnc(NC(C)C(C)(C)O)nc2n1-c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 3-[6-[(2-chloro-phenyl)-hydroxy-methyl}-7-(2,6-difluoro-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino]-2-methyl-butan-2-ol, 9, (0.47 g, 1.00 mmol) and triethylamine (0.60 ml, 4.0 mmol), in pyridine (5 ml) is added dropwise acetyl chloride (0.08 ml, 2.20 mmol). The reaction mixture is stirred under argon at room temperature for 48 hours. Ethyl acetate is added to the mixture and the resulting mixture is washed with water, brine, dried (MgSO4), filtered and concentrated in vacuo. The resulting residue is purified over silica (40% EtOAc/hexanes) to afford 30 mg of the desired: 1H NMR (300 MHz, CDCl3) δ 8.42 (s, 1H), 7.52-7.10 (m, 7H), 6.11 (d, J=5.3 Hz, 1H), 4.00-3.91 (m, 1H), 1.97 (d, J=5.9 Hz, 3H), 1.50 (br s, 1H), 1.23 (s, 3H), 1,19 (s, 3H); HRMS calcd for C26H25ClF2N4O3 (M+H)+ 515.1662, found 515.1644.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.S([O-])(=O)(=O)C>C1COCC1.CCOC(C)=O>[C:5]1([C:8]#[C:9][CH2:10][NH:1][C@H:2]2[CH2:3][CH2:4][C@H:5]([C:8]3[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=3)[CH2:6][CH2:7]2)[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1
Reactant: N[C@H]1CC[C@H](c2ccc(O)cc2)CC1
Agent: CS(=O)(=O)[O-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Oc1ccc([C@H]2CC[C@H](NCC#Cc3ccccc3)CC2)cc1

Procedure:
A mixture of trans-4-(4-hydroxyphenyl)cyclohexylamine 5 (0.35 g, 1.8 mmol) and mesylate 7 (0.32 g, 1.5 mmol) in THF (15 mL) was refluxed under N2 for 17 hours. The reaction mixture was diluted with EtOAc (40 mL) and washed with H2O, then saturated NaCl, dried (Na2SO4), filtered, and concentrated under reduced pressure. Purification by flash chromatography (silica, 99:1 CHCl3:MeOH to 97:3 CHCl3:MeOH) and conversion to the maleate salt gave trans-4-[4-(3-phenylprop-2-ynylamino)cyclohexyl]phenol (160 mg, 26%) as a white solid: mp 171-179° C.; IR (KBr): 2938, 1700, 1516cm−1; 1H NMR (300 MHz, CD3OD) δ 7.52-7.35 (m, 5H), 7.04 (d, J=8 Hz, 2H), 6.69 (d, J=8 Hz, 2H), 6.25 (s, 2H), 4.21 (s, 2H), 3.45-3.35 (obs m, 1H) 2.52-2.42 (m, 1H), 2.31-2.20 (m, 2H), 2.05-1.60 (m, 2H), 1.67-1.48 (m, 4H); CI-MS (methane) (m/z): 306 [M+H]+; HPLC: method A, 7.63 minutes (97.9%); method B, 14.01 minutes (97.6%); Anal. Calcd for C21H23NO.C4H4O4: C, 71.24; H, 6.46; N, 3.32. Found: C, 71.21; H, 6.51; N, 3.22.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:18]([OH:20])=O)=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.C(N(CC)CC)C.Cl.[CH3:41][NH:42][O:43][CH3:44]>C1COCC1>[CH3:44][O:43][N:42]([CH3:41])[C:18]([C:9]1[O:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:11][C:10]=1[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:20]
Reactant: O=C(O)c1oc(-c2ccccc2)nc1-c1ccccc1
Reactant: CNOC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1oc(-c2ccccc2)nc1-c1ccccc1
Temperature: 50 °C
Yield: 74.7 %

