Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH2:7][OH:8].CC([O-])(C)C.[K+].C1COCC1.[C:20]([C:24]1[S:28]/[C:27](=[N:29]\[C:30](=[O:42])[C:31]2[CH:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[CH:33][C:32]=2F)/[N:26]([CH2:43][C@H:44]2[CH2:48][CH2:47][CH2:46][O:45]2)[CH:25]=1)([CH3:23])([CH3:22])[CH3:21]>C1COCC1>[C:20]([C:24]1[S:28]/[C:27](=[N:29]\[C:30](=[O:42])[C:31]2[CH:36]=[C:35]([C:37]([F:39])([F:38])[F:40])[CH:34]=[CH:33][C:32]=2[O:8][CH2:7][C:3]2[N:2]([CH3:1])[CH:6]=[CH:5][N:4]=2)/[N:26]([CH2:43][C@H:44]2[CH2:48][CH2:47][CH2:46][O:45]2)[CH:25]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: Cn1ccnc1CO
Reactant: CC(C)(C)c1cn(C[C@H]2CCCO2)/c(=N/C(=O)c2cc(C(F)(F)F)ccc2F)s1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cn1ccnc1COc1ccc(C(F)(F)F)cc1C(=O)/N=c1\sc(C(C)(C)C)cn1C[C@H]1CCCO1
Reaction time: 0.25 h
Yield: 48.9 %

Procedure:
A solution of (1-methyl-1H-imidazol-2-yl)methanol (109 mg, 0.94 mmol) in THF (5 mL) was treated with a 1 M KOtBu/THF (0.95 mL, 0.944 mmol) and stirred for 15 min. A solution of Example 1A (190 mg, 0.47 mmol) was added to the reaction mixture and stirred for 6 hours. The reaction mixture was quenched with saturated NH4Cl solution, concentrated in vacuo and partitioned between EtOAc and brine, dried (MgSO4), filtered, and concentrated. The residue was purified by using an Analogix® Intelliflash280™ (SiO2, 0-60% ethyl acetate in hexanes) to afford the title compound (120 mg, 33% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.31 (s, 9 H), 1.50-1.66 (m, 1 H), 1.68-1.96 (m, 3 H), 3.55-3.84 (m, 5 H), 4.05-4.32 (m, 3 H), 5.29 (s, 2 H), 6.86 (s, 1 H), 7.20 (s, 1 H), 7.26 (s, 1 H), 7.52 (d, J=8.8 Hz, 1 H), 7.79 (dd, J=9.0, 2.2 Hz, 1 H), 8.01 (d, J=2.4 Hz, 1 H). MS (DCI/NH3) m/z 523 (M+H)+. Anal. calcd for C25H29F3N4O3S: C, 57.46; H, 5.59; N, 10.72. Found: C, 56.96; H, 5.57; N, 10.46.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1F.[CH3:11][C@H:12]([OH:16])[CH2:13][CH:14]=[CH2:15].[H-].[Na+]>C1COCC1.CCOCC>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:16][C@H:12]([CH2:13][CH:14]=[CH2:15])[CH3:11]
Reactant: C=CC[C@H](C)O
Reactant: N#Cc1ccc(Br)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CC[C@H](C)Oc1cc(C#N)ccc1Br
Reaction time: 5 h
Yield: 70.6 %

