Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si](C)(C)[N:13]1[CH2:17][CH2:16][CH2:15][C:14]1=[O:18]>>[C:1]1([S:7]([N:13]2[CH2:17][CH2:16][CH2:15][C:14]2=[O:18])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: C[Si](C)(C)N1CCCC1=O
Product: O=C1CCCN1S(=O)(=O)c1ccccc1
Reaction time: 0.5 h
Yield: 37.1 %

Procedure:
To 7.06 g of benzenesulfonyl chloride (0.04 mole) was added 6.9 g of N-trimethylsilyl-2-pyrrolidone (0.044 mole), and the mixture was stirred at the reflux temperature for 30 minutes. The reaction mixture was subjected to chromatography on a column (D 40 mm×L 250 mm) of 150 g of silica gel (Wako Gel C-200). Elution with a mixed solvent of hexane-ethyl acetate (3:2) gave a crystalline product, which was recrystallized from a mixed solvent of chloroform-ether to give 3.34 g of N-benzenesulfonyl-2-pyrrolidone as colorless crystals.
Reaction SMILES: [CH2:1](O)[CH3:2].Cl.[F:5][C:6]1[CH:7]=[CH:8][C:9]([OH:28])=[C:10]([CH2:12][CH2:13][NH:14][CH:15]2[CH2:24][CH2:23][CH2:22][C:21]3[N:20]=[C:19]([C:25]([OH:27])=[O:26])[CH:18]=[CH:17][C:16]2=3)[CH:11]=1.C(=O)(O)[O-].[Na+]>O1CCOCC1.C(OCC)(=O)C>[F:5][C:6]1[CH:7]=[CH:8][C:9]([OH:28])=[C:10]([CH2:12][CH2:13][NH:14][CH:15]2[CH2:24][CH2:23][CH2:22][C:21]3[N:20]=[C:19]([C:25]([O:27][CH2:1][CH3:2])=[O:26])[CH:18]=[CH:17][C:16]2=3)[CH:11]=1
Reactant: O=C(O)c1ccc2c(n1)CCCC2NCCc1cc(F)ccc1O
Reactant: CCO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc2c(n1)CCCC2NCCc1cc(F)ccc1O
Temperature: 25 °C

Procedure:
40 ml of anhydrous ethanol and 4 ml of a 4 N solution of hydrogen chloride in dioxane were added to 1.93 g (5.84 mmol) of rac-5-{[2-(5-fluoro-2-hydroxyphenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid, and the mixture was stirred under reflux overnight. The reaction solution was then cooled to room temperature, and first ethyl acetate and then, slowly, saturated aqueous sodium bicarbonate solution were added. The organic phase was separated off, dried over magnesium sulphate, filtered and concentrated to dryness. This gave 1.67 g (4.66 mmol, 80% of theory) of the target compound.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([C:13]([C:28]4[CH:29]=[CH:30][C:31]([C:34]#[N:35])=[N:32][CH:33]=4)=[C:14]([C:16]#[C:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)[N:15]=3)[N:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.[N-:36]=[N+:37]=[N-:38].[Na+].Cl.C(N(CC)CC)C>CN(C=O)C>[NH:36]1[C:34]([C:31]2[N:32]=[CH:33][C:28]([C:13]3[N:9]4[N:10]=[CH:11][CH:12]=[C:7]([N:4]5[CH2:3][CH2:2][O:1][CH2:6][CH2:5]5)[C:8]4=[N:15][C:14]=3[C:16]#[C:17][C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)=[CH:29][CH:30]=2)=[N:35][N:38]=[N:37]1
Reactant: N#Cc1ccc(-c2c(C#Cc3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cn1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C(#Cc1nc2c(N3CCOCC3)ccnn2c1-c1ccc(-c2nnn[nH]2)nc1)c1ccc2ccccc2n1
Temperature: 25 °C

