Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[C:4](=[CH:8][C:9]2[CH:36]=[CH:35][C:12]([O:13][C:14]3[N:19]=[CH:18][N:17]=[C:16]([O:20][CH:21]4[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]4)[C:15]=3[CH3:34])=[CH:11][CH:10]=2)[S:3]1.[H-].[Na+].Br[CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42]>CN(C)C=O>[CH2:44]([O:43][C:41](=[O:42])[CH2:40][N:6]1[C:5](=[O:7])/[C:4](=[CH:8]/[C:9]2[CH:10]=[CH:11][C:12]([O:13][C:14]3[N:19]=[CH:18][N:17]=[C:16]([O:20][CH:21]4[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])[CH2:23][CH2:22]4)[C:15]=3[CH3:34])=[CH:35][CH:36]=2)/[S:3][C:2]1=[O:1])[CH3:45]
Reactant: CCOC(=O)CBr
Reactant: Cc1c(Oc2ccc(C=C3SC(=O)NC3=O)cc2)ncnc1OC1CCN(C(=O)OC(C)(C)C)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN1C(=O)S/C(=C\c2ccc(Oc3ncnc(OC4CCN(C(=O)OC(C)(C)C)CC4)c3C)cc2)C1=O
Temperature: 30 °C
Reaction time: 1 h
Yield: 54.7 %

Procedure:
To a solution of tert-butyl 4-((6-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)phenoxy)-5-methylpyrimidin-4-yl)oxy)piperidine-1-carboxylate (250 mg, 0.0004882 mole) in dimethyl formamide (10 ml), sodium hydride (50%, 23.4 mg, 0.0004882 mole) was added at 0° C. and reaction mixture was stirred for 1 hours 30° C. and then ethyl bromoacetate (0.08 ml, 0.000733 mole) was added at 0° C., then reaction mixture was stirred for 3 hours at 30° C. Then reaction mixture was poured into ice cold water and extracted with ethyl acetate. Organic extract was washed with water and brine, dried over sodium sulfate and evaporated under reduced pressure to yield crude product. Then crude product was purified through column chromatography using 18% ethyl acetate in hexane as an eluent to yield the product as white solid (160 mg). 1HNMR: δ 1.30 (t, J=7.0 Hz, 3H), 1.48 (s, 9H), 1.76-1.81 (m, 2H), 1.96-2.01 (m, 2H), 2.18 (s, 3H), 3.34-3.41 (m, 2H), 3.71-3.76 (m, 2H), 4.25 (q, J=7.2 Hz, 2H), 4.48 (s, 2H), 5.33-5.35 (m, 1H), 7.55 (d, J=9.6 Hz, 2H), 7.57 (d, J=8.4 Hz, 2H), 7.93 (s, 1H), 8.25 (s, 1H).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7](=[O:20])[N:8]([C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=2[Cl:19])[N:9]=1)[CH2:2][CH2:3][CH3:4].[C:21]([NH:25][S:26]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]1[CH:40]=[CH:39][C:38]([CH2:41]Br)=[CH:37][CH:36]=1)(=[O:28])=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[CH2:1]([C:5]1[N:6]([CH2:41][C:38]2[CH:39]=[CH:40][C:35]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[S:26](=[O:28])(=[O:27])[NH:25][C:21]([CH3:22])([CH3:24])[CH3:23])=[CH:36][CH:37]=2)[C:7](=[O:20])[N:8]([C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=2[Cl:19])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(CBr)cc1
Reactant: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2Cl)c(=O)[nH]1
Product: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2Cl)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1
Yield: 83 %

