Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](F)=[CH:4][C:3]=1[O:9][CH3:10].[C:11](#[N:15])[CH:12]([CH3:14])[CH3:13].C[Si]([N-][Si](C)(C)C)(C)C.[K+].Cl>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]([CH3:14])([CH3:13])[C:11]#[N:15])=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: COc1cc(F)ccc1Cl
Reactant: CC(C)C#N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [K+]
Solvent: Cc1ccccc1
Product: COc1cc(C(C)(C)C#N)ccc1Cl
Temperature: 65 °C
Reaction time: 2 h
Yield: 31 %

Procedure:
1-Chloro-4-fluoro-2-methoxy-benzene (4.3 g, 26.78 mmol) and isobutyronitrile (9.61 mL, 4.0 eq.) were dissolved in toluene (9.0 mL), added with KHMDS (80 mL, 0.5 M toluene solution) and stirred at 65° C. for 2 hr. The reaction solution was cooled to room temperature, added with aqueous solution of 1 N hydrochloric acid and then extracted with MTBE. The organic layer was washed with saturated brine and dried over magnesium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (1.72 g, 31%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1[O:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]2[S:21][CH:22]=[C:23]([CH3:25])[N:24]=2)[CH:14]=1.C(N(CC)CC)C.C(Cl)(=O)OCC.[CH3:39][N:40]([CH3:44])[CH2:41][CH2:42][NH2:43].[OH-].[Na+]>CN(C=O)C>[ClH:2].[Cl:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:43][CH2:42][CH2:41][N:40]([CH3:44])[CH3:39])=[O:9])=[CH:5][C:4]=1[O:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]2[S:21][CH:22]=[C:23]([CH3:25])[N:24]=2)[CH:14]=1
Reactant: Cc1csc(Nc2cc(Oc3cc(C(=O)O)ccc3Cl)ccn2)n1
Reactant: CN(C)CCN
Agent: CCOC(=O)Cl
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1csc(Nc2cc(Oc3cc(C(=O)NCCN(C)C)ccc3Cl)ccn2)n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 28.9 %

Procedure:
A 3 dram vial was charged with 4-chloro-3-(2-(4-methylthiazol-2-ylamino)pyridin-4-yloxy)benzoic acid hydrochloride (0.100 g, 0.2511 mmol), triethylamine (0.1016 g, 1.004 mmol) and DMF (3 mL). The reaction mixture was cooled to 0° C. and ethyl carbonochloridate (0.02641 mL, 0.2762 mmol) was added. The reaction mixture was at 0° C. for 3 hours. N,N-dimethylethylenediamine (0.04427 g, 0.5022 mmol) was added and the reaction mixture was stirred at room temperature overnight, and then 2N NaOH was added. The reaction mixture was extracted with ethyl acetate, dried over magnesium sulfate, filtered and concentrated. The residue was purified using prepacked silica gel column with 50% ethyl acetate in hexanes followed by 15% (ammoniated) methanol in ethyl acetate. 2M HCl in ether was added and the resulting solids were dried over high vacuum to afford 4-chloro-N-(2-(dimethylamino)ethyl)-3-(2-(4-methylthiazol-2-ylamino)pyridin-4-yloxy)benzamide hydrochloride (0.017 g, 13.01% yield) as an off white solid. 1H NMR (DMSO) δ 11.21 (bs, 1H), 9.82 (bs, 1H), 8.95 (t, 1H), 8.24 (d, 1H), 7.90 (dd, 1H), 7.86 (d, 1H), 7.84 (d, 1H), 6.57 (m, 3H), 3.61 (q, 2H), 3.24 (q, 2H), 2.82 (s, 3H), 2.81 (s, 3H), 2.21 (d, 3H); Mass spectrum (esi) m/z=432 (100) (M+H—HCl).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:4]=1[C:5]([O:7]C)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+].[CH2:37]1COC[CH2:38]1>>[CH2:37]([CH:5]([C:4]1[C:3]([O:2][CH3:1])=[N:12][C:11]([CH3:13])=[CH:10][CH:9]=1)[OH:7])[CH3:38]
Reactant: C1CCOC1
Reactant: COC(=O)c1ccc(C)nc1OC
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Product: CCC(O)c1ccc(C)nc1OC
Temperature: 0 °C
Reaction time: 1.25 h