Procedure:
A solution of the above-prepared 2,4-diphenyl-oxazole-5-carboxylic acid (427 mg, 1.61 mmole, 1.0 eq) in dry THF was treated with carbonyldiimidazole (340 mg, 2.09 mmole, 1.3 eq) and the mixture heated at 50° C. for 3 hours. Triethylamine (360 uL, 2.58 mmole, 1.6 eq) and N,O-dimethylhydroxylamine-HCl (236 mg, 2.42 mmole, 1.5 eq) were added and the mixture heated at 50° C. for 3 hours. The mixture was partitioned between ethyl acetate and water. The organic phase was washed with 5% KHSO4 and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to a brown oil. The crude oil was chromatographed on silica gel eluting with (7:3) hexanes-ether to give 371 mg (75%) of the title compound as a brown crystalline solid. 1H NMR (CDCl3) δ 3.35 (s, 3H), 3.8 (s, 3H), 7.3-7.6 (m, 6H), 7.95 (dd, 2H), 8.15 (dd, 2H).
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([CH2:9]P(=O)(OCC)OCC)#[N:8].O=[C:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1>C1COCC1.O>[C:7]([CH:9]=[C:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1)#[N:8]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CCOP(=O)(CC#N)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(=CC#N)CC1
Temperature: 0 °C

Procedure:
To a three necked round bottom flask equipped with a mechanical stirring bar was added potassium tert-butoxide (263 mL, 263 mmol, 1.0 M in THF) and THF (200 mL). The mixture was cooled to 0° C., followed by the addition of diethyl (cyanomethyl)phosphonate (43.7 mL, 276 mmol) slowly by syringe. The reaction mixture was maintained at 0° C. for 10 minutes, then warmed to ambient temperature and maintained for 1 hour. The mixture was cooled to 0° C. and treated with the dropwise addition of tert-butyl 4-oxopiperidine-1-carboxylate (50.0 g, 251 mmol) in THF (150 mL) over 30 minutes. After addition, the mixture was maintained at 0° C. for 20 minutes, then warmed to ambient temperature and maintained for 18 hours. The reaction mixture was then diluted with water (800 mL) and extracted with EtOAc (700 mL×2). The combined organic extracts were washed with water, brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford the title compound as a light pink solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([C:22]#[N:23])=[C:16]3[C:21]=2[N:20]=[CH:19][CH:18]=[CH:17]3)(=[O:10])=[O:9])=[C:4]([N+:24]([O-])=O)[CH:3]=1.Cl[Sn]Cl.Cl>CCO>[NH2:24][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[S:8]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([C:22]#[N:23])=[C:16]2[C:21]=1[N:20]=[CH:19][CH:18]=[CH:17]2)(=[O:9])=[O:10]
Reactant: N#Cc1ccc(NS(=O)(=O)c2ccc(Cl)cc2[N+](=O)[O-])c2ncccc12
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Product: N#Cc1ccc(NS(=O)(=O)c2ccc(Cl)cc2N)c2ncccc12
Yield: 139.4 %

