Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:28]([N:31]2[CH:35]=[N:34][N:33]=[N:32]2)=[CH:27][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C@@:9]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)([CH2:12][CH2:13]OS(C)(=O)=O)[CH2:8]1)=[O:6].I.[CH2:37]([O:39][CH2:40][CH2:41][N:42]1[C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=2[N:44]=[C:43]1[N:51]1[CH2:57][CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1)[CH3:38]>>[CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:28]([N:31]2[CH:35]=[N:34][N:33]=[N:32]2)=[CH:27][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C@:9]([CH2:12][CH2:13][N:54]2[CH2:55][CH2:56][CH2:57][N:51]([C:43]3[N:42]([CH2:41][CH2:40][O:39][CH2:37][CH3:38])[C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=4[N:44]=3)[CH2:52][CH2:53]2)([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)[CH2:8]1)=[O:6]
Reactant: CCOCCn1c(N2CCCNCC2)nc2ccccc21
Reactant: COc1ccc(-n2cnnn2)cc1C(=O)N1CC[C@](CCOS(C)(=O)=O)(c2ccc(Cl)c(Cl)c2)C1
Agent: I
Product: CCOCCn1c(N2CCCN(CC[C@]3(c4ccc(Cl)c(Cl)c4)CCN(C(=O)c4cc(-n5cnnn5)ccc4OC)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 47.3 using (S)-1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(3,4-dichlorophenyl)-3-(2-methanesulfonyloxyethyl)pyrrolidine and 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic acid salt to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]=[O:18])=[CH:13][N:12]=1)[C:5]#[N:6].C(=O)([O-])[O-:20].[K+].[K+].OO.O>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]=[O:18])=[CH:13][N:12]=1)[C:5]([NH2:6])=[O:20]
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccc(Oc2ccc(C=O)cn2)c(Br)c1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: NC(=O)c1ccc(Oc2ccc(C=O)cn2)c(Br)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 100.5 %

Procedure:
Combine 3-bromo-4-(5-formyl-pyridin-2-yloxy)-benzonitrile (1.60 g, 5.28 mmol) and potassium carbonate (365 mg, 2.64 mmol) in DMSO (40 mL). Cool the reaction mixture at 0° C. Add hydrogen peroxide (1.59 mL, 5.28 mmol) dropwise and let the reaction stir at room temperature for 2 h. Pour into water and triturate to a white solid with stirring. Filter the white solid and dry to give (852 mg, 82%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:27])=[CH:4][C:5]([F:26])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([N+:19]([O-:21])=[O:20])=[C:15](F)[CH:16]=3)[C:11](=[O:22])[C:10]([C:23]([OH:25])=[O:24])=[CH:9]2)[CH:7]=1.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)[OH:33]>>[NH2:1][C:2]1[C:3]([F:27])=[CH:4][C:5]([F:26])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([N+:19]([O-:21])=[O:20])=[C:15]([OH:33])[CH:16]=3)[C:11](=[O:22])[C:10]([C:23]([OH:25])=[O:24])=[CH:9]2)[CH:7]=1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc([N+](=O)[O-])c(F)cc32)c(F)cc1F
Agent: [Na+]
Agent: [OH-]
Product: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc([N+](=O)[O-])c(O)cc32)c(F)cc1F
Temperature: 40 °C
Reaction time: 2 h

Procedure:
1-(5-Amino-2,4-difluorophenyl)-7-fluoro-6-nitro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (60 mg) was added to a 5% aqueous solution (3 ml) of sodium hydroxide, and the mixture was stirred at 40° C. for 2 hours. The reaction mixture was acidified with a 3% aqueous solution of citric acid, and solids formed were collected by filtration. The solids were subjected to azeotropic distillation with ethanol and toluene. Hexane was added to the residue to conduct filtration, thereby obtaining the title compound (49 mg) as a yellow powder.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([OH:17])=O)[CH:13]=2)[CH:8]=[CH:7][N:6]=1)[CH2:2][CH3:3].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:51][C@@H:52]([CH2:66][C:67]1[CH:72]=[C:71]([F:73])[CH:70]=[C:69]([F:74])[CH:68]=1)[C@H:53]([OH:65])[CH2:54][NH:55][CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[C:59]([CH2:63][CH3:64])[CH:58]=1>C(Cl)Cl>[F:73][C:71]1[CH:72]=[C:67]([CH:68]=[C:69]([F:74])[CH:70]=1)[CH2:66][C@H:52]([NH:51][C:15]([C:12]1[CH:13]=[C:14]2[C:9]([CH:8]=[CH:7][N:6]=[C:5]2[NH:4][CH2:1][CH2:2][CH3:3])=[CH:10][CH:11]=1)=[O:17])[C@H:53]([OH:65])[CH2:54][NH:55][CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[C:59]([CH2:63][CH3:64])[CH:58]=1
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Reactant: CCCNc1nccc2ccc(C(=O)O)cc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCNc1nccc2ccc(C(=O)N[C@@H](Cc3cc(F)cc(F)c3)[C@H](O)CNCc3cccc(CC)c3)cc12
Reaction time: 18 h
Yield: 34 %

