Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=O.C(N(CC)CC)C.C(Cl)(=O)OCC(C)C.[NH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.Cl>ClCCl>[Cl:1][C:2]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([NH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:10]
Reactant: Nc1ccccc1
Reactant: O=C(O)CCCOc1ccc(Cl)cc1Cl
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCCOc1ccc(Cl)cc1Cl)Nc1ccccc1
Temperature: -30 °C
Reaction time: 3 h
Yield: 77.1 %

Procedure:
To a solution of the 4-(2,4-dichloro-phenoxy)-butyric acid (9.8 g, 40 mmol) and triethylamine (6.0 ml, 40 mmol) in dichloromethane (150 mL) was added dropwise isobutyl chlorocarbonate (6 mL, 40 mol) at −30° C. After stirring at −30° C. for 3 h, aniline (4 mL 40 mol) was added dropwise. The reaction mixture was stirred for 3 h at −30° C. and then allowed to warm up to RT. Aqueous HCl (5%, 100 mL) was added and stirring was continued for 0.5 h. The phases were separated, the aqueous layer was extracted with dichloromethane (2×200 mL). The combined organic extracts were washed with water and brine, dried over Na2SO4 and concentrated in vacuo to give the product (10 g, 77.5%). 1H-NMR (CDCl2): δ 7.49 (d, 2H, J=8.0 Hz), 7.38 (d, 1H, J=2.4 Hz), 7.31 (t, 2H, J=8.0 Hz), 7.18 (dd, 1H, J1=8.8 Hz, J2=2.4 Hz) 7.12 (t, 1H, J=8.0), 6.87 (d, 1H, J=8.8 Hz), 4.12 (t, 2H, J=6.4 Hz), 2.64 (t, 2H, J=6.4 Hz), 2.25 (p, 2H, J=6.4 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.Cl.[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([CH:27]2[CH2:31][CH2:30][NH:29][CH2:28]2)(=[O:26])=[O:25])=[CH:20][CH:19]=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([N:29]2[CH2:30][CH2:31][CH:27]([S:24]([C:21]3[CH:22]=[CH:23][C:18]([CH3:17])=[CH:19][CH:20]=3)(=[O:26])=[O:25])[CH2:28]2)=[O:15])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)C2CCNC2)cc1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Agent: Cl
Product: Cc1ccc(-c2oncc2C(=O)N2CCC(S(=O)(=O)c3ccc(C)cc3)C2)cc1

Procedure:
The title compound was prepared from 5-(4-methylphenyl)isoxazole-4-carboxylic acid (10.2 mg, 0.050 mmol) and 3-(4-methylphenylsulfonyl)pyrrolidine hydrochloride (15.7 mg, 0.060 mmol) as described in synthetic method B and thereafter purified by preparative HPLC method B to give a solid (12.1 mg). Calcd for C22H22N2O4S: 410.1300, found 410.1303.
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[O:10][C:11]3[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:12]=3[C:13]=2[CH3:14])O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:22])=O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[Cl:22][CH:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:9]1[O:10][C:11]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:12]=2[C:13]=1[CH3:14]
Reactant: O=S(Cl)Cl
Reactant: Cc1c(C(O)C2CCCCC2)oc2cc(F)ccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1c(C(Cl)C2CCCCC2)oc2cc(F)ccc12
Temperature: 100 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
To a solution (20 mL) of cyclohexyl(6-fluoro-3-methyl-1-benzofuran-2-yl)methanol (931 mg) synthesized above in toluene was added thionyl chloride (311 μL), and the mixture was stirred at 100° C. for 1 hr. The reaction mixture was poured into ice-cooled saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give the title object compound (945 mg, 95%) as a yellow oil.
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[CH:11]=[CH:10][C:9]([Cl:13])=[CH:8][C:7]=2[C:6]2[CH2:14][N:15]([CH3:18])[CH2:16][CH2:17][C:5]1=2)[CH:2]=[CH2:3].Br[C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C1COCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:13][C:9]1[CH:10]=[CH:11][C:12]2[N:4]([CH2:1]/[CH:2]=[CH:3]/[C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)[C:5]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][C:6]=3[C:7]=2[CH:8]=1
Reactant: Brc1ccncc1
Reactant: C=CCn1c2c(c3cc(Cl)ccc31)CN(C)CC2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN1CCc2c(c3cc(Cl)ccc3n2C/C=C/c2ccncc2)C1
Temperature: 25 °C

