Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:11][CH3:12])[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.[H-].[Na+].C([Li])(C)(C)C.CN(C)[CH:22]=[O:23]>O1CCCC1>[CH3:12][O:11][C:4]1[CH:5]=[C:6]2[C:10](=[C:2]([CH:22]=[O:23])[CH:3]=1)[NH:9][N:8]=[CH:7]2
Reactant: COc1cc(Br)c2[nH]ncc2c1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Li]C(C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(C=O)c2[nH]ncc2c1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 107.5 %

Procedure:
To a solution of 7-bromo-5-methoxy-1H-indazole (1.32 g, 5.81 mmol) in tetrahydrofuran (27 mL) at 0° C. was added sodium hydride (0.465 g, 11.62 mmol). The ice bath was removed and stirring continued for 20 min. The solution was cooled to −78° C. and treated with tert-butyllithium (1.7 M in pentane, 6.84 mL, 11.63 mmol) dropwise. The reaction was stirred at −78° C. for 10 min, allowed to warm gradually in the dewar to −50° C., recooled to −78° C., and then treated with dimethylformamide (1.8 mL, 23.25 mmol). After 15 min, the ice bath was removed and stirring continued for 1 h. The reaction was poured onto ice/1 M hydrochloric acid (20 mL). The mixture was extracted with ethyl acetate (2×). The organics were washed with water, then brine, dried over magnesium sulfate, and concentrated to give 1.1 g of 5-methoxy-1H-indazole-7-carbaldehyde (100%) as a tan solid. 1H-NMR (CDCl3, 300 MHz) δ 10.08 (s, 1H), 8.04 (s, 1H), 7.52 (s, 1H), 7.44 (m, 1H), 3.90 (s, 3H); Mass spec.: 177.09 (MH)+.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([NH2:21])[CH2:18][CH2:19][CH3:20]>>[CH2:17]([NH:21][C:8](=[O:9])[CH:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:18][CH2:19][CH3:20]
Reactant: CCCCN
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Product: CCCCNC(=O)C(c1ccccc1)c1ccccc1

Procedure:
The title compound, white solid, m.p. 96° C. and MS: m/e=268.4 (M+H+) was prepared in accordance with the general method of example 1 from diphenylacetyl chloride and butylamine.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]([O:16]CC)=O.[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1>C1(C)C=CC=CC=1>[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH:25][C:14]([C:3]2[CH:4]=[N:5][C:6]3[C:11]([C:2]=2[OH:1])=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=3)=[O:16])=[CH:22][CH:21]=1
Reactant: CCOC(=O)c1cnc2ccc(OC)cc2c1O
Reactant: NCc1ccc(Cl)cc1
Solvent: Cc1ccccc1
Product: COc1ccc2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Temperature: 210 °C
Reaction time: 1 h

Procedure:
A mixture of 320 mg of ethyl 4-hydroxy-6-methoxy-3-quinolinecarboxylate (J. Amer. Chem. Soc., 68, 1204 (1946)) and 1.0 mL of 4-chlorobenzylamine is stirred for 1 h at 210° C. The mixture is cooled to 25° C. and it is diluted with 2.0 mL of toluene. The mixture is filtered and the filtrant is dissolved in a minimum volume of refluxing glacial acetic acid. The hot solution is treated with distilled water dropwise until it becomes cloudy, and it is allowed to cool to 25° C. The precipitate is collected by filtration and it is washed with a small amount of dilute aqueous acetic acid. It is dried in a stream of air and then it is dissolved in 7 mL of refluxing acetonitrile. The solution is allowed to cool to 25° C. and after an additional 2 h the precipitate is collected by filtration. The solid is dried for 48 h at torr and 85° C. This procedure gives the title compound as 64 mg of a light tan solid.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=[CH:19][CH:18]=[CH:17]2.C(OCC)(=O)C>C(O)(=O)C.[Pt](=O)=O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[NH:20][CH2:19][CH2:18][CH2:17]2
Reactant: c1ccc2cc(Nc3cccc4cccnc34)ccc2c1
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: c1cc2c(c(Nc3ccc4ccccc4c3)c1)NCCC2
Reaction time: 4 h
Yield: 101.4 %

