Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:21])[NH:3][C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:7]([C:13]([F:16])([F:15])[F:14])=[C:6](Cl)[C:5]=1[N+:18]([O-:20])=[O:19].[NH3:22].C(O)C>O>[CH3:1][N:2]([NH:3][C:4]1[C:5]([N+:18]([O-:20])=[O:19])=[C:6]([NH2:22])[C:7]([C:13]([F:16])([F:15])[F:14])=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH3:21]
Reactant: N
Reactant: CN(C)Nc1c([N+](=O)[O-])cc(C(F)(F)F)c(Cl)c1[N+](=O)[O-]
Solvent: CCO
Solvent: O
Product: CN(C)Nc1c([N+](=O)[O-])cc(C(F)(F)F)c(N)c1[N+](=O)[O-]
Temperature: 65 °C
Reaction time: 8 h

Procedure:
A 50 ml. Pyrex ampule was charged with N-dimethylamino-3-chloro-2,6-dinitro-4-trifluoromethylaniline (5.0 g.; 0.015 mole), ethanolic ammonia (8.54 g. of 6.06% w/w solution; 0.03 mole) and enough absolute ethanol to bring the liquid level to within one inch of the neck. The ampule was chilled in a bath of dry iceacetone, sealed, heated with hot water (65° - 75° C.) until the starting material was in solution, and then placed in an oven at 65° C. After heating at 65° C. for 72 hours, the ampule was opened and the reaction mixture was transferred to a flask and evaporated to dryness under vacuum. Cyclohexane (200 ml.) was added to the residue. The resultant mixture was heated under reflux for one hour, then filtered hot and allowed to cool to 40° C., at which temperature the product began to crystallize. The solution was decanted away from a small amount of solids and the product was allowed to crystallize slowly from the decantate by standing at room temperature overnight. The crystalline product was collected by filtration to obtain 2.7 g., m.p. 150° - 153.5° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH3:11])[C:4]=1[NH2:5])[CH3:2].C=O.[CH3:14]N(C)C.CCCCCCC>O>[CH2:14]=[N:5][C:4]1[C:6]([CH2:10][CH3:11])=[CH:7][CH:8]=[CH:9][C:3]=1[CH2:1][CH3:2]
Reactant: CN(C)C
Reactant: CCc1cccc(CC)c1N
Agent: C=O
Solvent: O
Solvent: CCCCCCC
Product: C=Nc1c(CC)cccc1CC

Procedure:
2,6-Diethylaniline (149.2 grams; 1.0 mole), paraformaldehyde (40 grams), a 25% solution of trimethylamine (1.7 grams) and heptane were charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser connected to a Dean-Stark trap. The reaction mixture was heated and the water formed removed by azeotropic distillation. When no more water could be removed, the reaction mixture was stripped of solvent and distilled to yield the desired product N-methylene-2,6-diethylaniline as a colorless oil having a boiling point of 65°C.
Reaction SMILES: C(O[C@@H](C1C(C2C=CC(Cl)=CC=2)=C2C(=CC=1C)N=C(CN(C)C1C=CC=CC=1)C=C2)C(O)=O)(C)(C)C.[C:37]1([C:66]2[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=2)[CH:42]=[CH:41][C:40]([C:43]2[C:52]([CH:53]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])[C:54]([O:56]CC)=[O:55])=[C:51]([CH3:64])[CH:50]=[C:49]3[C:44]=2[CH:45]=[CH:46][C:47]([CH3:65])=[N:48]3)=[CH:39][CH:38]=1.C([O-])(=O)C>>[C:37]1([C:66]2[CH:67]=[CH:68][CH:69]=[CH:70][CH:71]=2)[CH:38]=[CH:39][C:40]([C:43]2[C:52]([CH:53]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])[C:54]([OH:56])=[O:55])=[C:51]([CH3:64])[CH:50]=[C:49]3[C:44]=2[CH:45]=[CH:46][C:47]([CH3:65])=[N:48]3)=[CH:41][CH:42]=1
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)cc2nc(C)ccc2c1-c1ccc(-c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: Cc1cc2nc(CN(C)c3ccccc3)ccc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Product: Cc1ccc2c(-c3ccc(-c4ccccc4)cc3)c(C(OC(C)(C)C)C(=O)O)c(C)cc2n1