Procedure:
5-Allyl-8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (400 mg, 1.52 mmol, 1 equiv.) and 4-bromopyridine (240 mg, 1.52 mmol, 1 equiv.) were heated to 100° C. with palladium acetate (10 mg, 0.046 mmol), triphenyl phosphine (24 mg, 0.092 mmol) and triethyl amine (0.44 mL, 2 equiv.) in 10 mL of THF for 14 h. The reaction mixture was cooled to RT and diluted with THF (10 mL), filtered over a Celite bed and concentrated. The concentrate was dissolved in EtOAc (40 mL) and washed with water (10 mL) followed by brine. The organic layer was dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain crude product that was purified by HPLC. 1H NMR (DMSO-d6) δ (ppm): 0.64 (bs, 1H), 8.68-8.66 (d, 2H), 7.79-7.77 (d, 2H), 7.6-7.56 (m, 2H),7.2-7.1(d, 1H), 7.0-6.9 (m, 1H), 6.5-6.4 (d, 1H), 5.15-5.03 (m, 2H), 4.64-4.60 (d, 1H), 4.3-4.25 (m, 1H), 3.79-3.76 (m, 1H), 3.52-3.50 (m, 1H), 3.17 (bs, 2H), 2.98 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2.C([Li])CCC.Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>O1CCCC1.C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-]>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[C:5]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:6][NH:7]2
Reactant: COc1cccc2[nH]ccc12
Reactant: CCOC(=O)CBr
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1c[nH]c2cccc(OC)c12
Reaction time: 2 h

Procedure:
To a solution of 2.94 gm (20 mmol) of 4-methoxyindole in 150 ml of tetrahydrofuran was added slowly 13 ml of n-butyl lithium (1.6M in hexane; 20 mmol) followed by the slow addition of 20 ml of zinc chloride (1.0M in ethyl ether; 20 mmol) at 0-5° C. The cooling bath was removed and the solution stirred for 2 hours and then treated with 2.1 ml (25 mmol) of ethyl bromoacetate for 19 hours, diluted with ethyl acetate, washed with water, washed with brine, dried over sodium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel eluting with a gradient hexane/10-50% ethyl ether to give starting material (40%) and then product, 2.3 gm, 50%, as an oil. 1H NMR (CDCl3) δ: 1.25 (t, 3H), 3.85 (s, 3H), 3.90 (s, 2H), 4.10 (q, 2H), 6.45 (d, 1H), 6.90 (d, 1H), 6.95 (s, 1H), 7.05 (t, 1H), 8.00 (br s, 1H).
Reaction SMILES: C(N)C1C=CC=CC=1.C(OC([NH:19][C@H:20]([C:22]([NH:24][C@H:25]([P:27](=[O:30])([OH:29])[OH:28])[CH3:26])=[O:23])[CH3:21])=O)C1C=CC=CC=1>>[NH2:19][C@H:20]([C:22]([NH:24][C@H:25]([P:27](=[O:28])([OH:30])[OH:29])[CH3:26])=[O:23])[CH3:21]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](C)P(=O)(O)O
Solvent: NCc1ccccc1
Product: C[C@H](N)C(=O)N[C@@H](C)P(=O)(O)O

Procedure:
In a manner analogous to that described in the last paragraph of Example A, starting from the benzylamine salt of (1R)-1-[(N-benzyloxycarbonyl-L-alanyl)amino]-ethylphosphonic acid there was obtained (1R)-1-(L-alanylamino)-ethylphosphonic acid of melting point 295°-296° C (decomposition); [α]D20 = -45.6° (c = 1% in water).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH:3]=1.[Br:11][C:12]1[CH:13]=[CH:14][C:15]([Cl:20])=[C:16]([CH:19]=1)[CH:17]=O>>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([Cl:20])=[C:16]([CH2:17][C:7]2[S:6][C:5]3[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][C:4]=3[CH:8]=2)[CH:19]=1
Reactant: O=Cc1cc(Br)ccc1Cl
Reactant: Clc1ccc2sccc2c1
Product: Clc1ccc2sc(Cc3cc(Br)ccc3Cl)cc2c1