Procedure:
To methyl 2-methoxy-6-methylnicotinate (5.60 g, 30.9 mmol) in THF (155 mL, 30.9 mmol) to 0° C. was added lithium aluminum hydride (1.23 g, 30.9 mmol) and the mixture was stirred at 0° C. for 75 minutes. The mixture was diluted with 30 mL THF and a scoop of Celite was added. The mixture was stirred for a few minutes. Sodium sulfate decahydrate was added to quench the reaction. The mixture was filtered and the filtrate was concentrated to give the product (4.7 g).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([N:22]3[CH2:25][CH:24]([C:26]([O:28]C)=[O:27])[CH2:23]3)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.O.[Li+].[OH-]>CO>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([N:22]3[CH2:23][CH:24]([C:26]([OH:28])=[O:27])[CH2:25]3)=[O:21])[N:14]=2)[CH:4]=[C:3]([C:2]([F:1])([F:30])[F:31])[CH:8]=1
Reactant: COC(=O)C1CN(C(=O)/C=C\n2cnc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C1CN(C(=O)/C=C\n2cnc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 61.9 %

Procedure:
(Z)-methyl 1-(3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)azetidine-3-carboxylate (0.1 g, 1.0 eq.) was dissolved in methanol:water (10 mL, 1:1). LiOH (0.010 g, 1.0 eq.) was added. The reaction mixture was stirred at room temperature for 1-2 h. The reaction mixture was quenched with 10 mL water and acidified with dilute HCl until pH=2-3. The aqueous layer was extracted with ethyl acetate (10 mL×3). The organic layer was washed with brine, dried over sodium sulphate and concentrated under reduced pressure to afford 0.060 g of (Z)-1-(3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)azetidine-3-carboxylic acid (62.5% yield). 1H NMR (400 MHz, DMSO) δ=9.38 (s, 1H), 8.54 (s, 2H), 8.29 (s, 1H), 7.40-7.42 (d, J=10.4 Hz, 1H), 5.93-5.96 (d, J=10.4 Hz, 1H), 4.23-4.27 (m, 2H), 4.12-4.16 (m, 3H). LCMS calcd. for C17H13F6N4O3 [M+H]+: 435.29. Found: 435.14, at 2.55 min retention time.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].COC1C=C(OC)C=CC=1C[NH:10][CH:11]1[C:20]2[CH2:19][S:18][N:17]=[C:16]([N:21](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[C:15]3=[N:36][N:37]([CH2:39][C:40]4[C:45]([CH3:46])=[C:44]([O:47][CH3:48])[C:43]([CH3:49])=[CH:42][N:41]=4)[N:38]=[C:13]([C:14]=23)[CH2:12]1.N1C=CC=CC=1>ClCCl>[NH2:21][C:16]1[C:15]2[C:14]3[C:13](=[N:38][N:37]([CH2:39][C:40]4[C:45]([CH3:46])=[C:44]([O:47][CH3:48])[C:43]([CH3:49])=[CH:42][N:41]=4)[N:36]=2)[CH2:12][CH:11]([NH:10][C:1](=[O:3])[CH3:2])[C:20]=3[CH2:19][S:18][N:17]=1
Reactant: CC(=O)Cl
Reactant: COc1ccc(CNC2CC3=NN(Cc4ncc(C)c(OC)c4C)N=C4C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=NSCC2=C34)c(OC)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1c(C)cnc(CN2N=C3CC(NC(C)=O)C4=C3C(=N2)C(N)=NSC4)c1C
Reaction time: 3 h
Yield: 76 %