Procedure:
In a similar fashion using route 1 general procedure 4, 4-chloro-N-(5-cyano-quinolin-8-yl)-2-nitro-benzenesulfonamide (Intermediate 273) (90 mg, 0.2 mmol), SnCl2 (28 mg, 1.3 mmol), 6N HCl (cat) and EtOH (6 ml) at 85° C. for 3 h gave the title compound (100 mg) which was used in the next step without further purification.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH:10]1[CH:14]=[CH:13][N:12]=[CH:11]1.C(=O)(O)[O-].[Na+].O>CO>[C:4]1([CH2:3][CH2:2][N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: c1c[nH]cn1
Reactant: BrCCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: c1ccc(CCn2ccnc2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
(2-Bromoethyl)benzene (41.62 g, 0.225 mol) was added dropwise to a stirred mixture of imidazole (13.6 g, 0.2 mol) and sodium bicarbonate (16.8 g, 0.2 mol) in methanol (100 ml). Following the addition, the reaction mixture was stirred at ambient temperature for 24 h, and then stirred and heated under reflux for 6 h. After concentration of the reaction mixture under reduced pressure, the residue was treated with water (100 ml), and this mixture was extracted with chloroform (3×75 ml). The combined extracts were dried (magnesium sulphate), and the solution was then evaporated under reduced pressure. The resulting brown oil was distilled to afford 1-(2-phenylethyl)imidazole, b.p. 122°/0.2 mmHg. The slightly impure product was purified using a silica gel column and by elution with ethyl acetate/methanol (9:1). The product fractions were pooled, concentrated, under reduced pressure, and then distilled, to afford the pure product, b.p. 110°/0.1 mmHg.
Reaction SMILES: [C:1]([C:3]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=2)=[CH:6][NH:5][C:4]=1[NH:16][CH:17]=[NH:18])#[N:2].NC1NC=C(C2C=CC=C(OC)C=2)C=1C#N>C(OCC)(OCC)OCC>[CH3:15][O:14][C:10]1[CH:9]=[C:8]([C:7]2[C:3]3[C:1]([NH2:2])=[N:18][CH:17]=[N:16][C:4]=3[NH:5][CH:6]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: COc1cccc(-c2c[nH]c(NC=N)c2C#N)c1
Agent: COc1cccc(-c2c[nH]c(N)c2C#N)c1
Solvent: CCOC(OCC)OCC
Product: COc1cccc(-c2c[nH]c3ncnc(N)c23)c1
Temperature: 140 °C
Reaction time: 1 h

Procedure:
N-[3-Cyano-4-(3-methoxy-phenyl)-1H-pyrrol-2-yl]formamidine: 5.30 g of 2-amino4-(3-methoxy-phenyl)-1H-pyrrole-3-carbonitrile are dissolved in 50 ml of triethyl orthoformate, and the solution is stirred for 1 hour at 140° C. The triethyl orthoformate is removed under a high vacuum and the residue is dissolved in methanol saturated with ammonia. Stirring is carried out for 20 hours at room temperature, followed by filtration. The product is recrystallised from ethanol. M.p.: 188-190° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:11]2[C:6](=[CH:7][C:8]([C:12](O)=O)=[CH:9][CH:10]=2)[N:5]([CH2:15][CH3:16])[C:4](=[O:17])[CH2:3]1.CC1(C)C2C(=CC(C(O)=O)=CC=2)[NH:23]C(=O)C1.CC1(C)C2C(=CC(C#N)=CC=2)NC(=O)C1.ICC.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:1][C:2]1([CH3:18])[C:11]2[C:6](=[CH:7][C:8]([C:12]#[N:23])=[CH:9][CH:10]=2)[N:5]([CH2:15][CH3:16])[C:4](=[O:17])[CH2:3]1
Reactant: CC1(C)CC(=O)Nc2cc(C(=O)O)ccc21
Reactant: CCN1C(=O)CC(C)(C)c2ccc(C(=O)O)cc21
Agent: CC1(C)CC(=O)Nc2cc(C#N)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCI
Product: CCN1C(=O)CC(C)(C)c2ccc(C#N)cc21
Temperature: 25 °C
Yield: 48 %

Procedure:
One prepared 4,4-dimethyl-1-ethyl-1,2,3,4-tetrahydro-2-oxo-7-quinolinecarboxylic acid analogously to the procedure for 4,4-dimethyl-1,2,3,4-tetrahydro-2-oxo-7-quinolinecarboxylic acid (DE-A-3,818,830) as follows: one stirred 4,4-dimethyl-1,2,3,4-tetrahydro-2-oxo-7-quinolinecarbonitrile (2.0 g, 10.0 mmol), iodoethane (1 ml, 12.0 mmol) and potassium carbonate (1.70 g, 12.0 mmol) for one hour at 60° C., again added iodoethane (2 ml, 24 mmol) and potassium carbonate (2.5 g, 25 mmol) thereto and stirred for one hour at 60° C. One allowed to cool to room temperature, stirred the solution into water, filtered off the precipitate with suction and dried in a vacuum. One obtains 4,4-dimethyl-1-ethyl-1,2,3,4-tetrahydro-2-oxo-7-quinolinecarbonitrile (1.1 g, 48%) with the m.p.=120°-121° C.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:9]#[C:10][Si](C)(C)C)[C:5]([NH2:8])=[N:6][CH:7]=1.[H-].[Na+].[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>CN(C=O)C>[Br:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:10][N:8]([S:23]([C:20]3[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=3)(=[O:25])=[O:24])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C[Si](C)(C)C#Cc1nc(Br)cnc1N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(Br)cnc32)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 55.3 %

