Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:20]([OH:22])=[O:21])[C:10]2[C:9]([C:11]([OH:13])=[O:12])=[CH:8][CH:7]=[C:6]([C:14]([OH:16])=[O:15])[C:5]=2[C:4]([C:17](O)=[O:18])=[CH:3][CH:2]=1.C(N(CC)CC)C.[NH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(O)(=O)C>O>[C:31]1([N:30]=[C:17]([C:4]2[C:5]3[C:6]([C:14]([OH:16])=[O:15])=[CH:7][CH:8]=[C:9]([C:11]([OH:13])=[O:12])[C:10]=3[C:1]([C:20]([OH:22])=[O:21])=[CH:2][CH:3]=2)[OH:18])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(O)c1ccc(C(=O)O)c2c(C(=O)O)ccc(C(=O)O)c12
Reactant: Nc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: O=C(O)c1ccc(C(=O)O)c2c(C(O)=Nc3ccccc3)ccc(C(=O)O)c12
Temperature: 25 °C
Yield: 83 %

Procedure:
53.6 g of naphthalene-1,4,5,8-tetracarboxylic acid dianhydride (0.2 mol) or 60.8 g of naphthalene-1,4,5,8-tetracarboxylic acid (0.2 mol) are dissolved in 1 l of water at 90° C. with addition of 84 g of triethylamine (0.9 mol), treated with 18.6 g of aniline (0.2 mol) with stirring and adjusted to pH 6 by dropwise addition of about 20 ml of glacial acetic acid at 90° C. The mixture is stirred for about 8 hours at 90° C., the pH value being maintained between 7 and 6 by further dropwise addition of glacial acetic acid (6 ml in total). The mixture is cooled to room temperature, a few undissolved components are filtered off, and the filtrate is adjusted to pH 1 by dropwise addition of about 160 ml of concentrated hydrochloric acid. The crystalline precipitate is filtered off by suction, washed with water until the washings have pH 5, and dried at 70° C. in vacuo. 63 g (87% of theory) of naphthalene-1,4,5,8-tetracarboxylic acid monophenylimide are obtained as an almost colourless crystalline powder of melting point >300° C.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](O)=[O:11])=[CH:5][CH:4]=1.S(Cl)([Cl:17])=O>>[F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([Cl:17])=[O:11])=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1
Product: O=C(Cl)Cc1ccc(C(F)(F)F)cc1
Temperature: 100 °C

Procedure:
Under an argon atmosphere, to 4-trifluoromethylphenylacetic acid (51) (817 mg, 4.00 mmol) was added thionyl chloride (5.00 mL, 68.9 mmol), and heated to reflux (100° C.) for 1.5 h. After cooling to room temperature, the mixture was concentrated under reduced pressure to give 4-trifluoromethylphenylacetyl chloride (52) as a brown oily crude product, which was used in the next reaction without further purification.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][C:6]#[N:7])C.[NH2:11][C:12]1[CH:19]=[C:18]([Br:20])[CH:17]=[CH:16][C:13]=1[CH:14]=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:20][C:18]1[CH:19]=[C:12]2[C:13]([CH:14]=[C:5]([C:6]#[N:7])[CH:4]=[N:11]2)=[CH:16][CH:17]=1
Reactant: CCOC(CC#N)OCC
Reactant: Nc1cc(Br)ccc1C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: N#Cc1cnc2cc(Br)ccc2c1
Yield: 75.1 %