Procedure:
To a stirred solution of 1-(propylamino)isoquinoline-7-carboxylic acid (81 mg, 0.396 mmol) and N,N-diisopropyl ethylamine (3.75 μL, 2.16 mmol) in methylene chloride (5.0 mL) was added HBTU (152 mg, 0.396 mmol) and the reaction stirred for 0.5 h. (2R,3S)-3-Amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol (150 mg, 0.36 mmol) was added in one portion and the reaction mixture was stirred under nitrogen for 18 h. The reaction mixture was then diluted with additional methylene chloride and washed with saturated sodium bicarbonate, saturated sodium chloride, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 0-5% methanol/methylene chloride) gave N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-1-(propylamino)isoquinoline-7-carboxamide (67 mg) which was characterized as its bis-HCl salt: mp 262° C. dec; ESI MS m/z 547 [M+H]+
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[NH:24][C:23](=O)[C:22]3[C:17](=[CH:18][C:19]([O:31][CH3:32])=[C:20]([O:26][CH2:27][CH2:28][O:29][CH3:30])[CH:21]=3)[N:16]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:36])=O>C(Cl)Cl.CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[N:24]=[C:23]([Cl:36])[C:22]3[C:17](=[CH:18][C:19]([O:31][CH3:32])=[C:20]([O:26][CH2:27][CH2:28][O:29][CH3:30])[CH:21]=3)[N:16]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCOc1cc2c(=O)[nH]c(-c3cccc(OCc4ccccc4)c3)nc2cc1OC
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COCCOc1cc2c(Cl)nc(-c3cccc(OCc4ccccc4)c3)nc2cc1OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 44.5 %

Procedure:
To a suspension of 2-(3-(benzyloxy)phenyl)-7-methoxy-6-(2-methoxyethoxy)quinazolin-4(3H)-one (3.28 g, 7.58 mmol) in CH2Cl2 (100 mL) was added oxalyl chloride (2.20 mL, 24.8 mmol) and 2 drops of DMF. The mixture was stirred at RT for 6 h. An additional aliquot of oxalyl chloride (1.20 mL, 13.5 mmol) was added. Stirring was continued at RT overnight, upon which the mixture was concentrated in vacuo, taken up in CHCl3 (100 mL) and washed with sat. NaHCO3 (3×50 mL), water (2×50 mL) and brine (1×50 mL). The organic layer was dried (Na2SO4), filtered and concentrated in vacuo to give 2-(3-(benzyloxy)phenyl)-4-chloro-7-methoxy-6-(2-methoxyethoxy)quinazoline (1.52 g, 3.37 mmol, 45%). MS 451 (M+1 Cl isotope pattern). HPLC retention time 10.84 mins. (10-95-13 method).
Reaction SMILES: [CH3:1][CH:2]([CH3:36])[CH2:3][CH:4]([NH:20][C:21]1[CH:35]=[CH:34][C:24]([C:25]([NH:27][CH2:28][CH2:29][C:30]([O:32]C)=[O:31])=[O:26])=[CH:23][N:22]=1)[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[N:12]2)=[CH:7][CH:6]=1.[OH-].[Li+].Cl>O.O1CCCC1>[CH3:1][CH:2]([CH3:36])[CH2:3][CH:4]([NH:20][C:21]1[CH:35]=[CH:34][C:24]([C:25]([NH:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:26])=[CH:23][N:22]=1)[C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH:15]=[C:14]([C:16]([F:17])([F:18])[F:19])[CH:13]=[N:12]2)=[CH:9][CH:10]=1
Reactant: COC(=O)CCNC(=O)c1ccc(NC(CC(C)C)c2ccc(-n3cc(C(F)(F)F)cn3)cc2)nc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)CC(Nc1ccc(C(=O)NCCC(=O)O)cn1)c1ccc(-n2cc(C(F)(F)F)cn2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.6 %