Procedure:
2-(5-(Biphenyl-4-yl)-2,7-dimethylquinolin-6-yl)-2-tert-butoxyacetic acid was prepared following the procedure used to prepare compound (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-((methyl(phenyl)amino) methyl)quinolin-6-yl)acetic acid of Example 14, except that ethyl 2-(5-(biphenyl-4-yl)-2,7-dimethylquinolin-6-yl)-2-tert-butoxyacetate was used instead of (S)-ethyl 2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(methyl(phenyl)amino)methyl)quinolin-6-yl)acetate. 1H-NMR 300 MHz, (CD3OD) 8.40 (d, 1H), 7.96 (s, 1H), 7.95-7.90 (m, 2H), 7.70-7.60 (m, 4H), 7.55-7.40 (m, 4H), 5.39 (s, 1H), 2.96 (s, 3H), 2.80 (s, 3H), 0.98 (s, 9H); LCMS-ESI+ (m/z): [M+H]+ calcd for C29H30NO3: 440.6. Found: 440.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:32][C:33]([OH:36])([CH3:35])[CH3:34])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20](B4OC(C)(C)C(C)(C)O4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[C:38]1[N:39]=[CH:40][C:41]([C:44]#[N:45])=[N:42][CH:43]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@:8]2([CH2:32][C:33]([OH:36])([CH3:34])[CH3:35])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:18]=[CH:19][C:20]([C:38]4[N:39]=[CH:40][C:41]([C:44]#[N:45])=[N:42][CH:43]=4)=[CH:21][CH:22]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: N#Cc1cnc(Cl)cn1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccc(F)cc2)OC1=O
Product: C[C@@H](c1ccc(-c2cnc(C#N)cn2)cc1)N1CC[C@](CC(C)(C)O)(c2ccc(F)cc2)OC1=O

Procedure:
The title compound was prepared from (S)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 5-chloropyrazine-2-carbonitrile following a procedure analogous to that described in Example 14. LC-MS Method 1 tR=1.64 min, m/z=497 (M+Na); 1H NMR (CDCl3) 8.98 (d, 2H), 7.89 (d, 2H), 7.27 (m, 1H), 7.17 (m, 2H), 7.04 (m, 3H), 5.72 (q, 1H), 4.40 (br s, 1H), 2.98 (m, 1H), 1.59 (d, 3H), 1.13 (d, 6H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=2)[CH:3]=1.C([Li])CCC.[C:19](OCC)(=[O:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21].[Li]C1C=CC2C(=CC=C(OC)C=2)C=1>>[O:25]=[C:19]([C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=2)[CH:3]=1)[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)C(=O)OCC
Reactant: COc1ccc2cc(Br)ccc2c1
Agent: [Li]CCCC
Agent: [Li]c1ccc2cc(OC)ccc2c1
Product: CCOC(=O)C(=O)c1ccc2cc(OC)ccc2c1

Procedure:
2-Bromo-6-methoxynaphthalene was converted to the 2-lithio derivative by reaction with n-butyllithium. Diethyl oxalate was then reacted with the 2-lithio-6-methoxynaphthalene to afford ethyl α-keto-6-methoxy-naphth-2-ylacetate. The latter compound was reacted with hydroxylamine hydrochloride and sodium acetate to provide ethyl α-hydroxyimino-6-methoxynaphth-2-ylacetate. A solution of 17.55 g of the oxime in 600 ml of methanol containing 5.3 g of zinc metal dust and 135 ml of 50% (v/v) aqueous formic acid was stirred at 0° C. for three hours. After filtering the reaction mixture, the solvent was removed by evaporation to give 10.3 g of ethyl α-amino-α-(6-methoxynaphth-2-yl)acetate.
Reaction SMILES: C([O:8][CH:9]1[CH2:14][O:13][CH2:12][O:11][CH2:10]1)C1C=CC=CC=1.[OH:15]C1COCOC1.OCC(CO)O.[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>Cl.N1C=CC=CC=1>[OH:8][CH:9]1[CH2:14][O:13][CH2:12][O:11][CH2:10]1.[C:28]([OH:35])(=[O:15])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: c1ccc(COC2COCOC2)cc1
Agent: Cl
Agent: OC1COCOC1
Solvent: OCC(O)CO
Solvent: c1ccncc1
Product: O=C(O)c1ccccc1

