Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=2)=[O:9])[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:29][N:30]([CH3:45])[C:31]1[CH:40]=[CH:39][CH:38]=[C:37]2[C:32]=1[CH:33]=[CH:34][CH:35]=[C:36]2[S:41](Cl)(=[O:43])=[O:42]>C(Cl)Cl>[CH3:29][N:30]([CH3:45])[C:31]1[CH:40]=[CH:39][CH:38]=[C:37]2[C:32]=1[CH:33]=[CH:34][CH:35]=[C:36]2[S:41]([N:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]([F:19])([F:20])[F:21])=[CH:13][CH:12]=2)=[O:9])[CH2:3][CH2:2]1)(=[O:43])=[O:42]
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)NC1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)c1cccc2c(S(=O)(=O)N3CCC(NC(=O)Nc4ccc(OC(F)(F)F)cc4)CC3)cccc12

Procedure:
Intermediate 42 (200 mg, 0.7 mmol) was dissolved in DCM (7 mL) and triethylamine (100 μL, 0.7 mmol) added followed by 5-(dimethylamino)-1-naphthalenesulfonyl chloride (207 mg, 0.77 mmol). The reaction was evaporated, reconstituted in EtOAc and washed with 1N HCl and 1N K2CO3. Flash chromatography eluted with 2:1 EtOAc:hexanes afforded compound 59 (338 mg, 93%) as a tan solid: Mp 102-107° C. 1H NMR (500 MHz, DMSO-d6□ 8.52 (d, J=8.5 Hz, 1H), 8.45 (s, 1H), 8.28 (d, J=8.7 Hz, 1H), 8.14 (d, J=7.3 Hz, 1H), 7.67 (t, J=7.5 Hz, 1H), 7.62 (t, J=8.1 Hz, 1H), 7.43 (d, J=9.1 Hz, 2H), 7.28 (d, J=7.5 Hz, 1H), 7.19 (d, J=8.7 Hz, 2H), 6.24 (d, J=7.5 Hz, 1H), 3.60-3.53 (m, 3H), 2.88 (t, J=10.5 Hz, 2H, obscured by s δ 2.84), 2.84 (s, 6H), 1.84 (dd, J=12.9, 3.0 Hz, 2H), 1.38 (dq, J=10.6, 3.6 Hz, 2H). Purity 97%. HRMS calculated for C25H27F3N4O4S+H+ 537.1783. found (ESI(+), [M+H]) 537.1785.
Reaction SMILES: N1C=CC=CC=1.Cl.[CH3:8][NH:9][O:10][CH3:11].[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1>C(Cl)Cl>[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([N:9]([O:10][CH3:11])[CH3:8])=[O:18])=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CNOC
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CON(C)C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Pyridine (27.6 mL, 343 mmol) was added to N,O-dimethylhydroxylamine hydrochloride (16.7 g, 172 mmol) in DCM (400 mL). 4-Chlorobenzoyl chloride (20 mL, 156 mmol) was then added and the mixture was stirred at room temperature for 3 days. Solids were removed by vacuum filtration, washing with DCM. The filtrate was washed with 1 N HCl followed by water. The organic phase was dried (Na2SO4), filtered, and concentrated, affording the crude title compound as a colorless liquid which was used without purification in the next step.
Reaction SMILES: C[Al](C)C.[F:5][C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[N:10][CH:11]=1.[OH:13][C@@H:14]([CH2:19][O:20][C@H:21]([CH3:34])[CH2:22][O:23][Si:24]([CH:31]([CH3:33])[CH3:32])([CH:28]([CH3:30])[CH3:29])[CH:25]([CH3:27])[CH3:26])[C:15](OC)=[O:16]>C1(C)C=CC=CC=1>[F:5][C:6]1[CH:7]=[CH:8][C:9]([NH:12][C:15](=[O:16])[C@@H:14]([OH:13])[CH2:19][O:20][C@@H:21]([CH3:34])[CH2:22][O:23][Si:24]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:26])[CH3:27])[CH:31]([CH3:32])[CH3:33])=[N:10][CH:11]=1
Reactant: Nc1ccc(F)cn1
Reactant: COC(=O)[C@@H](O)CO[C@H](C)CO[Si](C(C)C)(C(C)C)C(C)C
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CC(C)[Si](OC[C@H](C)OC[C@H](O)C(=O)Nc1ccc(F)cn1)(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 75.1 %