Procedure:
A mixture of 3,3-diethoxypropanenitrile (1.80 mL, 12.00 mmol), 2-amino-4-bromobenzaldehyde (2 g, 10.00 mmol) and p-toluenesulfonic acid monohydrate (0.380 g, 2.000 mmol) in toluene (30 mL) was heated under reflux using Dean-Stark apparatus for 3 h. The reaction was cooled, evaporated under reduced pressure, and the residue was dissolved in a small amount of DMF, diluted with chloroform, and washed with aq. sodium bicarbonate solution. The aqueous layer was extracted with chloroform, and the combined extracts were washed with brine, dried (Na2SO4), and concentrated in vacuo. Purification by flash chromatography (0-3% methanol in dichloromethane) followed by trituration in diethyl ether provided the title compound (1.75 g, 75%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.95 (dd, J=8.72, 1.89 Hz, 1 H) 8.08 (d, J=8.84 Hz, 1 H) 8.38 (d, J=2.02 Hz, 1 H) 9.13 (d, J=1.52 Hz, 1 H) 9.21 (d, 1 H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([NH2:8])[CH2:4][CH2:3]1.[CH2:9]([O:11][C:12]([C:14]1[C:19]([O:20][CH2:21][CH3:22])=[C:18]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:17]=[C:16]([C:29]2[CH:34]=[CH:33][C:32]([NH:35][C:36](OC3C=CC=CC=3)=[O:37])=[CH:31][CH:30]=2)[N:15]=1)=[O:13])[CH3:10].CCN(CC)CC>O1CCOCC1>[CH2:9]([O:11][C:12]([C:14]1[C:19]([O:20][CH2:21][CH3:22])=[C:18]([N:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)[N:17]=[C:16]([C:29]2[CH:30]=[CH:31][C:32]([NH:35][C:36]([NH:8][N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)=[O:37])=[CH:33][CH:34]=2)[N:15]=1)=[O:13])[CH3:10]
Reactant: CN1CCN(N)CC1
Reactant: CCOC(=O)c1nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)nc(N2CCOCC2)c1OCC
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1nc(-c2ccc(NC(=O)NN3CCN(C)CC3)cc2)nc(N2CCOCC2)c1OCC
Yield: 45 %

Procedure:
4-methyl-piperazin-1-ylamine (0.52 ml, 2 eq.) was added to a stirred solution of 5-ethoxy-6-morpholin-4-yl-2-(4-phenoxycarbonylamino-phenyl)-pyrimidine-4-carboxylic acid ethyl ester (100 mg, 1 eq.) and Et3N (0.085 ml, 3 eq.) in dioxane (3 ml), the mixture was reacted at 80° C. overnight. The reaction mixture was concentrated, and purified by flash chromatography to give a product (49.2 mg, 45%).
Reaction SMILES: Cl[C:2](=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH2:9][C:10]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:11]=1[C:12]([NH2:14])=[O:13]>N1C=CC=CC=1>[Cl:19][C:16]1[CH:15]=[C:11]2[C:10](=[CH:18][CH:17]=1)[NH:9][C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[N:14][C:12]2=[O:13]
Reactant: NC(=O)c1cc(Cl)ccc1N
Reactant: CCOC(=O)C(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1nc(=O)c2cc(Cl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Ethyl chlorooxoacetate (2.0 ml) was added to a solution of 2-amino-5-chlorobenzamide (2.50 g) in pyridine (15 ml), and the mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, and the resultant residue was dissolved in acetic acid (50 ml). Acetic anhydride (5.0 ml) was added to the solution, and the mixture was heated under reflux for 16 hours. The solvent was distilled off under reduced pressure, and ethanol was added to the residue. Crystals deposited were collected by filtration and washed to obtain the title compound (2.71 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH:9]([NH:12][C:13]3[O:14][CH2:15][C:16]4[CH:22]=[C:21]([NH2:23])[CH:20]=[CH:19][C:17]=4[N:18]=3)[CH2:10][O:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.[N:24]1([S:30](Cl)(=[O:32])=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH3:1][O:2][C:3]1[C:8]2[CH:9]([NH:12][C:13]3[O:14][CH2:15][C:16]4[CH:22]=[C:21]([NH:23][S:30]([N:24]5[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]5)(=[O:32])=[O:31])[CH:20]=[CH:19][C:17]=4[N:18]=3)[CH2:10][O:11][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2c1C(NC1=Nc3ccc(N)cc3CO1)CO2
Reactant: O=S(=O)(Cl)N1CCCCC1
Product: COc1cccc2c1C(NC1=Nc3ccc(NS(=O)(=O)N4CCCCC4)cc3CO1)CO2
Yield: 47.6 %

