Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:6]([CH3:7])=[C:5]([C:8]2[CH:9]=[C:10]([C:13]([O:15]C)=[O:14])[S:11][CH:12]=2)[N:4]([CH3:17])[N:3]=1.[OH-].[Na+]>O1CCCC1>[Cl:1][C:2]1[C:6]([CH3:7])=[C:5]([C:8]2[CH:9]=[C:10]([C:13]([OH:15])=[O:14])[S:11][CH:12]=2)[N:4]([CH3:17])[N:3]=1
Reactant: COC(=O)c1cc(-c2c(C)c(Cl)nn2C)cs1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1c(Cl)nn(C)c1-c1csc(C(=O)O)c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 66.2 %

Procedure:
To a 100 mL round-bottomed flask was added methyl 4-(3-chloro-1,4-dimethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (2.15 g, 7.94 mmol) in Tetrahydrofuran (THF) (30 ml). 6N NaOH (30 mL, 180 mmol) was added slowly and the reaction stirred at 70° C. overnight. The reaction was cooled to room temperature, partitioned between CHCl3 and H2O and the pH of the aqueous layer adjusted to ˜3 by the addition of 6N HCl. The layers were separated, the organic layer dried with Na2SO4 and solvent removed affording the title compound (1.35 g, 5.26 mmol, 66%) which was used in the next step without further purification LC-MS (ES) m/z=257 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH:9]2[NH:13][N:12]=[C:11]3[C:14](=[CH:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=4)[CH2:15][S:16](=[O:19])(=[O:18])[CH2:17][CH:10]23)[CH:6]=[CH:7][CH:8]=1.O.[C:34](OC(=O)C)(=[O:36])[CH3:35]>C(O)(=O)C>[C:34]([N:13]1[CH:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:31])([F:1])[F:32])[CH:4]=2)[CH:10]2[CH2:17][S:16](=[O:19])(=[O:18])[CH2:15][C:14](=[CH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:29])[F:30])[CH:22]=3)[C:11]2=[N:12]1)(=[O:36])[CH3:35]
Reactant: CC(=O)OC(C)=O
Reactant: O=S1(=O)CC(=Cc2cccc(C(F)(F)F)c2)C2=NNC(c3cccc(C(F)(F)F)c3)C2C1
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)N1N=C2C(=Cc3cccc(C(F)(F)F)c3)CS(=O)(=O)CC2C1c1cccc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
A suspension of 2,3,3a,4,6,7-hexahydro-3-[3-(trifluoromethyl)phenyl]-7-[[3-(trifluoromethyl)phenyl]methylene]thiopyrano[4,3-c]pyrazole-5,5-dioxide in 2ml of acetic anhydride and 25ml of acetic acid is heated on a steam bath for 15 minutes with occasional swirling. About 10ml of hot water is added and the solution is allowed to cool to room temperature. The solids are collected and washed with acetic acid/water (3/2) and water, and dried in vacuo over phosphorus pentoxide at 50°C to give 1.56g of the title compound, melting point 200°-202.5°C.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:12]=[CH:11][C:10]2[CH:9]=[N:8][CH:7]=[CH:6][C:5]=2[C:4]=1[NH2:13].[F:16][C:17]([F:29])([F:28])[C:18]1[CH:27]=[CH:26][C:21]([CH2:22][N:23]=[C:24]=[O:25])=[CH:20][CH:19]=1>C1(C)C=CC=CC=1.C(Cl)Cl>[F:15][C:2]([F:1])([F:14])[C:3]1[C:4]([NH:13][C:24]([NH:23][CH2:22][C:21]2[CH:20]=[CH:19][C:18]([C:17]([F:16])([F:29])[F:28])=[CH:27][CH:26]=2)=[O:25])=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[N:8][CH:7]=[CH:6]2
Reactant: Nc1c(C(F)(F)F)ccc2cnccc12
Reactant: O=C=NCc1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=C(NCc1ccc(C(F)(F)F)cc1)Nc1c(C(F)(F)F)ccc2cnccc12
Reaction time: 96 h
Yield: 4 %

