Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.C(N(CC)CC)C.[CH2:18]([O:25][C:26]([N:28]1[CH2:33][CH2:32][CH:31]([CH:34]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:35][S:36](Cl)(=[O:38])=[O:37])[CH2:30][CH2:29]1)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>ClCCl>[CH2:18]([O:25][C:26]([N:28]1[CH2:33][CH2:32][CH:31]([CH:34]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:35][S:36]([N:2]2[CH2:3][CH2:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:1]2)(=[O:38])=[O:37])[CH2:30][CH2:29]1)=[O:27])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)C(CS(=O)(=O)Cl)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: c1ccc2c(c1)CCNC2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C(CS(=O)(=O)N1CCc2ccccc2C1)C1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 64 h
Yield: 83 %

Procedure:
1,2,3,4-Tetrahydroisoquinoline (0.17 ml) was dissolved in dichloromethane (40 ml) at room temperature under nitrogen. Triethylamine (0.19 ml) was added, followed by 4-(1-tert-butoxycarbonyl-2-chlorosulfonyl-ethyl)-piperidine-1-carboxylic acid benzyl ester (500 mg) as a solution in dichloromethane (1.5 ml). The reaction was left to stir for 64 h then diluted with dichloromethane (60 ml), washed with 10% citric acid solution (2×50 ml), water (2×50 ml), saturated sodium bicarbonate solution (2×50 ml) and brine (50 ml). The organic layer was then dried (MgSO4), filtered and the solvent removed under reduced pressure to give the title compound (506 mg, 83%) as a yellow oil.
Reaction SMILES: [CH2:1]([CH:3]([N:6]1[CH2:11][C:10](=O)[N:9]([CH3:13])[C:8]2[C:14]([O:19][C:20]3[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=3[CH3:28])=[N:15][C:16]([CH3:18])=[CH:17][C:7]1=2)[CH2:4][CH3:5])[CH3:2].CSC.B>C1COCC1>[CH2:1]([CH:3]([N:6]1[CH2:11][CH2:10][N:9]([CH3:13])[C:8]2[C:14]([O:19][C:20]3[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=3[CH3:28])=[N:15][C:16]([CH3:18])=[CH:17][C:7]1=2)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)N1CC(=O)N(C)c2c1cc(C)nc2Oc1c(C)cc(C)cc1C
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: CCC(CC)N1CCN(C)c2c1cc(C)nc2Oc1c(C)cc(C)cc1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
A mixture of 1-(1-Ethyl-propyl)-4,7-dimethyl-5-(2,4,6-trimethyl-phenoxy)-1,4-dihydro-2H-pyrido[3,4-b]pyrazin-3-one (21 mg, 0.055 mmol) and 2 M borane dimethylsulfide complex (BH3•DMS) (0.07 ml, 0.14 mmol) in 2 ml of dry THF was heated at reflux for 3 hours. The mixture was cooled to 0° C. and quenched with 0.2 ml of meoh and 0.2 ml of concentrated hydrochloric acid (HCl). The resulting mixture was stirred at room temperature for 2 hours and concentrated to dryness. The residue was quenched with water and extracted with chloroform. The organic layer was dried and concentrated to give 19 mg of a clear oil that was purified through silica gel column chromatography using 10% ethyl acetate in hexane as eluent to give 11 mg of the title compound as white crystals, mp 78-80° C.; 1H NMR (CDCl3) δ 6.85(s,2H), 6.28(s,1H), 3.73(m,1H), 3.12 (m,4H), 2.85(s,3H), 2.29(s,3H), 2.,13(s,3H), 2.11 (s,6H), 1.61(m,4H), 0.90(t,6H) ppm.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:19]=[N:20][C:21]([N:24]2[CH2:29][CH2:28][CH2:27][CH:26]([NH:30]C(=O)OC(C)(C)C)[CH2:25]2)=[N:22][CH:23]=1.[Cl:38][C:39]1[CH:44]=[C:43](B2OC(C)(C)C(C)(C)O2)[CH:42]=[C:41]([F:54])[C:40]=1[OH:55]>>[NH2:30][CH:26]1[CH2:27][CH2:28][CH2:29][N:24]([C:21]2[N:20]=[CH:19][C:18]([NH:17][C:5]3[C:4]4[C:9](=[CH:10][CH:11]=[C:2]([C:43]5[CH:42]=[C:41]([F:54])[C:40]([OH:55])=[C:39]([Cl:38])[CH:44]=5)[CH:3]=4)[N:8]=[CH:7][C:6]=3[C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])=[CH:23][N:22]=2)[CH2:25]1
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)NC1CCCN(c2ncc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cn2)C1
Product: NC1CCCN(c2ncc(Nc3c(C(=O)C4CC4)cnc4ccc(-c5cc(F)c(O)c(Cl)c5)cc34)cn2)C1
Yield: 20.2 %