Procedure:
Prepared from rac-N2-(4-methoxy-2,3-dihydro-benzofuran-3-yl)-4H-benzo[d][1,3]oxazine-2,6-diamine (Example 6) (100 mg, 0.321 mmol) and piperidine-1-sulfonyl chloride (65 mg, 0.353 mmol) according to the procedure described for Example 27. Obtained the title compound as a light red foam (70 mg, 48%), MS (ISP) m/e=459.3 [(M+H)+].
Reaction SMILES: O[CH:2]([C:4]1[CH:21]=[CH:20][C:7]2/[C:8](=[CH:17]/[C:18]#[N:19])/[C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[CH2:11][CH2:12][C:6]=2[CH:5]=1)[CH3:3].[CH2:22]([C:24]1[NH:34][C:27]2=[N:28][C:29]([CH3:33])=[CH:30][C:31]([CH3:32])=[C:26]2[N:25]=1)[CH3:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[CH2:22]([C:24]1[N:34]([CH:2]([C:4]2[CH:21]=[CH:20][C:7]3/[C:8](=[CH:17]/[C:18]#[N:19])/[C:9]4[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=4[CH2:11][CH2:12][C:6]=3[CH:5]=2)[CH3:3])[C:27]2=[N:28][C:29]([CH3:33])=[CH:30][C:31]([CH3:32])=[C:26]2[N:25]=1)[CH3:23]
Reactant: CCc1nc2c(C)cc(C)nc2[nH]1
Reactant: CC(O)c1ccc2c(c1)CCc1ccccc1/C2=C\C#N
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCc1nc2c(C)cc(C)nc2n1C(C)c1ccc2c(c1)CCc1ccccc1/C2=C\C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.6 %

Procedure:
[step 3] (E)-[2-(1-Hydroxyethyl)-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene]acetonitrile (100 mg, 0.36 mmol) obtained in step 2 and 2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine (193 mg, 1.10 mmol) were dissolved in THF (1.5 mL), polymer-supported triphenylphosphine (734 mg, 15 mmol) and di-tert-butyl azodicarboxylate (70 mg, 0.305 mmol) were added, and the mixture was stirred at room temperature for 1 hr. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=40/60 to 30/70) to give (E)-{2-[1-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)ethyl]-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene}acetonitrile (71 mg, 45%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@H:11]2[C@@H:15]([OH:16])[C@H:14]([OH:17])[CH2:13][S:12]2)=[C:4](Cl)[N:3]=1.[F:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23][NH2:24]>C(O)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@H:11]2[C@H:15]([OH:16])[C@H:14]([OH:17])[CH2:13][S:12]2)=[C:4]([NH:24][CH2:23][C:22]2[CH:25]=[CH:26][CH:27]=[C:20]([F:19])[CH:21]=2)[N:3]=1
Reactant: O[C@H]1[C@H](O)CS[C@H]1n1cnc2c(Cl)nc(Cl)nc21
Reactant: NCc1cccc(F)c1
Solvent: CCO
Product: O[C@@H]1[C@H](O)CS[C@H]1n1cnc2c(NCc3cccc(F)c3)nc(Cl)nc21
Yield: 80 %