Procedure:
In another method of preparing the 5-benzyloxy-1,3-dioxane, the starting material was 5-hydroxy-1,3-dioxane (Tetrahedron 7, 10-18 (1959)). The latter was prepared by first reacting glycerol with trioxymethylene, in the presence of HCl as a catalyst to form a mixture of cyclic acetals (J. Am. Chem. Soc. 50, 3124 (1928)) which was then esterified with benzoyl chloride, in the presence of pyridine, yielding on recrystallization the benzoate 5-hydroxy-1,3-dioxane melting at 71°-72° C (J. Am. Chem. Soc. 50, 3120 (1928)). This ester was then split by reaction with sodium methylate in chloroform, to produce the purified 5-hydroxy-1,3-dioxane which was taken off as a cut boiling at 95°-96° C at 22 mm. Three grams (0.029 mol) of the latter product and 100 ml of benzene were placed in a flask equipped with a stirrer, condenser, thermometer and addition funnel. While stirring, 1.1 g of sodium hydride was added portionwise; hydrogen evolved. Next, after the resulting slurry had been kept at room temperature for 1/2 hour without further addition of ingredients while stirring continued, 3.65 g of benzyl chloride was added dropwise over a fifteen minute period. When all the benzyl chloride had been added the mixture was heated to 80° C and maintained at this temperature for 24 hours while stirring continued. The slurry thus obtained was then washed twice with 100 ml portions of water and the resulting organic layer was dried over MgSO4. This drying agent was then filtered off and the solvent was removed under reduced pressure, yielding an oil which was then distilled under reduced pressure to give a fraction (5-benzyloxy-1,3-dioxane) boiling at 80°-82° C at 0.15 mm and having an estimated purity of about 85%.
Reaction SMILES: C([O:5][C:6]([C@:8]1([CH2:38][CH:39]([CH3:41])[CH3:40])[CH2:12][C@H:11]([C:13]2[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[CH:15][N:14]=2)[C@H:10]([C:21]2[S:25][CH:24]=[N:23][CH:22]=2)[N:9]1[C:26](=[O:37])[C:27]1[CH:32]=[CH:31][C:30]([C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:29][CH:28]=1)=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>>[C:33]([C:30]1[CH:29]=[CH:28][C:27]([C:26]([N:9]2[C@@H:10]([C:21]3[S:25][CH:24]=[N:23][CH:22]=3)[C@@H:11]([C:13]3[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[CH:15][N:14]=3)[CH2:12][C@@:8]2([CH2:38][CH:39]([CH3:40])[CH3:41])[C:6]([OH:7])=[O:5])=[O:37])=[CH:32][CH:31]=1)([CH3:35])([CH3:34])[CH3:36]
Reactant: CC(C)C[C@@]1(C(=O)OC(C)(C)C)C[C@H](c2cc(C#N)ccn2)[C@H](c2cncs2)N1C(=O)c1ccc(C(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C[C@@]1(C(=O)O)C[C@H](c2cc(C#N)ccn2)[C@H](c2cncs2)N1C(=O)c1ccc(C(C)(C)C)cc1

Procedure:
The tert-butyl ester from stage A was deprotected with TFA in a similar manner to that described in Example 1. Purification was achieved by reverse phase HPLC on a C18 column using a two-solvent gradient elution with (A) water containing formic acid (0.1%) and (B) acetonitrile-water (95:5 v/v) containing formic acid (0.05%) as the eluents, and analysis of the fractions by electrospray mass spectroscopy. This afforded the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:16])[C:5]([NH2:15])=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.O.C(=O)(O)[O-].[Na+].[F:23][C:24]([F:35])([F:34])[C:25]([F:33])([F:32])[C:26]([F:31])([F:30])[C:27](O)=O>>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][C:11]([Cl:14])=[CH:12][CH:13]=2)=[CH:6][C:5]2[NH:15][C:27]([C:26]([F:30])([F:31])[C:25]([F:32])([F:33])[C:24]([F:35])([F:34])[F:23])=[N:16][C:4]=2[CH:3]=1
Reactant: O=C(O)C(F)(F)C(F)(F)C(F)(F)F
Reactant: Nc1cc(Cl)c(-c2ccc(Cl)cc2)cc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: FC(F)(F)C(F)(F)C(F)(F)c1nc2cc(Cl)c(-c3ccc(Cl)cc3)cc2[nH]1
Yield: 62 %