Procedure:
To a solution of 4-bromo-3-fluorobenzonitrile (1.0 g, 5.00 mmol, 1 equiv) and (S)-pent-4-en-2-ol (0.52 g, 6.00 mmol, 1.2 equiv) in THF (25 mL) was added NaH (0.24 g of a 60% suspension in mineral oil, 6.00 mmol, 1.2 equiv). Slow gas evolution with considerable foaming observed. After 5 h, dilute with ether then wash with water and brine. The ether layer was dried (MgSO4) and concentrated in vacuo. The crude product was purified by flash column chromatography (0-10% EtOAc in hexane) to provide the product as a colorless oil (0.94 g, 71%). 1H NMR (400 MHz, CDCl3) δ 7.69-7.62 (m, 1H), 7.15-7.08 (m, 2H), 5.89 (ddt, J=17.1, 10.1, 7.2 Hz, 1H), 5.23-5.12 (m, 2H), 4.54-4.42 (m, 1H), 2.61-2.51 (m, 1H), 2.51-2.40 (m, 1H), 1.39 (d, J=6.0 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:12])=[O:11].C(NC(C)C)(C)C.[Li]CCCC.C=O.N1C=CC=CC=1.[CH3:39][C:40]([O:42][C:43](C)=O)=[O:41]>C1COCC1>[C:40]([O:42][CH2:43][CH:9]([C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])[S:10]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:12])=[O:11])(=[O:41])[CH3:39]
Reactant: O=S(=O)(Cc1ccc(Cl)cc1Cl)c1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CC(C)NC(C)C
Product: CC(=O)OCC(c1ccc(Cl)cc1Cl)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
The crude sulfone (2) (1 eq) in THF was added dropwise via addition funnel to a freshly prepared solution of diisopropylamine (1.3 eq), n-BuLi 2.5 M in hexanes (1.1 eq) and THF under N2 at −78° C. with stirring. After 30 min., the paraformaldehyde was added (2.1 eq). The reaction was stirred for an additional 30 min. at which time the reaction was allowed to warm to room temperature over 4.5 h. The reaction was then quenched with sat. aq. NH4Cl. The aqueous layer was extracted with EtOAc, dried (Na2SO4), filtered and concentrated under reduced pressure to yield the crude sulfonyl hydrin which was used without further purification. The crude sulfonyl hydrin was dissolved in CH2Cl2 (excess) and pyridine (1.2 eq) followed by the addition of Ac2O (1.1 eq). After stirring at room temperature for 14.5 h, the reaction was quenched with sat. aq. NH4Cl. The layers were separated, and the aqueous layer was extracted with Et2O. The combined organic layers were dried (Na2SO4), filtered, and concentrated to give the 2-(2,4-dichlorophenyl)-2-(phenylsulfonyl)ethyl acetate (3) (94% yield) in high purity.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]2[C:14](=[O:15])[C:13]3[CH:16]=[C:17]([CH2:19][CH2:20][CH3:21])[S:18][C:12]=3[NH:11][C:10]2=[O:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:37]2[N:41]=[C:40](C(Cl)(Cl)Cl)[O:39][N:38]=2)=[CH:27][CH:26]=1.C(=O)([O-])[O-:47].[K+].[K+]>C(#N)C>[O:47]=[C:40]1[O:39][N:38]=[C:37]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[C:28]2[CH:29]=[CH:30][C:25]([CH2:24][N:11]3[C:12]4[S:18][C:17]([CH2:19][CH2:20][CH3:21])=[CH:16][C:13]=4[C:14](=[O:15])[N:9]([CH2:8][CH2:7][C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:10]3=[O:22])=[CH:26][CH:27]=2)[NH:41]1
Reactant: O=C([O-])[O-]
Reactant: ClC(Cl)(Cl)c1nc(-c2ccccc2-c2ccc(CBr)cc2)no1
Reactant: CCCc1cc2c(=O)n(CCc3ccccc3)c(=O)[nH]c2s1
Agent: [K+]
Solvent: CC#N
Product: CCCc1cc2c(=O)n(CCc3ccccc3)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.2 %