Procedure:
(2R,3S,4S)-2-(2,6-dichloro-9H-purin-9-yl)tetrahydrothiophen-3,4-diol (1 equivalent), prepared in Step 2, and 3-fluorobenzylamine (1.5 equivalents) were dissolved in ethanol (5 ml) at room temperature for 2-3 hrs with stirring. The reaction mixture was concentrated in a vacuum and the concentrate was purified through silica gel column chromatography using a mixture of dichloromethane:methanol (20:1, v/v) as an elution solvent to afford the object compound (0.10 g, 80%).
Reaction SMILES: C1C=CC2N(O)N=[N:7]C=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.CCN(C(C)C)C(C)C.C(OC([N:40]1[CH2:45][CH2:44][CH:43]([C:46]2[CH:51]=[CH:50][C:49]([NH:52][C:53]3[N:58]=[C:57]([CH2:59][CH2:60][C:61]4[CH:66]=[CH:65][CH:64]=[CH:63][C:62]=4[CH2:67][C:68]([OH:70])=O)[C:56]([O:71][CH3:72])=[CH:55][N:54]=3)=[CH:48][CH:47]=2)[CH2:42][CH2:41]1)=O)(C)(C)C.C(=O)([O-])[O-].[NH4+].[NH4+]>C1COCC1.CN(C=O)C>[CH3:72][O:71][C:56]1[C:57]([CH2:59][CH2:60][C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][C:62]=2[CH2:67][C:68]([NH2:7])=[O:70])=[N:58][C:53]([NH:52][C:49]2[CH:50]=[CH:51][C:46]([CH:43]3[CH2:42][CH2:41][NH:40][CH2:45][CH2:44]3)=[CH:47][CH:48]=2)=[N:54][CH:55]=1
Reactant: COc1cnc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)nc1CCc1ccccc1CC(=O)O
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cnc(Nc2ccc(C3CCNCC3)cc2)nc1CCc1ccccc1CC(N)=O
Temperature: 25 °C
Reaction time: 66 h

Procedure:
HOBt (0.032 g, 0.24 mmol), EDCl.HCl (0.045 g, 0.24 mmol) and DIPEA (0.16 mL, 0.91 mmol) were added to a solution of 2-(2-(2-(2-((4-(1-(tert-butoxycarbonyl)piperidin-4-yl)phenyl)amino)-5-methoxypyrimidin-4-yl)ethyl)phenyl)acetic acid (A101) (0.099 g, 0.18 mmol) in dry THF (6 mL) and dry DMF (1 mL) under nitrogen. After 10 minutes ammonium carbonate (0.087 g, 0.91 mmol) was added in one portion and the resulting mixture was stirred at room temperature for 66 hours. The volatiles were removed in vacuo and the residue partitioned between EtOAc (50 mL) and saturated aqueous NaHCO3 (50 mL). The aqueous layer was extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine (50 mL) and dried over MgSO4. The solvent was removed in vacuo and the residue purified by silica gel column chromatography (Biotage Isolera, 24 g SiO2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C. followed by 0-20% MeOH in EtOAc) to give the title compound A102 as a clear oil (0.094 g, 92%); 1H NMR (400 MHz, d4-MeOH) δ 8.00 (s, 1H), 7.53 (d, J=8.6 Hz, 2H), 7.22 (dd, J=7.0, 3.8 Hz, 1H), 7.20-7.13 (m, 3H), 7.10 (d, J=8.6 Hz, 2H), 4.18 (d, J=13.0 Hz, 2H), 3.78 (s, 3H), 3.65 (s, 2H), 3.10-3.00 (m, 2H), 3.00-2.92 (m, peak obscured, 2H), 2.90-2.71 (m, peak obscured, 2H), 2.62 (tt, J=11.9, 3.2 Hz, 1H), 1.78 (d, J=12.2 Hz, 2H), 1.60-1.49 (m, 2H), 1.47 (s, 9H). LCMS-A: rt 6.20 min; m/z 546.4 [M+H]+.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1([NH:11][C:12](=[O:14])[CH3:13])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:15](Cl)([CH3:18])([CH3:17])[CH3:16].Cl>ClCCCl>[C:15]([C:8]1[CH:9]=[CH:10][C:5]([NH:11][C:12](=[O:14])[CH3:13])=[CH:6][CH:7]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(=O)Nc1ccccc1
Reactant: CC(C)(C)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(=O)Nc1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Yield: 86.2 %

