Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([C:19]1([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:21][CH2:20]1)[N:13]=2)[CH:5]=O.[NH:28]1[CH2:31][CH2:30][CH2:29]1.C(O)(=O)C.ClCCl.CO.C([BH3-])#N.[Na+]>>[N:28]1([CH2:5][C:4]2[CH:7]=[CH:8][C:9]([C:10]3[S:11][C:12]4[C:17]([N:18]=3)=[CH:16][CH:15]=[C:14]([C:19]3([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[CH2:21][CH2:20]3)[N:13]=4)=[C:2]([F:1])[CH:3]=2)[CH2:31][CH2:30][CH2:29]1
Reactant: C1CNC1
Reactant: O=Cc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CC(=O)O
Product: Fc1cc(CN2CCC2)ccc1-c1nc2ccc(C3(c4ccccc4)CC3)nc2s1
Reaction time: 0.17 h

Procedure:
A solution of 3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzaldehyde (0.102 g, 0.27 mmol), azetidine (0.037 mL, 0.54 mmol) and acetic acid (0.063 mL, 1.1 mmol) in dichloromethane (3.00 mL, 0.27 mmol) and methanol (2.00 mL, 0.27 mmol), was stirred for 60 min at ambient temperature. The reaction mixture was treated with sodium cyanoborohydride (0.0086 g, 0.14 mmol) and was stirred for 10 min, concentrated in vacuo, and adsorbed onto silica gel. Silica gel chromatography (20-30% EtOAc/hexanes, followed by 40% (3% Et3N/EtOAc)/hexanes gave the title compound. MS (ESI) m/z: Calculated: 415.2; Observed: 416.1 (M++1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[N:10]=[C:9]([OH:19])[CH:8]=2)[CH2:3][CH2:2]1.[NH2:20][C:21]1[N:26]=[CH:25][C:24]([CH:27]=O)=[CH:23][N:22]=1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.ClCCl>[NH2:20][C:21]1[N:26]=[CH:25][C:24]([CH2:27][N:1]2[CH2:6][CH2:5][CH:4]([C:7]3[N:12]=[C:11]([N:13]4[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]4)[N:10]=[C:9]([OH:19])[CH:8]=3)[CH2:3][CH2:2]2)=[CH:23][N:22]=1
Reactant: Nc1ncc(C=O)cn1
Reactant: Oc1cc(C2CCNCC2)nc(N2CCCCC2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: Nc1ncc(CN2CCC(c3cc(O)nc(N4CCCCC4)n3)CC2)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
A mixture of 6-piperidin-4-yl-2-piperidin-1-yl-pyrimidin-4-ol (2.0 mmol), 2-amino-pyrimidine-5-carbaldehyde (2.6 mmol), triethylamine (4.0 mmol) and 3 drops of acetic acid in dry dichloromethane (20 mL) was stirred at room temperature for 3 hours. Then sodium triacetoxyborohydride (6.0 mmol) was added in portions and stirring was continued for 48 hours (monitored by TLC). The mixture was quenched with saturated aqueous sodium bicarbonate solution (20 mL), and the product was extracted with dichloromethane (2×10 mL). The extracts were washed with brine and dried over sodium sulfate. The solvent was evaporated in vacuo to give a crude product. Purification via column chromatography (silica gel, ethyl acetate/hexane) afforded 6-[1-(2-Amino-pyrimidin-5-ylmethyl)-piperidin-4-yl]-2-piperidin-1-yl-pyrimidin-4-ol (606 mg, 82%)
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1[CH3:13])([O-:3])=[O:2].[CH2:14]([O:16][C:17](=[O:23])[C:18](OCC)=[O:19])[CH3:15].CC[O-].[Na+].Cl>C(O)C>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1[CH2:13][C:18](=[O:19])[C:17]([O:16][CH2:14][CH3:15])=[O:23])([O-:3])=[O:2]
Reactant: Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(=O)Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Temperature: 40 °C
Reaction time: 2 h