Procedure:
To a solution of 5-chloro-2-nitroaniline (50 g, 289.74 mmol) in AcOH (200 ml) was added NIS (63 g, 280.02 mmol) with stirring overnight at room temperature. Then the solids were collected by filtration and washed with water (50 ml). The solid was dried in an oven under reduced pressure to afford 5-chloro-4-iodo-2-nitroaniline as a yellow solid (70 g, 81%). Next, to a solution of 5-chloro-4-iodo-2-nitroaniline (15 g, 50.26 mmol) in dioxane (200 ml) and water (20 ml) was added (4-chlorophenyl)boronic acid (15.7 g, 100.40 mmol), K3PO4 (21.2 g, 99.87 mmol) and Pd(PPh3)4 (3 g, 2.60 mmol) with stirring for 6 h at 95° C. maintained with an inert atmosphere of nitrogen. Then the resulting mixture was concentrated under vacuum to give a residue, which was purified by a silica gel column with 5%˜10% ethyl acetate in petroleum ether to afford 5-chloro-4-(4-chlorophenyl)-2-nitroaniline as a yellow solid (9 g, 63%). To a solution of 5-chloro-4-(4-chlorophenyl)-2-nitroaniline (12 g, 42.39 mmol) in ethanol (150 ml) was added hydrogen chloride (conc, 10 ml) to this was followed by the addition of Zn powder (16.6 g, 253.34 mmol) in portions at room temperature. The resulting solution was stirred for 4 h at 85° C. Then the resulting mixture was concentrated under vacuum, dissolved in water (200 ml) and extracted with ethyl acetate (3×200 ml). The combined organic layers was dried and concentrated under vacuum to give a residue, which was purified by a silica gel column with 10%˜20% ethyl acetate in petroleum ether to produce 4-chloro-5-(4-chlorophenyl)benzene-1,2-diamine as an off-white solid (8.7 g, 81%). Finally, a solution of 4-chloro-5-(4-chlorophenyl)benzene-1,2-diamine (7 g, 27.65 mmol) in heptafluorobutanoic acid (70 ml) was stirred for 1.5 h at 120° C. Then the mixture was poured into water (200 ml), adjusted pH value of the solution to 7 with aqueous sodium bicarbonate and extracted with ethyl acetate (3×200 ml). The combined organic layers was dried over anhydrous magnesium sulfate and concentrated under vacuum to give a residue, which was purified by a silica gel column with 5% ethyl acetate in petroleum ether to afford 5-chloro-6-(4-chlorophenyl)-2-(heptafluoropropyl)-1H-1,3-benzodiazole as an off-white solid (7.3977 g, 62%).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH2:9])=[CH:4][CH:3]=1.Cl[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12].C([O-])([O-])=O.[K+].[K+]>O1CCCC1.O>[I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:11](=[O:12])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(NCc1ccc(I)cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of (4-iodophenyl)methanamine (5 g, 18.5 mmol) and benzyl chloroformate (3.47 g) in a mixture of tetrahydrofuran (20 mL) and H2O (50 mL) was added K2CO3 (10.2 g, 74 mmol) at 5° C. The reaction mixture was stirred at room temperature for 5 hours, and partitioned between ethyl acetate and brine. The organic phase was washed with brine, dried over MgSO4, filtered, and concentrated to afford the title compound. LC-MS (ESI): m/z 368 (M+H), RT: 2.25 min; 1H NMR (400 MHz, CDCl3): δ 4.32 (d, J=6.0 Hz, 2H), 5.13 (s, 2H), 7.03 (d, J=7.6 Hz, 2H), 7.32-7.36 (m, 5H), 7.65 (d, J=8.0 Hz, 2H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:17][N:16]([C:18]([C:20]3[CH:21]=[C:22]4[C:27](=[CH:28][CH:29]=3)[NH:26][CH2:25][CH2:24][CH2:23]4)=[O:19])[CH2:15]2)[CH2:10][CH2:9]1)=[O:7].C([O-])([O-])=O.[K+].[K+]>CC#N>[CH2:18]([N:26]1[C:27]2[C:22](=[CH:21][C:20]([C:18]([N:16]3[CH2:17][CH:14]([N:11]4[CH2:12][CH2:13][N:8]([C:6]([C:2]5[S:1][CH:5]=[CH:4][N:3]=5)=[O:7])[CH2:9][CH2:10]4)[CH2:15]3)=[O:19])=[CH:29][CH:28]=2)[CH2:23][CH2:24][CH2:25]1)[C:20]1[CH:21]=[CH:22][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(c1ccc2c(c1)CCCN2)N1CC(N2CCN(C(=O)c3nccs3)CC2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(c1ccc2c(c1)CCCN2Cc1ccccc1)N1CC(N2CCN(C(=O)c3nccs3)CC2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 764.6 %