Procedure:
By the procedure of Example 13, Step A, 5-n-butyl-2-(2-chloro-5-nitrophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (from Step A) was alkylated with [2'-(N-t-butylsulfamoyl)biphenyl-4-yl]methyl bromide (from Example 12, Step D). Flash chromatography of the crude product on silica gel (gradient elution with 0.5-5.0% MeOH in CH2Cl2) gave an 83% yield of the title compound as an orange solid, mp >75° C. (gradual), homogeneous by TLC (98:2 CH2Cl2 --MeOH), mass spectrum (FAB) m/e 598 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[S:6][CH:5]=[C:4]([CH:7]=O)[CH:3]=1.Cl.[C:10]([NH:14][C:15]([CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]>>[C:10]([NH:14][C:15]([CH:17]1[CH2:22][CH2:21][N:20]([CH2:7][C:4]2[CH:3]=[C:2]([Br:1])[S:6][CH:5]=2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)NC(=O)C1CCNCC1
Reactant: O=Cc1csc(Br)c1
Agent: Cl
Product: CC(C)(C)NC(=O)C1CCN(Cc2csc(Br)c2)CC1

Procedure:
The title compound is prepared according to the reaction 3.01c described above using 5-bromo-thiophene-3-carbaldehyde and piperidine-4-carboxylic acid tert-butylamide hydrochloride as in 3.01c: LC-MS A: tR=0.64 min; [M+H]+=360.95.
Reaction SMILES: CN(C)[CH:3]=[C:4]1[CH2:9][CH2:8][CH2:7][CH:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]1=O.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[F:25][C:26]1[CH:27]=[C:28]([NH:38][C:39]([NH2:41])=[NH:40])[CH:29]=[CH:30][C:31]=1[N:32]1[CH:36]=[C:35]([CH3:37])[N:34]=[CH:33]1>>[F:25][C:26]1[CH:27]=[C:28]([NH:38][C:39]2[N:41]=[CH:3][C:4]3[CH2:9][CH2:8][CH2:7][CH:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]=3[N:40]=2)[CH:29]=[CH:30][C:31]=1[N:32]1[CH:36]=[C:35]([CH3:37])[N:34]=[CH:33]1
Reactant: CCOC(=O)C1CCCC(=CN(C)C)C1=O
Reactant: Cc1cn(-c2ccc(NC(=N)N)cc2F)cn1
Solvent: O=[N+]([O-])O
Product: CCOC(=O)C1CCCc2cnc(Nc3ccc(-n4cnc(C)c4)c(F)c3)nc21

Procedure:
The title compound was prepared from crude ethyl 3-[1-dimethylamino-methylidene]-2-oxo-cyclohexanecarboxylate (165 mg, 0.5 mmol) and N-[3-fluoro-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate (134 mg, 0.37 mmol) using in analogous manner the procedure described in example 45b). Obtained as an off-white solid (27 mg, 18%). MS ISP (m/e): 396.4 [(M+H)+]. mp 142-145° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:11]1([C@H:14]2[CH2:18][N:17]([C@H:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH3:20])[C:16](=O)[CH2:15]2)[CH2:13][CH2:12]1)[CH2:9][CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]>O1CCCC1>[C:1]([O:5][C:6]([N:8]([C:11]1([C@@H:14]2[CH2:15][CH2:16][N:17]([C@H:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH3:20])[CH2:18]2)[CH2:12][CH2:13]1)[CH2:9][CH3:10])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCN(C(=O)OC(C)(C)C)C1([C@@H]2CC(=O)N([C@@H](C)c3ccccc3)C2)CC1
Solvent: C1CCOC1
Product: CCN(C(=O)OC(C)(C)C)C1([C@@H]2CCN([C@@H](C)c3ccccc3)C2)CC1
Temperature: 25 °C
Yield: 98.2 %