Procedure:
Methyl 3-(6-(3-methyl-1-(4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)butylamino)nicotinamido)propanoate (50 mg, 0.099 mmol) was dissolved in water (5 mL) and tetrahydrofuran (5 mL). Lithium hydroxide (0.387 mL, 2N in water, 0.774 mmol) was added. The mixture was stirred at room temperature for 2 hours. The mixture was neutralized with 1N aqueous hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated. Purification by HPLC (column: Boston Analytics Symmetrix ODS-H 150×30 mm, 5 μm; modifier: formic acid 0.225%; gradient: 10 to 80% acetonitrile in water) gave (+/−)-3-(6-(3-methyl-1-(4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)butylamino)nicotinamido)propanoic acid (25 mg, 52%). 1H NMR (400 MHz, CD3OD, δ): 8.70 (s, 1H), 8.40 (s, 1H), 7.97 (s, 1H), 7.82 (d, 1H), 7.74 (d, 2H), 7.53 (d, 2H), 6.59 (d, 1H), 5.12-5.02 (m, 1H), 3.57 (m, 2H), 2.59 (m, 2H), 1.89-1.69 (m, 2H), 1.68-1.58 (m, 1H), 1.02 (d, 3H), 0.98 (d, 3H). MS (M+1): 490.5.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:10]=2[C:11]([NH2:20])=[N:12][C:13]([NH2:19])=[N:14]3)[CH2:3][CH2:2]1.[F:21][C:22]1[CH:23]=[C:24]([S:29](Cl)(=[O:31])=[O:30])[CH:25]=[CH:26][C:27]=1[F:28]>>[F:21][C:22]1[CH:23]=[C:24]([S:29]([C:4]2([CH2:7][O:8][C:9]3[CH:18]=[CH:17][CH:16]=[C:15]4[C:10]=3[C:11]([NH2:20])=[N:12][C:13]([NH2:19])=[N:14]4)[CH2:5][CH2:6][NH:1][CH2:2][CH2:3]2)(=[O:30])=[O:31])[CH:25]=[CH:26][C:27]=1[F:28]
Reactant: O=S(=O)(Cl)c1ccc(F)c(F)c1
Reactant: Nc1nc(N)c2c(OCC3CCNCC3)cccc2n1
Product: Nc1nc(N)c2c(OCC3(S(=O)(=O)c4ccc(F)c(F)c4)CCNCC3)cccc2n1
Yield: 99 %

Procedure:
The sulfonamide was obtained by reacting 5-(piperidin-4-ylmethoxy)quinazoline-2,4-diamine (50 mg; 0.18 mmol) and 3,4-difluorobenzenesulfonyl chloride (79 mg; 0.37 mmol) via Method AA to yield 80 mg. (99% yield). 1HNMR (400 MHz, DMSO-d6) δ 7.88 (m, 1H), 7.73 (m, 1H), 7.65 (m, 1H), 7.33 (t, J=8.0 Hz, 1H), 7.11 (br s, 2H), 6.75 (dd, J=8.0, 0.4 Hz, 1H), 6.50 (d, J=7.6 Hz, 1H), 5.93 (br s, 2H), 3.97 (d, J=6.0 Hz, 2H), 3.69 (br d, J=11.6 Hz, 2H), 2.34 (m, 2H), 1.87 (m, 3H), 1.36 (m, 2H). MS m/z (ESI) 450 (M+H)+.
Reaction SMILES: [ClH:1].[CH3:2][NH:3][O:4][CH3:5].[NH2:6][C:7]1[N:15]=[CH:14][C:13]([Br:16])=[CH:12][C:8]=1[C:9](O)=[O:10].CN1CCOCC1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>ClCCl>[ClH:1].[CH3:5][O:4][N:3]([CH3:2])[C:9](=[O:10])[C:8]1[CH:12]=[C:13]([Br:16])[CH:14]=[N:15][C:7]=1[NH2:6]
Reactant: Nc1ncc(Br)cc1C(=O)O
Reactant: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CON(C)C(=O)c1cc(Br)cnc1N
Temperature: 25 °C
Reaction time: 5 h
Yield: 74 %