Procedure:
A solution of compound 39a (0.20 g, 0.44 mmol), sodium azide (50 mg, 0.77 mmol), and triethylamine hydrochloride (0.10 g, 0.73 mmol) in DMF (5 mL) was stirred at 100° C. for 1 h. After cooling to rt, the reaction was quenched with water (20 mL). The resulting mixture was extracted with DCM (2×30 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue obtained was purified by flash column chromatography on silica gel (MeOH:CH2Cl2 (1:50, v/v)) to obtain a residue, which was further purified by reverse phase Prep-HPLC. This resulted in the title compound 21 as a yellow solid. 1H-NMR (300 MHz, DMSO-d6) δ (ppm): 8.85-8.91 (m, 1H), 8.34 (d, J=8.7 Hz, 1H), 8.30-8.23 (m, 2H), 7.98-7.60 (m, 6H), 6.51 (d, J=6.0 Hz, 1H), 3.90-3.81 (m, 4H), 3.64-3.53 (m, 4H). Mass Spectrum (LCMS, ESI pos.): Calcd. for C22H20N10O: 501.2 (M+H). Found: 501.2.
Reaction SMILES: [C:1]1([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([CH3:13])[C:8]([N:10]=[C:11]=[O:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:20]([OH:23])[CH:21]=[CH2:22]>>[CH2:20]([O:23][C:11](=[O:12])[NH:10][C:8](=[O:9])[C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:13])[CH:21]=[CH2:22]
Reactant: C=CCO
Reactant: CC(C(=O)N=C=O)(c1ccccc1)c1ccccc1
Product: C=CCOC(=O)NC(=O)C(C)(c1ccccc1)c1ccccc1

Procedure:
The title compound, white solid, m.p.=89° C. and MS: m/e=309.4 (M+H+) was prepared in accordance with the general method of example 1 from 2,2-diphenylpropionyl isocyanate and prop-2-en-1-ol.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:20]=[C:14]2[C:15](=[O:19])[NH:16][CH2:17][CH2:18][N:13]2[N:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:22][CH:23]1[CH2:25][CH2:24]1>CN(C=O)C.O>[CH2:3]([O:10][C:11]1[CH:20]=[C:14]2[C:15](=[O:19])[N:16]([CH2:22][CH:23]3[CH2:25][CH2:24]3)[CH2:17][CH2:18][N:13]2[N:12]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: BrCC1CC1
Reactant: O=C1NCCn2nc(OCc3ccccc3)cc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2cc(OCc3ccccc3)nn2CCN1CC1CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 78.5 %

Procedure:
A 60% dispersion of sodium hydride in mineral oils (8.14 mg, 0.2 mmol) was added to a stirred solution of 2-(benzyloxy)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (0.045 g, 0.18 mmol) in DMF (2.7 mL) at 0° C. The mixture was stirred at 0° C. for 15 minutes. Then (bromomethyl)cyclopropane (22 μL, 0.22 mmol) was added at 0° C. The mixture was stirred at 0° C. for 1 hour and then allowed to warm to room temperature and stirred for 16 hours. The mixture was diluted with water and extracted with AcOEt. The organic layer was separated, washed with a saturated solution of NH4Cl, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in DCM 0/100 to 20/80). The desired fractions were collected, the solvents evaporated in vacuo and the residue was triturated with DIPE to yield 2-(benzyloxy)-5-(cyclopropylmethyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (42 mg, 76% yield) as a white solid. C17H19N3O2. 1H NMR (500 MHz, CDCl3) δ ppm 0.25-0.36 (m, 2H), 0.51-0.62 (m, 2H), 0.98-1.08 (m, 1H), 3.43 (d, J=6.9 Hz, 2H), 3.83 (dd, J=6.9, 5.5 Hz, 2H), 4.23 (dd, J=6.9, 5.5 Hz, 2H), 5.20 (s, 2H), 6.26 (s, 1H), 7.29-7.35 (m, 1H), 7.37 (t, J=7.4 Hz, 2H), 7.41-7.48 (m, 2H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][NH:11][C:12]2[CH:16]=[CH:15][NH:14][C:13]=2[C:17]([O:19]CC)=O)=[CH:2]1.C([N:30]=[C:31]=[S:32])(=O)C1C=CC=CC=1>CO.C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][N:11]2[C:12]3[CH:16]=[CH:15][NH:14][C:13]=3[C:17](=[O:19])[NH:30][C:31]2=[S:32])=[CH:2]1
Reactant: CCOC(=O)c1[nH]ccc1NCc1c[nH]c2ccccc12
Reactant: O=C(N=C=S)c1ccccc1
Solvent: ClCCl
Solvent: CO
Product: O=c1[nH]c(=S)n(Cc2c[nH]c3ccccc23)c2cc[nH]c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.7 %