Procedure:
4-(R)-[1-[N-(tert-butoxycarbonyl)-N-(ethyl)amino]cyclopropyl]-1-[1-(S)-phenylethyl]pyrrolidin-2-one (4.56 g, 12.1 mmol) was dissolved in anhydrous tetrahydrofuran (80 ml), and a 1.0M borane-tetrahydrofuran complex/tetrahydrofuran solution (48.0 ml, 48.0 mmol) was added dropwise in while stirring and cooling with ice. After completion of dripping, the reaction solution was stirred for 16 hours under the condition of from ice cooling to room temperature. After concentrating the reaction solution under a reduced pressure, a 9:1 mixed solution (100 ml) of ethanol and water was added thereto, and after adding triethylamine (5 ml), it was heated under reflux for 4 hours. After cooling the reaction solution to room temperature, concentration was performed under a reduced pressure, saturated sodium bicarbonate water (100 ml) was added to the residue, extraction with chloroform (100 ml×2) was performed, and then the combined organic layer was washed with saturated saline solution (100 ml) and then dried over anhydrous sodium sulfate. After filtering, the filtrate was concentrated under a reduced pressure, the concentrate was applied to a silica gel chromatography, and 4.26 g (99%) of the title compound was obtained in the form of a colorless syrup from a chloroform:methanol=100:1 to 95:5 eluate.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Cl[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=1>>[F:19][C:18]([F:21])([F:20])[C:15]1[CH:16]=[CH:17][C:12]([O:10][C:7]2[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][OH:1])=[CH:5][CH:6]=2)=[N:13][CH:14]=1
Reactant: OCCc1ccc(O)cc1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Product: OCCc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1

Procedure:
The title compound was prepared by a procedure similar to that described for D3 starting from 4-(2-hydroxyethyl)phenol and 2-chloro-5-(trifluoromethyl)pyridine. LC-MS (ESI): m/z 284 [M+H]+; 2.97 min (ret time).
Reaction SMILES: O1CCOCC1.[OH-].[Li+].[CH:9]1([C:14]([N:16]2[CH2:21][CH:20]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)[CH2:19][CH:18]([C:32]([O:34]CC)=[O:33])[CH2:17]2)=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10]1>O>[CH:9]1([C:14]([N:16]2[CH2:21][CH:20]([C:22]3[CH:23]=[CH:24][C:25]([C:28]([F:30])([F:31])[F:29])=[CH:26][CH:27]=3)[CH2:19][CH:18]([C:32]([OH:34])=[O:33])[CH2:17]2)=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CCOC(=O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)C2CCCC2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)C2CCCC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
99 ml of dioxane, 50 ml of water and 1.37 g (57.0 mmol) of lithium hydroxide were added to 5.9 g (14.3 mmol) of ethyl 1-(cyclopentylcarbonyl)-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylate. The mixture was stirred at RT overnight. For work-up, the dioxane was removed under reduced pressure, water was added to the reaction mixture and the mixture was acidified using aqueous 1 N hydrochloric acid solution. The mixture was extracted with dichloromethane. The organic phase was dried with sodium sulphate and concentrated under reduced pressure. Yield: 5.3 g (95% of theory)
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH2:5]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[O:13][C:12](=[O:17])[CH:11]=[C:10]2[OH:18])[CH3:6]>C(Cl)(Cl)Cl>[CH2:5]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[O:13][C:12](=[O:17])[C:11]([N+:1]([O-:4])=[O:2])=[C:10]2[OH:18])[CH3:6]
Reactant: CCc1ccc2oc(=O)cc(O)c2c1
Reactant: O=[N+]([O-])O
Solvent: ClC(Cl)Cl
Product: CCc1ccc2oc(=O)c([N+](=O)[O-])c(O)c2c1

Procedure:
Fuming nitric acid (33 ml) was added to a stirred suspension of 6-ethyl-4-hydroxycoumarin (m.p. 216°-8°; 5.52g) in chloroform (500 ml) at room temperature over 1 hour. After standing for a further hour, the solvent was removed in vacuo at room temperature and 6N hydrochloric acid (100 ml) added to the residue. Filtration gave the product m.p. 114°-5°, (C11H9NO5 requires C, 56.17; H, 3.86 N, 5.96. Found: C, 55.86; H, 3.80; N, 5.86). Recrystallisation from benzene-petroleum ether (b.p. 40°-60°) raised the melting point to 117°-9°.
Reaction SMILES: N[C:2]1[C:10]2[O:9][C:8]([CH3:12])([CH3:11])[CH2:7][C:6]=2[C:5]([Br:13])=[CH:4][C:3]=1[Cl:14].C1(C)C=CC=CC=1.S(=O)(=O)(O)O.N([O-])=O.[Na+]>C(O)C>[Br:13][C:5]1[C:6]2[CH2:7][C:8]([CH3:11])([CH3:12])[O:9][C:10]=2[CH:2]=[C:3]([Cl:14])[CH:4]=1
Reactant: CC1(C)Cc2c(Br)cc(Cl)c(N)c2O1
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC1(C)Cc2c(Br)cc(Cl)cc2O1
Temperature: 75 °C
Reaction time: 0.5 h
Yield: 76.5 %