Procedure:
Acetyl chloride (18 μL) was added dropwise to a mixture composed of di-tert-butyl {8-[(2,4-dimethoxybenzyl)amino]-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-2,7,8,9-tetrahydro-6-thia-1,2,3,5-tetraazabenzo[cd]azulen-4-yl}imidodicarbonate of Example 42 (36 mg), pyridine (40 μL) and dehydrated dichloromethane (0.7 mL) under cooling in an ice bath. The ice bath was removed and the mixture was stirred for three hours. The reaction mixture was diluted with chloroform and then washed with a 0.2 N hydrochloric acid solution. The organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and dichloromethane (1 mL) and 1,3-dimethoxybenzene (12 μL) were added to the resulting residue. Then, trifluoroacetic acid (1 mL) was added and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in chloroform and sequentially washed with a saturated sodium bicarbonate solution and brine. The organic layer was dried over anhydrous sodium sulfate and filtered. Then, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel thin-layer chromatography (chloroform-methanol) to obtain the title compound (15.6 mg, 76%) as a solid.
Reaction SMILES: [C:1]([OH:7])(=[O:6])[C:2]#[C:3][CH2:4][CH3:5].C1(N=C=NC2CCCCC2)CCCCC1.O[N:24]1[C:29](=[O:30])[C:28]2[CH:31]=[CH:32][CH:33]=[CH:34][C:27]=2[N:26]=[N:25]1>C1COCC1>[O:30]=[C:29]1[N:24]([O:6][C:1](=[O:7])[CH2:2][CH2:3][C:4]#[CH:5])[N:25]=[N:26][C:27]2[CH:34]=[CH:33][CH:32]=[CH:31][C:28]1=2
Reactant: CCC#CC(=O)O
Reactant: O=c1c2ccccc2nnn1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: C#CCCC(=O)On1nnc2ccccc2c1=O
Temperature: -10 °C
Reaction time: 1 h

Procedure:
Pentynoic acid (200 mg, 2.04 mmol) was dissolved in THF (4 mL). The solution was cooled in a brine-icewater bath. A solution of dicyclohexylcarbodiimide (421 mg, 2.04 mmol) in THF (2 mL) was added. 3-Hydroxy-1,2,3-benzotriazin-4(3H)-one (333 mg, 2.04 mmol) was added after 5 minutes. The reaction mixture was stirred 1 h at −10° C. and then 2 h at room temperature. TLC indicated full conversion of 3-hydroxy-1,2,3-benzotriazin-4(3H)-one (eluent: ethyl acetate). Precipitated salts were filtered off. The filtrate was concentrated in vacuo and crystallized from hexane (4 mL). The crystals were filtered off and dried. Yield: 450 mg, 93%. RF=0.8 (ethyl acetate).
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[C:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1.[H-].[Na+].Br[CH2:20][CH2:21][CH2:22][O:23][CH3:24].O>CN(C)C=O>[CH3:24][O:23][CH2:22][CH2:21][CH2:20][N:1]1[C:9]2[CH:8]=[C:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1
Reactant: CC(C)(C)OC(=O)c1cc2[nH]ccc2cn1
Reactant: COCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCCn1ccc2cnc(C(=O)OC(C)(C)C)cc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94.7 %

Procedure:
To a solution of tert-butyl 1H-pyrrolo[3,2-c]pyridine-6-carboxylate (2.0 g) in N,N-dimethylformamide (15 mL) was added drop by drop 60% oil-based sodium hydride (385 mg) under ice-cooling, and then the mixture was stirred at room temperature for 15 minutes. Then, thereto was added dropwise a solution of 1-bromo-3-methoxypropane (1.47 g) in N,N-dimethylformamide (5 mL) under ice-cooling, and then the mixture was stirred at room temperature for 18 hours. To the reaction mixture was added water under ice-cooling, and the mixture was extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/1) to give tert-butyl 1-(3-methoxypropyl)-1H-pyrrolo[3,2-c]pyridine-6-carboxylate [REx(25-1)] (2.52 g) as a yellow oil.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([CH3:11])[CH3:10].[Mg].CN(C)[CH:15]=[O:16]>C(OCC)C>[CH:9]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=1[CH:15]=[O:16])([CH3:11])[CH3:10]
Reactant: CN(C)C=O
Reactant: Cc1cccc(C(C)C)c1Br
Agent: [Mg]
Solvent: CCOCC
Product: Cc1cccc(C(C)C)c1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 33 %