Procedure:
In a nitrogen flushed flask 3.00 g (30.76 mmol) of N,O-dimethylhydroxylamine hydrochloride and 3.53 g (16.27 mmol) of 2-amino-5-bromonicotinic acid are dissolved in a mixture of 350 ml of dichloromethane, and 30 ml of N-methylmorpholine. 12.70 g (24.40 mmol) of PyBOP (1-benzotriazolyloxy-tris(pyrrolidino)phosphonium hexafluorophosphate) is added and the reaction mixture stirred at room temperature for 5 hours. The mixture is then washed with 150 ml of a 2 M solution of sodium hydroxide in water and then twice with 100 ml of a 10% aqueous citric acid solution and dried over sodium sulfate. The solvent is evaporated and the resulting oil is dissolved in 300 ml of ether. The precipitate formed is filtered off and discarded. The clear filtrate is concentrated to about half its volume and diluted with 30-60 ml of dichloromethane. The resulting solution is stirred vigorously and a 1 M solution of hydrogen chloride in anhydrous ether is added until formation of the resulting precipitate is complete. The precipitate is filtered off, washed with ether and dried by suction to afford 3.15 g (12.04 mmol, 74% yield) of N-methoxy-N-methyl-2-amino-5-bromonicotinamide hydrochloride as an off-white to beige-brown powder. 1H-NMR (d6-DMSO) δ: 8.24 [1H] d, 7.97 [1H] d, 3.56 [3H] s, 3.26 [3H] s. MS: m/z 260 [MH+]
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:31]([CH3:33])[CH3:32])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:10]([CH2:34][OH:35])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.CCOCC>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:31]([CH3:32])[CH3:33])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:10]([CH:34]=[O:35])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CO)C(C)C)ccc1OC
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOCC
Product: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2C=O)C(C)C)ccc1OC

Procedure:
To a well-stirred mixture of (3S*,4R*)-3-hydroxymethyl-4-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (600 mg, 1.21 mmol) and Dess-Martin periodinane (272 mg, 1.21 mmol) in CH2Cl2 (10 mL), slowly wet CH2Cl2 (24 μL of water in 2 mL of CH2Cl2) is added. The clear solution becomes cloudy towards the end of wet CH2Cl2 addition. The mixture is diluted with Et2O and concentrated to a few mL of solvent by rotary evaporation. The residue is taken up in Et2O, and washed with a 1:1 10% Na2S2O3/saturated aqueous solution of NaHCO3, followed by H2O and brine. The aqueous washings are back-extracted with Et2O, and this organic layer is washed with H2O and brine. The combined organic layers are dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material is used without further purification in the next step. TLC, Rf (CH2Cl2/MeOH 95:5)=0.3. tR (HPLC, Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 ml/min): 5.16 min.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]([CH:8]=[CH:9][CH2:10][OH:11])=[CH:6][CH:5]=1)([O-])=O>[Pd].C(O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][CH2:9][CH2:10][OH:11])=[CH:12][CH:13]=1
Reactant: O=[N+]([O-])c1ccc(C=CCO)cc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(CCCO)cc1
Temperature: 22 °C

Procedure:
To a round bottomed flask equipped with a magnetic stirrer was added 4-nitrocinnamyl alcohol (2.0 g, 11.16 mmol), 10% Pd on carbon (200 mg) and absolute ethanol (150 mL). The solution was purged with hydrogen and stirred at 22° C. under a hydrogen atmosphere. When TLC indicated the reaction was complete (4 h), the solution was purged with argon and filtered through Celite. The filtrate was concentrated in vacuo to provide 3-(4-aminophenyl)propanol, 1.72 g (>100%), as a viscous oil which solidified on standing.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:13]([CH:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH2:14][C:15]([F:18])([F:17])[F:16])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[OH-].[Na+]>C1COCC1.CO>[Br:1][C:2]1[CH:3]=[C:4]([N:13]([CH:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH2:14][C:15]([F:16])([F:18])[F:17])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(Br)cc(N(CC(F)(F)F)C2CCOCC2)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(C(=O)O)cc(Br)cc1N(CC(F)(F)F)C1CCOCC1
Temperature: 50 °C
Reaction time: 5.5 h
Yield: 91.4 %