Procedure:
Following general procedure D, tert-butyl 1-(5-(6-bromo-3-(cyclopropanecarbonyl)quinolin-4-ylamino)pyrimidin-2-yl)piperidin-3-ylcarbamate (150 mg, 0.26 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (106 mg, 0.39 mmol) to obtain the protected intermediate which was subjected to general procedure A-2 to afford the desired product (28 mg, 23% over 2 steps) as a yellow solid. NMR (500 MHz, MeOD+TFA-d) δ 9.34 (br s, 1H), 8.45 (s, 2H), 8.25 (dd, J=8.8, 1.9 Hz, 1H), 8.21 (br s, 1H), 8.04 (d, J=8.8 Hz, 1H), 7.25 (br s, 1H), 4.81-4.74 (m, 1H), 4.47 (d, J=12.8 Hz, 1H), 3.48-3.31 (m, 3H), 2.80 (br s, 1H), 2.24-2.16 (m, 1H), 1.97-1.87 (m, 1H), 1.81-1.62 (m, 2H), 1.21-1.16 (m, J=7.3 Hz, 4H); ESI MS m/z 533 [C28H26ClFN6O2+H]+; HPLC>99.0% (AUC), tR=10.89 min.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[CH2:12][C:13](=[O:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>[I-].[K+].CC(C)=O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:12][C:13](=[O:15])[CH3:14])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)COc1ccc([N+](=O)[O-])cc1
Reaction time: 3 h
Yield: 88.6 %

Procedure:
A mixture consisting of 35 g of 4-nitrophenol, 35 g of chloroacetone, 35 g of potassium carbonate, 1 g of potassium iodide and 500 ml of acetone was heated at reflux with stirring for 3 hr. Reaction mixture was concentrated underd reduced pressure; the concentrate was extracted with ethyl acetate; the ethyl acetate layer was washed consecutively with 5% aqueous solution of sodium hydroxide, water and saturated saline; and dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure; the residue was dissolved in 300 ml of ethanol, added with 100 ml of n-hexane; and subsequently left standing overnight at room temperature. Yellow crystals thus isolated were filtered off, dried and yielded 43.5 g of 4-nitrophenoxyacetone.
Reaction SMILES: CCN(CC)CC.[CH2:8]([O:10][C:11](=[O:36])[CH2:12][CH2:13][NH:14][C:15]([C:17]1[N:22]=[CH:21][C:20]([C:23]2[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:24]=2[C:25](O)=[O:26])=[CH:19][CH:18]=1)=[O:16])[CH3:9].[Cl:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]2[CH:49]=[CH:48][C:47]([NH2:50])=[CH:46][CH:45]=2)=[C:40]([CH3:51])[CH:39]=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[Cl:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]2[CH:49]=[CH:48][C:47]([NH:50][C:25]([C:24]3[CH:28]=[CH:29][C:30]([C:32]([F:34])([F:35])[F:33])=[CH:31][C:23]=3[C:20]3[CH:19]=[CH:18][C:17]([C:15]([NH:14][CH2:13][CH2:12][C:11]([O:10][CH2:8][CH3:9])=[O:36])=[O:16])=[N:22][CH:21]=3)=[O:26])=[CH:46][CH:45]=2)=[C:40]([CH3:51])[CH:39]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2cc(C(F)(F)F)ccc2C(=O)O)cn1
Reactant: Cc1cc(Cl)ccc1-c1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CCNC(=O)c1ccc(-c2cc(C(F)(F)F)ccc2C(=O)Nc2ccc(-c3ccc(Cl)cc3C)cc2)cn1
Temperature: 25 °C