Procedure:
To a solution of 6-(trifluoromethyl)isoquinolin-5-amine (Description 98; 100 mg, 0.47 mmol) in anhydrous toluene (5 ml) was added [4-(trifluoromethyl)benzyl]isocyanate (Description 58) [0.506M soln in DCM] (1.88 ml; 0.94 mmol) and the mixture heated at reflux overnight. Further [4-(trifluoromethyl)benzyl]isocyanate [0.506M soln in DCM] (1.88 ml; 0.94 mmol) was added and heating continued for 4 days. The toluene was removed, the residue dissolved in methanol (10 ml) and a spatula end of potassium carbonate added. The mixture was then heated at reflux for 15 mins. The mixture was cooled and filtered and the filtrate evaporated. The residue was purified by mass directed HPLC to give the title compound (8 mg, 4%) as a white solid. m/z (ES+) 414 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:35]2[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH:36]=2)O1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[CH:3]=[C:2]([C:35]2[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH:36]=2)[N:7]=[C:6]2[N:8]([CH:11]([CH3:13])[CH3:12])[N:9]=[CH:10][C:5]=12)=[O:15]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)nc3c2cnn3C(C)C)c(=O)[nH]1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(CNC(=O)c2cc(C3=CCN(C(=O)OC(C)(C)C)CC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 100 °C
Reaction time: 1 h
Yield: 72.7 %

Procedure:
A solution of 6-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (3.1 g, 7.4 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (2.7 g, 8.7 mmol) and Pd(PPh3)4 (0.428 g, 0.370 mmol) in 1,4-dioxane (20 mL) was purged with argon for 10 min. Then, 2M Na2CO3 (2.8 g, 26.41) was added to it and again argon was purged through it for 10 min. The reaction mixture was stirred at 100° C. for 1 h. After completion of the reaction, water was added to it and extraction was carried out using EtOAc. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography to give the desired intermediate (2.8 g, 73.7%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([NH:20][N:21]2[CH2:25][CH2:24][CH2:23][CH:22]2[O:26][CH2:27][CH3:28])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@H:9]1[O:17][C@H:14]([CH2:15]O)[C@@H:12]([OH:13])[C@H:10]1[OH:11].S(Cl)([Cl:31])=O.N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>C(#N)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:20][N:21]2[CH2:25][CH2:24][CH2:23][CH:22]2[O:26][CH2:27][CH3:28])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@H:9]1[O:17][C@H:14]([CH2:15][Cl:31])[C@@H:12]([OH:13])[C@H:10]1[OH:11]
Reactant: CCOC1CCCN1Nc1nc(Cl)nc2c1ncn2[C@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: c1ccncc1
Product: CCOC1CCCN1Nc1nc(Cl)nc2c1ncn2[C@H]1O[C@H](CCl)[C@@H](O)[C@H]1O
Reaction time: 8 h