Procedure:
To a solution of 1-bromo-2-isopropyl-6-methylbenzene (6.9 g, 32.4 mmol) in diethyl ether (50 ml) was added magnesium turnings (0.9 g, 37 mmol) and the mixture was refluxed in nitrogen atmosphere until the reaction was started and was then stirred overnight at room temperature. Dimethylformamide (4 ml) was added dropwise during 10 min. and the mixture was stirred for 30 min. Saturated ammmoniumchloride solution (30 ml) was added and the mixture was stirred for 1 h. The organic layer was separated, filtrated and evaporated under reduced pressure. Purification by column chromatography on silica gel using hexane:methylene chloride (3:2) as eluent gave 1.75 g (33%) of the title compound .
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].O[N:11]1C(=O)C2=CC=CC=C2C1=O>>[NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][O:5][NH2:11]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: Nc1ccccc1CO
Product: NOCc1ccccc1N

Procedure:
Prepared by a similar procedure as described for preparation 31 starting from 2-amino-benzylalcohol and N-hydroxyphthalimide. 13C-NMR (CDCl3) δ 146.4, 131.2, 129.7, 121.4, 118.1, 115.9, 76.6.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[F:32])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([O:26][CH3:27])[C:10](=[O:25])[N:11]3[CH2:21][CH2:20][CH:19]([OH:22])[CH2:18][N:17]([CH3:23])[C:16](=[O:24])[C:12]3=2)[C:7]1=[O:28].C[N+]1([O-])CCOCC1>ClCCl.[Ru+3].C([N+](CCC)(CCC)CCC)CC>[Cl:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[F:32])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([O:26][CH3:27])[C:10](=[O:25])[N:11]3[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][N:17]([CH3:23])[C:16](=[O:24])[C:12]3=2)[C:7]1=[O:28]
Reactant: COc1c2c(c3n(c1=O)CCC(O)CN(C)C3=O)CCN(Cc1ccc(F)c(Cl)c1)C2=O
Agent: [Ru+3]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: COc1c2c(c3n(c1=O)CCC(=O)CN(C)C3=O)CCN(Cc1ccc(F)c(Cl)c1)C2=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 11-(3-chloro-4-fluorobenzyl)-4-hydroxy-9-methoxy-2-methyl-3,4,5,6,12,13-hexahydro-2H[1,4]diazocino[2,1-a]-2,6-naphthyridine-1,8,10(11H)-trione (50 mg, 0.11 mmol), molecular sieves (4A), N-methylmorpholine N-oxide (19 mg, 0.16 mmol), and tetra-n-propylammonium ruthenium tetroxide in dichloromethane was stirred at room temperature for two hrs. The mixture was filtered, and the filtrate concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 0-15% methanol in dichloromethane gradient. Collection and concentration of appropriate fractions provided the title compound.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]1[S:13][C:14]([C:17](=[O:25])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])=[CH:15][N:16]=1)(C)(C)C.Cl.C(=O)(O)[O-].[Na+]>C(OCC)C>[NH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]1[S:13][C:14]([C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])=[O:25])=[CH:15][N:16]=1
Reactant: Cc1ccccc1C(=O)c1cnc(NCCCNC(=O)OC(C)(C)C)s1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: Cc1ccccc1C(=O)c1cnc(NCCCN)s1
Yield: 87.7 %