Procedure:
A solution of 4.08 grams of N-2-naphthylquinolin-8-amine from above in acetic acid (10 mL) and ethyl acetate (150 mL) containing 0.24 grams of platinum(IV) oxide was hydrogenated at 45 psi for four hours on a Parr low-pressure hydrogenator. The solution was filtered through diatomaceous earth; concentrated in vacuo; and neutralized with 3N aqueous sodium hydroxide. The aqueous phase was diluted with water and extracted three times with ethyl acetate. The combined ethyl acetate layers were washed with brine; dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to yield 4.2 grams of the desired product as a purple oil. 1H NMR (CDCl3/D2O) δ 7.7 (m, 2H), 7.6 (d,1H), 7.35 (t, 1H), 7.25 (m, 1H), 7.05 (m, 2H), 6.9 (m, 2H), 6.6 (t, 1H), 3.3 (t, 2H), 2.85 (t, 2H), 1.95 (p, 2H).
Reaction SMILES: ClC1C=CC(C[N:7]2[CH2:11][CH2:10][C@H:9]([NH:12][C:13](=[O:28])[CH2:14][NH:15][C:16](=[O:27])[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=3)[CH2:8]2)=CC=1>C(O)=O.CO.[OH-].[OH-].[Pd+2]>[F:26][C:23]([F:24])([F:25])[C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[C:16]([NH:15][CH2:14][C:13]([NH:12][C@H:9]1[CH2:10][CH2:11][NH:7][CH2:8]1)=[O:28])=[O:27]
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@H]1CCN(Cc2ccc(Cl)cc2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: O=CO
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@H]1CCNC1
Temperature: 60 °C
Reaction time: 3 h
Yield: 81 %

Procedure:
A suspension of (S)-1-(4-chlorobenzyl)-3-[N-{3-(trifluoromethyl)benzoyl}glycyl]aminopyrrolidine (2.93 g, 6.66 mmol) and Pd(OH)2 in 5% HCO2H/methanol (70 mL) was stirred at 60° C. for 3 h. The Pd catalyst was filtered off through Celite, and the filtrate was concentrated. To the residue was added 2N aqueous NaOH solution (100 mL) and the mixture was extracted with ethyl acetate (100 mL×3). The combined extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography (SiO2, AcOEt/MeOH/Et3N=85/10/5-60/30/5) gave (S)-3-[N-{3-(trifluoromethyl)benzoyl}glycyl]aminopyrrolidine (1.70 g, 81%) as an oil: 1H NMR (CDCl3, 270 MHz) δ1.76 (d, J=7.3 Hz, 1 H), 2.07-2.25 (m, 1 H), 2.81-2.98 (m, 2 H), 3.02-3.11 (m, 2 H), 4.12 (s, 2 H), 4.41 (br, 1 H), 6.90 (br, 1 H), 7.45 (br, 1 H), 7.58 (dd, J=7.3 and 7.3 Hz, 1 H), 7.77 (d, J=7.3 Hz, 1 H), 8.02 (d, J=7.3 Hz, 1 H), 8.11 (s, 1H); ESI/MS n/e 316.0 (M++H, C14H16F3N3O2).
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[C:5]([C:8]1[CH:13]=[C:12]([C:14](=[O:16])[CH3:15])[C:11]([OH:17])=[CH:10][C:9]=1[NH:18][CH2:19][CH3:20])(=[O:7])[CH3:6].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:1]([O:17][C:11]1[CH:10]=[C:9]([C:8]([C:5](=[O:7])[CH3:6])=[CH:13][C:12]=1[C:14](=[O:16])[CH3:15])[NH:18][CH2:19][CH3:20])[CH:2]=[CH2:3]
Reactant: CCNc1cc(O)c(C(C)=O)cc1C(C)=O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOc1cc(NCC)c(C(C)=O)cc1C(C)=O
Yield: 93 %

Procedure:
Allyl bromide (2 g) was added to a stirred solution of 4,6-diacetyl-3-ethylaminophenol (0.016 M) in dimethylformamide (30 ml) containing potassium carbonate (2 g). The mixture was heated at 60°-70° C. for two hours, and was then poured into water (100 ml), stirred, and the precipitated product isolated by filtration. Yield 93%, mp 82°-83° C.
Reaction SMILES: [S:1]([N:11]=[C:12]1[NH:16][CH2:15][CH2:14][NH:13]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[C:17](Cl)([Cl:19])=[O:18].C(N(CC)CC)C>O1CCCC1>[Cl:19][C:17]([N:16]1[CH2:15][CH2:14][N:13]=[C:12]1[NH:11][S:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=1)(=[O:2])=[O:3])=[O:18]
Reactant: Cc1ccc(S(=O)(=O)N=C2NCCN2)cc1
Reactant: O=C(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)NC2=NCCN2C(=O)Cl)cc1
Temperature: 0 °C