Procedure:
A crude mixture of ethyl 3-[(1H-indol-3-ylmethyl)amino]-1H-pyrrole-2-carboxylate (max 0.49 mmol) was added to CH2Cl2 (5 mL). A few drops of methanol were added to increase solubility. Benzoylisothiocyanate (0.072 g, 0.53 mmol) was added and the mixture was stirred at r.t. for 1 h. The mixture was concentrated in vacuo. Ammonia (7N in methanol, 3 mL) was added and the mixture was heated at 80° C. for 2 h. The mixture was concentrated and purified by preparative HPLC, obtaining the title compound (0.030 g, 21%) as a solid.
Reaction SMILES: [F:1][C:2]([CH3:18])([CH3:17])[CH2:3][O:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11]C)=[O:10])=[CH:7][C:6]=1[O:15][CH3:16].[OH-].[Na+]>CO.O>[F:1][C:2]([CH3:18])([CH3:17])[CH2:3][O:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1[O:15][CH3:16]
Reactant: COC(=O)c1ccc(OCC(C)(C)F)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc(C(=O)O)ccc1OCC(C)(C)F
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 4-(2-fluoro-2-methyl-propoxy)-3-methoxy-benzoate (450 mg, 1.76 mmol) in MeOH (3.6 mL) and water (900 μL) was added NaOH (210 mg, 5.27 mmol) and the mixture was stirred at 40° C. for 1 hour. The MeOH was evaporated and the pH of the solution was adjusted to 3 with 1N HCl. The precipitate was filtered, washed with water, and desiccated to give 4-(2-fluoro-2-methylpropoxy)-3-methoxybenzoic acid. ESI-MS m/z calc. 242.2, found 243.7 (M+1)+; Retention time: 1.25 minutes (3 min run).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[C:9](=[O:23])[O:10][C:11]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[C:12]=2[C:13]=1[CH3:14])(=O)=O.[C:24]1([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH3:22][O:21][C:15]1[C:12]2[C:13]([CH3:14])=[C:8]([CH2:7][CH2:6][N:33]3[CH2:34][CH2:35][CH:30]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:31][CH2:32]3)[C:9](=[O:23])[O:10][C:11]=2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: COc1cc(OC)c2c(C)c(CCOS(C)(=O)=O)c(=O)oc2c1
Product: COc1cc(OC)c2c(C)c(CCN3CCC(c4ccccc4)CC3)c(=O)oc2c1
Yield: 18 %

Procedure:
Process B; starting materials: 3-[2-(methanesulphonyloxy)ethyl]-5,7-dimethoxy-4-methyl-2H-1-benzopyran-2-one (Example 35) and 4-phenylpiperidine; yield 18% of crude crystalline product.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH2:11][CH2:12][NH:13]C(=O)OC(C)(C)C.Cl>O1CCOCC1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH2:11][CH2:12][NH2:13]
Reactant: CC(C)(C)OC(=O)NCCNc1nc2ccccc2o1
Agent: Cl
Solvent: C1COCCO1
Product: NCCNc1nc2ccccc2o1
Reaction time: 3 h