Procedure:
900 mg {3-[5-(2-Methyl-benzoyl)-thiazol-2-ylamino]-propyl}-carbamic acid tert-butyl ester was dissolved in diethyl ether and hydrogen chloride in ether added dropwise with stirring. The mixture was stirred overnight at room temperature and poured into saturated aqueous sodium bicarbonate solution. The organics were extracted with dichloromethane (3×25 ml), dried over magnesium sulfate and evaporated under reduced pressure to afford [2-(3-Amino-propylamino)-thiazol-5-yl]-o-tolyl-methanone as a yellow gum (579 mg, 88%). A solution of 0.22 ml tert-butanol in hexane (2 ml) was cautiously added to a stirred solution of 0.2 ml chlorosulfonyl isocyanate in hexane (5 ml). The resulting white precipitate was stirred until it had dissolved (1.5 h) and the mixture cooled to −78° C. before the slow addition of a solution of [2-(3-Amino-propylamino)-thiazol-5-yl]-o-tolyl-methanone and 0.4 ml triethylamine in dichloromethane. The cooling bath was removed and the yellow mixture allowed to reach room temperature and stirred 2 h at room temperature. The mixture was poured into water and the organics extracted with ethyl acetate (2×25 ml). The combined organics were washed with brine, dried over magnesium sulfate and evaporated. The resulting oil was purified by column chromatography on silica gel (150 g, 2:1 ethyl acetate/hexane) to afford the title compound (241 mg, 24%) as a pale yellow oil. MS (m/e): 409.3 (M−H, 100%)
Reaction SMILES: C(O)C(C)C.[O:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[C:11]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:12].[NH2:19][C:20]1[C:29]2[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=2)[N:23]=[C:22](Cl)[N:21]=1>O>[CH3:31][O:30][C:27]1[CH:28]=[C:29]2[C:20]([NH2:19])=[N:21][C:22]([N:16]3[CH2:15][CH2:14][N:13]([C:11]([CH:7]4[O:6][CH2:10][CH2:9][CH2:8]4)=[O:12])[CH2:18][CH2:17]3)=[N:23][C:24]2=[CH:25][C:26]=1[O:32][CH3:33]
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Reactant: O=C(C1CCCO1)N1CCNCC1
Solvent: O
Solvent: CC(C)CO
Product: COc1cc2nc(N3CCN(C(=O)C4CCCO4)CC3)nc(N)c2cc1OC
Temperature: 25 °C
Yield: 109.2 %

Procedure:
To a solution of iso-butanol (306 ml), water (34 ml) and N-(2-tetrahydrofuroyl)piperazine (20 g) were added, while stirring, 4-amino-2-chloro-6,7-dimethoxyquinazoline (22.2 g). The reaction mixture was heated to reflux and the reflux was maintained for about 13 hours. Then the reaction mixture was cooled to room temperature and stirred at this temperature for about 12 hours. The crystals were collected by filtration, washed with iso-butanol and dried in vacuo at 40° C. to yield 39.2 g (91.9%) of Terazosin.HCl dihydrate. See Trial A in Table I.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[S:5][CH:6]=[C:7](/[C:9](=[N:15]/[OH:16])/[C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:8]=1.[C:17](Cl)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1>[NH2:3][C:4]1[S:5][CH:6]=[C:7](/[C:9](=[N:15]/[O:16][C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)/[C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:8]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)/C(=N\O)c1csc(N)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)/C(=N\OC(c1ccccc1)(c1ccccc1)c1ccccc1)c1csc(N)n1