Procedure:
5-Chlorobenzo[b]thiophene (see Tilak, B. D. Tetrahedron 9 (1960) 76-95) and 5-bromo-2-chlorobenzaldehyde obtained in Reference Example 16-(1) were treated in a manner similar to Reference Example 7 to give the target compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[C:6]([F:9])[C:5]([CH3:10])=[CH:4][CH:3]=1.C1OCCOCCOCCOCCOCCOC1.CC(C)([O-])C.[K+].F[C:36]1[CH:37]=[C:38]([CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=1)[C:39]#[N:40]>CS(C)=O.O>[Cl:1][C:2]1[C:7]([O:8][C:36]2[CH:37]=[C:38]([CH:41]=[C:42]([C:44]([F:45])([F:47])[F:46])[CH:43]=2)[C:39]#[N:40])=[C:6]([F:9])[C:5]([CH3:10])=[CH:4][CH:3]=1
Reactant: Cc1ccc(Cl)c(O)c1F
Reactant: N#Cc1cc(F)cc(C(F)(F)F)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc(Cl)c(Oc2cc(C#N)cc(C(F)(F)F)c2)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.2 %

Procedure:
To a solution of 6-chloro-2-fluoro-3-methylphenol (8.49 g, 52.9 mmol) and 18-crown-6 (13.98 g, 52.9 mmol) in dimethyl sulfoxide (80 ml) was added potassium t-butoxide (20% wt solution in THF) (31.2 g, 55.5 mmol) (31.2 mL) and the mixture was stirred at rt for 30 minutes. Next, 3-fluoro-5-(trifluoromethyl)benzonitrile (10.00 g, 52.9 mmol) was added and the mixture was heated with stirring for 5 hours at 135° C. The reaction mixture was cooled to 0° C., poured into 700 mL water, and the precipitate was filtered off to give the title compound (12.6 g, 38.2 mmol, 72% yield) as a grey solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.10 (s, 1H), 7.80 (s, 1H), 7.74 (s, 1H), 7.39-7.49 (m, 1H), 7.34 (t, 1H), 2.28 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C@H:4]([CH3:19])[CH2:5][N:6]1[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:19][C@H:4]([CH2:5][N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)[C:3]([O:2][CH3:1])=[O:20]
Reactant: COC(=O)[C@H](C)CN1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@H](C)CN1CCNCC1
Reaction time: 0.17 h
Yield: 91.8 %

Procedure:
A solution of 565 (523 mg, 1.83 mmol) and TFA (5 ml) in DCM (15 ml) was stirred at rt for 3.5 h. The reaction mixture was concentrated (azeotropes with DCM), diluted with water, stirred for 10 min, and the pH was adjusted to around 9 with a saturated aqueous solution of sodium bicarbonate and 1N NaOH. The alkaline solution was extracted with DCM; the extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under high vacuum to afford the desired product 566 (314 mg, 1.68 mmol, 92% yield) as a yellow oil that was used crude in the next step without any further purification. MS (m/z): 187.2 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5](Cl)=[O:6].[NH2:13][C:14]([CH3:30])([CH2:17][N:18]1[CH:26]=[C:25]2[C:20]([C:21]([Cl:29])=[C:22]([Cl:28])[CH:23]=[C:24]2[Cl:27])=[N:19]1)[C:15]#[N:16]>C1COCC1>[C:15]([C:14]([NH:13][C:5](=[O:6])[C:4]1[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:2]([F:1])[CH:3]=1)([CH3:30])[CH2:17][N:18]1[CH:26]=[C:25]2[C:20]([C:21]([Cl:29])=[C:22]([Cl:28])[CH:23]=[C:24]2[Cl:27])=[N:19]1)#[N:16]
Reactant: CC(N)(C#N)Cn1cc2c(Cl)cc(Cl)c(Cl)c2n1
Reactant: COc1ccc(C(=O)Cl)cc1F
Solvent: C1CCOC1
Product: COc1ccc(C(=O)NC(C)(C#N)Cn2cc3c(Cl)cc(Cl)c(Cl)c3n2)cc1F