Procedure:
A stirred solution of 5.1 grams (0.018 mole) of 7-amino-4-bromo-6-chloro-2,3-dihydro-2,2-dimethylbenzofuran and 25 mL of toluene in 100 mL of ethanol was cooled in an ice bath, and 2 mL (0.036 mole) of concentrated sulfuric acid was added slowly. Upon completion of addition, 2.0 grams (0.029 mole) of sodium nitrite was then added. The ice bath was then removed, and the reaction mixture was warmed to 75° C., where it stirred for 30 minutes. After this time the reaction mixture was warmed to 95° C., where it stirred for one hour. The reaction mixture was then cooled and poured into 200 mL of water. The mixture was extracted with two 150 mL portions of diethyl ether. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel. Elution was accomplished using petroleum ether. The product-containing fractions were combined and concentrated under reduced pressure, yielding 3.6 grams of 4-bromo-6-chloro-2,3-dihydro-2,2-dimethylbenzofuran. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH:11]=[N:12][OH:13])=[CH:10][C:5]=2[C:4]([CH3:15])([CH3:14])[O:3]1.C1C(=O)N([Cl:23])C(=O)C1>CN(C=O)C>[OH:13][N:12]=[C:11]([Cl:23])[C:9]1[CH:8]=[CH:7][C:6]2[B:2]([OH:1])[O:3][C:4]([CH3:15])([CH3:14])[C:5]=2[CH:10]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC1(C)OB(O)c2ccc(C=NO)cc21
Solvent: CN(C)C=O
Product: CC1(C)OB(O)c2ccc(C(Cl)=NO)cc21
Temperature: 40 °C
Reaction time: 2 h
Yield: 85.7 %

Procedure:
To a solution of 1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbaldehyde oxime (8 mg, 0.039 mmol) in DMF (1.0 mL) at rt was added NCS (6.2 mg, 0.047 mmol). The reaction mixture was stirred for 2 h, warmed to 40° C. and stirred for 3 h. The mixture was cooled to rt, poured into ice-water (10 mL) and extracted with EA (20 mL). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give N,1-dihydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbimidoyl chloride (8 mg; yield 86%) as a white solid. 1H NMR (400 MHz, CDCl3): δ 12.50 (s, 1 H), 7.90 (s, 1 H), 7.70-7.79 (m, 2 H), 1.61 (s,6 H) ppm.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:11]([C:12](=[O:19])[C:13]4[C:18]=2[C:17]=1[CH:16]=[CH:15][CH:14]=4)=[CH:10][CH:9]=[CH:8][CH:7]=3.S(=O)(=O)(O)O.N([O-])=O.[Na+]>O>[CH:4]1[C:5]2=[C:18]3[C:13]([C:12]([C:11]4[C:6]2=[CH:7][CH:8]=[CH:9][CH:10]=4)=[O:19])=[CH:14][CH:15]=[CH:16][C:17]3=[CH:2][CH:3]=1
Reactant: Nc1ccc2c3c(cccc13)C(=O)c1ccccc1-2
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=C1c2ccccc2-c2cccc3cccc1c23
Temperature: 0 °C