Procedure:
Trimethylaluminium (5.98 mL, 11.96 mmol) was added to 5-fluoropyridin-2-amine (1.340 g, 11.96 mmol) in toluene (20 mL) cooled to 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 20 minutes. (S)-Methyl 2-hydroxy-3-((R)-1-(triisopropylsilyloxy)propan-2-yloxy)propanoate (Intermediate AU5) (2 g, 5.98 mmol) in toluene (6 mL) was added and the reaction was allowed to warm to room temperature and then refluxed for 6 hours. The reaction mixture was allowed to cool and concentrated in vacuo. The residue was neutralised with citric acid (1M, aq) and then diluted with water (25 mL) and extracted with EtOAc (2×50 mL). The combined organics were washed with brine (20 mL), then dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, eluting with 30 to 50% EtOAc in isohexane to afford the product (1.863 g, 75%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]2[CH:21]=[CH:22][C:23]([CH3:25])=[CH:24][C:4]=2[N:3]=1.Br[CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[CH3:25][C:23]1[CH:22]=[CH:21][C:5]2=[C:6]3[C:11](=[C:2]([NH2:1])[N:3]=[C:4]2[CH:24]=1)[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[CH:18][CH:19]=1)=[CH:7]3
Reactant: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(O)cc3)cc12
Reactant: BrCCN1CCOCC1
Product: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(OCCN4CCOCC4)cc3)cc12

Procedure:
8-Methyl-2-(4-(2-morpholinoethoxy)phenethyl)benzo[f][1,7]naphthyridin-5-amine was prepared from 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenol (from Example 170) following the procedure described for Example 139, but using 4-(2-bromoethyl)morpholine. 1H NMR (Acetone-d6): δ 8.78 (s, 1H), 8.72 (s, 1H), 8.30 (d, 1H), 7.46 (s, 1H), 7.17-7.24 (m, 3H), 6.85 (d, 2H), 4.08 (t, 2H), 3.56-3.62 (m, 4H), 3.45-3.53 (m, 2H), 3.24 (t, 2H), 3.07 (t, 2H), 2.73 (t, 2H), 2.52-2.56 (m, 2H), 2.49 (s, 3H). LRMS [M+H]=443.2
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](O)=[C:4]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:17]=2[CH2:18][OH:19])[CH:3]=1.O>C1(C)C=C(C)C=C(C)C=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]3[N:10]=[C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][N:12]4[C:17]=3[CH2:18][O:19][C:5]2=[CH:6][CH:7]=1
Reactant: OCc1c(-c2cc(Br)ccc2O)nc2ccccn12
Solvent: O
Solvent: Cc1cc(C)cc(C)c1
Product: Brc1ccc2c(c1)-c1nc3ccccn3c1CO2
Temperature: 170 °C
Reaction time: 6 h
Yield: 553.5 %