Procedure:
Using a procedure similar to that described in Example 60, except using a solution of 3-fluoro-4-methoxybenzoyl chloride (0.16 mmole) in THF and a solution of 2-amino-2-methyl-3-(4,6,7-trichloro-2H-indazol-2-yl)propionitrile (0.075 mmole, described in Example 147) in THF mixed with TEA (3% v./v.), the title compound was isolated as solid residue (6.6 mg). It was dissolved in DMSO for further biological evaluation and analyzed by LCMS. MS (ES): M/Z [M+H]=455, RT=0.69 min.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:47][C:48]1[CH:49]=[C:50]([CH:53]=[C:54]([CH3:56])[CH:55]=1)[CH2:51][NH2:52]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:35][CH2:36][CH:37]([CH2:40][C:41]([NH:52][CH2:51][C:50]4[CH:53]=[C:54]([CH3:56])[CH:55]=[C:48]([CH3:47])[CH:49]=4)=[O:43])[CH2:38][CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Reactant: Cc1cc(C)cc(CN)c1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)NCc2cc(C)cc(C)c2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with 3,5-dimethylbenzylamine (Trans World chemicals) to give the title product. LC-MS (ES+) 782 [(M+H)+].
Reaction SMILES: [H-].[Na+].[Si:3]([O:20][CH2:21][CH2:22][O:23][CH2:24][C@H:25]([OH:30])[C:26]([O:28][CH3:29])=[O:27])([C:16]([CH3:19])([CH3:18])[CH3:17])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:32]1[N:37]=[CH:36][N:35]=[C:34]2[N:38]([C:41]3[CH:46]=[C:45]([CH3:47])[CH:44]=[CH:43][C:42]=3[CH3:48])[N:39]=[CH:40][C:33]=12.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[Si:3]([O:20][CH2:21][CH2:22][O:23][CH2:24][C@H:25]([O:30][C:32]1[N:37]=[CH:36][N:35]=[C:34]2[N:38]([C:41]3[CH:46]=[C:45]([CH3:47])[CH:44]=[CH:43][C:42]=3[CH3:48])[N:39]=[CH:40][C:33]=12)[C:26]([O:28][CH3:29])=[O:27])([C:16]([CH3:19])([CH3:18])[CH3:17])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)[C@@H](O)COCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: Cc1ccc(C)c(-n2ncc3c(Cl)ncnc32)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)[C@H](COCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)Oc1ncnc2c1cnn2-c1cc(C)ccc1C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 57.5 %

Procedure:
60% sodium hydride (0.187 g, 4.67 mmol) was added to (S)-methyl 3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-hydroxypropanoate (Intermediate AB3) (1.568 g, 3.90 mmol) in anhydrous THF (20 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes and then 4-chloro-1-(2,5-dimethylphenyl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate AJ3)(1.008 g, 3.90 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was neutralised with 1M citric acid and the majority of the THF removed in vacuo. The residue was diluted with water (20 mL) and EtOAc (100 mL). The organic layer was separated and the aqueous layer re-extracted with EtOAc (100 mL). The combined organics were washed with saturated brine (75 mL), dried (MgSO4) and evaporated to give the crude product. This was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in isohexane to afford the product (1.400 g, 57.5%). m/z (ES+) (M+H)+=625; HPLC tR=3.53 min.
Reaction SMILES: C1C(=O)[N:5](Br)[C:3](=O)C1.[Cl:9][C:10]1[C:11]([O:17][CH3:18])=[C:12]([CH3:16])[CH:13]=[CH:14][CH:15]=1.[C-]#N.[K+]>C(Cl)(Cl)(Cl)Cl.O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Cl:9][C:10]1[C:11]([O:17][CH3:18])=[C:12]([CH:13]=[CH:14][CH:15]=1)[CH2:16][C:3]#[N:5]
Reactant: COc1c(C)cccc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: [C-]#N
Agent: [K+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: COc1c(Cl)cccc1CC#N
Reaction time: 16 h
Yield: 81.1 %