Procedure:
Neat Et3N (0.28 mL, 2.0 mmol) was added to a DCM mixture (3 mL) of 2-(6-((3-ethoxy-3-oxopropyl)carbamoyl)pyridin-3-yl)-4-(trifluoromethyl)benzoic acid (˜40% pure) (616 mg, 0.6 mmol), 4′-chloro-2′-methyl-[1,1′-biphenyl]-4-amine (109 mg, 0.5 mmol), and EDCI (383 mg, 2.0 mmol) and the resulting mixture was stirred at room temperature. After 3 h the resulting mixture was directly purified via column chromatography to yield the title compound.
Reaction SMILES: Cl[O-].[Na+].C([O-])(=O)C.[Na+].[Br:9][C:10]1[C:11]([CH3:23])=[C:12]([C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][CH:18]=1)[CH:13]=[N:14][OH:15].[Cl:24][CH2:25][C:26]([CH2:28][Cl:29])=[CH2:27]>C(Cl)Cl>[Br:9][C:10]1[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[C:12]([C:13]2[CH2:27][C:26]([CH2:28][Cl:29])([CH2:25][Cl:24])[O:15][N:14]=2)[C:11]=1[CH3:23]
Reactant: Cc1c(Br)ccc(S(C)(=O)=O)c1C=NO
Reactant: C=C(CCl)CCl
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Product: Cc1c(Br)ccc(S(C)(=O)=O)c1C1=NOC(CCl)(CCl)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
At room temperature, 50 ml of sodium hypochlorite solution (which contained 3.8 g (51.4 mmol) of NaOCl, admixed with a spatula tip of sodium acetate) were added dropwise with stirring to a solution of 15 g (51.4 mmol) of 3-bromo-2-methyl-6-methylsulfonylbenzaldehyde oxime and 7.1 g (56.5 mmol) of 2-chloromethyl-3-chloropropene in 250 ml of methylene chloride. The reaction mixture was stirred at room temperature overnight. The phases were separated, and the organic phase was washed three times with water, dried and evaporated to dryness. The residue was chromatographed on silica gel using, as mobile phase, first cyclohexane, then cyclohexane/ethyl acetate 90:10 and finally cyclohexane/ethyl acetate 80:20. This gave 13.5 g of a white powder (63.3% of theory). M.p.: 144-145° C. The 1H-NMR spectrum found corresponds to the given structure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[CH:5]=[O:6].[CH3:14][Mg]Br>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]([OH:6])[CH3:14])[CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=1
Reactant: C[Mg]Br
Reactant: O=Cc1cc(Cl)cc(C(F)(F)F)c1
Solvent: C1CCOC1
Product: CC(O)c1cc(Cl)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 94.5 %

Procedure:
To a stirred solution at −10° C. of 3-chloro-5-(trifluoromethyl)benzaldehyde (Reference Example 31, 1.15 g, 5.51 mmol) in THF (20.0 mL) was added dropwise methyl magnesium bromide (2.30 mL, 3.0 M in ethyl ether, 6.90 mmol). After the addition was complete, the reaction mixture was stirred for an additional 1.5 h, then the reaction was quenched with saturated ammonium hydrochloride (30.0 mL), and the mixture was warmed to room temperature. The reaction mixture was diluted with ethyl acetate, washed with water, and saturated sodium chloride, dried (Na2SO4), filtered and concentrated under reduced pressure to provide 1-(3-chloro-5-(trifluoromethyl)phenyl)ethanol (1.17 g, 94%) as a pale yellow oil, which was used without further purification or characterization.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14](=[O:40])[CH:15]([C:31]2[CH:36]=[CH:35][C:34]3[O:37][CH2:38][O:39][C:33]=3[CH:32]=2)[O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25]C)=[O:24])=[CH:19][C:18]=2[CH2:27][CH:28]([CH3:30])[CH3:29])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[OH-].[Na+].C(Cl)(Cl)Cl>CO>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14](=[O:40])[CH:15]([C:31]2[CH:36]=[CH:35][C:34]3[O:37][CH2:38][O:39][C:33]=3[CH:32]=2)[O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([OH:25])=[O:24])=[CH:19][C:18]=2[CH2:27][CH:28]([CH3:30])[CH3:29])(=[O:11])=[O:12])=[CH:8][CH:9]=1)([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(OC(C(=O)NS(=O)(=O)c2ccc(C(C)C)cc2)c2ccc3c(c2)OCO3)c(CC(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(C)Cc1cc(C(=O)O)ccc1OC(C(=O)NS(=O)(=O)c1ccc(C(C)C)cc1)c1ccc2c(c1)OCO2
Temperature: 60 °C
Yield: 82.7 %