Procedure:
A 2 g amount of 3-aminobenzanthrone was dissolved in a mixture of 60 g of ice, 60 g of water and 15 ml of conc-sulfuric acid to obtain a solution. A solution of 2g of NaNO2 in 10 ml of water was gradually added to the solution. The mixture was stirred to react the components in order to obtain a diazonium salt of benzanthrone. The diazonium salt was gradually added to a solution of 5 g of KI in 10 ml of water and a small amount of copper powder was added to the solution. The mixture was heated to 80° C and reacted at 80° C for 1 hour and further at about 110° C for 1 hour. The resulting solid was extracted with hot benzene and treated with activated carbon and recrystallized from benzene whereby 3-iodobenzanthrone was obtained.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[C:15]([CH:17]=[CH:18][C:19]2[C:20]([CH3:32])([CH3:31])[O:21][C:22](=[C:26]([C:29]#[N:30])[C:27]#[N:28])[C:23]=2[C:24]#[N:25])[CH:14]=[CH:13][C:12]=1[NH2:33])C.Cl.O.C(=O)(O)[O-].[Na+]>C(O)(=O)C>[NH2:33][C:12]1[CH:13]=[CH:14][C:15]([CH:17]=[CH:18][C:19]2[C:20]([CH3:32])([CH3:31])[O:21][C:22](=[C:26]([C:29]#[N:30])[C:27]#[N:28])[C:23]=2[C:24]#[N:25])=[CH:16][C:11]=1[O:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]([OH:34])=[O:3]
Reactant: CCOC(=O)CCCCCOc1cc(C=CC2=C(C#N)C(=C(C#N)C#N)OC2(C)C)ccc1N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC1(C)OC(=C(C#N)C#N)C(C#N)=C1C=Cc1ccc(N)c(OCCCCCC(=O)O)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.9 %

Procedure:
To a solution of 6-{2-amino-5-[2-(4-cyano-5-dicyanomethylene-2,2-dimethyl-2,5-dihydro-furan-3-yl)-vinyl]-phenoxy}-hexanoic acid ethyl ester (0.33 g, 0.71 mmol), in acetic acid (6 ml) was added 5 mls of 6M HCl. The mixture was allowed to stir at room temperature for 16 hours. After being poured into 50 mls of water, it was neutralized with a solution of saturated sodium bicarbonate and extracted with ethyl acetate. Both phases of the separatory funnel remained highly colored so solid sodium chloride was added resulting in the decoloration of the aqueous layer. The organic phase was separated and dried over magnesium sulfate and rotovapped to dryness. Purification by column chromatography (60% EtOAc, 35% Hexane, 5% EtOH) provided 6-{2-amino-5-[2-(4-cyano-5-dicyanomethylene-2,2-dimethyl-2,5-dihydro-furan-3-yl)-vinyl]-phenoxy}-hexanoic acid as a shiny green solid (0.23 g, 74%). 1H NMR (400 MHz, CDCl3) δ: 7.57 (d, 1H, J=16.0 Hz), 7.17 (dd, 1H, J=8.4 Hz, J=1.6 Hz), 7.04 (d, 1H, J=1.6 Hz), 6.79 (d, 1H, J=16.0 Hz), 6.72 (d, 1H, J=8.4 Hz), 4.12 (t, 2H, J=7.2 Hz), 2.45 (t, 2H, J=6. Hz), 1.93 (m, 2H), 1.79 (m, 8H), 1.62 (m, 2H). 13C NMR (400 MHz, CDCl3) δ: 176.65, 174.34, 174.17, 148.78, 146.49, 143.21, 127.15, 124.20, 113.86, 112.45, 112.36, 111.64, 111.13, 110.16, 109.82, 97.35, 68.62, 33.27, 30.95, 29.72, 29.28, 28.75, 26.81
Reaction SMILES: Br[C:2]1[C:3]([F:17])=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[CH:5]2.C(N(CC)CC)C.[CH2:25]([OH:29])[CH2:26][C:27]#[CH:28]>CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[F:17][C:3]1[C:2]([C:28]#[C:27][CH2:26][CH2:25][OH:29])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[N:6][N:7]2[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1
Reactant: C#CCCO
Reactant: Fc1c(Br)ccc2c1cnn2C1CCCCO1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: OCCC#Cc1ccc2c(cnn2C2CCCCO2)c1F
Temperature: 60 °C
Reaction time: 16 h
Yield: 74.1 %