Procedure:
A mixture of 3-(2-phenylethyl)-6-propylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (0.40 g), 3-[4′-(bromomethyl)biphenyl-2-yl]-5-(trichloromethyl)-1,2,4-oxadiazole (0.68 g), potassium carbonate (0.35 g) and acetonitrile (16 mL) was stirred at room temperature for 2 hr. Insoluble material was filtered off, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography and dissolved in tetrahydrofuran (4 mL) and methanol (4 mL). 1N Aqueous sodium hydroxide solution (4 mL) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was adjusted to pH 4 with water and 1N hydrochloric acid, and extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.44 g, 61%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14]2[N:15]([CH3:31])[C:16](=[O:30])[C:17]([CH3:29])=[C:18]([NH:19][C:20]3[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=3)[C:23]([OH:25])=O)[C:13]=2[C:12](=[O:32])[N:11]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[C:10]1=[O:42].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.[NH:75]1[CH2:79][CH2:78][CH:77]([OH:80])[CH2:76]1>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14]2[N:15]([CH3:31])[C:16](=[O:30])[C:17]([CH3:29])=[C:18]([NH:19][C:20]3[CH:28]=[CH:27][CH:26]=[C:22]([C:23]([N:75]4[CH2:79][CH2:78][CH:77]([OH:80])[CH2:76]4)=[O:25])[CH:21]=3)[C:13]=2[C:12](=[O:32])[N:11]([CH2:33][C:34]2[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=2)[C:10]1=[O:42]
Reactant: COc1ccc(Cn2c(=O)c3c(Nc4cccc(C(=O)O)c4)c(C)c(=O)n(C)c3n(-c3ccc(I)cc3F)c2=O)cc1
Reactant: OC1CCNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Cn2c(=O)c3c(Nc4cccc(C(=O)N5CCC(O)C5)c4)c(C)c(=O)n(C)c3n(-c3ccc(I)cc3F)c2=O)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 62.4 %

Procedure:
To a stirred solution of 3-((1-(2-fluoro-4-iodophenyl)-3-(4-methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidin-5-yl)amino)benzoic acid (2b) (800 mg, 1.172 mmol) in THF (5 ml) was added EDC.HCl (494 mg, 2.58 mmol), HOBT (395 mg, 2.58 mmol), DIPEA (0.819 ml, 4.69 mmol) and pyrrolidin-3-ol hydrochloride (290 mg, 2.35 mmol). The reaction mixture was stirred at room temperature under N2 atm for 6 h. The reaction mixture was then partitioned between water and ethyl acetate. Organic phase was removed, washed with brine and dried over sodium sulphate. The solvent was evaporated in vacuop to afford crude 1-(2-fluoro-4-iodophenyl)-5-((3-(3-hydroxypyrrolidine-1-carbonyl)phenyl)amino)-3-(4-methoxybenzyl)-6,8-dimethylpyrido[2,3-d]pyrimidine-2,4,7(1H,3H,8H)-trione (2c) (550 mg) which was carried forward for the next step without further purification.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH3:7][C:8]1C=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:9]=1C(O)=O>CN(C=O)C.C(Cl)Cl>[CH3:7][C:8]1[CH:9]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][C:1]=1[C:2]([Cl:4])=[O:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc([N+](=O)[O-])cc1C(=O)Cl
Temperature: 0 °C
Reaction time: 5 h

Procedure:
Oxalyl chloride (0.31 g) was added dropwise to a stirred mixture of 2-methyl-5-nitrobenzoic acid (0.4 g), DMF (a few drops) and methylene chloride (25 ml) which had been cooled to 0° C. The mixture was allowed to warm to ambient temperature and was stirred for five hours. The mixture was evaporated to give 2-methyl-5-nitrobenzoyl chloride which was dissolved in methylene chloride (10 ml) and added dropwise to a stirred mixture of 3-(4-methylpiperazin-1-ylmethyl)aniline (0.44 g), triethylamine (0.49 g) and methylene chloride (10 ml). The mixture was stirred at ambient temperature for 16 hours. The mixture was washed with a saturated aqueous sodium bicarbonate solution. The organic phase was evaporated and the residue was purified by column chromatography on an isolute SCX ion exchange column using initially methanol and then a 99:1 mixture of methanol and a saturated aqueous ammonium hydroxide solution as eluent. There was thus obtained N-[3-(4-methylpiperazin-1-ylmethyl)phenyl]-2-methyl-5-nitrobenzamide(0.46 g); Mass Spectrum: M+H+ 369.
Reaction SMILES: C([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]2[C:20]3[C:15](=[C:16]([Cl:22])[CH:17]=[C:18]([Cl:21])[CH:19]=3)[CH2:14][N:13]([CH3:23])[CH2:12]2)[CH:6]=1)C.[OH-].[K+]>CO>[Cl:21][C:18]1[CH:19]=[C:20]2[C:15](=[C:16]([Cl:22])[CH:17]=1)[CH2:14][N:13]([CH3:23])[CH2:12][CH:11]2[C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=1)[C:4]([OH:24])=[O:3]
Reactant: CCOC(=O)c1cccc(C2CN(C)Cc3c(Cl)cc(Cl)cc32)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(C(=O)O)c2)C1
Yield: 65.9 %