Procedure:
A reactor was charged with 1,2-dichloroethane (50 L), followed by aluminum chloride (6.08 kg, 45.6 mol), The mixture was stirred for ten minutes at room temperature and then cooled to 5° C. N-phenylacetamide (5 kg, 37.0 mol) was added slowly, after which the mixture was cooled to −12° C. A solution of t-butylchloride (5.03 kg, 54.3 mol) in 1,2-dichloroethane (5 L) was added to the reaction over ten minutes and then stirred for 1 hour at that temperature. The reaction mixture was added to ice water (50 L) and concentrated hydrochloric acid (2.5 L) at 5-10° C., over one hour. The mixture was heated slowly to 40° C., held at that temperature for thirty minutes and the layers then allowed to separate. The aqueous was extracted further with dichloroethane (50 L) and the combined extracts concentrated, under vacuum, to low volume. Hexane (5 L) was added and the mixture concentrated in vacuo. The residue was slurried with hexane (25 L), cooled to 5° C. and stirred for thirty minutes. The solids were isolated by filtration and dried at room temperature to provide 6.1 kg of the title compound.
Reaction SMILES: [C:1]([Si:5]([CH3:24])([CH3:23])[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[N:21][OH:22])[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].C1COCC1.C([Li])CCC.[CH3:35][O:36][C:37]([C:39]1([C:42](OC)=[O:43])[CH2:41][CH2:40]1)=[O:38]>CCCCCC>[CH3:35][O:36][C:37]([C:39]1([C:42]2([OH:43])[O:22][N:21]=[C:13]([C:10]3[CH:11]=[CH:12][C:7]([O:6][Si:5]([C:1]([CH3:2])([CH3:4])[CH3:3])([CH3:24])[CH3:23])=[CH:8][CH:9]=3)[CH:14]2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:41][CH2:40]1)=[O:38]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C(Cc2ccccc2)=NO)cc1
Reactant: COC(=O)C1(C(=O)OC)CC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(=O)C1(C2(O)ON=C(c3ccc(O[Si](C)(C)C(C)(C)C)cc3)C2c2ccccc2)CC1
Temperature: -9 °C
Reaction time: 0.05 h

Procedure:
An oven-dried 1 L three-neck flask equipped with magnetic stir bar, nitrogen gas inlet valve, and digital thermometer probe, and addition funnel had been charged with 1-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-2-phenyl-ethanone oxime (Compound B, 26.6 g) and anhydrous THF (140 mL.) The reaction vessel is submerged in an ice-methanol bath equipped with a thermometer reading −18° C. The internal solution temperature is cooled to −9.0° C. A solution consisting of 2.5 M n-butyllithium in hexane (31 mL, 78 mmol) is added dropwise over 25 minutes (bath temperature −18 to −16° C., internal mixture temperature −9.0 to −0.6° C.), over which time the solution color turned from yellow after addition of the first few drops to orange at the first endpoint. The reaction mixture is stirred for three minutes as the internal mixture temperature cooled to −3.3° C. (bath temperature −14° C.) Another 31 mL of 2.5 M n-butyllithium in hexane is added over 11 minutes (bath temperature −14 to −16° C., internal mixture temperature −3.3 to −0.3° C. with a peak temperature in that time period of +0.2° C.) The reaction mixture is stirred for 31 minutes as the internal mixture temperature cooled to −10.1° C. (bath temperature −14° C.) Cyclopropane-1,1-dicarboxylic acid dimethyl ester (26.0 mL) is added over less than one minute to give an internal mixture temperature of +4.6° C. (bath temperature −13° C.) The reaction mixture is stirred for one hour and is quenched with the addition of brine solution (100 mL.) The layers are separated and the organic phase is dried over anhydrous magnesium sulfate and is concentrated under reduced pressure to afford an oil (59.9 g.) The product is purified by flash silica gel column chromatography to afford the foam product (24.0 g.)
Reaction SMILES: O=[C:2]1[CH2:6][CH2:5][O:4][CH2:3]1.[C:7]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:10])[NH:8][NH2:9]>CO>[O:4]1[CH2:5][CH2:6][C:2](=[N:9][NH:8][C:7]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:3]1
Reactant: NNC(=O)OCc1ccccc1
Reactant: O=C1CCOC1
Solvent: CO
Product: O=C(NN=C1CCOC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 105 %