Procedure:
2,6-Dinitrotoluene (10.0 g, 54.9 mmol) and oxalic acid diethylester (16.1 g, 110 mmol) are dissolved in ethanol (100 ml). Sodium ethylate (apx 2.5 N in ethanol, 54.9 mmol) is added, the mixture is stirred at 40° C. for 2 h. The solution is cooled to room temperature, adjusted to pH=3-4 with 2N hydrochloric acid, the solvent is evaporated in vacuo, the residue is partitioned between ethyl acetate and water, the organic layer is washed with water twice, dried over magnesium sulfate, filtered and evaporated. The crude product is purified with column chromatography on silica gel (eluent: cyclohexane/ethyl acetate, 2:1). Yield: 3.15 g (20%), mixture of keto/enol tautomers
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[Br:21]Br>C(Cl)Cl.C(O)(=O)C>[Br:21][C:10]1[S:9][C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[C:12]([C:13]2[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=2)[CH:11]=1
Reactant: CSc1ccc(-c2ccsc2-c2ccc(F)cc2)cc1
Reactant: BrBr
Solvent: ClCCl
Solvent: CC(=O)O
Product: CSc1ccc(-c2cc(Br)sc2-c2ccc(F)cc2)cc1
Reaction time: 1.5 h

Procedure:
A solution of 2-(4-fluorophenyl)-3-(4-methylthiophenyl)thiophene (7.5 g, 25 mmole) in methylene chloride (75 ml) was diluted with 75 ml of acetic acid, cooled to about 5°, and treated dropwise with a 1M solution of bromine in acetic acid (28 ml, 1.1 equiv). The reaction mixture was stirred at 5° for 1.5 hours and then concentrated in vacuo. The residue was dissolved in ethyl acetate and the solution washed with saturated aqueous sodium bicarbonate and brine, dried, and evaporated. Recrystallization from methanol, with cooling in Dry Ice, gave the title compound in two crops (7.60 g), m.p. 75°-78°. Infrared and NMR spectral data were consistent with the assigned structure.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][C:3]=1B(O)O.[NH2:13][C:14]1[C:19](Cl)=[N:18][CH:17]=[CH:16][N:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.C1C=CC=CC=1.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>[NH2:13][C:14]1[C:19]([C:3]2[CH:4]=[C:5]([Cl:9])[CH:6]=[C:7]([Cl:8])[C:2]=2[Cl:1])=[N:18][CH:17]=[CH:16][N:15]=1
Reactant: Nc1nccnc1Cl
Reactant: OB(O)c1cc(Cl)cc(Cl)c1Cl
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: CCO
Solvent: c1ccccc1
Product: Nc1nccnc1-c1cc(Cl)cc(Cl)c1Cl

Procedure:
A solution of 2,3,5-trichlorobenzeneboronic acid (1.54 g, 6.82 mmol) in absolute ethanol (1-5 ml) was added slowly to a mixture of 2-amino-3-chloropyrazine (0.589 g, 4.54 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.299 g, 0.259 mmol) in benzene (10.5 ml)/2M aqueous sodium carbonate (4.54 ml). The mixture was refluxed for 17 hours. The cooled reaction mixture was partitioned between water and ethylacetate (50 ml). The organic layer was washed with water (2×30 ml), dried (MgSO4) and evaporated. The crude product was purified by flash chromatography using chloroform to 0.5%methanol/chloroform as the eluent. The product was then crystallised from 40-60 petrol. Yield 0.15 g, 12% M.p. 142-143° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:12])[CH2:6][CH2:5]2.[N+:18]([O-])([O:20]C(C)C)=[O:19].O>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([N+:18]([O-:20])=[O:19])[CH:10]=1)[N:7]([C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:12])[CH2:6][CH2:5]2
Reactant: CCOC(=O)C(=O)N1CCc2cc(Br)ccc21
Reactant: CC(C)O[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOC(=O)C(=O)N1CCc2cc(Br)cc([N+](=O)[O-])c21
Temperature: 0 °C
Reaction time: 1 h
Yield: 83.6 %