Procedure:
4-bromo-2-(3-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)phenol (0.2 g, 0.06 mmol) was dissolved in mesitylene (1 mL). The mixture was stirred at 170° C. for 6 hours, and then cooled to 25° C. H2O (20 mL) was added and extracted with EtOAc (3*50 mL), washed by brine (50 mL). After concentrated, the resulting residue was purified using Prep-TLC (petroleum ether:EtOAc=1:1) to provide 2-bromo-6H-chromeno[4′,3′:4,5]imidazo[1,2-a]pyridine (100 mg, yield: 53.0%). 1H-NMR (CDCl3, 400 MHz) δ 7.98˜7.99 (m, 1H), 7.74˜7.76 (m, 1H), 7.66˜7.68 (m, 1H), 7.21˜7.28 (m, 2H), 6.82˜6.90 (m, 2H), 5.70 (s, 2H). MS (M+H)+: 301/303.
Reaction SMILES: [CH3:1][N:2]([CH3:41])[CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[C:12]([C:17]([F:20])([F:19])[F:18])[CH:11]=2)[N:7]=[C:6]1[CH:21]1[CH2:26][CH2:25][N:24]([C:27]2[N:32]=[CH:31][N:30]=[C:29]([NH2:33])[C:28]=2[C:34]2[CH:39]=[CH:38]C(F)=[CH:36][CH:35]=2)[CH2:23][CH2:22]1.[N:42]1C=CC(B2OC(C)(C)C(C)(C)O2)=CC=1>>[CH3:41][N:2]([CH3:1])[CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[C:12]([C:17]([F:18])([F:20])[F:19])[CH:11]=2)[N:7]=[C:6]1[CH:21]1[CH2:26][CH2:25][N:24]([C:27]2[N:32]=[CH:31][N:30]=[C:29]([NH2:33])[C:28]=2[C:34]2[CH:39]=[CH:38][N:42]=[CH:36][CH:35]=2)[CH2:23][CH2:22]1
Reactant: CC1(C)OB(c2ccncc2)OC1(C)C
Reactant: CN(C)CCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2ccc(F)cc2)CC1
Product: CN(C)CCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2ccncc2)CC1

Procedure:
The title compound was prepared in an analogous manner as 6-{4-[1-(2-Dimethylamino-ethyl)-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-5-(4-fluoro-phenyl)-pyrimidin-4-ylamine using 4-pyridinylboronic acid pinacol ester instead of 4-fluorophenylboronic acid. LC-MS: (M+1=555, obsd.=555).
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[O:11]=[C:12]([CH3:22])[CH2:13][C:14]([O:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:15]>N1CCCCC1.C(O)(=O)CCCCC.C1C=CC=CC=1>[Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[C:13]([C:12](=[O:11])[CH3:22])[C:14]([O:16][CH:17]1[CH2:18][CH2:19][CH2:20][CH2:21]1)=[O:15]
Reactant: O=Cc1cccc(Cl)c1Cl
Reactant: CC(=O)CC(=O)OC1CCCC1
Solvent: c1ccccc1
Solvent: C1CCNCC1
Solvent: CCCCCC(=O)O
Product: CC(=O)C(=Cc1cccc(Cl)c1Cl)C(=O)OC1CCCC1
Temperature: 25 °C
Yield: 109 %

Procedure:
A solution of 2,3-dichlorobenzaldehyde (2.5 g, 14.3 mmoles), cyclopentyl 3-oxobutanoate (2.42 g, 14.3 mmoles), piperidine (8 drops) and hexanoic acid (11 drops) in dry benzene (80 ml) was heated at reflux for 4 hours using a Dean and Stark apparatus. The solution was allowed to cool to room temperature and the solvent removed in vacuo to leave the sub-title compound as an oil 5.1 g.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[S-:11][C:12]#[N:13].[NH4+].C(O)(=O)C.BrBr>O>[NH2:13][C:12]1[S:11][C:3]2[CH:4]=[C:5]([C:6]([OH:8])=[O:7])[CH:9]=[CH:10][C:2]=2[N:1]=1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: N#C[S-]
Agent: BrBr
Agent: [NH4+]
Solvent: O
Solvent: CC(=O)O
Product: Nc1nc2ccc(C(=O)O)cc2s1
Temperature: 15 °C
Reaction time: 8 h