Procedure:
The title compound was prepared according to general method C. (S)-2-Chloro-N-[2-(methylmethoxy)-1-pyrrolidinyl]adenosine [Knutsen, L. J. S., Lau, J., Sheardown, M. J., Thomsen, C.; Bioorganic and Medicinal Chemistry Letters, 1993, 3, 2661-2666](0.35 g, 0.8 mmol) was dissolved in acetonitrile (5 ml) and cooled on an ice-water bath. Under a nitrogen atmosphere, thionyl chloride (0.34 g, 0.2 ml, 2.4 mmol) (see Borchardt, R. T., Huber, J. A. and Wu, Y. S., Journal of Organic Chemistry, 1976, 41, 565-567) was added and a precipitate appeared which dissolved over the following 15 min. Pyridine (0.13 ml, 0.13 g, 1.6 mmol) was introduced gradually, the reaction mixture became yellow in colour and was allowed to reach room temperature gradually. After stirring the mixture overnight, ice was added and the reaction mixture was neutralised to pH 7 with aqueous sodium bicarbonate prior to extraction with ethyl acetate (2×10 ml). The combined extracts were dried (MgSO4) and evaporated to provide the intermediate 2,3-O-sulphinyl derivative (0.35 g), to which was added methanol (5 ml), water (1 ml) and 25% aqueous ammonia solution (0.25 ml) and this mixture was stirred for 16 h. The solution was evaporated in vacuo, and the resultant residue was purified by flash chromatography on silica gel eluting with a mixture of dichloromethane and 10% ammonia in ethanol (17:3), to provide the title (S)-2,5'-dichloro-5'-deoxy-N-[2-(methylmethoxy)-1-pyrrolidinyl]adenosine (0.12 g, 34%) as a foam, 1H-NMR (400 MHz, DMSO-d6) δ1.50-1.60 (1H, br, pyrrolidine C--H), 1.78 (2H, br q, pyrrolidine C--H), 1.92-2.03 (1H, br, pyrrolidine C--H), 3.85, 3.95 (2H, ABX, H-5'a and H-5'b), 4.09 (1H, br dd, H-4'), 4.17 (1H, dd, H-3'), 4.67 (1H, dd, H-2'), 5.49, 5.62 (2H, 2d, 2'- and 3'-OH), 5.87 (1H, d, H-1'), 8.38 (1H, s, H-8), 9.34 (1H, br s, --NH). HPLC retention time 9.65 min. (gradient elution over 30 min.; 20-80% acetonitrile/0.1% TFA in water, 99% purity at 250 nm). C16H22Cl2N6O4.0.25 H2O requires C, 43.9; H, 5.2; N, 19.2. Found: C, 43.7; H, 5.4; N, 19.4%.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([CH2:11][C:12]([OH:14])=[O:13])[CH:3]=1>C(OC(=O)C)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:9][CH:10]=1)[C:6](=[O:8])[O:14][C:12](=[O:13])[CH2:11]2
Reactant: O=C(O)Cc1cc(Br)ccc1C(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C1Cc2cc(Br)ccc2C(=O)O1

Procedure:
A solution of 4-bromo-2-carboxymethyl-benzoic acid (200 mg, 1.1 mmol) in 2 mL acetic anhydride was refluxed for 10 h. Then the mixture was concentrated to dryness and the crude 6-bromoisochroman-1,3-dione was used into the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]2=[O:12].[N+:13]([CH3:16])([O-:15])=[O:14]>O>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]2([OH:12])[CH2:16][N+:13]([O-:15])=[O:14]
Reactant: O=C1Nc2c(Cl)cccc2C1=O
Reactant: C[N+](=O)[O-]
Solvent: O
Product: O=C1Nc2c(Cl)cccc2C1(O)C[N+](=O)[O-]
Temperature: 30 °C
Reaction time: 24 h

Procedure:
7-chloroisatin (0.09 g) and nitromethane (0.1 ml) were added to water and the reaction mixture was vigorously stirred at a temperature of 30° C. for 24 hours. The obtained product was extracted with ethyl acetate and the solvent was removed to give pure product.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([OH:22])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20]=[CH2:21].C(N(CC)CC)C>C(Cl)Cl.O>[CH:11](=[O:22])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20]=[CH2:21]
Reactant: C=CCCCCCCCCCO
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCCCCCCCCC=O
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 102.7 %