Procedure:
tert-Butyl 2-(benzo[d]oxazol-2-ylamino)ethylcarbamate (515.7 mg, 1.86 mmol) was dissolved in warm p-dioxane (6 mL) and was treated with 4N HCl in 1,4-dioxane (6 mL, 24.0 mmol). The resulting mixture was stirred for 3 h as a solid separated from the acidic solution. Then, additional 4N HCl (2 mL, 8.0 mmol) was added and the resulting mixture stirred for 1 h, then stored in the freezer overnight. The resulting solid was collected by filtration, washed with 1,4-dioxane, then dried in vacuum oven overnight at room temperature to yield the corresponding hydrochloride salt of N1-(benzo[d]oxazol-2-yl)ethane-1,2-diamine as a white powder.
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH:6]=[C:5]([C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=2)[CH:4]=[CH:3]1>CC(O)=O>[O:1]=[C:2]1[NH:7][CH2:6][CH:5]([C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CCOC(=O)c1ccc(-c2ccc(=O)[nH]c2)cc1
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc(C2CCC(=O)NC2)cc1
Temperature: 25 °C
Reaction time: 9 h
Yield: 74.1 %

Procedure:
Ethyl 4-(6-oxo-1,6-dihydro-pyridin-3-yl)-benzoate (450 mg, 1.8 mmol) (reference example 36f) is dissolved in HOAc (15 mL), and the the solution is degassed several times by alternating N2/vacuum. 50 mg of PtO2 is added and the mixture is degassed for several minutes before being placed under a H2 atmosphere. The mixture is stirred at room temperature for 9 hours then degassed several times by alternating N2/vacuum then filtered through a plug of celite. The plug is washed thoroughly with HOAc and the filtrate concentrated. The residue is chromatographed first on silica gel (3% MeOH/CH2Cl2), and then by Reverse-Phase HPLC to afford 330 mg of the title compound (72%) as a white solid. 1H NMR (CDCl3) δ 1.39 (t, J=7 Hz, 3H), 2.12 (m, 2H), 2.56 (m, 2H), 3.13 (m, 1H), 3.41 (dd, J=11.3, 11.3, 1H), 3.53 (m, 1H), 4.37 (q, J=7, 2H), 6.78 (bs, 1H), 7.16 (d, J=8 Hz, 2H), 8.01 (d, J=8 Hz, 2H). MS (Ion spray) m/z 248 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([NH:15][NH2:16])=[O:14].[CH2:17]([O:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](O)=O)[CH3:18]>>[CH2:17]([O:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22]1[O:14][C:13]([C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:15][N:16]=1)[CH3:18]
Reactant: CCOc1ccccc1C(=O)O
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NN
Product: CCOc1ccccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Yield: 42 %

Procedure:
As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide (200 mg, 0.92 mmol) was converted using 2-ethoxybenzoic acid instead of o-toluic acid to the title compound (SiO2, heptane:ethyl acetate=80:20 to 50:50, 135 mg, 42%) which was obtained as an off-white solid. MS: m/e=348.3 [M+H]+.
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]([NH:15][CH2:16][C:17]2([C:23]#[N:24])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:12]([F:25])=[CH:11][CH:10]=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[Pd]>[F:25][C:12]1[C:13]([NH:15][CH2:16][C:17]2([C:23]#[N:24])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[N:14][C:9]([OH:8])=[CH:10][CH:11]=1
Reactant: N#CC1(CNc2nc(OCc3ccccc3)ccc2F)CCOCC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: N#CC1(CNc2nc(O)ccc2F)CCOCC1
Temperature: 70 °C
Reaction time: 0.75 h
Yield: 95.8 %

Procedure:
A mixture of 4-((6-(benzyloxy)-3-fluoropyridin-2-ylamino)methyl)tetrahydro-2H-pyran-4-carbonitrile (200 mg, 0.586 mmol), AMMONIUM FORMATE (111.3 mg, 1.758 mmol) and Pd—C (10%, wet, 25 mg) in methanol (4 ml) was stirred at 70° C. for 45 min and cooled. The mixture was then filtered to remove Pd—C and inorganics, the filterate was then concentrated and dried further via high vacuum to afford 141 mg (96% yield) of the crude product as a light pink solid. LCMS (m/z): 252.1 [M+H]+; retention time=0.540 min.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1)[CH3:5].ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:32][CH2:33][C:34]1[C:35]([OH:42])=[N:36][C:37]([CH3:41])=[CH:38][C:39]=1[CH3:40]>ClCCl>[OH:42][C:35]1[C:34]([CH2:33][NH:32][C:10](=[O:12])[C:9]2[CH:8]=[CH:7][C:6]([CH:4]([CH2:3][CH2:2][OH:1])[CH3:5])=[CH:14][CH:13]=2)=[C:39]([CH3:40])[CH:38]=[C:37]([CH3:41])[N:36]=1
Reactant: CC(CCO)c1ccc(C(=O)O)cc1
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2ccc(C(C)CCO)cc2)c(O)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 8.3 %