Procedure:
39.4 g (221.3 mmol) of NBS and 100 mg of benzoyl peroxide are added to 31.6 g (201.7 mmol) of 3-chloro-2-methoxytoluene in 500 ml of CCl4. It is refluxed over 16 hours, allowed to cool and filtered. Solvent is removed from the filtrate, and the filtrate is dissolved in 214 ml of N,N-dimethylformamide and 142 ml of water. 20.9 g (322.1 mmol) of potassium cyanide is added at 0° C. and stirred over 16 hours. The reaction mixture is diluted with water and extracted several times with tert-butyl-methyl ether. The organic phase is washed several times with saturated sodium chloride solution and dried on sodium sulfate. The solvent is removed in a vacuum and after chromatographic purification on silica gel (hexane/ethyl acetate 20%), 29.7 g of product is obtained.
Reaction SMILES: [OH:1][C:2]1([CH2:8][CH2:9][N:10]2[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[S:12][CH:11]2[CH2:18][CH2:19][CH2:20][C:21]2[CH:31]=[CH:30][C:24]([C:25]([O:27]CC)=[O:26])=[CH:23][CH:22]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1>C(#N)C.O>[OH:1][C:2]1([CH2:8][CH2:9][N:10]2[C:14](=[O:15])[C:13]([CH3:16])([CH3:17])[S:12][CH:11]2[CH2:18][CH2:19][CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:30][CH:31]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: CCOC(=O)c1ccc(CCCC2SC(C)(C)C(=O)N2CCC2(O)CCCCC2)cc1
Solvent: O
Solvent: CC#N
Product: CC1(C)SC(CCCc2ccc(C(=O)O)cc2)N(CCC2(O)CCCCC2)C1=O

Procedure:
The product of Step A above is saponified exactly as described in Example 2, Step C, to yield the title product as a crystalline solid, m.p. 132°-137° C. (from acetonitrile-water).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH2:7][CH:6]([OH:10])[CH2:5]1)(=[O:3])[CH3:2].CN(C)C=O.[H-].[Na+].[CH2:18](Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O>[C:1]([N:4]1[CH2:9][CH2:8][CH2:7][CH:6]([O:10][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCCC(O)C1
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N1CCCC(OCc2ccccc2)C1
Reaction time: 0.5 h

Procedure:
1-Acetyl-3-hydroxypiperidine (0.10 mole) is dissolved in 50 ml. of dimethylformamide. 0.12 Mole of sodium hydride (56%) is added over a 10 minute period, and the reaction mixture is stirred for 30 minutes. Benzyl chloride (0.12 mole) is added dropwise over a 30 minute period, and the reaction mixture is then heated on a steam bath for 30 minutes. Water (3 volumes) is added, the solution extracted with ether, the ether extract washed with water and the ether removed by evaporation. A yellow oil is obtained on distillation at 136°-140° C. (0.01 mm Hg.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([S:20][CH3:21])[CH:19]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH:22][CH:23]([CH3:25])[CH3:24].ClC1C=CC=C(C(OO)=[O:34])C=1.[OH-].[Na+]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([S:20]([CH3:21])=[O:34])[CH:19]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH:22][CH:23]([CH3:25])[CH3:24]
Reactant: CSc1cncc(COc2cc3ncnc(NC(C)C)c3cc2Br)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CC(C)Nc1ncnc2cc(OCc3cncc(S(C)=O)c3)c(Br)cc12
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 74 %