Procedure:
12 parts by weight of 2-tosylimino-imidazolidine (produced as described by Gompper and Hagele, Ber. 99, 2892 [1966]) were partly dissolved by 10 minutes' boiling in 150 parts by volume of absolute tetrahydrofurane, and thereafter rapidly cooled to 0°C by swirling in an ice bath. 6 parts by weight of phosgene were added to the suspension while stirring, the mixture was stirred for 30 minutes at 0°C, 5 parts by weight of triethylamine were then added dropwise and the whole was then stirred for a further 3 hours at room temperature. The excess phosgene was blown out by means of a stream of dry air and the precipitated triethylamine hydrochloride was removed from the tetrahydrofurane solution by filtration and was thoroughly eluted with absolute tetrahydrofurane. The combined solutions were evaporated to dryness in vacuo and the residual oil was caused to crystallize by trituration with methylene chloride and ether, filtered off and dried in vacuo.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1.[CH3:35][O:36][CH2:37][C:38](Cl)=[O:39]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][CH:29]4[CH2:30][CH2:31][N:32]([C:38](=[O:39])[CH2:37][O:36][CH3:35])[CH2:33][CH2:34]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1
Reactant: COc1cc(-c2ncnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c(OCC2CC2)cc1F
Reactant: COCC(=O)Cl
Agent: Cl
Product: COCC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4cc(OC)c(F)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-6-methyl-N-piperidin-4-yl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f35) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][CH:12]2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=2)=[O:7])=[CH:4][CH:3]=1.[CH3:25][N:26]=[C:27]=[O:28].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[CH3:25][NH:26][C:27](=[O:28])[O:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([CH:12]2[CH2:13][CH2:14][CH2:15][N:11]2[CH2:10][CH2:9][NH:8][C:6](=[O:7])[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:24][CH:23]=2)[CH:17]=1
Reactant: O=C(NCCN1CCCC1c1cccc(O)c1)c1ccc(Cl)cc1
Reactant: CN=C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CNC(=O)Oc1cccc(C2CCCN2CCNC(=O)c2ccc(Cl)cc2)c1
Reaction time: 2 h
Yield: 94 %

Procedure:
The 4-chloro-N-{2-[2-(3-hydroxyphenyl)-1-pyrrolidinyl]ethyl}benzamide (0.29 g) was dissolved in tetrahydrofuran (20 ml), and methyl isocyanate (50.0 μl) and milled potassium carbonate (0.17 g) at ambient temperature were added, under nitrogen. The reaction mixture was stirred for 2 hrs and filtered through a pad of celite. The filter cake was washed with ethyl acetate, and the combined filtrates were concentrated. Crystallization of the residue with ether/petroleum ether gave 0.32 g (94%) of product. Recrystallization from ether gave the analytical sample, mp 103°-106° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:12]([N:18]=[C:19]=[S:20])[CH:13]1[O:17][CH2:16][CH2:15][CH2:14]1>C(O)C>[Br:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[NH:1][C:19](=[S:20])[N:18]([CH2:12][CH:13]1[CH2:14][CH2:15][CH2:16][O:17]1)[C:4]2=[O:6]
Reactant: S=C=NCC1CCCO1
Reactant: Nc1ccc(Br)cc1C(=O)O
Solvent: CCO
Product: O=c1c2cc(Br)ccc2[nH]c(=S)n1CC1CCCO1
Temperature: 25 °C
Yield: 90.7 %

Procedure:
A mixture of 2-amino-5-bromobenzoic acid (8.0 g, 37.0 mmol), tetrahydrofurfuryl isothiocyanate (5.0 g, 34.9 mmol) and triethylarine (5.0 mL, 3.6 g, 35.6 mmol) in ethanol (48 mL) was heated at reflux for 2 h. The reaction mixture was then allowed to cool to room temperature and filtered. The resulting filter cake was washed with 50 mL of cold ethanol, followed by 50 mL of hexanes to provide 10.8 g of the title compound of Step A as a solid melting at 230-232° C. IH NMR (400 MHz, Me2SO-d6): δ 1.63-2.0 (m,4H), 3.58-3.68 (m,1H), 3.74-3.82 (m,1H), 4.32 (dd,1H), 4.39-4.50 (m,1H), 4.58 (dd,1H), 7.37 (d,1H), 7.91 (d,1H), 8.02 (s,1H), 13.1 (br s,1H).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:27])=[C:4]2[C:9]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[C:8]([C:24]#[N:25])[CH:7]=[N:6][N:5]2[CH:26]=1.[O:28](S(C(F)(F)F)(=O)=O)[S:29]([C:32]([F:35])([F:34])[F:33])(=O)=[O:30]>C(Cl)Cl.CCOC(C)=O>[C:24]([C:8]1[CH:7]=[N:6][N:5]2[CH:26]=[C:2]([O:1][S:29]([C:32]([F:35])([F:34])[F:33])(=[O:30])=[O:28])[C:3]([CH3:27])=[C:4]2[C:9]=1[NH:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:15][CH:16]=1)#[N:25]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Cc1c(O)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1c(OS(=O)(=O)C(F)(F)F)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Reaction time: 0.08 h
Yield: 95.5 %