Procedure:
To a solution of 0.294 g (0.52 mmol) of the product of Example 60 dissolved in 3.0 mL of methanol was added 1.0 mL of a 5.0 N aqueous solution of sodium hydroxide. The reaction mixture was magnetically stirred at 60° C. After 3 hours TLC analysis (CHCl3 --MeOH--NH4OH80:15:1) indicated complete hydrolysis of the ester. The reaction was cooled to room temperature, adjusted to pH=5 with dropwise addition of 1.0 N HCI, then partitioned between EtOAc and water. The organic layer was separated, washed with saturated aqueous NaCl, dried (MgSO4), filtered and evaporated. The residue was dried in vacuo to afford 0.238 g (83%) of the title compound as an amorphous powder.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.Cl.[F:19][C:20]([F:27])([F:26])[C:21]1([OH:25])[CH2:24][NH:23][CH2:22]1>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([N:23]3[CH2:24][C:21]([OH:25])([C:20]([F:27])([F:26])[F:19])[CH2:22]3)=[O:17])=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Reactant: OC1(C(F)(F)F)CNC1
Agent: Cl
Product: O=C(c1ccc(C2CC2)c(OCC2CC2)n1)N1CC(O)(C(F)(F)F)C1
Yield: 22.9 %

Procedure:
In analogy to the procedure described in Example 127 e), 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 3 c, 20 mg, 85.7 μmol) was reacted with 3-(trifluoromethyl)azetidin-3-ol hydrochloride (CAN 848192-96-1, 18.3 mg, 103 μmol) to obtain the title compound (7 mg, 23%) as colorless oil, MS (EI): m/e=357.3 [MH+].
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:18])=O.CN(C=O)C>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([Cl:18])=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CCCCCc1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)CCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 6-phenylhexanoic acid [5581-75-9] (1.45 g, 7.6 mmol) in CH2Cl2 (15 ml) was treated with oxalyl chloride (0.72 ml, 8.6 mmol) in the presence of a catalytic amount of DMF. The solution was stirred for 2 h at ambient temperature. The solvent was evaporated to give crude 6-phenylhexanoic acid chloride, which was used without further purification in the next step.
Reaction SMILES: C1C=CC(O[C:8]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:9][C:10]#[N:11])=CC=1.[F:19][C:20]([F:33])([F:32])[C:21]1[CH:22]=[C:23]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[NH2:24].C(N(CC)CC)C>ClCCl>[F:19][C:20]([F:32])([F:33])[C:21]1[CH:22]=[C:23]([NH:24][C:8](=[N:9][C:10]#[N:11])[O:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:25]=[C:26]([C:28]([F:29])([F:31])[F:30])[CH:27]=1
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#CN=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Oc1ccccc1
Reaction time: 2 h
Yield: 73.7 %