Procedure:
Under an argon atmosphere, a stirred solution of 82.0 grams (0.646 mole) of oxalyl chloride in 600 ml of methylene chloride was cooled to -50° to -60° C., and a solution of 100.9 grams (1.292 moles) of dimethyl sulfoxide in 120 ml of methylene chloride was added dropwise during a 10-15 minute period. The reaction mixture temperature was maintained at -50° to -60° C. during the addition. Upon completion of addition, the reaction mixture was stirred for two minutes, and then a solution of 100.0 grams (0.587 mole) of 10-undecen-1-ol in 130 ml of methylene chloride was added dropwise during a 15 minute period while maintaining the reaction mixture temperature at -50° to -60° C. Upon completion of addition, the reaction mixture was stirred for 15 minutes, and then 297.1 grams (2.936 moles) of triethylamine was added dropwise during a five minute period while still maintaining the reaction mixture temperature at -50° to -60° C. Upon completion of addition, the reaction mixture was stirred as it was allowed to warm to ambient temperature. After this time 700 ml of water was stirred with the reaction mixture. The water layer was separated and washed with two 160 ml portions of methylene chloride. The washes were combined with the organic layer, and the combination was washed with three 160 ml portions of an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate and was then filtered. The filtrate was concentrated under reduced pressure to an oil/solid residue. The residue was stirred with 400 ml of pentane, and the solid was separated by filtration. The filtrate was concentrated under reduced pressure yielding 101.4 grams of 10-undecenal as an oil. The ir spectrum was consistent with the proposed structure.
Reaction SMILES: [CH2:1]1[CH:5]([OH:6])[CH2:4][NH:3][CH2:2]1.[C:7]1([NH:13][C:14]([C:16]2[CH:21]=[C:20](Br)[CH:19]=[CH:18][N:17]=2)=[O:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(Cl)(Cl)Cl.CO>C(O)CCC>[C:7]1([NH:13][C:14]([C:16]2[CH:21]=[C:20]([N:3]3[CH2:2][CH2:1][CH:5]([OH:6])[CH2:4]3)[CH:19]=[CH:18][N:17]=2)=[O:15])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: OC1CCNC1
Reactant: O=C(Nc1ccccc1)c1cc(Br)ccn1
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CCCCO
Product: O=C(Nc1ccccc1)c1cc(N2CCC(O)C2)ccn1
Yield: 61.5 %

Procedure:
A solution of dl-3-pyrrolidinol (0.17 g, 1.95 mmol) and 4-bromo-pyridine-2-carboxylic acid phenylamide (0.36 g, 1.3 mmol) in 1-butanol (25 mL) was heated at 100° C. for 15 hours. The reaction was applied to silica gel (25 g) and eluted with chloroform then chloroform:methanol 9:1 to give the title compound 227 mg (0.80 mmol, 61%).
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:8]([CH:9]2[CH2:11][CH2:10]2)[C:7]2[C:12]([C:16]([NH:18][CH3:19])=[O:17])=[CH:13][CH:14]=[CH:15][C:6]=2[N:5]=1)[CH3:3].Cl[C:21]1[N:26]=[CH:25][N:24]=[C:23]([NH2:27])[C:22]=1[I:28].CCN(C(C)C)C(C)C>C(O)CCC>[NH2:27][C:23]1[N:24]=[CH:25][N:26]=[C:21]([NH:1][C@H:2]([C:4]2[N:8]([CH:9]3[CH2:10][CH2:11]3)[C:7]3[C:12]([C:16]([NH:18][CH3:19])=[O:17])=[CH:13][CH:14]=[CH:15][C:6]=3[N:5]=2)[CH3:3])[C:22]=1[I:28]
Reactant: Nc1ncnc(Cl)c1I
Reactant: CNC(=O)c1cccc2nc([C@H](C)N)n(C3CC3)c12
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1cccc2nc([C@H](C)Nc3ncnc(N)c3I)n(C3CC3)c12
Temperature: 120 °C
Reaction time: 18 h