Procedure:
220 parts of the β-acetoxyethyl ester of p-aminobenzoic acid and 333 parts of ammonium thiocyanate are suspended in 1000 parts of acetic acid. The suspension is cooled to 15° C. and then a solution of 176 parts of bromine in 300 parts of acetic acid is gradually added in a period of two hours, without allowing the temperature to exceed 15° C. The mixture is stirred for an hour at 15° C. and then allowed to stand overnight and is subsequently run into 2500 parts of water containing 15 parts of 19° Be hydrochloric acid. Then it is heated to 95° C., filtered at 95° C., and the cooled filtrate is neutralised by the addition of 700 parts of sodium carbonate, filtered again, and the precipitate is washed with 2000 parts of water, drained and dried at 60° C. 215 parts of β-acetoxyethyl ester of 2-amino-benzothiazole-6-carboxylic acid, m.p. 191°-192° C, are thus obtained.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]([N:11]1[CH2:65][CH2:64][C:14]2([CH2:19][N:18]([CH2:20][CH2:21]/[CH:22]=[CH:23]/[C:24]3[CH:29]=[CH:28][C:27]([CH2:30][C:31]4[C:32]([O:39][C@@H:40]5[O:57][C@H:56]([CH2:58][O:59][C:60](=[O:62])[CH3:61])[C@@H:51]([O:52][C:53](=[O:55])[CH3:54])[C@H:46]([O:47][C:48](=[O:50])[CH3:49])[C@H:41]5[O:42][C:43](=[O:45])[CH3:44])=[N:33][NH:34][C:35]=4[CH:36]([CH3:38])[CH3:37])=[C:26]([CH3:63])[CH:25]=3)[CH2:17][CH2:16][CH2:15]2)[CH2:13][CH2:12]1)=[O:10])(C)(C)C.[ClH:67]>ClCCl>[ClH:67].[ClH:67].[C:43]([O:42][C@@H:41]1[C@@H:46]([O:47][C:48](=[O:50])[CH3:49])[C@H:51]([O:52][C:53](=[O:55])[CH3:54])[C@@H:56]([CH2:58][O:59][C:60](=[O:62])[CH3:61])[O:57][C@H:40]1[O:39][C:32]1[C:31]([CH2:30][C:27]2[CH:28]=[CH:29][C:24](/[CH:23]=[CH:22]/[CH2:21][CH2:20][N:18]3[CH2:17][CH2:16][CH2:15][C:14]4([CH2:64][CH2:65][N:11]([C:9](=[O:10])[CH2:8][NH2:7])[CH2:12][CH2:13]4)[CH2:19]3)=[CH:25][C:26]=2[CH3:63])=[C:35]([CH:36]([CH3:37])[CH3:38])[NH:34][N:33]=1)(=[O:45])[CH3:44]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(/C=C/CCN3CCCC4(CCN(C(=O)CNC(=O)OC(C)(C)C)CC4)C3)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cl
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(/C=C/CCN3CCCC4(CCN(C(=O)CN)CC4)C3)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.7 %

Procedure:
A mixture of tert-butyl[2-(2-{(3E)-4-[3-methyl-4-({5-(propan-2-yl)-3-[(2,3,4,6-tetra-O-acetyl-beta-D-glucopyranosyl)oxy]-1H-pyrazol-4-yl}methyl)phenyl]but-3-en-1-yl}-2,9-diazaspiro[5.5]undec-9-yl)-2-oxoethyl]carbamate (12.10 g, 13.09 mmoles), dichloromethane (121.00 mL), and hydrogen chloride (4M in 1,4-dioxane; 16.37 mL, 65.47 mmoles) is stirred at ambient temperature for 4 hours. The mixture is concentrated under reduced pressure to provide the title compound (11.70 g; 99.6% yield). Mass spectrum (m/z): 824 (M+1 for free base).
Reaction SMILES: [CH3:1][CH:2]([CH2:4][C:5](=O)[CH2:6][CH2:7][CH3:8])[CH3:3].C([O-])(=O)C.[NH4+].C([BH3-])#[N:16].[Na+]>CO>[CH3:1][CH:2]([CH2:4][CH:5]([NH2:16])[CH2:6][CH2:7][CH3:8])[CH3:3]
Reactant: CCCC(=O)CC(C)C
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CCCC(N)CC(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 77.2 %