Procedure:
A solution of diphenylcyanocarbonimidate (2 mmol, 476 mg), 3,5-bis(trifluoromethyl)aniline (2 mmol, 458 mg) and triethylamine (2 mmol, 202 mg) in dichloromethane (15 ml) was stirred under nitrogen for 12 h. After concentration the residue was stirred with toluene (5 ml) for 2 h and the solid was collected by filtration giving 550 mg of N-[3,5-bis(trifluoromethyl)phenyl]-N'-cyano-O-phenylisourea (73.6%);
Reaction SMILES: [NH2:1][C@@:2]([C:8]1[CH:13]=[C:12]([Br:14])[CH:11]=[CH:10][C:9]=1[F:15])([CH3:7])[C:3]([CH3:6])([OH:5])[CH3:4].C(=O)([O-])O.[Na+].[Cl:21][CH2:22][C:23](Cl)=[O:24]>ClCCl>[Br:14][C:12]1[CH:11]=[CH:10][C:9]([F:15])=[C:8]([C@:2]([NH:1][C:23](=[O:24])[CH2:22][Cl:21])([CH3:7])[C:3]([OH:5])([CH3:4])[CH3:6])[CH:13]=1
Reactant: CC(C)(O)[C@](C)(N)c1cc(Br)ccc1F
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(O)[C@](C)(NC(=O)CCl)c1cc(Br)ccc1F
Reaction time: 1 h

Procedure:
A solution of (R)-3-amino-3-(5-bromo-2-fluoro-phenyl)-2-methyl-butan-2-ol (2.91 g, 10.5 mmol) in dichloromethane (35 ml) was stirred intensively together with a saturated sodium hydrogen-carbonate solution (30 ml) at 0° C. Chloroacetyl chloride (0.92 ml, 11.6 ml) was added and stirring continued for 1 hour at 0° C. For the workup, the aqueous layer was separated and extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, then evaporated. The title compound was obtained as a white solid (3.5 g, 94% of theory) which was used in the next step without further purification. Mass (calculated) C13H16BrClFNO2 [352.629]; (found) [M+H]+=352, [M+2-H]+=354.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]=[C:10]=[S:11].[CH2:12]([CH2:14][NH2:15])[OH:13]>CC(C)=O>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([NH:15][CH2:14][CH2:12][OH:13])=[S:11]
Reactant: NCCO
Reactant: Cc1ccc(N=C=S)c(C)c1
Solvent: CC(C)=O
Product: Cc1ccc(NC(=S)NCCO)c(C)c1
Temperature: 4 °C

Procedure:
To 20 g. (0.12 mole) of 2,4-dimethylphenylisothiocyanate in 30 ml. of acetone was added dropwise 10 g. (0.16 mole) of ethanolamine in 20 ml. acetone. The solution was refluxed 1 hour then cooled to 4° C., to give crystals which were filtered off, washed with cold ethanol and dried to afford 1-(2,4-dimethylphenyl)-3-(2-hydroxyethyl)-thiourea, 16.8 g. (54% yield) of white crystals m.p. 137.5°-139° C.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.[NH2:10][NH2:11]>O1CCOCC1>[Cl:8][C:7]1[C:2]([NH:10][NH2:11])=[N:3][CH:4]=[C:5]([Cl:9])[CH:6]=1
Reactant: Clc1cnc(Cl)c(Cl)c1
Reactant: NN
Solvent: C1COCCO1
Product: NNc1ncc(Cl)cc1Cl
Temperature: 25 °C
Yield: 71.5 %

Procedure:
To a 500 mL flask, 2,3,5-trichloropyridine (20.00 g, 0.110 mol), 80% hydrazine (34.30 g, 0.550 mol) and dioxane (200 mL) were added sequentially. The reaction mixture was heated to reflux for 20 hours. Then the reaction mixture was cooled down to room temperature overnight and white crystal was precipitated. The white crystal was isolated via filtration and dried to give the product (14.0 g) as a white solid in 72% yield. Melting point: 187-189° C. 1H NMR (300 MHz, DMSO-d6): 8.123 (d, 1H), 7.849 (d, 1H).
Reaction SMILES: [CH2:1]([C:4]1[N:5]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=O)[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3].C(Cl)(=O)C(Cl)=O.[CH2:31]([NH2:34])[CH2:32][CH3:33]>>[CH2:31]([NH:34][C:22](=[O:24])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][N:5]1[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=[C:4]1[CH2:1][CH2:2][CH3:3])[CH2:32][CH3:33]
Reactant: CCCN
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCCCC(=O)O
Agent: O=C(Cl)C(=O)Cl
Product: CCCNC(=O)CCCCCn1c(CCC)nc2cnc3ccccc3c21