Procedure:
To a solution of compound 357 (30 mg, 0.0073 mmol) in CH3CN (1 mL) was added compound 18a (0.01 mL, 0.0088 mmol), followed by the addition of K2CO3 (20 mg, 0.015 mmol). The reaction mixture was stirred at room temperature for 18 h. The resultant mixture was partitioned between CH2Cl2 and H2O. The organic solution was dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification of the residue by flash column chromatography (silica gel, 1% MeOH/EtOAc+0.5% Et3N) gave compound 370 (14 mg). 1H NMR (400 MHz, CDCl3): δ 7.88 (d, J=3.3 Hz, 1H), 7.54 (d, J=3.0 Hz, 1H), 7.38 (d, J=2.0 Hz, 1H), 7.30-7.36 (m, 2H), 7.19-7.30 (m, 4H), 6.44 (d, J=8.6 Hz, 1H), 4.54 (s, 2H), 3.97-4.52 (m, 6H), 3.77-3.96 (m, 2H), 3.40-3.47 (m, 2H), 3.15-3.24 (m, 1H), 2.83 (t, J=6.2 Hz, 2H), 2.38-2.59 (m, 4H), 1.98-2.05 (m, 2H); LC/MS m/z (M+H+) 502.2.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][O:10][C:11]1[C:12](=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:13]([O:15]C)=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si](C)(C)[O-].[K+]>>[C:1]([O:5][C:6]([NH:8][CH2:9][O:10][C:11]1[C:12](=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:13]([OH:15])=[O:14])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccccc1OCNC(=O)OC(C)(C)C
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Product: CC(C)(C)OC(=O)NCOc1ccccc1C(=O)O
Yield: 81 %

Procedure:
Methyl N-tert-butoxycarbonylaminomethylsalicylate (8.7 g, 30.9 mmoles) was dissolved in dry tetrahydroflran (100 mL), and potassium trimethylsilanolate (4.4 g, 30.9 mmoles, 90% pure) was added. The yellow solution was refluxed for 24 hours, during which time a tan precipitate formed and the solvent turned light brown. The mixture was evaporated to dryness, and the solid was dissolved in cold water (100 mL). The brown solution was chilled in an ice bath, and saturated aqueous potassium hydrogen sulfate solution was used to titrate the stirred solution to pH 2-3. An off-white solid precipitated during the titration. The solid was filtered, washed with cold water, and dried in vacuo over potassium hydroxide to afford 6.7 g, (81% yield) of crude N-tert-butoxycarbonylaminomethylsalicylic acid (m.p. 141°-1449 C., decomposes with effervescence on melting, open capillary, uncorrected).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[O:5][C:6]1[S:7][CH:8]=[C:9]([C:11]([OH:13])=O)[N:10]=1.O=S(Cl)Cl.[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[O:5][C:6]1[S:7][CH:8]=[C:9]([C:11]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:13])[N:10]=1
Reactant: Nc1ccccc1
Reactant: O=C(O)c1csc(Oc2cccc(Cl)c2)n1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(Nc1ccccc1)c1csc(Oc2cccc(Cl)c2)n1
Temperature: 25 °C
Yield: 82.8 %