Procedure:
To a stirred solution of methyl 5-bromo-2-methyl-3-[(oxan-4-yl)(2,2,2-trifluoroethyl)amino]benzoate (572 mg, 1.4 mmol) in a mixture of THF (14 ml) and MeOH (2.1 ml), was added 4M NaOH (aq) (13.9 ml). The reaction mixture was stirred at 50° C. for 5.5 hours and then stirred at room temperature for 17 hours. THF was removed by concentrating in-vacuo and the aqueous residue was acidified to pH 4 with 6M HCl (aq) (9.5 ml). The resulting suspension was allowed to stand at room temperature for 20 minutes before collecting the solid by filtration. The solid cake was washed with water (20 ml) and dried under high vacuum for 2 hours to give the title compound (507 mg, 90%) as a white solid. LC-MS 98%, 2.04 min (3.5 minute LC-MS method), m/z=395.9, 396.9, 397.9, 398.9; 1H NMR (500 MHz, Chloroform-d) δ ppm 7.97 (d, J=1.73 Hz, 1H) 7.48 (d, J=1.73 Hz, 1H) 4.02 (dd, J=11.35, 3.94 Hz, 2H) 3.65 (br. s, 2H) 3.33 (t, J=11.59 Hz, 2H) 3.00 (tt, J=11.49, 3.80 Hz, 3H) 2.55 (s, 3H) 1.82 (d, J=11.98 Hz, 2H) 1.55-1.69 (m, 2H). OH not visible.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH2:23])[CH:8]=2)[N:3]=1.[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl.[OH-].[Na+]>[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH:23][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[N:3]=[C:2]([CH3:1])[CH:11]=[C:10]3[N:12]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13]2)=[CH:28][CH:27]=1
Reactant: COc1ccc(C=O)cc1
Reactant: Cc1cc(N2CCC(c3ccccc3)C2)c2cc(N)ccc2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COc1ccc(CNc2ccc3nc(C)cc(N4CCC(c5ccccc5)C4)c3c2)cc1
Yield: 9 %

Procedure:
2-Methyl-6-amino-4-(3-phenylpyrrolidin-1-yl)quinoline (0.08 g; see Example 45 below), 4-methoxybenzaldehyde (0.071 g), sodium triacetoxyborohydride (0.165 g) and acetic acid (0.05 mL) in 1,2-dichloroethane (5 mL) was refluxed for 4 hours. The reaction mixture was diluted with 1 N sodium hydroxide and extracted with ethyl acetate, washed with water, dried (MgSO4), filtered and evaporated. The residue was purified by chromatography on silica, eluting with a mixture of dichloromethane, and methanol. The desired fractions were concentrated and the sample evaporated to dryness. Trituration from ether gave the title compound as a white powder (0.01 g).
Reaction SMILES: C([NH:8][C:9]1[C:18]2[N:19]=[CH:20][N:21]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1)C1C=CC=CC=1.C(O)C.[H][H]>[OH-].[OH-].[Pd+2].C(N(CC)CC)C>[NH2:8][C:9]1[C:18]2[N:19]=[CH:20][N:21]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: CC(C)Cn1cnc2c(NCc3ccccc3)nc3ccccc3c21
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)Cn1cnc2c(N)nc3ccccc3c21

Procedure:
1.0 gram of 4-(N-benzylamino)-1-isobutyl-1H-imidazo(4,5-c)quinoline is added to 10 mL of ethanol, followed by the addition of 0.03 gram triethylamine and 0.2 gram of Pearlman's catalyst (20% Pd(OH)2/C). The mixture is stirred at 40° C. under 1 atm hydrogen until completion. The mixture is then filtered through Celite® and the filtrate, containing 4-amino-1-isobutyl-1H-imidazo(4,5-c)quinoline (imiquimod), is concentrated in vacuo.
Reaction SMILES: [S:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3](=[O:10])[NH:2]1.C(N(CC)CC)C.[N:18]1([C:24](Cl)=[O:25])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>C(#N)C>[N:18]1([C:24]([N:2]2[C:3](=[O:10])[C:4]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[S:1]2)=[O:25])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: O=C(Cl)N1CCOCC1
Reactant: O=c1[nH]sc2ncccc12
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(N1CCOCC1)n1sc2ncccc2c1=O
Temperature: 60 °C
Reaction time: 3 h
Yield: 57.4 %