Procedure:
To a solution of 5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine (3.00 g, 11.1 mmol) in DMF (60 mL) at about 0° C. was added NaH (60% dispersion in mineral oil, 0.577 g, 14.4 mmol) in three portions. After about 15 min, p-toluenesulfonyl chloride (2.75 g, 14.4 mmol) was added and the reaction was allowed to warm slowly to ambient temperature. After about 16 h, the reaction mixture was poured onto ice-cold water (120 mL) and the precipitate was collected by vacuum filtration. The crude solid was dissolved in DCM (15 mL) and purified by silica gel chromatography eluting with DCM to give 2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (2.16 g, 52%): LC/MS (Table 1, Method c) Rt=1.58 min; MS m/z: 352, 354 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:30]=[CH:31][CH:32]=1)[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([NH:19][S:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])(=[O:22])=[O:21])=[O:18])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)([O-])=O.[H][H]>CO.C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:30]=[CH:31][CH:32]=1)[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([NH:19][S:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])(=[O:22])=[O:21])=[O:18])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1
Reactant: Cc1ccccc1S(=O)(=O)NC(=O)c1ccc2c(ccn2Cc2cccc([N+](=O)[O-])c2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1ccccc1S(=O)(=O)NC(=O)c1ccc2c(ccn2Cc2cccc(N)c2)c1

Procedure:
The nitrobenzylindole (Example 3) (2.7 g) was dissolved in methanol (125 ml) and ethyl acetate (125 ml), and 10% palladium on charcoal (0.5 g) added. The reaction mixture was hydrogenated in a Parr bottle at 50 p.s.i. with shaking until hydrogen uptake was complete (approximately 1 hour). The catalyst was filtered off through Celite and the solvent removed in vacuo to give N-[1-(3-aminobenzyl)indol-5-ylcarbonyl]-2-methylbenzene sulphonamide as a foam. This crude product was used in the next step without purification.
Reaction SMILES: [C:1]1([P:7]([Cl:10])([Cl:9])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[Cl:9][P:7]([Cl:10])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=P(Cl)(Cl)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: ClP(Cl)c1ccccc1
Yield: 54.6 %

Procedure:
50 g (0.256 mole) of phenylphosphonic acid dichloride and 40 g (0.153 mole) of triphenylphosphane were stirred for 12 hours at 230° C. under an atomosphere of nitrogen. Distillation was then carried out at 0.1 kPa until an internal temperature of 200° C. was reached. The distillate obtained was then fractionated using a silvered-jacketed column, 70 cm long, packed with Raschig rings. 25 g of dichlorophenylphosphane were obtained, as well as unreacted phenylphosphonic acid dichloride. This corresponds to a yield of 91% of theory, based on triphenylphosphane employed.
Reaction SMILES: [CH2:1]1[O:17][C:4]2([C:12]3[C:7](=[CH:8][C:9]([N+:14]([O-:16])=[O:15])=[C:10](Br)[CH:11]=3)[CH2:6][CH2:5]2)[O:3][CH2:2]1.[SH:18][C:19]1[S:20][CH:21]=[CH:22][N:23]=1.[OH-].[K+]>N1C=CC=CC=1>[CH2:1]1[O:17][C:4]2([C:12]3[C:7](=[CH:8][C:9]([N+:14]([O-:16])=[O:15])=[C:10]([S:18][C:19]4[S:20][CH:21]=[CH:22][N:23]=4)[CH:11]=3)[CH2:6][CH2:5]2)[O:3][CH2:2]1
Reactant: Sc1nccs1
Reactant: O=[N+]([O-])c1cc2c(cc1Br)C1(CC2)OCCO1
Agent: [K+]
Agent: [OH-]
Solvent: c1ccncc1
Product: O=[N+]([O-])c1cc2c(cc1Sc1nccs1)C1(CC2)OCCO1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 60.8 %