Procedure:
1 g (3.75 mmol) 2-(3-chlorophenoxy)thiazole-4-carboxylic acid was added to 1 ml of SOCl2 and refluxed until the mixture gave a clear solution. Excess SOCl2 was evaporated in vacuo and the remaining acid chloride dissolved in 25 ml toluene. To this solution was added a solution of 0.34 g (3.65 mmol) aniline and 0.37 g triethylamine in 20 ml toluene. After stirring over night at room temperature the solution was washed with 20 ml dil. HCl, 20 ml water, 20 ml dil. NaOH and 20 ml water. The organic layer was dried with NaSO4 and evaporated to dryness to give 1.0 g (82.8%) 2-(3-chlorophenoxy)thiazole-4-carbanilide (m.p.:94°-95° C.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][NH:5][CH2:6][C:7](=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH2:14])[C:9]=1[OH:15].[CH3:18][O:19][C:20]1[C:21](=O)[C:22](=[O:26])[C:23]=1[O:24]C>>[OH:15][C:9]1[C:10]([NH:14][C:21]2[C:22](=[O:26])[C:23](=[O:24])[C:20]=2[O:19][CH3:18])=[CH:11][CH:12]=[CH:13][C:8]=1[C:7]([CH2:6][NH:5][CH2:4][C:3]([O:2][CH3:1])=[O:17])=[O:16]
Reactant: COC(=O)CNCC(=O)c1cccc(N)c1O
Reactant: COc1c(OC)c(=O)c1=O
Product: COC(=O)CNCC(=O)c1cccc(Nc2c(OC)c(=O)c2=O)c1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 61.1 %

Procedure:
A mixture of 3.92 g (16.4 mmol, 1 eq) of methyl[(3-amino-2-hydroxybenzoyl)methylamino]acetate and 4.68 g (32.9 mmol, 1 eq) of 3,4-dimethoxy-3-cyclobutene-1.2-dione was stirred at ambient temperature for 24 hours. The solvent was evaporated off and the residue was chromatographed on silica gel (200 g prepacked column, eluent 20/80 then 0/100 heptane/ethyl acetate). 3.49 g of methyl {[2-hydroxy-3-(2-methoxy-3,4-dioxocyclobut-1-enylamino)benzoyl]methylamino}acetate were obtained in the form of a white solid. Yield=61%.
Reaction SMILES: [C:1]([NH2:4])(=[S:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[C:11](Cl)(=[O:21])[C:12]1[C:13](=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:14](Cl)=[O:15]>C1COCC1>[C:1]([N:4]1[C:14](=[O:15])[C:13]2[C:12](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11]1=[O:21])(=[S:3])[CH3:2]
Reactant: CC(N)=S
Reactant: O=C(Cl)c1ccccc1C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(=S)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 13.5 %

Procedure:
To a mixture of thioacetamide (10.04 g, 133.64 mmol) and K2CO3 (45.80 g, 331.38 mmol) in 100 ml THF at 0° C. add phthaloyl chloride (28.49 g, 140.32 mmol) dropwise. Raise the reaction temperature to 25° C. after 2 hours and allow it to stir for an additional 2 hours before cooling the reaction mixture to 0° C. again. Quench the reaction by adding 125 mL of ice water dropwise. Extract the reaction mixture with EtOAc (2×). Dry the organic layer with MgSO4 and remove the solvent in vacuo to yield 3.7 g of N-thioacetyl-isoindole-1,3-dione as a crude reddish solid.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3](Cl)=[N:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1.[CH2:16]([O:18][CH:19]([O:22][CH2:23][CH3:24])[C:20]#[CH:21])[CH3:17].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[I-].[K+]>C(#N)C.[Cu]I.O>[CH2:16]([O:18][CH:19]([O:22][CH2:23][CH3:24])[C:20]#[C:21][C:3](=[N:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)[C:2]([F:15])([F:14])[F:1])[CH3:17]
Reactant: C#CC(OCC)OCC
Reactant: COc1ccc(N=C(Cl)C(F)(F)F)cc1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [I-]
Solvent: CC#N
Solvent: O
Product: CCOC(C#CC(=Nc1ccc(OC)cc1)C(F)(F)F)OCC
Temperature: 60 °C