Procedure:
3-oxotetrahydrofuran (5.70 g) was dissolved in methanol (150 mL), and benzyl carbazate (10 g) was added to the solution. The mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated. 14.8 g of a residue was obtained as a crude purified product. This was used for the next reaction without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=S)=[CH:4][CH:3]=1.[C:11]([O:15][C:16]([C:18]1[CH:23]=[C:22]([O:24][C:25]2[CH:30]=[CH:29][C:28]([NH:31][CH3:32])=[C:27]([NH2:33])[CH:26]=2)[CH:21]=[CH:20][N:19]=1)=[O:17])([CH3:14])([CH3:13])[CH3:12]>CO>[C:11]([O:15][C:16]([C:18]1[CH:23]=[C:22]([O:24][C:25]2[CH:30]=[CH:29][C:28]3[N:31]([CH3:32])[C:9]([NH:8][C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)=[N:33][C:27]=3[CH:26]=2)[CH:21]=[CH:20][N:19]=1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CNc1ccc(Oc2ccnc(C(=O)OC(C)(C)C)c2)cc1N
Reactant: Fc1ccc(N=C=S)cc1
Solvent: CO
Product: Cn1c(Nc2ccc(F)cc2)nc2cc(Oc3ccnc(C(=O)OC(C)(C)C)c3)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A round bottom flask was charged with 4-fluorophenylisothiocyanate (1 eq), 4-(3-Amino-4-methylamino-phenoxy)-pyridine-2-carboxylic acid tert-butyl ester (1 eq), and MeOH. The reaction was maintained stirring at room temperature overnight. Ferric chloride, (1.5 eq) was added and the resulting mixture was stirred overnight. The reaction was partitioned with EtOAc and water, and filtered through Celite. The layers were separated and the aqueous phase was neutralized with saturated Na2CO3 solution. The resulting aqueous phase was extracted with EtOAc and the mixture was filtered through Celite. The phases were separated and the aqueous phase was again extracted and filtered. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated to give a brown solid. The crude residue was purified by trituration in hot toluene to furnish the desired product. LCMS m/z 435.6 (MH+), tR=2.12 min.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:10])=[O:9])=[CH:4][C:3]=1[CH3:11].[K].[CH3:13][O:14][C:15](=O)[O:16]C.Cl>O1CCCC1>[CH3:13][O:14][C:15](=[O:16])[CH2:10][C:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([CH3:11])[CH:4]=1)=[O:9]
Reactant: COC(=O)OC
Reactant: CC(=O)c1ccc(C)c(C)c1
Agent: Cl
Agent: [K]
Solvent: C1CCOC1
Product: COC(=O)CC(=O)c1ccc(C)c(C)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirring solution of 3,4-dimethylacetophenone (1.0 g, 6.8 mmol) in tetrahydrofuran (10 ML) at 0° C. under an atmosphere of nitrogen was added potassium hexamethyldisilylzide (1.46 g, 6.8 mmol). Resulting suspension was stirred for 10 min and dimethylcarbonate (0.58 mL, 6.8 mmol) added. Reaction stirred for 16 h warming to room temperature then poured onto wet ice (50 mL)/ hydrochloric acid (5 mL). Product extracted with ethyl acetate (50 mL) and organic washed with saturated sodium chloride then dried over magnesium sulfate. Product isolated as an amber oil after removal of solvent under vacuum. M+1=207.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]([CH3:14])[C:7](=[O:13])[CH2:8][CH2:9][C:10]([CH3:12])([CH3:11])[C:4]=2[CH:3]=1.Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:26]=2[C:27]([NH:29][CH2:30][CH3:31])=[O:28])[C:21]([Cl:37])=[CH:20][N:19]=1>>[Cl:37][C:21]1[C:22]([NH:24][C:25]2[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:26]=2[C:27]([NH:29][CH2:30][CH3:31])=[O:28])=[N:23][C:18]([NH:1][C:2]2[CH:16]=[CH:15][C:5]3[N:6]([CH3:14])[C:7](=[O:13])[CH2:8][CH2:9][C:10]([CH3:12])([CH3:11])[C:4]=3[CH:3]=2)=[N:19][CH:20]=1
Reactant: CN1C(=O)CCC(C)(C)c2cc(N)ccc21
Reactant: CCNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Product: CCNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)C(C)(C)CCC(=O)N3C)ncc1Cl