Procedure:
The bromide from Step 6 (410 mg, 1.37 mmol) and 2-mercaptothiazole (200 mg, 1.7 mmol) were mixed together in pyridine (3 mL) at room temperature. Aqueous KOH (8M, 213 μL, 1.7 mmol) was added and the resulting mixture was heated with an oil bath at 80° C. for 3 h, then at 100° C. for 1.5 h and finally 75° C. for 16 h. After cooling to room temperature the mixture was diluted and EtOAc and washed with water. The organic layer was dried over MgSO4 and concentrated in vacuo. Purification by flash chromatography on silica gel (from 5% acetone in 2:1 CH2Cl2 -hexanes to 10% acetone in CH2Cl2) yielded 280 mg of the title compound.
Reaction SMILES: CC(C[AlH]CC(C)C)C.C([O:12][C:13](=O)[CH2:14][CH2:15][C:16]1[S:17][C:18]([CH2:21][CH2:22][C:23](OCC)=[O:24])=[CH:19][CH:20]=1)C>C1COCC1>[OH:24][CH2:23][CH2:22][CH2:21][C:18]1[S:17][C:16]([CH2:15][CH2:14][CH2:13][OH:12])=[CH:20][CH:19]=1
Reactant: CCOC(=O)CCc1ccc(CCC(=O)OCC)s1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: OCCCc1ccc(CCCO)s1
Temperature: 25 °C
Yield: 85.1 %

Procedure:
A stirred solution of DIBAL (88 mL, 88 mmol, 1.0 M in cyclohexane) in THF (300 mL) was cooled to −78° C. and the intermediate from Step B (5.0 g, 17.6 mmol) was added dropwise. After complete addition, the reaction mixture was warmed to ambient temperature over 30 minutes. The reaction was then quenched by slowly adding 1N HCl (200 mL) and then DCM (400 mL) was added. The organic layer was removed and the aqueous layer was washed with DCM (4×100 mL). The combined organic layers were then washed with saturated NaCl (100 mL), dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to provide 3.0 g of the title intermediate (85% yield), which was used without further purification.
Reaction SMILES: C(OC(=O)C)(=O)C.[C:8]([O:12][C:13](=[O:39])[NH:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([CH:21]([CH:37]=[O:38])[CH:22]([C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[C:31]([O:34][CH3:35])[N:32]=3)[N:27]=[CH:26][C:25]=2[Cl:36])O)[CH2:17][CH2:16]1)([CH3:11])([CH3:10])[CH3:9]>N1C=CC=CC=1>[C:8]([O:12][C:13](=[O:39])[NH:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([C:21]([CH:37]=[O:38])=[CH:22][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[C:31]([O:34][CH3:35])[N:32]=3)[N:27]=[CH:26][C:25]=2[Cl:36])[CH2:17][CH2:16]1)([CH3:11])([CH3:9])[CH3:10]
Reactant: COc1ccc2ncc(Cl)c(C(O)C(C=O)[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)c2n1
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: COc1ccc2ncc(Cl)c(C=C(C=O)[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)c2n1
Temperature: 25 °C
Reaction time: 90 h

Procedure:
Acetic anhydride (9.95 g, 97.5 mmol, 10.0 eq) is added at room temperature to a stirred solution of {trans-4-[2-(3-chloro-6-methoxy-[1,5]naphthyridin-4-yl)-1-formyl-2-hydroxy-ethyl]-cyclohexyl}-carbamic acid tert-butyl ester (4.5 g, 9.7 mmol, 1.0 eq) in anhydrous pyridine (100 mL). After 30 hours stirring at room temperature and 90 hours stirring at 50° C., solvent is removed and the residue is extracted with ethyl acetate (3×100 mL) and a saturated sodium hydrogen carbonate aqueous solution (100 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give the crude product that is purified by column chromatography (silica gel, eluent: petroleum ether:ethyl acetate:dichloromethane, 9:2:1 to 6:2:1, v/v/v) to afford {trans-4-[2-(3-chloro-6-methoxy-[1,5]naphthyridin-4-yl)-1-formyl-vinyl]-cyclohexyl}-carbamic acid tert-butyl ester as a white solid (3.40 g, 79% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH3:9][O:10][CH2:11]OC.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][O:10][CH3:11])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: COCOC
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCl
Product: COCOc1ccc(Br)cc1
Reaction time: 1 h
Yield: 57.9 %