Procedure:
A mixture of (S)-2-(1-aminoethyl)-1-cyclopropyl-N-methyl-1H-benzo[d]imidazole-7-carboxamide (Prepared in Example 20, 190 mg, 0.74 mmol), 6-chloro-5-iodopyrimidin-4-amine (188 mg, 0.736 mmol) and 1,1′-dimethyltriethylamine (256 μL, 1.47 mmol) in n-butanol (2 mL) was stirred at 120° C. After 18 h, the mixture was cooled to rt and concentrated under reduced pressure. The residue was purified by column chromatography on a silica gel column using 0 to 10% gradient of MeOH in DCM-EtOAc (1:1) as eluent to give (S)-2-(1-(6-amino-5-iodopyrimidin-4-ylamino)ethyl)-1-cyclopropyl-N-methyl-1H-benzo-[d]imidazole-7-carboxamide: 1H NMR (400 MHz, DMSO-d6) δ 8.46-8.40 (m, 1H), 7.87 (s, 1H), 7.67 (d, J=8 Hz, 1H), 7.24 (d, J=8 Hz, 1H), 7.20 (dd, J=8, 8 Hz, 1H), 6.46 (m, 1H), 6.37 (d, J=8 Hz, 1H), 5.82-5.75 (m, 1H), 2.84 (d, J=4 Hz, 3H), 1.60 (d, J=8 Hz, 3H), 1.14-1.04 (m, 2H), 0.93-0.90 (m, 1H), 0.85-0.76 (m, 1H); LC-MS (ESI) m/z 478.0 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1.[C:8]([OH:12])(=[O:11])[CH:9]=[CH2:10].C(=O)([O-])[O-].[K+].[K+].ClCCl>C(N(CCCC)CCCC)CCC.CC(O)=O.CC(O)=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[N:4]1[CH:3]=[C:2]([CH:10]=[CH:9][C:8]([OH:12])=[O:11])[CH:7]=[N:6][CH:5]=1
Reactant: Brc1cncnc1
Reactant: C=CC(=O)O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCCCN(CCCC)CCCC
Solvent: CC(=O)O
Product: O=C(O)C=Cc1cncnc1
Temperature: 152.5 °C
Reaction time: 4.5 h
Yield: 37.1 %

Procedure:
A mixture of 5-bromopyrimidine (100 g), acrylic acid (48 g), triphenylphosphine (2.5 g) and palladium II acetate (0.1 g) was refluxed in tri-n-butylamine (260 ml) with overhead stirring for 4.5 h at 145-160° C. The mixture was cooled and a 10% solution of potassium carbonate (2 L) added followed by dichloromethane (500 mL). The organic layer was separated and the aqueous phase extracted with diethyl ether (3×300 ml). The aqueous layer was brought to pH 3 with concentrated hydrochloric acid (ice-cooling) and the solid so formed was filtered and dried in vacuo to give 3-(5-pyrimidyl)acrylic acid (35 g). 1H-NMR (d6-DMSO) δ 6.82(1H, d), 7.60(1H, d) and 9.15(3H, 2xs)
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)=[O:10].Cl[C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][N:22]=1>CS(C)=O.C(OCC)(=O)C>[CH3:7][O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=[CH:23][N:22]=2)[CH:12]=1)=[O:10]
Reactant: Clc1nccc2ccccc12
Reactant: COC(=O)c1c[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cn(-c2nccc3ccccc23)c2ccccc12
Temperature: 20 °C
Reaction time: 1 h
Yield: 89.3 %