Procedure:
To a solution of 2-methylheptan-4-one (4.24 g, 33.07 mmol), in methanol (60 mL), were added ammonium acetate (25.50 g, 330.71 mmol) and sodium cyanoborohydride (2.08 g, 33.07 mmol). The reaction mixture was stirred at room temperature for about 24 hours. The solvent was removed under reduced pressure and the residue was diluted with water and basified with 15% NaOH aqueous and extracted with ether. The extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated to give 3.3 g of 2-methylheptan-4-amine (77%). MS (M+H, 130).
Reaction SMILES: [Cl:1][C:2]([Cl:20])([Cl:19])[CH2:3][O:4][C:5](=[O:18])[CH2:6][NH:7]C(OCC1C=CC=CC=1)=O.C(O)(=O)C.[BrH:25].CC(O)=O>C(OCC)C>[BrH:25].[Cl:1][C:2]([Cl:20])([Cl:19])[CH2:3][O:4][C:5](=[O:18])[CH2:6][NH2:7]
Reactant: O=C(CNC(=O)OCc1ccccc1)OCC(Cl)(Cl)Cl
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: NCC(=O)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A well stirred solution of 45.0 g. (0.13 mole) of carbobenzyloxyglycine 2,2,2-trichloroethyl ester in 100 ml. of glacial acetic acid is cooled to 20° and 100 ml. of 5N HBr-CH3CO2H is added. After 10 minutes, a vigorous evolution of gas occurs. The reaction mixture is stirred at room temperature for two hours. The mixture is then diluted with dry ethyl ether and the precipitate is filtered. The product is crystallized from acetonitrile to give aminoacetic acid 2,2,2-trichloroethyl ester, hydrobromide as white crystals; m.p. 238°-240° (d); 29.5 g. (78.9%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]=[O:22].[CH3:23][Mg]I.[Mg].IC>C(OCC)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]([OH:22])[CH3:23]
Reactant: C[Mg]I
Reactant: O=CCCCCCCCCCOc1ccc2ccccc2n1
Agent: [Mg]
Solvent: CCOCC
Solvent: CI
Product: CC(O)CCCCCCCCCOc1ccc2ccccc2n1

Procedure:
10-(2-Quinolinyloxy)decan-1-al (3.5 g) in dry diethyl ether (15 ml was treated with methyl magnesium iodide in dry ether (2 ml) prepared from magnesium (0.29 g) and iodomethane (0.75 ml). After quenching with satd. aqueous ammonium chloride the reaction was worked-up in the usual manner and the crude product purified by column chromatography on silica (8:2, hexane:ether) to give 11-(2-quinolinyloxy)undecan-2-ol (1.24 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[S:20][C:19]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[N:18][C:17]=2[CH3:27])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.CO.[ClH:30]>C(OCC)(=O)C>[ClH:30].[ClH:30].[CH3:27][C:17]1[N:18]=[C:19]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[S:20][C:16]=1[C:14]([N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)=[O:15]
Reactant: Cc1nc(-c2ccncc2)sc1C(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1nc(-c2ccncc2)sc1C(=O)N1CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 1-(tert-butoxycarbonyl)-4-[4-methyl-2-(4-pyridyl)-5-thiazolecarbonyl]piperazine (6.40 g) were added methanol (30 ml) and 4N hydrochloric acid in ethyl acetate (30 ml), and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated, and the residue was washed with ether and dried under reduced pressure to give powders of the title compound (5.8 g).
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=O)C=1.[CH2:12]([O:19][C:20]1[CH:29]=[CH:28][C:27]2[N:26]=[CH:25][C:24]3[N:30]=[C:31]([CH2:36][O:37][CH2:38][CH3:39])[N:32]([CH2:33][CH2:34][CH3:35])[C:23]=3[C:22]=2[CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.ClC(Cl)(Cl)C([N:44]=C=O)=O.[OH-].[NH4+]>ClCCl>[CH2:12]([O:19][C:20]1[CH:29]=[CH:28][C:27]2[N:26]=[C:25]([NH2:44])[C:24]3[N:30]=[C:31]([CH2:36][O:37][CH2:38][CH3:39])[N:32]([CH2:33][CH2:34][CH3:35])[C:23]=3[C:22]=2[CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCCn1c(COCC)nc2cnc3ccc(OCc4ccccc4)cc3c21
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: CCCn1c(COCC)nc2c(N)nc3ccc(OCc4ccccc4)cc3c21
Reaction time: 2 h