Procedure:
To a solution of 5-bromo-N-ethoxalylindoline (5.23 g, 17.5 mmol) in concentrated sulfuric acid was added slowly isopropyl nitrate (1.87 mL, 18.5 mmol) at 0° C. The mixture was stirred for 1 h at 0° C. and poured into a mixture of water and crashed ice. The mixture was extracted with ethyl acetate and the organic layer was washed with brine, dried over magnesium sulfate, and concentrated. The crude residue was purified by silica gel column chromatography to give 5.02 g of 5-bromo-7-nitro-N-ethoxalylindoline (83%): 1H NMR (270 MHz, CDCl3) δ7.91 (d, 1H, J=1 Hz), 7.62 (d, 1H, J=1 Hz), 4.39 (t, 2H, J=8 Hz), 4.38 (q, 2H, J=7 Hz), 3.22 (t, 2H, J=8 Hz), 1.39 (t, 3H, J=7 Hz).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:26])[N:10]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[CH:13]=2)=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:33](B(CC)CC)[CH3:34].O>CN(C)C=O>[CH2:33]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:26])[N:10]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[CH:13]=2)=[CH:4][N:3]=1)[CH3:34]
Reactant: CCB(CC)CC
Reactant: O=c1c(-c2ccc(Cl)nc2)cc(-c2ccccn2)cn1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1ccc(-c2cc(-c3ccccn3)cn(-c3ccccc3)c2=O)cn1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
13 mg of 3-(2-chloropyridin-5-yl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one was dissolved in 20 ml of dimethylformamide, followed by the addition of 10 mg of potassium carbonate and 2 mg of tetrakistriphenylphosphine palladium. Under stirring at room temperature in nitrogen atmosphere, triethylborane (1.0M tetrahydrofuran solution) was added dropwise thereinto, followed by heating under stirring at 100° C. for 1 hour in nitrogen atmosphere. After the reaction mixture was cooled to room temperature, water was added thereto, and extracted with ethyl acetate. The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel chromatography (hexane/ethyl acetate system), to give 4 mg of the title compound.
Reaction SMILES: C([O:8][CH2:9][CH2:10][N:11]1[C:17](=[O:18])[C@@H:16]([NH:19][C:20]([C@@H:22]([O:24][C:25](=[O:32])[NH:26][CH2:27][C:28]([F:31])([F:30])[F:29])[CH3:23])=[O:21])[C:15]2[CH:33]=[CH:34][CH:35]=[CH:36][C:14]=2[C:13]2[CH:37]=[CH:38][CH:39]=[CH:40][C:12]1=2)C1C=CC=CC=1.C(OCC)(=O)C>CCCCCCC>[OH:8][CH2:9][CH2:10][N:11]1[C:17](=[O:18])[C@@H:16]([NH:19][C:20]([C@@H:22]([O:24][C:25](=[O:32])[NH:26][CH2:27][C:28]([F:29])([F:30])[F:31])[CH3:23])=[O:21])[C:15]2[CH:33]=[CH:34][CH:35]=[CH:36][C:14]=2[C:13]2[CH:37]=[CH:38][CH:39]=[CH:40][C:12]1=2
Reactant: C[C@H](OC(=O)NCC(F)(F)F)C(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: C[C@H](OC(=O)NCC(F)(F)F)C(=O)N[C@@H]1C(=O)N(CCO)c2ccccc2-c2ccccc21
Yield: 70 %

Procedure:
Using (2,2,2-trifluoro-ethyl)-carbamic acid (S)-1-[(S)-5-(2-benzyloxy-ethyl)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-ylcarbamoyl]-ethyl ester, the title compound was prepared in the same manner as example 3. Final chromatography (silica, gradient of ethyl acetate in heptane 5-90%) afforded the title compound as white solid (70%). MS: m/e=466(M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C:7](=O)[CH2:6][CH2:5]2.[BH3-]C#[N:15].[Na+]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([NH2:15])[CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(Br)ccc2C1
Reactant: [BH3-]C#N
Agent: [Na+]
Product: NC1CCc2cc(Br)ccc2C1