Procedure:
1.73 g (12.5 mmol) of potassium carbonate are added at 20° C. under an argon atmosphere to 0.876 g (5 mmol) of 3-methoxycarbonyl-1H-indole in 10 cm3 of dimethyl sulphoxide. After stirring at 20° C. for 1 hour, 0.818 g (5 mmol) of 1-chloroisoquinoline is added. After stirring at 100° C. for 19 hours, the reaction mixture is cooled and diluted with 20 cm3 of ethyl acetate and then washed with 3 times 20 cm3 of water and 20 cm3 of saturated aqueous sodium chloride solution. After separating the phases by settling, the organic phase is dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) to give 1.35 g of 3-methoxycarbonyl-1-(isoquinol-1-yl)-1H-indole in the form of a white solid melting at 140° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:15](=[CH:16][CH:17]=1)[O:14][C:7]1[C:8]([F:13])=[N:9][C:10]([Cl:12])=[CH:11][C:6]=1[C:5]2=O.[CH3:19][C:20]([S:23]([NH2:25])=[O:24])([CH3:22])[CH3:21].C(=O)(O)[O-]>C1COCC1.[Cl-].[Na+].O.C(O[Ti](OCC)(OCC)OCC)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:15](=[CH:16][CH:17]=1)[O:14][C:7]1[C:8]([F:13])=[N:9][C:10]([Cl:12])=[CH:11][C:6]=1[C:5]2=[N:25][S:23]([C:20]([CH3:22])([CH3:21])[CH3:19])=[O:24]
Reactant: O=c1c2cc(Br)ccc2oc2c(F)nc(Cl)cc12
Reactant: CC(C)(C)S(N)=O
Agent: CCO[Ti](OCC)(OCC)OCC
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)S(=O)N=c1c2cc(Br)ccc2oc2c(F)nc(Cl)cc12
Temperature: 75 °C
Reaction time: 1 h

Procedure:
A mixture of 7-bromo-3-chloro-1-fluoro-5H-chromeno[2,3-c]pyridin-5-one (740 mg, 2.25 mmol, Example 4), 2-methyl-2-propane-sulfinamide (819 mg, 6.76 mmol, Aldrich), and tetraethoxytitanium (6.07 mL, 29.3 mmol, Aldrich) in dry THF (15 mL) was heated at 75° C. for 24 hours under nitrogen atmosphere. The mixture was cooled to RT and brine and aqueous, saturated bicarbonate solution were added while rapidly stirring. After 1 h, the resulting suspension was filtered through celite, and the filter cake was washed with EtOAc. The filtrate was washed with brine and dried over MgSO4. The solvent was removed under reduced pressure and the remaining residue was purified by flash chromatography on silica gel (0-20% EtOAc/hexanes) to afford the title product as an orange solid. MS m/z=423.8 [M+H]+. Calculated for C16H13BrClFN2O2S: 431.71.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=1.II.S([O-])([O-])(=O)=O.[Mg+2]>CC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[C:11]2[C:12](=[CH:13][CH:14]=1)[NH:15][C:4]([CH3:9])([CH3:5])[CH:3]=[C:8]2[CH3:7]
Reactant: COc1ccccc1-c1ccc(N)cc1
Agent: II
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC(C)=O
Product: COc1ccccc1-c1ccc2c(c1)C(C)=CC(C)(C)N2
Temperature: 120 °C
Yield: 34.2 %

Procedure:
A mixture of 10 g of 2-methoxy-4′-aminobiphenyl, 4.4 g of iodine, 44 g of magnesium sulfate and 600 mL of acetone was heated in a sealed flask at 120° C. overnight. The reaction mixture was cooled down to room temperature and filtered through diatomaceous earth. The residue was rinsed with acetone and the solvent was evaporated in vacuo. The residue was purified by flash chromatography to yield 2.4 g of 6-(2-methoxyphenyl)-2,2,4-trimethyl-1,2-dihydroquinoline as a foam.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([O:9][C:10]2[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=2)[CH:6]=[CH:7][CH:8]=1.[BH4-].[Na+]>CO>[F:1][C:2]([F:18])([F:19])[C:3]1[CH:4]=[C:5]([O:9][C:10]2[CH:17]=[CH:16][C:13]([CH2:14][OH:15])=[CH:12][CH:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=Cc1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 121.4 %