Procedure:
500 mg 3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinoline-4-yl)-benzoic-acid-ethyl-ester (Example 220) were dissolved in 15 ml methanol and treated with 10 ml of a 2 N KOH-solution. After 1 h at 50° C. the solvent was removed i. vac. The residue was taken up in water and was washed with ether. The aqueous phase was seperated and 2 N HCl was added until a pH-value of about 6 was reached. The precipitate was filtered off by suction and dried to give 304 mg of the title compound.
Reaction SMILES: C[Li].[OH:3][C:4]1C=C2[C:7]([CH:8]([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)[CH2:9]C(=O)O2)=[CH:6][CH:5]=1.O.[C:21]1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:32][CH2:33][O:34][CH2:35][CH3:36]>C1C=CC=CC=1>[CH3:32][C:33]1([CH3:21])[CH2:9][CH:8]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)[C:7]2[C:35](=[CH:36][C:4]([OH:3])=[CH:5][CH:6]=2)[O:34]1
Reactant: CCOCC
Reactant: O=C1CC(c2cccs2)c2ccc(O)cc2O1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Li]C
Solvent: c1ccccc1
Solvent: O
Product: CC1(C)CC(c2cccs2)c2ccc(O)cc2O1
Reaction time: 72 h

Procedure:
Methyl-lithium (150 ml of a 2 N solution) was added under dry N2 to a solution of 7-hydroxy-4-(2-thienyl) dihydrocoumarin (14.8 g) in dry ether (120 ml) and the mixture allowed to stand for 3 days. Water (500 ml) was added and the ether layer discarded. The aqueous layer was acidified, extracted with ether and the combined ether layers dried (MgSO4). Removal of the solvent under reduced pressure gave a black oil which was then dissolved in dry benzene (100 ml) containing a trace of p-toluene sulphonic acid. The mixture was heated under reflux for 3 hours in a Dean & Stark apparatus. Removal of the solvent under reduced pressure and chromatography on silica gave the required phenol (7 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[C:9]([CH3:15])C(N=[N+]=[N-])=O)=[CH:4][CH:3]=1.C([N:20]([CH2:25]CCC)CCCC)CCC.C1([O:35]C2C=CC=CC=2)C=CC=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([CH:8]=[C:9]([CH3:15])[NH:20][C:25]2=[O:35])=[CH:6][CH:7]=1
Reactant: CC(=Cc1ccc(Cl)cc1)C(=O)N=[N+]=[N-]
Reactant: c1ccc(Oc2ccccc2)cc1
Reactant: CCCCN(CCCC)CCCC
Product: Cc1cc2ccc(Cl)cc2c(=O)[nH]1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
3-(4-Chlorophenyl)-2-methyl-acryloyl azide (11.0 g, 50 mmol) is dissolved in 80 mL of diphenyl ether. The solution is added dropwise to a solution of tributyl amine (11.8 mL, 50 mmol) in 170 mL of diphenyl ether at 210° C. After 4 hours., the solution is cooled 50° C. and diluted with 1.5 L of hexanes. The resulting solid is collected by filtration giving the title compound as a white solid (7.2 g, 37 mmol). 1H NMR (d6-DMSO, 300 MHz) δ11.4 (bs, 1H), 8.02 (s, 1H), 7.67 (d, 1H), 7.55 (d, 1H), 6.34 (s, 1H), 2.18 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([S:20]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)(=[O:22])=[O:21])[CH:14]=3)[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[NH2:29][C:30]([CH3:35])([CH3:34])[C:31]([OH:33])=[O:32].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[CH3:18][C:16]1([CH3:19])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([S:20]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)(=[O:22])=[O:21])[CH:14]=2)[NH:9][CH:8]([C:4]2[CH:3]=[C:2]([NH:29][C:30]([CH3:35])([CH3:34])[C:31]([OH:33])=[O:32])[CH:7]=[CH:6][CH:5]=2)[CH2:17]1
Reactant: CC1(C)CC(c2cccc(Br)c2)Nc2ccc(S(=O)(=O)N3CCOCC3)cc21
Reactant: CC(C)(N)C(=O)O
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(Nc1cccc(C2CC(C)(C)c3cc(S(=O)(=O)N4CCOCC4)ccc3N2)c1)C(=O)O
Temperature: 25 °C
Yield: 55.9 %