Procedure:
(rac)-6-Bromo-1,2,3,4-tetrahydronaphthalen-2-ylamine is prepared from 6-Bromo-3,4-dihydro-1H-naphthalen-2-one (28) via a general procedure described previously for the reductive amination of ketones using NaBH3CN as reducing agent. (Borch, R. F.; Bernstein, M. D.; Durst, H. D. J. Am. Chem. Soc. 1971, 93, 2897-2904.). The purity of this material (brown oil) was >95%, as determined by 1H NMR spectroscopy, and was used without further purification. 1H NMR (CDCl3): δ 1.45 (br, 2H, NH2), 1.56 (m, 1H, H-3), 1.98 (m, 1H, H-3), 2.47 (dd, J=16.0 Hz, 9.5 Hz, 1H, H-1), 2.82 (m, 2H, H-4), 2.93 (dd, J=16.0 Hz, 4.5 Hz, 1H, H-1), 3.16 (m, 1H, H-2), 6.92 (d, J=8.0 Hz, 1H, H-8), 7.22 (m, 2H, overlapping H-5 and H-7). 13C NMR (CDCl3): δ 27.8 (CH2, C-4), 32.5 (CH2, C-3), 38.9 (CH2, C-1), 47.0 (CH, C-2), 119.3 (C—Br, C-6), 128.7 (CH, C-7), 130.9 (CH, C-8), 131.4 (CH, C-5), 134.3 (C-8a), 138.2 (C-4a). LCMS m/z calcd for C10H12BrN ([M]+) 225. Found 226 ([M+H]+).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH2:10]O.CS(OS(C)(=O)=O)(=O)=O.CC(=O)OCC.[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>C(Cl)Cl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH2:10][N:36]1[CH2:37][CH2:38][N:33]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][N:27]=2)[CH2:34][CH2:35]1
Reactant: OCc1cc2ccccc2s1
Reactant: c1ccc(N2CCNCC2)nc1
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: c1ccc(N2CCN(Cc3cc4ccccc4s3)CC2)nc1

Procedure:
The product from Example 8A (300 mg 1.8 mmol), methane sulfonic anhydride (313 mg, 1.8 mmol), and D1 EA (200 μL 5.4 mmol) were combined. After stirring, 1-(2-pyridinyl)piperazine (328 mg, 2.9 mmol) in 4 ml DCM was also combined and the mixture was processed as described in Example 8B to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 2.57 (m, 4H) 3.50 (m, 4H) 3.84 (s, 2H) 6.63 (m, 2H) 6.81 (d, J=8.48 Hz, 1H) 7.32 (m, 2H) 7.52 (m, 2H) 7.77 (m, 1H) 7.90 (m, 1H). (ESI) m/z 310 (M+H)+.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].C1C=CC=CC=1.S(=O)(=O)(O)[OH:13].[C:17]1([CH:24]=[CH:23][C:21]([OH:22])=[CH:20][CH:19]=1)O>O>[C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].[C:21]1(=[O:22])[O:13][CH2:20][CH2:19][CH2:17][CH2:24][CH2:23]1
Reactant: O=S(=O)(O)O
Reactant: Oc1ccc(O)cc1
Agent: C=CC(=O)O
Solvent: O
Solvent: c1ccccc1
Product: O=C1CCCCCO1
Temperature: 85 °C
Yield: 60 %