Procedure:
6-(2-Propyl-1H-imidazo[4,5-c]quinolin-1-yl)hexanoic acid (3.0 g, 9.2 mmol, prepared in Parts A through E of Example 6) was treated with oxalyl chloride (1.45 mL, 16.6 mmol) and n-propylamine (2.27 mL, 27.6 mmol) according to the method described in Part F of Example 6 to provide 3.4 g of N-propyl-6-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)hexanamide. The acid chloride solution was cooled to 0° C. before the addition of n-propylamine.
Reaction SMILES: [CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH:3]1[C:4](=[N:11]O)[C:5](=[O:10])[CH2:6]2.[C:13](O)(=[O:15])[CH3:14].C(OC(=O)C)(=O)C>[Ni]>[C:13]([NH:11][CH:4]1[C:5](=[O:10])[CH2:6][CH:7]2[N:2]([CH3:1])[CH:3]1[CH2:9][CH2:8]2)(=[O:15])[CH3:14]
Reactant: CN1C2CCC1C(=NO)C(=O)C2
Reactant: CC(=O)O
Agent: [Ni]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)NC1C(=O)CC2CCC1N2C
Reaction time: 5 h
Yield: 49 %

Procedure:
A solution of 8-methyl-8-azabicyclo[3.2.1]octane-2,3-dione-2-oxime (0.93 g, 5.5 mmol) in acetic acid/acetic anhydride (4:1, 40 mL) in a Parr bottle was treated with Raney nickel (Aldrich, 1/2 tsp.), then subjected to hydrogenation in a Parr apparatus at 45-50 psi for 5 h The solution was carefully evacuated of hydrogen, filtered through Celite® (wash filter cake carefully with methanol), and the filtrate was concentrated in vacuo. The residue was taken up in toluene and reconcentrated to remove most of the acetic acid. This residue was taken up in saturated sodium carbonate (40 mL), then treated with 15% sodium hydroxide (2 mL) and extracted with methylene chloride (3×50 mL) containing some 2-propanol. The combined extracts were dried (Na2SO4), concentrated in vacuo, and chromatographed on silica gel (eluted with 1:1 ethyl acetate/methanol) to afford a white solid, which contained some silica gel. This was removed by dissolving the product in warm ethyl acetate, filtering, and concentration in vacuo to afford 2-acetamido-8-methyl-8-azabicyclo[3.2.1]octan-3-one (0.53 g, 49%) as a white solid.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH2:5]([O:7][C:8](=[O:23])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][CH2:17]OS(C)(=O)=O)[CH:11]=1)[CH3:6]>CN(C)C=O>[CH2:5]([O:7][C:8](=[O:23])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][CH2:17][N:1]=[N+:2]=[N-:3])[CH:11]=1)[CH3:6]
Reactant: CCOC(=O)Cc1cccc(CCOS(C)(=O)=O)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1cccc(CCN=[N+]=[N-])c1
Temperature: 60 °C
Yield: 91.9 %