Procedure:
A mixture solution of 2-(3-bromo-phenyl)-4,4-dimethyl-6-(morpholine-4-sulfonyl)-1,2,3,4-tetrahydro-quinoline (150 mg, 0.33 mmol), copper(I) iodide (20 mg, 0.1 mmol), 2-amino-2-methyl-propionic acid (135 mg, 1.3 mmol) and potassium carbonate (110 mg, 1.0 mmol) in dimethyl sulfoxide (2.0 mL) was stirred at 120° C. for 16 h. Then the reaction mixture was cooled to room temperature and extracted with ethyl acetate (70 mL×2), washed with water (30 mL×3) and saturated aqueous ammonium chloride solution (30 mL×2), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-{3-[4,4-dimethyl-6-(morpholine-4-sulfonyl)-1,2,3,4-tetrahydro-quinolin-2-yl]-phenylamino}-2-methyl-propionic acid (90 mg, 56.0%) as a white solid: MS (ESI) M+1=488.0.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:18][C:19]([OH:21])=O)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.C(Cl)(=O)C([Cl:25])=O>ClCCl.CN(C)C=O>[ClH:25].[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:18][C:19]([Cl:25])=[O:21])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1
Reactant: Cc1ccc(-c2nc3ccc(C)cn3c2CC(=O)O)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(-c2nc3ccc(C)cn3c2CC(=O)Cl)cc1
Product: Cl
Temperature: 0 °C
Reaction time: 3 h
Yield: 118.2 %

Procedure:
To a magnetically stirred solution of (6-methyl-2-p-tolyl-imidazo[1,2-a]pyridin-3-yl)-acetic acid 1a (1.0 g, 3.57 mmol) in dichloromethane (DCM) (10.0 mL) at 0° C. under Ar atmosphere were added dimethylformamide (DMF) (1 drop) and oxalyl chloride (0.467 mL, 5.35 mmol). The reaction mixture was stirred at 0° C. for 3 h, then concentrated in vacuo to provide the title compound (1.06 g, 100%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 2.42 (s, 3H), 2.52 (s, 3H), 4.70 (s, 2H), 7.38 (d, J=7.3 Hz, 2H), 7.64 (m, 3H), 8.00 (s, 1H), 8.37 (d, J=8.0 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8](=[O:12])([O:10][CH3:11])N>[Cl-].[Zn+2].[Cl-].CO>[CH3:11][O:10][C:8](=[O:12])[NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(N)=O
Reactant: Nc1ccccc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CO
Product: COC(=O)Nc1ccccc1
Temperature: 190 °C
Yield: 82.3 %