Procedure:
To a mixture of 5-bromo-4-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (2.80 g, 9.36 mmol, Intermediate 21), Pd(PPh3)2Cl2 (660 mg, 0.94 mmol), CuI (180 mg, 0.94 mmol), and triethylamine (50 mL) was added but-3-yn-1-ol (2.0 g, 28.1 mmol) under N2 atmosphere. The resulting mixture was stirred at 60° C. for 16 hours. Upon completion, the reaction mixture was diluted with EtOAc, and washed with water (3×10 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified on silica gel column (0˜20% EtOAc in petroleum ether) affording the title compound (2.0 g). 1H NMR (300 MHz, DMSO-d6): δ 8.33 (s, 1H), 7.64 (d, 1H), 7.49 (dd, 1H), 5.94 (dd, 1H), 4.99 (t, 1H), 3.98-3.92 (m, 1H), 3.85-3.77 (m, 1H), 3.68 (t, 2H), 2.67 (t, 2H), 2.48-2.35 (m, 1H), 2.12-2.02 (m, 2H), 1.84-1.78 (m, 1H), 1.68-1.62 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([S:8][C:9]2[CH:21]=[CH:20][C:12]3[O:13][C:14]([CH3:19])([CH3:18])[C:15]([CH3:17])=[CH:16][C:11]=3[CH:10]=2)[CH:5]=[CH:6][CH:7]=1.N1C=CN=C1.[Si:27](Cl)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28].O>CN(C)C=O>[Si:27]([O:1][C:2]1[CH:3]=[C:4]([S:8][C:9]2[CH:21]=[CH:20][C:12]3[O:13][C:14]([CH3:18])([CH3:19])[C:15]([CH3:17])=[CH:16][C:11]=3[CH:10]=2)[CH:5]=[CH:6][CH:7]=1)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC1=Cc2cc(Sc3cccc(O)c3)ccc2OC1(C)C
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC1=Cc2cc(Sc3cccc(O[Si](C)(C)C(C)(C)C)c3)ccc2OC1(C)C
Temperature: 40 °C
Reaction time: 1 h
Yield: 93.3 %

Procedure:
6-(3-Hydroxyphenyl)thio-2,2,3-trimethyl-2H-benzo[b]pyran (2.2 g) (see Preparation 9) was dissolved in dry dimethylformamide (4 ml) and imidazole (1.1 g) and tert-butyidimethylsilyl chloride (1.2 g) were added. The flask was fitted with a calcium chloride drying tube and the mixture was stirred at 40° C. for one hour. Water was added and the mixture was extracted with diethyl ether. The organic extract was washed with aqueous sodium hydrogen carbonate solution (×2), dried (anhydrous sodium sulphate), the solvent removed under reduced pressure and the crude product chromatographed on silica using (4:1 hexane:dichloromethane as the eluent to yield 6-(3-tert-Butyldimethylsilyloxyphenyl)thio-2,2,3-trimethyl-2H-benzo[b]pyran (2.84 g) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[S:11](=[O:14])(=[O:13])[NH2:12].[S:15]1[CH:19]=[CH:18][C:17]2[CH:20]=[CH:21][CH:22]=[CH:23][C:16]1=2>C1(C)C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([C:18]2[C:17]3[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=3[S:15][CH:19]=2)=[O:7])=[CH:4][C:3]=1[S:11](=[O:14])(=[O:13])[NH2:12]
Reactant: c1ccc2sccc2c1
Reactant: NS(=O)(=O)c1cc(C(=O)Cl)ccc1Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: NS(=O)(=O)c1cc(C(=O)c2csc3ccccc23)ccc1Cl
Reaction time: 0.25 h