Procedure:
A 2000 ml glass reaction flask was equipped with a stirrer, thermometer and condenser, Dean-Stock trap air inlet and heating mantle and used as the reaction vessel. 300 grams of a trihydroxyfunctional polycaprolactone polyol with an average hydroxyl number of 310 and an average molecular weight of 540 (TONE-0305 obtained from Union Carbide Corporation), 88.4 g. of glacial acrylic acid, 150 ml. of benzene, 5 ml. of concentrated sulfuric acid and 5 g. of hydroquinone were added to the reaction flask at room temperature. The contents of the flask were then heated to about 85° C. over a period of one hour and maintained at reflux at atmospheric pressure until no further water was produced (about 4.5 hours). During the reaction, air was continually bubbled through the reaction. The reaction mixture was cooled to about 60° C. in a separatory funnel and about 50 ml of benzene added. Then, about 200 g of a 15 percent aqueous sodium hydroxide solution was dripped through the separatory funnel. A second aliquot of 200 g of a 15 percent aqueous sodium hydroxide solution was added and then the contents shaken. Excess acid and hydroquinone inhibitor were washed out by shaking the solution three times with 50 g of a 15 percent aqueous sodium hydroxide solution. After the contents settled, 10 g of magnesium sulfate was added while stirring to remove any remaining water, then the contents filtered to remove the magnesium sulfate. 100 parts per million of methylethyl hydroquinone based on the final product was added and the contents were then stripped of solvent. A 60 to 70% yield was obtained. The product had a viscosity of 250 centipoise.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([O:18][S:19]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)(=[O:21])=[O:20])=[CH:17][C:11]=2[N:10]=1.[CH:29]1([C:32](Cl)=[O:33])[CH2:31][CH2:30]1.C(N(CC)CC)C>ClCCl>[NH2:8][C:9]1[N:10]([C:32]([CH:29]2[CH2:31][CH2:30]2)=[O:33])[C:11]2[CH:17]=[C:16]([O:18][S:19]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)(=[O:20])=[O:21])[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: O=C(Cl)C1CC1
Reactant: Nc1nc2cc(OS(=O)(=O)c3ccc(F)cc3)ccc2[nH]1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc2ccc(OS(=O)(=O)c3ccc(F)cc3)cc2n1C(=O)C1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5.53 g of 4-fluoro-benzenesulfonic acid 2-amino-1H-benzoimidazol-5-yl ester trifluoroacetic acid salt were combinated with 1.8 ml of cyclopropanecarbonylchloride and 5 ml triethylamine in 75 ml dichloromethane. Reaction mixture was stirred at room temperature for 1 hour. Solvents were evaporated under reduced pressure. The residue was then taken up in dichloromethane, washed with water and dried with magnesium sulfate. Dichloromethane was evaporated under reduced pressure and precipitate obtained was dried on glass frit yielding 4.88 g of 4-fluoro-benzenesulfonic acid 2-amino-3-cyclopropanecarbonyl-3H-benzoimidazol-5-yl ester.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19](=[S:21])[NH2:20])=[CH:15]2)(=[O:8])=[O:7].Br[CH2:23][C:24](=O)[C:25]([O:27][CH2:28][CH3:29])=[O:26].C(O)C.CN(C)C(=O)C>O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]1[S:21][CH:23]=[C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:20]=1)=[CH:15]2)(=[O:7])=[O:8]
Reactant: CCOC(=O)C(=O)CBr
Reactant: NC(=S)c1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1
Solvent: CC(=O)N(C)C
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1csc(-c2cc3cccc(NS(=O)(=O)c4cccs4)c3[nH]2)n1
Temperature: 80 °C
Reaction time: 4 h
Yield: 36.3 %

Procedure:
A mixture of 7-[(2-thienylsulfonyl)amino]-1H-indole-2-carbothioamide (0.30 g), ethyl bromopyruvate (0.21 g), ethanol (2 mL) and N,N-dimethylacetamide (2 mL) was stirred at 80° C. for 4 hr. Water was added to the reaction mixture, and the obtained crystals were filtrated, washed with water and dried. The obtained crystals were recrystallized from ethyl acetate to give the title compound (0.14 g, yield 36%) as pale-yellow crystals. melting point 240-241° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([CH3:11])=[C:9]([O:12]C2CCCCO2)[CH:8]=[CH:7][C:4]=1[CH:5]=[O:6].Cl>C(O)C>[OH:12][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[C:3]([O:2][CH3:1])[C:10]=1[CH3:11]
Reactant: COc1c(C=O)ccc(OC2CCCCO2)c1C
Agent: Cl
Solvent: CCO
Product: COc1c(C=O)ccc(O)c1C
Yield: 72 %