Procedure:
838 g aniline, 676 g methyl carbamate, 1442 g methanol and 30.0 g anhydrous pulverized zinc chloride were introduced into the pressure vessel. The pressure vessel and the column were then purged with nitrogen. The mixture was subsequently heated (with stirring) to 190° C., and the top valve of the column was adjusted so that the pressure in the apparatus was just sufficient for the reactants to reach the reaction temperature. Ammonia which evolved was separated from the evaporating alcohol in the column and then removed from the top of the column. The reaction mixture was stirred for 6.5 hours at 190° C., while the ammonia which evolved was removed. The mixture was then cooled and removed from the pressure vessel after the pressure in the apparatus had been reduced. The mixture was filtered and then distilled at atmospheric pressure to remove the excess methanol. The product was then fractionally distilled at 0.2 m bar. 1120 g N-phenyl-carbamic acid methyl ester (82.3% of the theoretical yield) were collected and crystallized. The product had a melting point of 45° to 46° C.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH3:18])=[CH:11][C:10]=1[N+:19]([O-])=O)=[S:7])=[O:4]>CO.O>[CH3:1][O:2][C:3]([NH:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH3:18])=[CH:11][C:10]=1[NH2:19])=[S:7])=[O:4]
Reactant: CCCCc1ccc(NC(=S)NC(=O)OC)c([N+](=O)[O-])c1
Solvent: CO
Solvent: O
Product: CCCCc1ccc(NC(=S)NC(=O)OC)c(N)c1
Yield: 82.4 %

Procedure:
1-Methoxycarbonyl-3-(4n-butyl-2-nitrophenyl)-thiourea (69.0 g; 0.22 mole) and ferrous chloride tetrahydrate (9.2 g) were finely powdered together and suspended in a mixture of methanol (350 ml) and water (70 ml). The vigorously stirred suspension was then heated to reflux and reduced iron powder (42.0 g; 0.78 mole) was added in portions during forty-five minutes. When the addition was complete, the reaction mixture was refluxed for a further thirty minutes and filtered. On cooling a crystalline solid separated from the filtrate. The dark brown filter cake was extracted with boiling methanol (3 × 200 ml) and the combined methanol extracts were evaporated to dryness to give a solid residue. This was combined with the solid obtained from the cold filtrate and the combined solids were crystallised from methanol to give 1-methoxycarbonyl-3-(2-amino-4-n-butylphenyl)thiourea (51.0 g), m.p. 157°-159° C. (with decomposition).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:14])=[C:5]([CH:9]=[C:10]([O:12][CH3:13])[CH:11]=1)[C:6]([OH:8])=O.S(Cl)([Cl:17])=O.[C:19]12([CH2:29][NH2:30])[CH2:28][CH:23]3[CH2:24][CH:25]([CH2:27][CH:21]([CH2:22]3)[CH2:20]1)[CH2:26]2>ClCCl.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[C:4]([CH3:14])=[C:5]([CH:9]=[C:10]([O:12][CH3:13])[CH:11]=1)[C:6]([NH:30][CH2:29][C:19]12[CH2:26][CH:25]3[CH2:24][CH:23]([CH2:22][C:21]([Cl:17])([CH2:27]3)[CH2:20]1)[CH2:28]2)=[O:8]
Reactant: NCC12CC3CC(CC(C3)C1)C2
Reactant: COc1cc(OC)c(C)c(C(=O)O)c1
Reactant: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(OC)c(C)c(C(=O)NCC23CC4CC(CC(Cl)(C4)C2)C3)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 3,5-dimethoxy-2-methylbenzoic acid from Example 67 a) (0.15 g) and thionyl chloride (2 ml) was heated to reflux temperature for 2 minutes before cooling to room temperature and concentratedunder reduced pressure. The residue was dissolved in dichloromethane (1 ml) and added to a solution of 1-adamantanemethylamine (0.104 g) in dichloromethane (5 ml) and triethylamine (1 ml) and the resulting reaction mixture stirred for 2 days. The reaction was partitioned between dichloromethane (100 ml) and aqueous hydrochloric acid (0.5M, 50 ml). The organic phase was washed with a saturated aqueous solution of sodium hydrogen carbonate (50 ml), dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure. The residue was purified by HPLC over a Dynamax® column eluting with iso-hexane: ethyl acetate (4:1) to give the title compound as a colourless solid (0.090 g).
Reaction SMILES: C(N(CC)CC)C.[I-].[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]2[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=2SC)=[CH:12][CH:11]=1.[Cl-].[CH3:25][O:26][NH3+:27]>C(O)C>[CH3:25][O:26][N:27]=[C:21]1[CH2:20][CH2:19][CH2:18][CH2:17][N:16]1[C:13]1[CH:14]=[CH:15][C:10]([NH2:9])=[CH:11][CH:12]=1
Reactant: CSC1=[N+](c2ccc(N)cc2)CCCC1
Reactant: CO[NH3+]
Agent: [Cl-]
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CON=C1CCCCN1c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
3.5 ml (25 mmol) of triethylamine are added to a solution of 2.68 g (12.1 mmol) of 1-(4-aminophenyl)-6-methylsulfanyl-2,3,4,5-tetrahydro-pyridinium iodide and 1.01 g (12.1 mmol) of O-methylhydroxylammonium chloride in 30 ml of ethanol, and the mixture is stirred at room temperature for 20 hours. The reaction mixture is evaporated and taken up in water, and the resultant precipitate is filtered off, giving 1-(4-aminophenyl)-piperidin-2-one O-methyl oxime as a colourless solid; ESI 220.
Reaction SMILES: C(#N)C.CS(C)=O.[CH:8]([O-:10])=O.[Na+].Br[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[C:18]([NH:23][CH3:24])[N:17]=[C:16]2[O:25][CH2:26][CH3:27]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH2:26]([O:25][C:16]1[C:15]2[C:20](=[CH:21][CH:22]=[C:13]([CH:8]=[O:10])[CH:14]=2)[N:19]=[C:18]([NH:23][CH3:24])[N:17]=1)[CH3:27]
Reactant: CCOc1nc(NC)nc2ccc(Br)cc12
Reactant: O=C[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: CS(C)=O
Product: CCOc1nc(NC)nc2ccc(C=O)cc12
Reaction time: 48 h
Yield: 30.1 %

