Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][O:8][CH:7]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=2)[O:6][CH2:5]1)[CH2:2][CH3:3].C([Li])CCC.Br[C:24]1[CH:29]=[C:28]([F:30])[C:27]([C:31]([F:34])([F:33])[F:32])=[C:26]([F:35])[CH:25]=1.O>C1COCC1.CCCCCC.[Cl-].[Zn+2].[Cl-]>[CH2:1]([CH:4]1[CH2:5][O:6][CH:7]([C:10]2[CH:15]=[C:14]([F:16])[C:13]([C:24]3[CH:25]=[C:26]([F:35])[C:27]([C:31]([F:32])([F:33])[F:34])=[C:28]([F:30])[CH:29]=3)=[C:12]([F:17])[CH:11]=2)[O:8][CH2:9]1)[CH2:2][CH3:3]
Reactant: CCCC1COC(c2cc(F)cc(F)c2)OC1
Reactant: Fc1cc(Br)cc(F)c1C(F)(F)F
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: CCCC1COC(c2cc(F)c(-c3cc(F)c(C(F)(F)F)c(F)c3)c(F)c2)OC1
Temperature: -60 °C
Reaction time: 1.5 h
Yield: 24.3 %

Procedure:
5-Propyl-2-(3,5-difluorophenyl)-1,3-dioxane (5.0 g; 20.6 mmol), which had been synthesized in Step 1 of Example 1, was dissolved in THF (50 ml), and the solution was cooled to -60° C. in a nitrogen atmosphere. A solution (16.1 ml; 25.8 mmol) of 1.60M n-butyl lithium in hexane was added dropwise thereto so that the temperature of the mixture did not exceed -45° C. The mixture was stirred for 1.5 hours with the temperature being maintained below -45° C. Subsequently, a solution (51.6 ml; 25.8 mmol) of 0.5M zinc chloride in THF was added dropwise so that the temperature, of the mixture did not exceed -50° C. Thereafter, the mixture was warmed to room temperature and stirred for 30 minutes. Tetrakistriphenylphosphine palladium (0.5 g) and 1-bromo-3,5-difluoro-4-trifluoromethylbenzene (6.73 g; 25.8 mmol) were added, and the mixture was refluxed for 2 hours and 20 minutes. Water (100 ml) was added to the resultant reaction mixture, and the material produced was extracted with toluene. The extract was sequentially washed with saturated aqueous ammonium chloride solution, saturated sodium bicarbonate solution, and saturated brine, and then dried over magnesium sulfate. Subsequently, the solvent was evaporated. The residue was purified by column chromatography (eluent: toluene). The solvent was evaporated, and the residue was recrystallized twice from heptane, to thereby obtain 2.1 g (5.0 mmol) of 5-propyl-2-(4-(3,5-difluoro-4-trifluoromethylphenyl)-3,5-difluorophenyl)-1,3-dioxane. The yield of this compound from 5-propyl-2-(3,5-difluorophenyl)-1,3-dioxane was 24.3%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1Br.[Li]CCCC.FC(F)(F)S(O[Si:20]([CH3:23])([CH3:22])[CH3:21])(=O)=O>C1COCC1.CCCCCC.CCOCC>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Si:20]([CH3:23])([CH3:22])[CH3:21]
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: Brc1ccccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCCCCC
Product: C[Si](C)(C)c1ccccc1Br
Reaction time: 0 h
Yield: 69 %