Procedure:
A mixture of 4-(4-hydroxybutan-2-yl)benzoic acid (290 mg, 1.5 mmol), 1-ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride (432 mg, 2.25 mmol), N-hydroxybenzotriazole (3.4 mg, 2.25 mmol) and triethylamine (455 mg, 4.5 mmol) in dichloromethane (50 mL) was stirred for 30 minutes at room temperature. Then to the mixture, 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (228 mg, 1.5 mmol) was added. The resultant mixture was stirred at room temperature for 12 hours. Then the mixture was washed with water (30 mL×3). The organic layer was concentrated to give a residue and the residue was purified by column chromatography (silica gel, dichloro methane/methanol=20:1) to give N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-(4-hydroxybutan-2-yl)benzamide (41 mg, 8.3%). LRMS (M+H+) m/z: calcd 328.18 found 328; 1H. NMR (300 MHz, CD3OD): δ 7.73 (d, J=8.1 Hz, 2H), 7.30 (d, J=8.1 Hz, 2H), 6.11 (s, 1H), 4.49 (s, 2H), 3.44-3.42 (m, 2H), 2.94 (q, J=7.2 Hz, 1H), 2.36 (s, 3H), 2.42 (s, 3H), 1.82 (q, J=6.9 Hz, 2H), 1.26 (d, J=6.9 Hz, 3H).
Reaction SMILES: [CH3:1][C:2](=[CH:4][N:5](CC(C)C)[C:6]1[CH:11]=CC=C[CH:7]=1)[CH3:3].[C:16]1([CH3:23])[CH:21]=[CH:20][CH:19]=[C:18](C)[CH:17]=1>ClCCl.[Cl-].[Zn+2].[Cl-]>[CH3:7][C:6]1([CH3:11])[CH2:23][C:16]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:5]1[CH2:4][CH:2]([CH3:3])[CH3:1]
Reactant: Cc1cccc(C)c1
Reactant: CC(C)=CN(CC(C)C)c1ccccc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Product: CC(C)CN1c2ccccc2CC1(C)C
Yield: 71.4 %

Procedure:
A mixture of N-(2-methylprop-2-en-3-yl)-N-isobutylaniline (6.1 g) and zinc chloride (3.9 g) in m-xylene (50 cm3) was heated under reflux for 24 hours before dissolving in dichloromethane and filtering. The dichloromethane solution was washed with water, separated and dried over anhydrous magnesium sulphate. The magnesium sulphate was removed by filtration and the dichloromethane was separated to leave a crude oil which was purified by elution from silica with a 9:1 mixture of hexane:dichloromethane. The solvent was evaporated to leave 2,2-dimethyl N-isobutylindoline (4.3 g, 71.4%) as a colourless oil.
Reaction SMILES: [NH:1]([C:3]1[CH:4]=[CH:5][C:6]([O:14][CH3:15])=[C:7]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH:8]=1)[NH2:2].[CH:16]([O-])=[O:17].[Na+].C(O)=O>C(O)C>[CH:16]([NH:2][NH:1][C:3]1[CH:4]=[CH:5][C:6]([O:14][CH3:15])=[C:7]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH:8]=1)=[O:17]
Reactant: O=C[O-]
Reactant: COc1ccc(NN)cc1CCC(=O)O
Agent: [Na+]
Solvent: O=CO
Solvent: CCO
Product: COc1ccc(NNC=O)cc1CCC(=O)O