Procedure:
5.1 g of powdered 4-chloro-3-sulfamoylbenzoyl chloride are introduced into a solution of 3 g benzo[b]thiophene in 50 ml anhydrous toluene, and subsequently, 12 g titanium tetrachloride are added with agitation. Agitation is continued for 15 minutes at room temperature, the mixture is heated to boiling for about 15 minutes, cooled and poured onto a water/ice suspension. Extraction is carried out then with 70 acetic ester, the organic phase is separated and stirred for 5 hours with an aqueous sodium bicarbonate solution having a pH of 8.5. After separation of the organic phase and drying thereof over magnesium sulfate, the solvent is distilled off and the residue crystallized from toluene. M.p. 154°-156° C.
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[OH:22])[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[CH3:23][C:24](C)=[CH:25][CH2:26][CH2:27][CH:28]1[CH2:33][CH2:32][C:31]([C:34](O)=[O:35])=[CH:30][CH2:29]1.C1(N=C=NC2CCCCC2)CCCCC1.CN(C1C=CC=CN=1)C>O.O1CCCC1>[CH2:27]([CH:28]1[CH2:33][CH2:32][C:31]([C:34]([O:22][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:15][CH2:14][CH2:13][CH2:12][CH:9]2[CH2:8][CH2:7][CH:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:11][CH2:10]2)=[O:35])=[CH:30][CH2:29]1)[CH2:26][CH2:25][CH2:24][CH3:23]
Reactant: CC(C)=CCCC1CC=C(C(=O)O)CC1
Reactant: CCCCC[C@H]1CC[C@H](CCCCc2ccccc2O)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: C1CCOC1
Solvent: O
Product: CCCCCC1CC=C(C(=O)Oc2ccccc2CCCCC2CCC(CCCCC)CC2)CC1
Reaction time: 8 h

Procedure:
To a round-bottom flask equipped with a stirbar is added phenol 3H (R=pentyl) (5 g), (4-(4-Methyl-3-pentenyl)-1-cyclohexenyl)carboxylic acid (R=n-pentyl) (3.3 g), dicyclohexylcarbodiimide (5.11 g), dimethylaminopyridine (202 mg), and anhydrous tetrahydrofuran (50 mL). The reaction is stirred overnight, at which time the solution is poured into water and extracted with 1:1 hexanes:ethyl acetate. The combined organic layers are washed with brine and dried over potassium carbonate, and the solution is concentrated in vacuo. Filtration through silica gel using 10% ethyl acetate in hexanes gives the pure product.
Reaction SMILES: [OH-].[Na+].[NH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]1[NH:10][C:11]([NH:13][C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:21])=S.C1(C)C=CC(S(Cl)(=O)=O)=CC=1>O.C1COCC1>[Cl:21][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]([Cl:20])[C:14]=1[N:13]=[C:11]1[NH:10][CH:5]2[CH2:6][CH2:7][CH2:8][CH2:9][CH:4]2[NH:3]1
Reactant: NC1CCCCC1NC(=S)Nc1c(Cl)cccc1Cl
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Clc1cccc(Cl)c1N=C1NC2CCCCC2N1
Reaction time: 1 h
Yield: 98.6 %

Procedure:
A solution of sodium hydroxide (15.7 mg) and water (0.6 ml) was added under argon to a solution of 1-(2-aminocyclohexyl)-3-(2,6-dichlorophenyl)thiourea (50 mg) and THF (1.5 ml). Subsequently, a solution of p-toluenesulfonyl chloride (32.9 mg) and THF (0.5 ml) was added dropwise over fifteen minutes. After stirring for 60 minutes, the reaction mixture was added to water and extracted three times with ether. The combined organic phases were dried over magnesium sulfate, filtered and concentrated. 44 mg of the desired product were obtained.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][CH2:17][C:18]([OH:20])=[O:19]>>[C:18]([CH2:17][NH:16][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)([OH:20])=[O:19]
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Reactant: NCC(=O)O
Product: O=C(O)CNc1nc2ccc(Cl)cc2cc1C(=O)O
Yield: 52 %

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with glycine to provide the title compound in 52% yield as yellow needles (recrystallization from EtOH/water).