Procedure:
To a solution of 4-bromophenol (0.50 g, 2.89 mmol) and dimethoxymethane (2.6 mL, 29.39 mmol) in DCM (60 mL) was added P2O5 (1.50 g, 10.57 mmol). The reaction mixture was stirred at for 1 h and insoluble precipitate was filtered off. Solid Na2CO3 was added to the solution and stirred for additional 10 min. The solid was filtered off and the solution was concentrated. Purification on a silica gel column gave the desired product as a clear oil (363 mg). NMR (CDCl3): 7.38 (d, 2H), 6.93 (d, 2H), 5.15 (s, 2H), 3.47 (s, 3H).
Reaction SMILES: F[C:2](F)(F)C(O)=O.NN=CNC1C=C(C(NCC([NH:24][CH:25]([C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=2)[CH2:26][C:27]([OH:29])=[O:28])=O)=O)C=CC=1.[ClH:40].O1CCOCC1>CO>[ClH:40].[NH2:24][CH:25]([C:30]1[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=1)[CH2:26][C:27]([O:29][CH3:2])=[O:28]
Reactant: O=C(O)C(F)(F)F
Reactant: NN=CNc1cccc(C(=O)NCC(=O)NC(CC(=O)O)c2ccc3ccccc3c2)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)CC(N)c1ccc2ccccc2c1
Reaction time: 8 h

Procedure:
A suspension of the product of Step A (2.5 g) in methanol (100 ml) was treated with 4N HCl/dioxane (10 ml). The resulting solution was stirred overnight. The excess solvent was removed under reduced pressure and the semi solid was purified by HPLC (RP--CH3CN/H2O). The solid was dissolved in CH3CN/H2O, treated with 20% aqueous HCl (5 ml) and lyophilized to give methyl β-aminonaphthalene-2-propanoate hydrochloride (1.1 g). MS and 1H-NMR were consistent with the structure.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([OH:20])[CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[CH:10][C:9]=2[N:8]=[C:7]1[CH3:19].CI.[CH3:23]CCCCC>O1CCCC1.O>[CH3:23][O:20][CH:4]([CH3:3])[CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[CH:10][C:9]=2[N:8]=[C:7]1[CH3:19]
Reactant: CCCCCC
Reactant: Cc1nc2cnc3ccccc3c2n1CC(C)O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Solvent: C1CCOC1
Product: COC(C)Cn1c(C)nc2cnc3ccccc3c21

Procedure:
Sodium hydride (1 g of 60% ) was added to a suspension of 5 g (0.021 mole) of α,2-dimethyl-1H-imidazo[4,5-c]quinoline-1-ethanol in 100 mL of tetrahydrofuran. The resulting mixture was stirred for an hour. Methyl iodide (1.55 mL; 0.025 mole) was added and the reaction mixture was stirred for an hour. The reaction mixture was diluted with water then extracted three times with ethyl acetate. The ethyl acetate extracts were combined, dried over magnesium sulfate then concentrated under vacuum to provide 4.9 g of crude product as a brown oil. The oil was refluxed for one hour with 250 mL of hexane then filtered. The filtrate was cooled and the resulting precipitate was collected and dried to provide 2.4 g of a sticky light yellow powder. A sample was recrystallized from ether to provide 1-(2-methoxypropyl)-2-methyl-1H-imidazo[4,5c]quinoline as a white crystalline solid, m.p. 55°-57° C. The structure was confirmed by nuclear magnetic resonance spectroscopy.