Procedure:
3-(5-Amino-2-methoxyphenyl)propionic acid (4 g, 0.02 mole), concentrated hydrochloric acid (30 ml) and water (45 ml) were stirred together at 0°. The mixture was treated with sodium nitrite (1.38 g, 0.02 mole) in water (10 ml) at 0°. The solution was then stirred for a further one-half hour. The excess of nitrous acid was destroyed with urea. The above reaction mixture was added to a solution of stannous chloride (7.6 g) in concentrated hydrochloric acid (10 ml). The precipitate (5 g) was collected by filtration. Free hydrazine was obtained from a concentrated aqueous solution of the crude hydrochloride by addition of saturated aqueous solution of sodium acetate. A mixture of 3-(5-hydrazino-2-methoxyphenyl)propionic acid (8.8 g, 0.025 mole), sodium formate (2.8 g, 0.04 mole), formic acid (18 ml) and ethanol (60 ml) was heated under reflux for one hour. The solvents were removed under vacuum and the residue was dissolved in ethyl acetate (1 liter). The organic layer was then washed with water and dilute aqueous hydrochloric acid (1 percent). The organic layer was dried with sodium sulphate, the solvent was removed under reduced pressure and the residue crystallized from water (5 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:9](=[O:27])[N:10](CC3C=CC(OC)=CC=3OC)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4]>C(O)(C(F)(F)F)=O>[CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:9](=[O:27])[NH:10][CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4]
Reactant: COC(=O)c1ncc2c(=O)n(Cc3ccc(OC)cc3OC)ccc2c1O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ncc2c(=O)[nH]ccc2c1O
Yield: 61.7 %

Procedure:
7-(2,4-dimethoxy-benzyl)-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (60 mg, 0.162 mmol) in TFA (3 mL) was refluxed for 16 h. Solvent was evaporated in vacuo, and the residue was partitioned between CH2Cl2 and saturated NaHCO3. The aqueous layer was extracted with 10% MeOH/CH2Cl2 until the layers were free of solid. The organic layers were combined, dried over MgSO4, and concentrated in vacuo. The crude product was purified by silica gel chromatography (0-10% MeOH/CH2Cl2) to give 22 mg of the title compound as a pale brown solid. MS: (+) m/z 221.25 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH2:8][O:9][C:10](=[O:12])[NH:11][C:6]=2[CH:5]=[CH:4][C:3]=1[OH:13].[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([S:21][CH2:22][CH2:23][CH2:24][CH2:25]Cl)=[CH:17][CH:16]=1>>[Cl:1][C:2]1[C:7]2[CH2:8][O:9][C:10](=[O:12])[NH:11][C:6]=2[CH:5]=[CH:4][C:3]=1[O:13][CH2:25][CH2:24][CH2:23][CH2:22][S:21][C:18]1[CH:17]=[CH:16][C:15]([CH3:14])=[CH:20][CH:19]=1
Reactant: O=C1Nc2ccc(O)c(Cl)c2CO1
Reactant: Cc1ccc(SCCCCCl)cc1
Product: Cc1ccc(SCCCCOc2ccc3c(c2Cl)COC(=O)N3)cc1

Procedure:
Prepared analogously to Example 4 from 5-chloro-6-hydroxy-4H-3,1-benzoxazin-2-one and 4-(4-methyl-phenylmercapto)-butylchloride.
Reaction SMILES: C(O[C:4]([CH:6]1[CH2:11][NH:10][C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[O:7]1)=[O:5])C.[C:16]([O:20][C:21](=[O:24])[CH2:22][NH2:23])([CH3:19])([CH3:18])[CH3:17]>C1(C)C=CC=CC=1>[C:16]([O:20][C:21]([CH2:22][NH:23][C:4]([CH:6]1[CH2:11][NH:10][C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[O:7]1)=[O:5])=[O:24])([CH3:19])([CH3:18])[CH3:17]
Reactant: CCOC(=O)C1CNc2ccccc2O1
Reactant: CC(C)(C)OC(=O)CN
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)CNC(=O)C1CNc2ccccc2O1
Reaction time: 5 h