Procedure:
6-Bromo-N-isopropyl-7-{[5-(methylsulphanyl)pyridin-3-yl]methoxy}quinazolin-4-amine (430 mg, 1.03 mmol) is presented as an initial charge in 20 mL of chloroform and at 0° C. and at 0° C. admixed with meta-chloroperbenzoic acid (260 mg, 1.13 mmol). The batch is subsequently stirred at 0° C. for 45 minutes. The batch is introduced into 2N aqueous sodium hydroxide solution. The mixture is extracted with dichloro-methane, the organic phase is dried over sodium sulphate and the solvent is concentrated. Chromatography (silica gel, dichloromethane/methanol: 0→30% methanol) gives the desired product in 74% yield (330 mg).
Reaction SMILES: [C:1]1([C:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[NH:18][C:17]3=[O:25])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>CO.[Pd]>[C:26]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][N:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[NH:18][C:17]3=[O:25])[CH2:12][CH2:13]2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: [H][H]
Reactant: O=c1[nH]c2ccccc2n1CCN1CCC(=C(c2ccccc2)c2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: O=c1[nH]c2ccccc2n1CCN1CCC(C(c2ccccc2)c2ccccc2)CC1

Procedure:
A solution of 4 g of 1-[2-[4-diphenylmethylene-1-piperidinyl]ethyl]-1,3-dihydro-2(2H)-benzimidazolone in 150 cm3 of methanol is hydrogenated with the aid of a Parr apparatus, at ambient temperature, at a hydrogen pressure of 50 psi, in the presence of 5% palladium on charcoal. When the absorption of hydrogen has ended, the catalyst is filtered off and the filtrate is evaporated down. The product obtained is recrystallized from ethyl acetate. M.p.=195°-196° C.
Reaction SMILES: C(O)(=O)C.[N+:5]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][C:17]([N:19]2[CH2:23][CH2:22][S:21][CH2:20]2)=[O:18])=[CH:10][CH:9]=1)([O-])=O>[Zn].O>[NH2:5][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][CH2:16][C:17]([N:19]2[CH2:23][CH2:22][S:21][CH2:20]2)=[O:18])=[CH:12][CH:13]=1
Reactant: O=C(CCCc1ccc([N+](=O)[O-])cc1)N1CCSC1
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: Nc1ccc(CCCC(=O)N2CCSC2)cc1
Yield: 67 %

Procedure:
To a mixture of 9 ml of acetic acid, 6 ml of water, and 1.0 g of zinc powder was gradually added 2 mmol of N-[4-(4-nitrophenyl)butanoyl]thiazolidine at room temperature in small portions with stirring. After the addition, the mixture was stirred for 2 hours at the same temperature to complete the reaction. Zinc powder was removed by filtration. The filtrate was weakly alkalinized with 10% sodium hydroxide and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel to obtain 335 mg of colorless crystals of N-[4-(4-aminophenyl)butanoyl]thiazolidine (yield: 67%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[CH:7]1.[CH2:20]([N:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([C:36](Cl)=[O:37])=[CH:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[NH2:19][C:10]1[C:9]2[N:8]=[CH:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:36]([C:29]3[C:30]4[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=4)[N:27]([CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:28]=3)=[O:37])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
Reactant: O=C(Cl)c1cn(Cc2ccccc2)c2ccccc12
Product: Nc1nc2ccccc2c2c1ncn2CCCCNC(=O)c1cn(Cc2ccccc2)c2ccccc12

Procedure:
According to the general method of Example 14, 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine and 1-benzylindole-3-carbonyl chloride were combined to provide N3-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-1-benzyl-1H-3-indolecarboxamide as a white powder, m.p. 139.0° C. (decomposition). 1H NMR (300 MHz, DMSO-d6) δ 8.24 (s, 1H), 8.14 (t, J=7.8 Hz, 1H), 8.04 (m, 2H), 7.93 (m, 1H), 7.62 (d, J=8.4 Hz, 1H), 7.51 (d, J=7.8 Hz, 1H), 7.44-7.09 (m, 9H), 6.63 (s, 2H), 5.44 (s, 2H), 4.66 (t, J=6.6 Hz, 2H), 1.97-1.92 (m, 2H), 1.62-1.57 (m, 2H); MS (EI) m/e 488.2326 (488.2325 calcd for C30H28N6O).