Procedure:
To a suspension of isothiazolo[5,4-b]pyridin-3-one (5.0 g, 32.86 mmol) in acetonitrile (180 ml) was added dropwise triethylamine (14 ml, 99 mmol) and afterwards 4-morpholinecarbonyl chloride (3.8 ml, 32.9 mmol) at room temperature. The reaction mixture was stirred for 3 h at 60° C. The solvent was removed under reduced pressure. To the crude oil was added water (50 ml) and ethyl acetate (50 ml), the phases separated and the aqueous phase extracted with ethyl acetate. The organic layers were combined, washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. Purification of the residue by high performance liquid chromatography (RP silica gel, acetonitrile/water/trifluoroacetic acid) and lyophilization of the product fractions provided 5.0 g (57%) of the title compound as a white powder.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([N:22]2[CH:26]=[N:25][CH:24]=[N:23]2)=[N:10]1.Cl.[NH:28]1[CH2:33][CH2:32][O:31][CH:30]([CH2:34][C:35]([OH:37])=[O:36])[CH2:29]1>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([N:22]2[CH:26]=[N:25][CH:24]=[N:23]2)[NH:12][C:13]([CH2:20][N:28]2[CH2:33][CH2:32][O:31][CH:30]([CH2:34][C:35]([OH:37])=[O:36])[CH2:29]2)=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: O=C(O)CC1CNCCO1
Reactant: CCOC(=O)C1=C(CBr)NC(n2cncn2)=NC1c1ccc(F)cc1Br
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCOC(CC(=O)O)C2)NC(n2cncn2)=NC1c1ccc(F)cc1Br
Yield: 38.7 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(1H-1,2,4-triazol-1-yl)-1,4-dihydropyrimidine-5-carboxylate (0.5 g, 1.03 mmol) was reacted with 2-(morpholin-2-yl)acetic acid hydrochloride (0.19 g, 1.03 mmol) according to the procedure as described in Example 1, Step C to give the title compound as a yellow solid (0.22 g, 39%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[CH3:21][C:22]1[N:27]=[CH:26][C:25]([C:28](O)=[O:29])=[CH:24][CH:23]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:28]([C:25]3[CH:26]=[N:27][C:22]([CH3:21])=[CH:23][CH:24]=3)=[O:29])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:6][CH:7]=1
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Reactant: Cc1ccc(C(=O)O)cn1
Product: Cc1ccc(C(=O)Nc2cnc(OCC(F)(F)F)c(-c3ccc(Cl)cc3)c2)cn1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2, 2-trifluoro-ethoxy)-pyridin-3-ylamine and 6-methyl-3-pyridinecarboxylic acid as starting materials, MS (LC/MS): 420.4 (M−H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[NH:8])=[CH:5][CH:4]=1.[Cl:14][C:15]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:16]=1[CH:17]=[C:18]([C:21]#[N:22])[C:19]#[N:20]>>[NH2:22][CH2:21][C:18]1[C:19]([NH2:20])=[N:8][C:7]([C:6]2[CH:10]=[CH:11][C:3]([C:2]([F:12])([F:13])[F:1])=[CH:4][CH:5]=2)=[N:9][C:17]=1[C:16]1[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:15]=1[Cl:14]
Reactant: N=C(N)c1ccc(C(F)(F)F)cc1
Reactant: N#CC(C#N)=Cc1ccc(Cl)cc1Cl
Product: NCc1c(N)nc(-c2ccc(C(F)(F)F)cc2)nc1-c1ccc(Cl)cc1Cl

Procedure:
The title compound, MS: m/e=412.9 (M+H+), was prepared from 4-trifluoromethyl-benzamidine and 2-(2,4-dichloro-benzylidene)-malononitrile in analogy to the process described in Example 11 as a solid.
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=O.[CH:9]([C:12]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]([CH3:21])[CH3:20])[C:13]=1[NH2:14])([CH3:11])[CH3:10].C(O)=O>CO>[CH:9]([C:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:19]([CH3:21])[CH3:20])[C:2]=1[NH:14][C:13]1/[C:15](=[N:14]/[C:13]2[C:12]([CH:9]([CH3:11])[CH3:10])=[CH:18][CH:17]=[CH:16][C:15]=2[CH:19]([CH3:21])[CH3:20])/[CH2:16][CH2:17][CH2:18][CH:12]=1)([CH3:10])[CH3:11]
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: O=C1CCCCC1=O
Solvent: CO
Solvent: O=CO
Product: CC(C)c1cccc(C(C)C)c1/N=C1\CCCC=C1Nc1c(C(C)C)cccc1C(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 51.8 %

Procedure:
Synthesis based on literature procedure (Gates, D. P.; Svejda, S. A. Onate, E.; Killian, C. M.; Johnson, L. K.; White, P. S.; Brookhart M. Macromolecules, 2000; 33:2320-2334.). Cyclohexane-1,2-dione (2.062 g, 18.39 mmol) and 2,6-diisopropylaniline (6.52 g, 36.78 mmol) are dissolved in 70 mL of methanol. To this solution is added 1 mL of formic acid and the mixture is stirred for 3 days at room temperature. Precipitated white crystalline solid is collected on the frit, washed with methanol (2×15 mL) and dried under reduced pressure to give 4.1 g (51.8% yield) of title compound of Preparation 1.