Procedure:
Sodium azide (2.82 g, 43.3 mmol) was added in one portion to a stirred solution of ethyl(3-{2-[(methylsulfonyl)oxy]ethyl}phenyl)acetate (Preparation 56) (6.20 g, 21.7 mmol) in N,N-dimethylformamide (400 ml) at room temperature. The reaction was heated at 60° C. for 1 hour and then allowed to cool to room temperature and the solvent removed in vacuo. Ethyl acetate (200 ml) and water (75 ml) was added and the organics separated, the aqueous was washed with ethyl acetate (2×100 ml) and the combined organics evaporated in vacuo to yield an oil that was purified by flash column chromatography on silica gel eluting with ethyl acetate:penatane (5:95, by volume) to give the title compound as a colourless oil (4.65 g). 1H NMR (400 MHz, CDCl3): δ=7.27-7.23 (1H, t), 7.17-7.12 (3H, m), 4.15-4.06 (2H, m), 3.60 (2H, s), 3.51-3.47 (2H, t), 2.87-2.84 (2H, t), 1.24-1.20 (3H, t) ppm. LRMS (electrospray): M/Z [M+NA]+256, [M−H]− 232.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:46]2[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][CH:47]=2)[O:10][CH:11]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:12]2[O:16][CH:15]([N:17]3[C:25]4[C:20](=[CH:21][C:22]([N+:26]([O-:28])=[O:27])=[CH:23][CH:24]=4)[C:19]([C:29]#[C:30][CH2:31][NH:32]C(=O)C(F)(F)F)=[CH:18]3)[CH2:14][CH:13]2[OH:39])=[CH:5][CH:4]=1>N.CO>[NH2:32][CH2:31][C:30]#[C:29][C:19]1[C:20]2[C:25](=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=2)[N:17]([CH:15]2[O:16][CH:12]([CH:11]([C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[O:10][CH:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[C:46]3[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][CH:47]=3)[CH:13]([OH:39])[CH2:14]2)[CH:18]=1
Reactant: COc1ccc(C(OC(c2ccccc2)C2OC(n3cc(C#CCNC(=O)C(F)(F)F)c4cc([N+](=O)[O-])ccc43)CC2O)c2ccc(OC)cc2)cc1
Agent: N
Solvent: CO
Product: COc1ccc(C(OC(c2ccccc2)C2OC(n3cc(C#CCN)c4cc([N+](=O)[O-])ccc43)CC2O)c2ccc(OC)cc2)cc1
Temperature: 8 °C

Procedure:
11.0 g (15 mmol) N-[3-(1-{5-[Bis-(4-methoxy-phenyl)-phenyl-methoxymethyl]-4-hydroxy-tetrahydro-furan-2-yl}-5-nitro-1H-indol-3-yl)-prop-2-ynyl]-2,2,2-trifluoro-acetamide were dissolved in 260 ml 7N ammonia solution in methanol (Aldrich, 499145). The solution was maintained at 8° C. for 16 h. The solvent was removed in a vacuum on a rotary evaporator (water bath 38° C.). The residue was chromatographed on a silica gel column (Silica gel 60, Merck, 280×85 mm) with a solvent mixture of ethyl acetate:methanol:toluene 1:1:4 (v/v/v) with 0.2 vol % triethylamine (yield: 6.1 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](Br)=[CH:7][CH:6]=1)=[O:4].[CH2:16]([Sn](CCCC)(CCCC)CCCC)[CH:17]=[CH2:18]>C1(C)C=CC=CC=1.CCOCC.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>[CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH2:18][CH:17]=[CH2:16])=[CH:7][CH:6]=1)=[O:4]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)c1ccc(Br)c2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: C=CCc1ccc(C(=O)OC)c2ccccc12
Temperature: 120 °C
Yield: 89 %

Procedure:
To a solution of 4-bromo-naphthalene-1-carboxylic acid methyl ester (2.0 g, 7.9 mmol) in toluene (20 mL) was added allyltributyltin (2.7 mL), tetrakis(triphenylphosphine)palladium(0) (183 mg, 0.16 mmol) and 2 crystals of BHT. The system was purged under vacuum and nitrogen and allowed to heat to 120° C. under N2 for 4 h. TLC analysis (silica, 1:1 ethyl acetate-hexanes) showed the reaction to be completed with only one new fluorescent spot present. The mixture was diluted with ether, washed with H2O, 10% HCl, and then saturated sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (SiO2, 9:1 hexanes-ether) to give (1.6 g, 89%) 4-allylnaphthalene-1-carboxylic acid methyl ester as a colorless liquid. MS m/z 227.1 (M+1). 1H NMR (400 mHz) CDCl3 8.95(d 1H), 8.11(d, 1H), 8.08(d, 1H), 7.58(m, 2H), 7.37(d, 1H), 6.09(m, 1H), 5.11(m, 2H), 3.99(s, 3H), 3.88(d, 2H).