Procedure:
To a solution of 397A (32 mg, 0.090 mmol) in CH2Cl2 (1 ml) was added Tf2O (18 μl, 0.099 mmol) at −10° C. The reaction mixture was stirred for 5 min, diluted with EtOAc, washed with brine, dried and concentrated to give 397 (42 mg, 95%) LCMS Found: (M+H)+=489.0
Reaction SMILES: [Cl:1][C:2]1[C:19]([O:20]C)=[CH:18][C:5]2[C@H:6]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:7][N:8]([CH3:11])[CH2:9][CH2:10][C:4]=2[CH:3]=1.C(=O)(O)[O-].[Na+]>Br.O>[Cl:1][C:2]1[C:19]([OH:20])=[CH:18][C:5]2[C@H:6]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:7][N:8]([CH3:11])[CH2:9][CH2:10][C:4]=2[CH:3]=1
Reactant: COc1cc2c(cc1Cl)CCN(C)C[C@H]2c1ccccc1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CN1CCc2cc(Cl)c(O)cc2[C@H](c2ccccc2)C1

Procedure:
Heat and stir a mixture of 0.850 g (0.0028 moles) of the product of step D in 12 ml of 48% hydrobromic acid at 100° C. for 16 hours. Dilute with 75 ml of water and heat on a steam bath to dissolve. Adjust to about pH 8 with solid sodium bicarbonate, filter, and wash the resulting precipitate with water. Recrystallize from ethanol to obtain analytically pure (S)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine, m.p. 188°-189° C., [α]D26 =+44.8° (c=1, dimethylformamide).
Reaction SMILES: [CH3:1][C:2]1[CH:28]=[C:27]([N:29]2[C:33]([CH3:34])=[C:32]([CH3:35])[C:31]([CH3:36])=[N:30]2)[CH:26]=[CH:25][C:3]=1[O:4][CH2:5][C:6]1[C:11]([C:12]#[C:13][Si](C)(C)C)=[CH:10][CH:9]=[CH:8][C:7]=1[N:18]1[C:22](=[O:23])[N:21]([CH3:24])[N:20]=[N:19]1.C(=O)([O-])[O-].[K+].[K+].C(Cl)(Cl)Cl>CO>[C:12]([C:11]1[C:6]([CH2:5][O:4][C:3]2[CH:25]=[CH:26][C:27]([N:29]3[C:33]([CH3:34])=[C:32]([CH3:35])[C:31]([CH3:36])=[N:30]3)=[CH:28][C:2]=2[CH3:1])=[C:7]([N:18]2[C:22](=[O:23])[N:21]([CH3:24])[N:20]=[N:19]2)[CH:8]=[CH:9][CH:10]=1)#[CH:13]
Reactant: Cc1cc(-n2nc(C)c(C)c2C)ccc1OCc1c(C#C[Si](C)(C)C)cccc1-n1nnn(C)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: C#Cc1cccc(-n2nnn(C)c2=O)c1COc1ccc(-n2nc(C)c(C)c2C)cc1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 1-{2-(2-methyl-4-(3,4,5-trimethyl-pyrazol-1-yl)-phenoxymethyl)-3-trimethylsilylethynyl-phenyl}-4-methyl-1,4-dihydrotetrazole-5-one (described in Reference Preparation example 71) 0.2 g, potassium carbonate 0.7 g, chloroform 5 ml and methanol 5 ml was stirred at room temperature for three hours, and then the resulting mixture was heated to 60° C. and was stirred for three hours. The reaction mixture was filtered, and the filtrate was then concentrated under reduced pressure. The resulting residue was subjected to a silica gel column chromatography to give 1-{3-ethynyl-2-[2-methyl-4-(3,4,5-trimethyl-pyrazol-1-yl)-phenoxymethyl]-phenyl}-4-methyl-1,4-dihydrotetrazole-5-one (hereinafter, referred to as “Present compound 20”) 0.07 g.
Reaction SMILES: [CH2:1]1[CH2:10][C:8](=[O:9])[C:4]2[CH:5]=[CH:6][S:7][C:3]=2[CH2:2]1.C(O[CH:14](OCC)[N:15]([CH3:17])[CH3:16])C>>[CH3:14][N:15]([CH:17]=[C:10]1[CH2:1][CH2:2][C:3]2[S:7][CH:6]=[CH:5][C:4]=2[C:8]1=[O:9])[CH3:16]
Reactant: CCOC(OCC)N(C)C
Reactant: O=C1CCCc2sccc21
Product: CN(C)C=C1CCc2sccc2C1=O