Procedure:
mCPBA (60% pure, 27.5 g, 95.9 mmol) was added in small portions over a period of 20 minutes to 8-benzyloxy-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinoline (30.0 g, 79.9 mmol, prepared in Parts A through H of Example 2) in dichloromethane (400 mL). After the reaction was stirred for two hours, it was washed with 1% aqueous sodium carbonate (3×100 mL). The combined aqueous washings were extracted with chloroform (200 mL), and the combined organic fractions were dried over magnesium sulfate and filtered. Trichloroacetyl isocyanate (18.0 g, 95.9 mmol) was added dropwise to the filtrate, and then the reaction was stirred overnight at ambient temperature. Concentrated ammonium hydroxide (100 mL) was slowly added, and the mixture was stirred at ambient temperature for 30 minutes. The organic layer was separated and washed with 1% aqueous sodium carbonate (2×100 mL). The combined aqueous fractions were extracted with chloroform (3×75 mL). The organic fractions were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield a dark semi-solid. The crude product was purified on silica gel (1 kg, eluting sequentially with 2% methanol in chloroform and 5% methanol in chloroform) to provide 22 g of 8-benzyloxy-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine as an off-white solid.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[CH:18][C:17]([N:20]([CH3:40])[C:21](=[O:39])[C:22]([C:25]3[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:26]=3)([CH3:24])[CH3:23])=[C:16]([C:41]3[CH:46]=[CH:45][C:44]([F:47])=[CH:43][C:42]=3[CH3:48])[CH:15]=2)[C@H:10]([CH3:49])[CH2:9]1)C1C=CC=CC=1>C(O)(=O)C>[F:38][C:35]([F:36])([F:37])[C:27]1[CH:26]=[C:25]([C:22]([CH3:23])([CH3:24])[C:21]([N:20]([C:17]2[CH:18]=[N:19][C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][C@H:10]3[CH3:49])=[CH:15][C:16]=2[C:41]2[CH:46]=[CH:45][C:44]([F:47])=[CH:43][C:42]=2[CH3:48])[CH3:40])=[O:39])[CH:30]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:28]=1
Reactant: Cc1cc(F)ccc1-c1cc(N2CCN(Cc3ccccc3)C[C@H]2C)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CC(=O)O
Product: Cc1cc(F)ccc1-c1cc(N2CCNC[C@H]2C)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.6 %

Procedure:
A solution of 0.11 g (0.17 mmol) (R)-N-[6-(4-benzyl-2-methyl-piperazin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide in 3 ml acetic acid was deoxygenated by three cycles of evacuation and flushing with argon. After addition of 0.02 g palladium on charcoal (10%) the reaction vessel was evacuated and filled with hydrogen gas. The reaction mixture was stirred at room temperature under an atmosphere of hydrogen for 3 h. The reaction mixture was filtered over decalite followed by washing with tert-butyl methyl ether. The filtrate was washed with a 2 M aqueous solution of sodium hydroxide. The aqueous layer was extracted with three portions of tert-butyl methyl ether. The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give 98 mg (98%) of the crude title compound as an off-white solid, which was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][CH2:6]2.[Br:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:20]=1[CH:21]=O>>[Br:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:20]=1/[CH:21]=[C:8]1/[C:9](=[O:13])[C:10]2[C:5]([CH2:6][CH2:7]/1)=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2
Reactant: COc1ccc2c(c1)CCCC2=O
Reactant: O=Cc1ccncc1Br
Product: COc1ccc2c(c1)CC/C(=C\c1ccncc1Br)C2=O

Procedure:
The title compound 87 is prepared according to the procedure reported in Example 34.2 with 6-methoxy-1-tetralone (4.74 g, 26.9 mmol) and 3-bromo-4-pyridinecarboxaldehyde (5.0 g, 26.9 mmol) as reactants. White solid. (Yield 7.0 g, 76%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([S:10][CH3:11])[CH3:9])=[CH:4][N:3]=1.[N:12]#[C:13][NH2:14].C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH:8]([S:10]([CH3:11])=[N:14][C:13]#[N:12])[CH3:9])=[CH:6][N:7]=1
Reactant: CSC(C)c1cnc(Cl)nc1
Reactant: N#CN
Agent: CC(c1cnc(Cl)nc1)/S(C)=N/C#N
Solvent: Ic1ccccc1
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(c1cnc(Cl)nc1)S(C)=NC#N
Temperature: 25 °C