Procedure:
Sodium hydride (60% dispersion in mineral oil, 13.2 g, 0.33 mol) was added portionwise to a cold (0° C.) mixture of ethyl (Z)-(2-aminothiazol-4-yl)-2-hydroxyiminoacetate (64.5 g, 0.3 mol) in dry THF (1 L) with vigorous stirring and the mixture was stirred for 0.5 hr. at room temperature. To the mixture was added a solution of trityl chloride (92.0 g, 0.33 mol) in dry THF (0.2 L) with cooling and stirring. The mixture was stirred for 2 hr. at ambient temperature and evaporated under reduced pressure. Chloroform (1 L) was added to the residue and the mixture was washed with water. The insoluble material was filtered and the organic layer of the filtrate was separated. The insoluble material was extracted again with a mixture of chloroform (300 ml) and methanol (50 ml) by sonication for 10 min. and subsequent filtration. The extract was combined with the separated organic layer and evaporated under reduced pressure. The residue was triturated with toluene (0.3 L) to crystallize the product as colorless prisms, which were collected by filtration, washed with a small toluene and dried in vacuo. Yield, 91.2 g (66%). The filtrate was evaporated and treated with toluene to give 19.2 g of the second crop.
Reaction SMILES: [CH2:1]([CH:5]1[NH:14][C:13](=[O:15])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH:16]=[O:17])[CH:11]=2)[NH:6]1)[CH2:2][CH2:3][CH3:4].[C:18]1([Li])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCCC1>[CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([CH:16]([OH:17])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4]
Reactant: [Li]c1ccccc1
Reactant: CCCCC1NC(=O)c2cc(C=O)ccc2N1
Solvent: C1CCOC1
Product: CCCCc1nc(=O)c2cc(C(O)c3ccccc3)ccc2[nH]1
Reaction time: 1 h

Procedure:
To a stirred solution of 2.00 g of 2-butyl-1,2-dihydro-4-oxo-6-quinazolinecarboxaldehyde in 100 ml of tetrahydrofuran, cooled at 0° C., is added 13.0 ml of 2.0 M phenyllithium and stirring continued for 1 hour. The cooling is removed and the reaction allowed to reach room temperature followed by an additional 30 minutes at room temperature. The reaction is diluted with saturated ammonium chloride solution and extracted with ethyl acetate. The organic layer is dried, evaporated to a residue, which is purified by chromatography on silica gel by elution with 0.25:100 methanol-chloroform to give 0.932 g of the desired product. CI MASS SPEC 309(MH+).
Reaction SMILES: [CH3:1][CH:2]([CH3:34])[CH2:3][C@H:4]([N:23]1[C:31](=[O:32])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]1=[O:33])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:20]3[C:15](=[CH:16][N:17]=[CH:18][CH:19]=3)[CH:14]([CH:21]=[CH2:22])[O:13][C:11]=2[CH:12]=1>CO.[Pd]>[CH2:21]([CH:14]1[C:15]2=[CH:16][N:17]=[CH:18][CH:19]=[C:20]2[C:10]2[CH:9]=[CH:8][C:7]([O:6][CH2:5][C@@H:4]([N:23]3[C:31](=[O:32])[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:24]3=[O:33])[CH2:3][CH:2]([CH3:34])[CH3:1])=[CH:12][C:11]=2[O:13]1)[CH3:22]
Reactant: C=CC1Oc2cc(OC[C@H](CC(C)C)N3C(=O)c4ccccc4C3=O)ccc2-c2ccncc21
Agent: [Pd]
Solvent: CO
Product: CCC1Oc2cc(OC[C@H](CC(C)C)N3C(=O)c4ccccc4C3=O)ccc2-c2ccncc21
Yield: 33.5 %

Procedure:
To a stirred solution of 2-((2S)-4-methyl-1-((5-vinyl-5H-chromeno[3,4-c]pyridin-8-yl)oxy)pentan-2-yl)isoindoline-1,3-dione (0.3 g, 0.660 mmol) in methanol (15 mL) was added 10% palladium on carbon (0.070 g, 0.660 mmol). The resultant mixture was stirred at room temperature under a hydrogen atmosphere (1 atm) for 12 h. The reaction mixture was then filtered through celite and concentrated under reduced pressure to yield crude 2-((2S)-1-(5-ethyl-5H-chromeno[3,4-c]pyridin-8-yloxy)-4-methylpentan-2-yl)isoindoline-1,3-dione (0.28 g, 0.221 mmol, 33% crude yield); LCMS (ESI) m/e 457.2 [(M+H)+, calcd for C28H29N2O4 457.2]; LC/MS retention time (Method C): tR=2.32 min.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][CH2:10][CH:11]([CH3:13])[CH3:12].[CH:14]([C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1)=[O:15]>N1C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:10][CH:11]([CH3:13])[CH3:12])[S:22]([C:19]1[CH:18]=[CH:17][C:16]([CH:14]=[O:15])=[CH:21][CH:20]=1)(=[O:24])=[O:23]
Reactant: Cc1ccc(NCC(C)C)c(C)c1
Reactant: O=Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(C=O)cc2)c(C)c1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 101.9 %