Procedure:
The 5-(dimethylaminomethylene)-4-oxo-4,5,6,7-tetrahydrobenzo[b]-thiophene starting material was prepared from 4-keto-4,5,6,7-tetrahydrothianaphthene (5.0 g, 33 mmol) and N,N-dimethylformamide diethyl acetal (15 ml, 87.5 mmol) to give the desired product as large yellow crystals (2.3 g) after recrystallisation from ethyl acetate m.p. 106.9°. MS (ES+) 208 (MH+, 100%).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[C:9]([C:11](O)=[O:12])[S:8][C:7]=2[CH:14]=1.C(Cl)(C([Cl:21])=O)=O>C(Cl)Cl.CN(C=O)C>[F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[C:9]([C:11]([Cl:21])=[O:12])[S:8][C:7]=2[CH:14]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc2ccc(C(F)(F)F)cc2s1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cc2ccc(C(F)(F)F)cc2s1
Reaction time: 20 h

Procedure:
To a mixture of 6-(trifluoromethyl)benzo[b]thiophene-2-carboxylic acid 4a (65 mg, 0.26 mmol) in CH2Cl2 (2.5 mL) was added (COCl)2 (0.026 mL, 0.30 mmol), followed by DMF (1 drop) at room temperature. The reaction was kept at room temperature for 20 h. The resulting solution was concentrated to give compound 4b.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH2:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.[F:16][C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19](Cl)=[O:20]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][C:19](=[O:20])[C:18]3[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=3[F:16])[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: O=C(Cl)c1ccccc1F
Reactant: NC1CCCc2c1[nH]c1ccc(Br)cc21
Product: O=C(NC1CCCc2c1[nH]c1ccc(Br)cc21)c1ccccc1F

Procedure:
N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2-fluorobenzamide was prepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine and 2-fluorobenzoyl chloride in a similar manner as described above to give a yellow solid (57% yield). 1H-NMR (CDCl3): δ 8.91 (s, 1H), 8.15 (m, 1H), 7.62 (m, 1H), 7.50 (m, 1H), 7.30 (m, 1H), 7.23 (dd, 1H), 7.18 (d, 1H), 7.12 (m, 2H), 5.35 (m, 1H), 2.72 (m, 2H), 2.31 (m, 1H), 1.98 (m, 3H); MS m/z 387 (M−1).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[Br:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([NH:20]O)=[O:19])=[C:16]([OH:24])[CH:15]=1>O1CCCC1>[Br:13][C:14]1[CH:23]=[CH:22][C:17]2[C:18](=[O:19])[NH:20][O:24][C:16]=2[CH:15]=1
Reactant: O=C(NO)c1ccc(Br)cc1O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=c1[nH]oc2cc(Br)ccc12
Reaction time: 2 h
Yield: 71.6 %

Procedure:
A solution of carbonyldiimidazole (0.75 g) in dry tetrahydrofuran (15 ml) was added to a refluxing solution of 4-bromo-N,2-dihydroxybenzamide (Intermediate 23) (0.56 g) in dry tetrahydrofuran (10 ml) then stirred for 2 h. The solvent was removed under vacuum, the residue was suspended in water and 2N hydrochloric acid (10 ml) was added. The resulting precipitate was collected by filtration, washed with water then cyclohexane and dried to give the title compound as a cream solid (0.37 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:15])[CH:5]=[N:6][C:7]=1[O:8][C@@H:9]([CH3:14])[C:10]([F:13])([F:12])[F:11].[Cl:16][C:17]1[C:18](F)=[CH:19][C:20]([F:33])=[C:21]([CH:32]=1)[C:22]([O:24][C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1)=[O:23].C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[Cl:16][C:17]1[C:18]([O:15][C:4]2[CH:5]=[N:6][C:7]([O:8][C@@H:9]([CH3:14])[C:10]([F:11])([F:12])[F:13])=[C:2]([Cl:1])[CH:3]=2)=[CH:19][C:20]([F:33])=[C:21]([CH:32]=1)[C:22]([O:24][C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1)=[O:23]
Reactant: Cc1ccc(OC(=O)c2cc(Cl)c(F)cc2F)cc1
Reactant: C[C@H](Oc1ncc(O)cc1Cl)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1ccc(OC(=O)c2cc(Cl)c(Oc3cnc(O[C@@H](C)C(F)(F)F)c(Cl)c3)cc2F)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 85.7 %