Procedure:
1.0 g of 2(R,S)-ethoxycarbonyl-3,4-dihydro-2H-1,4-benzoxazine and 1.2 g of glycine-tert-butyl ester are heated at 80° C. in 10 ml of toluene. After 5 h, the mixture is evaporated and pure 2(R,S)-(tert-butoxycarbonylmethylaminocarbonyl)-3,4-dihydro-2H-1,4-benzoxazine is isolated by means of FC over 100 g of silica gel (mobile phase Z): Rf (Z)=0.38.
Reaction SMILES: [ClH:1].[CH:2]([CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[C:7]=1[F:16])O)=[CH2:3]>O1CCOCC1>[Cl:1][CH2:3][CH:2]=[CH:4][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[C:7]=1[F:16]
Reactant: C=CC(O)c1cccc(C(F)(F)F)c1F
Reactant: Cl
Solvent: C1COCCO1
Product: Fc1c(C=CCCl)cccc1C(F)(F)F

Procedure:
334 ml of concentrated HCl are added over 10 minutes to a solution of 404.5 g (1.84 mol) of α-ethenyl-2-fluoro-3-(trifluoromethyl)benzenemethanol (prepared according to Example I1) in 3.7 1 of dioxane and the mixture is then heated for 2 h at reflux. 83.5 ml of concentrated HCl are added and the mixture is heated for a further 2 h at reflux.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[N:7][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:9]=1[CH3:10])=[O:4].[CH3:17][O:18][C:19](=[O:28])[C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[C:22]([NH2:27])[CH:21]=1>CCO>[CH3:17][O:18][C:19](=[O:28])[C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[C:22]([NH:27][CH2:2][C:3]([C:5]2[CH:6]=[N:7][N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:9]=2[CH3:10])=[O:4])[CH:21]=1
Reactant: COC(=O)c1ccc(C)c(N)c1
Reactant: Cc1c(C(=O)CBr)cnn1-c1ccccc1
Solvent: CCO
Product: COC(=O)c1ccc(C)c(NCC(=O)c2cnn(-c3ccccc3)c2C)c1
Yield: 52 %

Procedure:
A solution of 2-bromo-1-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-ethanone (829 mg; 2.97 mmol) and 3-amino-4-methyl benzoic acid methyl ester in 6 mL of EtOH was stirred at 75° C. for 6 h. The mixture was cooled, and the resulting precipitate was filtered and washed with cold EtOH to provide 564 mg (1.55 mmol; 52%) of 4-methyl-3-[2-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-2-oxo-ethylamino]-benzoic acid methyl ester as a white powder.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:19][O:20][CH2:21][CH3:22])[N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([OH:23])=[CH:5][C:4]=2[N:3]=1.[CH3:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28]Br.C(=O)([O-])[O-].[Cs+].[Cs+].CN1CCCC1=O>CN(C=O)C>[CH2:21]([O:20][CH2:19][C:13]1[N:14]([CH2:15][CH:16]([CH3:17])[CH3:18])[C:10]2[C:9]3[CH:8]=[CH:7][C:6]([O:23][CH2:24][C:25]4[CH:32]=[CH:31][CH:30]=[C:27]([CH3:28])[CH:26]=4)=[CH:5][C:4]=3[N:3]=[C:2]([NH2:1])[C:11]=2[N:12]=1)[CH3:22]
Reactant: Cc1cccc(CBr)c1
Reactant: CCOCc1nc2c(N)nc3cc(O)ccc3c2n1CC(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: CN(C)C=O
Product: CCOCc1nc2c(N)nc3cc(OCc4cccc(C)c4)ccc3c2n1CC(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.1 %

Procedure:
The general method described for Examples 22-32 was followed using the following modifications. 4-Amino-2-ethoxymethyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-ol (310 mg, 0.97 mmol) was dissolved in DMF (15 mL) with heating but precipitated from the solution as it cooled to room temperature. A solution of 3-methylbenzyl bromide (197 mg, 1.07 mmol) in DMF (0.5 mL) was added followed by solid cesium carbonate (643 mg, 1.97 mmol). N-Methylpyrrolidone (1 mL) was added to the reaction, and the reaction was stirred overnight. The crude product was purified by column chromatography on silica gel (eluting with chloroform:methanol), triturated with acetonitrile, and isolated by filtration to provide 175 mg of 2-ethoxymethyl-7-(3-methylbenzyloxy)-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, mp 207.0-208.0° C.