Procedure:
A solution of 2-chloro-5-[1-(methylthio)ethyl]pyrimidine (0.49 g, 2.61 mmol) and cyanamide (120 mg, 2.86 mmol) in 20 mL of CH2Cl2 was cooled to 0° C. and treated with iodobenzene diacetate (860 mg, 2.59 mmol). The mixture was allowed to warm to room temperature over an hour, the solvent was removed under reduced pressure and the residue was partitioned between hexanes and acetonitrile. The acetonitrile was removed under reduced pressure and the residue was further purified by flash column chromatography on silica gel using a 50% mixture of acetone and petroleum ether as the eluant. The solvents were removed under reduced pressure to yield 0.44 g (74%) of (1E)-[1-(2-chloropyrimidin-5-yl)ethyl](methyl)-λ4-sulfanylidenecyanamide (C) as a pale orange syrup. This material was a 2:1 mixture of diastereomers. The physical properties of the major diastereomer were: 1H NMR (CDCl3) δ 8.68 (s, 2H), 4.38 (q, J=8.3 Hz, 1H), 2.68 (s, 3H), 1.92 (d, J=8.3 Hz, 3H); LC-MS (ESI) m/z 229 (M+H).
Reaction SMILES: BrC(C)C([C:5]1[CH:6]=[CH:7][C:8]2[S:12][C:11](=[O:13])[NH:10][C:9]=2[CH:14]=1)=O.NC1C=CC=CN=1>C(O)C>[S:12]1[C:8]2[CH:7]=[CH:6][CH:5]=[CH:14][C:9]=2[NH:10][C:11]1=[O:13]
Reactant: CC(Br)C(=O)c1ccc2sc(=O)[nH]c2c1
Agent: Nc1ccccn1
Solvent: CCO
Product: O=c1[nH]c2ccccc2s1
Yield: 70.8 %

Procedure:
5-(3-Methylimidazo[1,2-? ? pyridin-2-yl)2-benzothiazolinone (1.07 g) was prepared in the substantially same manner as that of Example 2 from 5-(2-bromopropionyl)-2-benzothiazolinone (2.86 g) and 2-aminopyridine (2.8 g). mp.>290° C.(from aqueous ethanol),
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:13]#[N:14])=[CH:6][CH:5]=1.Br[C:22]1[CH:23]=[N:24][CH:25]=[N:26][CH:27]=1>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][C:12]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([C:22]2[CH:23]=[N:24][CH:25]=[N:26][CH:27]=2)[C:13]#[N:14])=[CH:8][CH:9]=1
Reactant: Brc1cncnc1
Reactant: N#CC(CCc1ccc(Cl)cc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(CCc1ccc(Cl)cc1)(c1ccccc1)c1cncnc1
Reaction time: 0.75 h

Procedure:
In a 250 ml. 3 neck round bottomed flask under nitrogen was charged 1.2 g of 60% NaH (1.5 eq., 0.0293 moles), washed 2 times with 15 ml. hexanes, in 40 ml. DMF. Dropwise was added 5.0 g. of 4-(4-chlorophenyl)-2-phenylbutanenitrile (1.0 eq., 0.0195 moles) in 10 ml. of DMF and was stirred for one hour at rt. This was followed by the addition of 4.67 g. of 5-bromopyrimidine (1.5 eq., 0.0293 moles) in 10 ml. of DMF to the reaction mixture which resulted in an exotherm to 35° C. After 45 min. GLC analysis showed no unreacted nitrile. The reaction was quenched by the addition of 100 ml. Water and then extracted with 250 ml. EtOAc. The organic phase Was washed with 2 times 100 ml. water, dried over MgSO4 and concentrated to give 7.3 g. of oil. 6.0 g. of crude product was purified by flash chromatography with 3:7 EtOAc/hexane to give 2.3 g. of a white solid mp. 89°-91° C. (43.1% based on chromatographic portion).