Procedure:
In a typical reaction, 2,2,2-trifluoro-N-(4-methoxyphenyl)acetimidoyl chloride and a slight excess of 3,3-diethoxyprop-1-yne are mixed with about 0.3 equivalents of copper (I) iodide and slight excesses of potassium phosphate and potassium iodide in anhydrous acetonitrile. The mixture is heated at about 60° C. under a nitrogen atmosphere until the reaction is complete. After cooling, an extraction solvent like a halogenated hydrocarbon is added to the mixture along with water. The organic layer is recovered, washed with brine and dried. The solvent is evaporated to provide crude N-(5,5-diethoxy-1,1,1-trifluoro-pent-3-yn-2-ylidene)-4-methoxyaniline.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[Cl:12])[CH:5]=[C:4]([C@@H:13]([NH:15][C:16]2[N:24]=[CH:23][N:22]=[C:21]3[C:17]=2[N:18]=[CH:19][N:20]3[CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[CH3:14])[N:3]=1.[CH:34]1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=C[CH:35]=1.C([Sn](CCCC)(CCCC)C=C)CCC>C1COCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:12][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[C:2]([CH:34]=[CH2:35])=[N:3][C:4]([C@@H:13]([NH:15][C:16]1[N:24]=[CH:23][N:22]=[C:21]3[C:17]=1[N:18]=[CH:19][N:20]3[CH2:25][C:26]1[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=1)[CH3:14])=[CH:5]2
Reactant: COc1ccc(Cn2cnc3c(N[C@@H](C)c4cc5cccc(Cl)c5c(Cl)n4)ncnc32)cc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: [Pd+2]
Agent: C=C[Sn](CCCC)(CCCC)CCCC
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Product: C=Cc1nc([C@H](C)Nc2ncnc3c2ncn3Cc2ccc(OC)cc2)cc2cccc(Cl)c12
Temperature: 25 °C

Procedure:
To a stirred mixture of (S)—N-(1-(1,8-dichloroisoquinolin-3-yl)ethyl)-9-(4-methoxybenzyl)-9H-purin-6-amine 1 (2.58 g, 5.4 mmol, 1 eq), Pd(OAc)2 (363 mg, 1.62 mmol, 0.3 eq) and PPh3 (846 mg, 3.24 mol, 0.6 eq) in THF (50 mL) at RT, tributyl(vinyl)tin (1.97 g, 5.94 mmol, 1.1 eq) was added and the resulting mixture was stirred at reflux overnight. The mixture was allowed to cool to RT and filtered through silica gel (10 g). The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (1-5% MeOH-DCM) to afford the product (S)—N-(1-(8-chloro-1-vinylisoquinolin-3-yl)ethyl)-9-(4-methoxybenzyl)-9H-purin-6-amine 2.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([C:12]1[CH:21]=[C:20]2[C:15]([C:16](=[O:24])[CH2:17][C:18]([CH2:22][CH3:23])=[N:19]2)=[CH:14][CH:13]=1)(OCC)=[O:8].O.C(OCC)(=O)C>C1COCC1>[CH2:22]([C:18]1[CH2:17][C:16](=[O:24])[C:15]2[C:20](=[CH:21][C:12]([CH2:7][OH:8])=[CH:13][CH:14]=2)[N:19]=1)[CH3:23]
Reactant: CCOC(=O)c1ccc2c(c1)N=C(CC)CC2=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC1=Nc2cc(CO)ccc2C(=O)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Lithium aluminium hydride (0.6 g) was added to a solution of 7-carboethoxy-2-ethyl-4-quinolone (2.65 g) in THF (200 ml) and the resulting suspension stirred for 2 hours at ambient temperature. Water (100 ml) was slowly added, followed by ethyl acetate (100 ml). The suspension was filtered and washed with ethyl acetate (100 ml). The phases of the filtrate were separated and the aqueous layer re-extracted with ethyl acetate (100 ml). The combined organic phases were dried (MgSO4) and evaporated to give a solid which on recrystallisation from ethyl acetate gave 2-ethyl-7-hydroxymethyl-4-quinolone as a white powder, m.p. 254°-257° C.