Procedure:
To a solution of (2,4-dimethylphenyl)(2-methylpropyl)amine (400 mg, 2.256 mmol) in pyridine (5 mL), stirred in air at room temperature, was added 4-formylbenzene-1-sulfonyl chloride (760 mg, 3.71 mmol) in one charge. The reaction mixture was stirred at 20° C. for 30 minutes, then left to stand 6 hours. The solvent was removed in vacuo and the crude material purified by flash (Si) chromatography (using a 0-25% ethyl acetate-cyclohexane gradient). The appropriate fractions were combined and evaporated in vacuo to give the required product (794 mg) as a colourless gum. LCMS (M+1) 346, RT 1.33 mins.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:13]=3[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH:20]1[C:25]([C:26]([OH:28])=[O:27])=[CH:24][C:23]2[C:29]([O:31][C:32](=O)[C:22]=2[CH:21]=1)=[O:30]>>[CH3:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:13]=3[N:14]=2)=[CH:3][C:2]=1[N:1]1[C:29](=[O:30])[C:23]2[C:22](=[CH:21][CH:20]=[C:25]([C:26]([OH:28])=[O:27])[CH:24]=2)[C:32]1=[O:31]
Reactant: COc1ccc(-c2nc3cc(Cl)ccc3o2)cc1N
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Product: COc1ccc(-c2nc3cc(Cl)ccc3o2)cc1N1C(=O)c2ccc(C(=O)O)cc2C1=O

Procedure:
Prepared by the method of Example 1b), from 2-(3-amino-4-methoxyphenyl)-5-chlorobenzoxazole (63 mg, 0.23 mmol) and 1,2,4-benzenetricarboxylic anhydride (50 mg, 0.26 mmol) the title compound was obtained, 62 mg (60%). 1H NMR (DMSO) δ 8.45(dd, 1H), 8.33(m, 3H), 8.12(d, 1H), 7.89(d, 1H), 7.80(d, 1H), 7.47(m, 2H), 3.89(s, 3H). MS 447 m/z (M−H)−.
Reaction SMILES: C([O:3][C:4](=O)[NH:5][C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][C:7]=1[C:13]#[N:14])C.[CH3:16][O:17][CH2:18][C:19]([NH:21][NH2:22])=O>>[Br:12][C:9]1[CH:10]=[CH:11][C:6]2[NH:5][C:4](=[O:3])[N:22]3[N:21]=[C:19]([CH2:18][O:17][CH3:16])[N:14]=[C:13]3[C:7]=2[CH:8]=1
Reactant: CCOC(=O)Nc1ccc(Br)cc1C#N
Reactant: COCC(=O)NN
Product: COCc1nc2c3cc(Br)ccc3[nH]c(=O)n2n1
Yield: 92 %

Procedure:
As described for example 1a) (4-bromo-2-cyano-phenyl)-carbamic acid ethyl ester (19.9 g, 74.2 mmol) instead of (4-chloro-2-cyano-phenyl)-carbamic acid ethyl ester using methoxymethyl-carboxylic acid hydrazide instead of cyclopropane-carboxylic acid hydrazide, was converted to the title compound (21.1 g, 92%) which was obtained as a light yellow solid. MS: m/e=308.9/310.9 [M+H]+.