Procedure:
To a mixture of 5-chloro-6-[(1S)-2,2,2-trifluoro-1-methylethoxy]pyridin-3-ol (Preparation 231, 60 mg, 0.25 mmol) and 4-methylphenyl 5-chloro-2,4-difluorobenzoate (Preparation 26, 70 mg, 0.25 mmol) in DMSO (1 mL) was added K2CO3 (69 mg, 0.50 mmol) at room temperature under N2 and the resulting mixture was stirred for 4 hours. The reaction mixture was warmed up to 50° C. and stirred for 1 hour before cooling to room temperature and stirring for 18 hours. The reaction was quenched with water and partitioned between water and DCM (3×5 mL). The mixture was filtered through a phase separation cartridge, the organic phase was washed with brine (3 mL) and filtered through another phase separation cartridge. The filtrate was dried by N2 blowing to give a crude product that was purified by silica gel column chromatography eluting with 0-20% EtOAc in heptane to give the title compound (108 mg, 86%) as colourless gum.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4].Br[CH2:32][C:33]([O:35][CH3:36])=[O:34]>>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([O:30][CH2:32][C:33]([O:35][CH3:36])=[O:34])=[CH:28][CH:29]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(O)cc1
Reactant: COC(=O)CBr
Product: COC(=O)COc1ccc(Cn2c(C(=O)OC)c(-c3ccccc3)c3cc(Br)ccc3c2=O)cc1

Procedure:
The present compound was synthesized by a method similar to that in Example 259 and using 6-bromo-2-(4-hydroxybenzyl)-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (310 mg) and methyl bromoacetate. Colorless crystals (300 mg). 1H-NMR (CDCl3) δ: 3.23 (3H, s), 3.78 (3H, s), 4.59 (2H, s), 5.34 (2H, s), 6.82 (2H, d, J=8.7 Hz), 7.22 (2H, d, J=8.7 Hz), 7.24-7.31 (2H, m), 7.37 (1H, d, J=1.8 Hz), 7.40-7.49 (3H, m), 7.65 (1H, dd, J=1.8, 8.7 Hz), 8.39 (1H, d, J=8.7 Hz). HPLC analysis: purity 100% (retention time: 4.80 min). MS (ESI+): 536 (M+H), 538.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[N:7]([CH3:19])[C:8]1[S:12][C:11]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[N:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:21]N1C(=O)CCC1=O>C(#N)C>[C:1]([O:5][C:6](=[O:20])[N:7]([C:8]1[S:12][C:11]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[N:10][C:9]=1[Cl:21])[CH3:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CN(C(=O)OC(C)(C)C)c1cnc(-c2cccnc2)s1
Solvent: CC#N
Product: CN(C(=O)OC(C)(C)C)c1sc(-c2cccnc2)nc1Cl
Temperature: 45 °C
Reaction time: 16 h
Yield: 62.6 %

Procedure:
To a solution of methyl-(2-pyridin-3-yl-thiazol-5-yl)-carbamic acid tert-butyl ester (3.0 g, 10.29 mmol) in acetonitrile (60 mL) was added N-chlorosuccinimide (2.75 g, 20.58 mmol) in one portion and the reaction mixture was stirred at 45° C. for 16 h. The reaction mixture was concentrated and the crude product was purified by silica gel chromatography (0 to 100% ethyl acetate/hexanes) to give the desired product as a yellow solid (2.10 g, 62%): mp 119-122° C.; IR (KBr) 1718 cm−; 1H NMR (300 MHz, CDCl3) δ 9.08 (s, 1H), 8.67 (d, J=4.2 Hz, 1H), 8.22-8.16 (m, 1H), 7.39 (dd, J=7.9, 5.0 Hz, 1H), 3.26 (s, 3H), 1.46 (s, 9H); ESIMS m/z 326 (M+1).