Procedure:
A solution of 4-{[3-(Trifluoromethyl)phenyl]oxy}benzaldehyde (4.1 g, 9.55 mmol) in methanol (50 mL) at 0° C. was added sodium borohydride (1.0 g, 26.4 mmol) in portions. The reaction mixture was allowed to warm to rt and stirred for 1 h, then quenched with acetone, concentrated. Purification via ISCO system afforded the title product (3.11 g) as a colorless liquid. LC-MS (ESI): m/z 251 [M-OH]+; 3.23 min (ret time).
Reaction SMILES: CCN(C(C)C)C(C)C.CN([C:13]([O:17][N:18]1N=NC2C=CC=C[C:19]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:34][C:35]1[CH:46]=[CH:45][C:38]2[C:39]([C:42](O)=[O:43])=[N:40][S:41][C:37]=2[CH:36]=1.Cl.CNOC>CN(C=O)C>[Br:34][C:35]1[CH:46]=[CH:45][C:38]2[C:39]([C:42]([N:18]([O:17][CH3:13])[CH3:19])=[O:43])=[N:40][S:41][C:37]=2[CH:36]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C(O)c1nsc2cc(Br)ccc12
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1nsc2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.4 %

Procedure:
DIEA (11.7 mL, 67.4 mmol) and HBTU (7.03 g, 18.5 mmol) were added to a solution of 6-bromobenzo[d]isothiazole-3-carboxylic acid (4.35 g, 16.9 mmol) and N,O-dimethylhydroxylamine hydrochloride (2.14 g, 21.9 mmol) in DMF (100 mL). The reaction was stirred at room temperature for 2 hours. The mixture was partitioned between water and EtOAc. The organic layer was washed with aqueous NaHCO3 solution and brine, dried and concentrated. The residue was purified by column chromatography (hexane:EtOAc, 3:1) to give 6-bromo-N-methoxy-N-methylbenzo[d]isothiazole-3-carboxamide (4.60 g, 91%) as a solid. 1H NMR (CDCl3, 400 MHz) δ □8.12 (m, 2H), 8.59 (d, J=8.8 Hz, 1H), 3.83 (s, 3H), 3.49 (s, 3H).
Reaction SMILES: [C:1]([O:4][C:5]1[C:13]([O:14][CH3:15])=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][C:6]=1[O:16][CH3:17])(=[O:3])[CH3:2].S(Cl)([Cl:20])=O>C(COC)OC>[C:1]([O:4][C:5]1[C:13]([O:14][CH3:15])=[CH:12][C:8]([C:9]([Cl:20])=[O:10])=[CH:7][C:6]=1[O:16][CH3:17])(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: COc1cc(C(=O)O)cc(OC)c1OC(C)=O
Solvent: COCCOC
Product: COc1cc(C(=O)Cl)cc(OC)c1OC(C)=O
Reaction time: 1.5 h
Yield: 102.5 %

Procedure:
4-Acetoxy-3,5-dimethoxy-benzoic acid (1.45 g) was heated with thionyl chloride (0.86 g) in 3 mL of dimethoxyethane. After 1.5 hours the mixture was stripped under vacuum leaving 1.60 g of 4-acetoxy-3,5-dimethoxy-benzoyl chloride as an oil. 1H NMR (CDCl3, 300 MHz) δ (ppm): 2.26 (s, 3H), 3.89 (s, 9H), 7.34 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C@H:3]1[CH2:8][O:7][CH2:6][C@@H:5]([C:9]([O:11]C)=[O:10])[CH2:4]1.[Li+].[OH-]>CO>[CH3:1][O:2][C@H:3]1[CH2:8][O:7][CH2:6][C@@H:5]([C:9]([OH:11])=[O:10])[CH2:4]1
Reactant: COC(=O)[C@@H]1COC[C@H](OC)C1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CO[C@H]1COC[C@@H](C(=O)O)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 10.55 mmol of methyl (cis)-5-methoxytetrahydropyran-3-carboxylate in 45 ml of methanol is mixed with 45 ml of 1M LiOH and stirred at room temperature for one hour. The reaction mixture is evaporated, and the residue is taken up in dichloromethane. The pH is adjusted to 2 with 2M HCl, the phases are separated, and the aqueous phase is extracted with dichloromethane (2×). The combined organic phases are dried with sodium sulphate and evaporated. The crude title compound is identified by means of the Rf from the residue.