Procedure:
To a combined solution of acetonitrile (40 mL) and DMSO (40 mL) was added tetrakis(triphenylphosphine)palladium(0) (1.65 g, 1.43 mmol), anhydrous sodium formate (5.82 g, 85.6 mmol) followed by powder (6-bromo-4-ethoxy-quinazolin-2-yl)-methyl-amine (4 g, 14.3 mmol) and the resultant mixture was heated to 85° C., 50 psi under CO atmosphere. After being stirred for 48 hours, the cooled mixture was poured to water and extracted with DCM (3×200 mL). The combined organic phase was washed with brine, dried over Na2SO4, evaporated to give a brown solid which was purified by column to afford 4-ethoxy-2-methylamino-quinazoline-6-carbaldehyde (1 g, 4.3 mmol, 30%) as a pale solid. 1H NMR (DMSO-d6): δ 9.95 (s, 1H), 8.38 (s, 1H), 8.00-7.97 (d, 1H), 7.59-7.56 (m, 1H), 7.46-7.44 (d, 1H), 4.53-4.48 (q, 2H), 2.89-2.87 (d, 3H), 1.44-1.40 (t, 3H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].Br[C:8]1[CH:13]=[CH:12][C:11]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[CH:24][N:23]=3)[CH2:18][CH2:17]2)=[O:15])=[C:10]([F:30])[CH:9]=1>>[CH3:28][C:27]1[C:22]([N:19]2[CH2:20][CH2:21][N:16]([C:14]([C:11]3[CH:12]=[CH:13][C:8]([N:1]4[CH2:5][CH2:4][CH2:3][C:2]4=[O:6])=[CH:9][C:10]=3[F:30])=[O:15])[CH2:17][CH2:18]2)=[N:23][CH:24]=[C:25]([CH3:29])[CH:26]=1
Reactant: O=C1CCCN1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCC4=O)cc3F)CC2)c(C)c1
Yield: 64.8 %

Procedure:
Using pyrrolidin-2-one (51 mg) and (4-bromo-2-fluorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (240 mg) described in Preparation Example 114 and by the reaction and treatment in the same manner as in Example 1, the title compound (154 mg) was obtained.