Procedure:
2-[5-Chloro-2-(1,5,5-trimethyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino)-pyrimidin-4-ylamino]-N-ethyl-3-fluoro-benzamide was prepared from 7-amino-1,5,5-trimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-ethyl-3-fluoro-benzamide in an analogous manner to Example 308c. Product isolated as a white solid (96 mg, 68%). m.p.=251-253° C.; LCMS (m/e) 511 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.77 (s, 1H), 8.11 (s, 1H), 7.63 (d, 1H, J=8.6 Hz), 7.41-7.34 (m, 1H), 7.33-7.26 (m, 2H), 7.16 (s, 1H), 6.99 (d, 1H, J=8.6 Hz), 6.93 (s, 1H), 6.14-6.06 (m, 1H), 3.48-3.39 (m, 2H), 3.27 (s, 3H), 2.32-2.24 (m, 2H), 2.05-1.95 (m, 2H), 1.26 (s, 6H), 1.18 (t, 3H, J=7.3 Hz).
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[NH2:13][C:14]1[C:19]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)=[CH:18][CH:17]=[C:16]([O:34][CH3:35])[N:15]=1>C(#N)C>[CH3:35][O:34][C:16]1[N:15]=[C:14]2[NH:13][C:1](=[O:2])[N:20]([CH:21]3[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])[CH2:23][CH2:22]3)[C:19]2=[CH:18][CH:17]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)c(N)n1
Solvent: CC#N
Product: COc1ccc2c(n1)[nH]c(=O)n2C1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Carbonyldiimidazole (1.6 g, 9.8 mmol) was added to a solution of 2-amino-3-[(1-t-butoxycarbonylpiperidin-4-yl)amino]-6-methoxypyridine (1.29 g, 4.00 mmol) in acetonitrile (100 mL) at room temperature. The reaction was stirred until all the starting material was consumed. Methanol was added to the reaction and the solution stirred for several hours, then the solvent was evaporated in vacuo. The residue was dissolved in ethyl acetate, washed with water and saturated brine, and then dried over magnesium sulfate. The crude product was purified by chromatography (silica gel, 2.5% to 5% methanol in methylene chloride gradient elution), which gave the title compound. MS 349 (M+1) 1H NMR (500 MHz, CDCl3) δ 8.50 (br s, 1H), 7.29 (d, J=8 Hz, 1H), 6.43 (d, J=8 Hz, 1H), 4.46 (m, 1H), 4.31 (br s, 2H), 3.90 (s, 3H), 2.85 (br s, 2H), 2.13 (m, 2H), 1.85 (d, J=12 Hz, 2H), 1.50 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([S:9]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:6]=[C:5]([O:21][CH3:22])[CH:4]=1.[NH4+].[Cl-]>CO.O.[Fe]>[CH3:22][O:21][C:5]1[CH:6]=[C:7]([S:9]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)(=[O:10])=[O:11])[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cc(OC)cc(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: COc1cc(OC)cc(S(=O)(=O)c2ccc(N)cc2)c1
Yield: 90.2 %

Procedure:
0.22 g (0.00068 mol) of 1,3-dimethoxy-5-(4-nitrophenylsulphonyl)-benzene was suspended in a mixture of 15 ml of methanol and 7.5 ml of water, treated with 0.30 g of iron powder and 0.30 g of NH4Cl and heated at reflux for 1 hr. After cooling the mixture was diluted with 50 ml of methanol, treated in an ultrasound bath for a short time and suction filtered. The filter material was washed with a large amount of methanol and the filtrate was concentrated. The residue was suspended in water and treated in an ultrasound bath. The precipitate which thereby resulted was filtered off under suction and dried in a high vacuum. There was obtained 0.18 g (90%) of 4-(3,5-dimethoxybenzenesulphonyl)-phenylamine as white crystals; m.p.: 128-130° C.