Procedure:
2-Methoxy-3-methyl-4-(tetrahydro-2H-pyran-2-yloxy)benzaldehyde—for preparation see e.g. Journal of Medicinal Chemistry, 41, 4819-4832 (1998)—(2.10 g, 8.4 mmol) was dissolved in ethanol (40 mL) and then HCl (2M, 40 mL) was added. After 20 minutes the solution was concentrated under reduced pressure. The aqueous residue was extracted twice with EtOAc and the combined organic solutions were washed with brine. The solution was dried over Na2SO4 and the solvent was removed by evaporation. The product was washed with petroleum-ether. There was obtained 1.0 g (72%) of 52A as a solid. 1H NMR (500 MHz, CDCl3): δ 2.05 (s, 3H), 3.78 (s, 3H), 6.74 (d, 1H), 7.49 (d, 1H), 10.05 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1.CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:8]=[CH:14][N:15]([CH3:17])[CH3:16])=[O:7])=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(Br)ccc1C(N)=O
Reactant: COC(OC)N(C)C
Product: Cc1cc(Br)ccc1C(=O)N=CN(C)C
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
A mixture of 0.84 g of 4-bromo-2-methyl benzoic acid amide and 18 mL of N,N-dimethylformamide dimethylacetal was stirred at 70° C. for 30 minutes. After the completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was washed with 5 mL of hexane to obtain 0.67 g of the aimed product as white crystal.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C1(C)C=CC=CC=1.O>[CH3:19][S:20]([O:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=1)(=[O:22])=[O:21]
Reactant: CC(C)(C)c1cccc(O)c1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cccc(OS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 0.1 %

Procedure:
8.00 g (53.3 mol) of 3-tert-butylphenol and 5.93 g (58.6 mol) of triethylamine were dissolved in 80 mL of toluene followed by dropping in 6.71 g (58.6 mol) of methanesulfonyl chloride over the course of 10 minutes at 10° C. followed by stirring for 10 minutes at 25° C. and confirming the 3-tert-butylphenol to no longer be present by gas chromatography. The reaction liquid was placed in water and following separation of the organic layer, was washed three times with water, once with saturated aqueous NaHCO3 solution and once with saturated brine followed by drying with MgSO4, concentrating and purifying the resulting residue by vacuum distillation to obtain 10.7 g (yield: 88%) of 3-tert-butylphenyl methanesulfonate.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:8])=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:17]2[CH:18]=[N:19][N:20](C(OC(C)(C)C)=O)[CH:21]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>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>[F:8][C:5]1[CH:4]=[CH:3][C:2]([C:17]2[CH:18]=[N:19][NH:20][CH:21]=2)=[CH:7][N:6]=1
Reactant: Fc1ccc(Br)cn1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
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
Product: Fc1ccc(-c2cn[nH]c2)cn1
Temperature: 100 °C
Reaction time: 8 h
Yield: 54 %

Procedure:
To a solution of 5-bromo-2-fluoropyridine (1.0 g, 5.68 mmol) in dioxane (30 ml) was added tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (1.671 g, 5.68 mmol), Na2CO3 (1.205 g, 11.36 mmol) and Pd(Ph3P)4 (0.657 g, 0.568 mmol). The reaction mixture was stirred at 100° C. under Ar atmosphere for overnight. The reaction was cooled and concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM/MeOH=30/1) to afford the title compound as white solid (0.5 g, 44.2% yield). 1H-NMR (400 MHz, DMSO-d6) δ ppm 13.0 (s, 1H), 8.29 (s, 1H), 8.2 (d, 1H), 8.18 (d, 1H), 7.99 (s, 1H), 7.18 (dd, 1H). LCMS (method B): [M+H]+=164, tR=1.73 min.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=[O:3].[F:11][C:12]([F:23])([F:22])[O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Br)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.O>[F:11][C:12]([F:22])([F:23])[O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][O:10][C:7]2[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH3:1])=[CH:5][CH:6]=2)=[CH:16][CH:15]=1
Reactant: CC(=O)c1ccc(O)cc1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)c1ccc(OCc2ccc(OC(F)(F)F)cc2)cc1
Yield: 102.6 %

Procedure:
A stirred mixture of 4-hydroxyacetophenone (0.9 g, 6.6 mmol), 4-(trifluoromethoxy)benzyl bromide (2.0 g, 7.8 mmol) and potassium carbonate (1.4 g, 10 mmol) in acetone (25 mL) was heated at reflux for 7 hours. The mixture was then cooled, diluted with H2O (50 mL) and extracted with EtOAc (2×100 mL). The organic portions were combined, washed with brine and dried (Na2SO4). Filtration and removal of solvent in vacuo afforded 2.1 g of a crude yellow semi-solid which was used without further purification.