Procedure:
A microsystem composed of three T-shaped micromixers (M1, M2 and M3) and two microtube reactors (R1 and R2) was used. The whole microsystem was dipped in a cooling bath (−78° C.). A solution of o-dibromobenzene (0.27 M) in THF (flow rate: 6 mL/min, 1.62 mmol/min) and a solution of n-BuLi (1.5 M) in n-hexane (flow rate: 1.2 mL/min, 1.8 mmol/min) were introduced to the first T-shaped mixer M1 (inner diameter: 250 μm) by using syringe pumps. The resulting solution was passed through the tube reactor R1 and was mixed with trimethylsilyl trifluoromethanesulfonate (Me3SiOTf) (0.65 M) in Et2O (flow rate: 3 mL/min, 1.95 mmol/min) in the second T-shaped mixer M2 (inner diameter: 500 μm). The resulting solution was passed through the tube reactor R2 and was introduced to the third T-shaped mixer M3 (inner diameter: 500 μm), where the solution was quenched with methanol (neat, flow rate=3.0 mmol/min). The residence time of the tube reactor R1 (inner diameter: 500 μm, length=50 cm) was 0.82 second. The residence time of the tube reactor R2 (inner diameter: 1,000 μm, length=100 cm) was 4.62 second. After finishing the reaction, an aliquot of the product solution was taken (15 sec) and was analyzed by GC (column, CBP1; 0.25 mm×25 m; initial oven temperature, 50° C.; rate of temperature increase, 10° C./min). As a result, 2-bromophenyltrimethylsilane (GC retention time: 15.9 min) was obtained in 69% yield. 1H NMR (400 MHz, CDCl3) δ: 0.39 (s, 9H), 7.18 (dt, J=8.0, 2.0 Hz, 1H), 7.26 (dt, J=8.0, 2.0 Hz, 1H), 7.42 (dd, J=7.6, 1.6 Hz, 1H), 7.51 (dd, J=7.6, 1.6 Hz, 1H) 13C NMR (100 MHz, CDCl3) δ: −0.4, 126.2, 130.4, 130.5, 132.6, 135.9, 141.0. HRMS (EI) m/z: calcd. for C9H13BrSi 227.9970, found 227.9967.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][CH:3]=1.[CH3:10][NH:11][CH:12]=[O:13].[H-].[Na+]>C1COCC1>[CH3:10][N:11]([CH:12]=[O:13])[CH2:8][C:5]1[CH:6]=[CH:7][N:2]=[CH:3][CH:4]=1
Reactant: ClCc1ccncc1
Reactant: CNC=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C=O)Cc1ccncc1
Yield: 76.5 %

Procedure:
To a stirring, argon-purged solution of 4-picolyl chloride-HCl (15g, 91.4 mmol) and N-methylformamide (53.4 ml, 914 mmol) in 300 ml of THF at room temperature was added portionwise over a 20 minute period a suspension of 80% NaH (5.48g, 183mmol). The reaction was quenched 18 h later by the addition of ice, partitioned between methylene chloride and water, washed with water and brine, dried over MgSO4, and evaporated to dryness to afford a dark oil. Flash chromatography on silica gel provided 10.5 g (76%) of the titled compounds a pale yellow oil. TLC; silica gel (9:1 CHCl/MeOH) Rf=0.54.
Reaction SMILES: Cl.[C:2]1([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=2)[NH:13][N:12]=[C:11]3[CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]1([S:32](Cl)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.CN(C=O)C>[C:2]1([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=2)[NH:13][N:12]=[C:11]3[CH:20]2[CH2:25][CH2:24][N:23]([S:32]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:34])=[O:33])[CH2:22][CH2:21]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCNCC3)n[nH]c12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(S(=O)(=O)c4ccccc4)CC3)n[nH]c12
Yield: 8.9 %

Procedure:
This compound was prepared in a fashion analogous to the procedure described in Example 3. Thus, 5-phenyl-3-(4-piperidinyl)-1H-indazole-7-carboxamide hydrochloride (0.057 g, 0.17 mmol) was reacted with phenylsulfonyl chloride (0.022 mL, 0.17 mmol) in the presence of triethylamine (0.1 mL, 0.71 mmol) and DMAP (0.0021 g, 0.017 mmol) in DMF (3 mL) to give 0.007 g of pale yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([CH:14]([NH:24][C:25]([C:27]2[CH:36]=[C:35]([C:37]([NH:39][CH:40]([C:50]([O:52]C)=[O:51])[CH2:41][CH2:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=[O:38])[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:28]=2)=[O:26])[CH2:15][CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Li+].[OH-].C1COCC1.O.Cl>C(OCC)(=O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12]([CH:14]([NH:24][C:25]([C:27]2[CH:36]=[C:35]([C:37]([NH:39][CH:40]([C:50]([OH:52])=[O:51])[CH2:41][CH2:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=[O:38])[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:28]=2)=[O:26])[CH2:15][CH2:16][C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])=[O:13])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)C(CCC(=O)OC(C)(C)C)NC(=O)c2cc(C(=O)NC(CCC(=O)OC(C)(C)C)C(=O)OC)c3ccccc3n2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CCN(C(=O)C(CCC(=O)OC(C)(C)C)NC(=O)c2cc(C(=O)NC(CCC(=O)OC(C)(C)C)C(=O)O)c3ccccc3n2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 90 %

Procedure:
2-[1-(4-(Ethoxycarbonyl)piperazin-1-yl)carbonyl-3-(1,1-dimethylethoxycarbonyl)propyl]aminocarbonyl-4-[(1-(methoxycarbonyl)-3-(1,1-dimethylethoxycarbonyl)propyl)aminocarbonyl]quinoline (170 mg, 0.229 mmol) was treated with LiOH (2.0 eq.) in a solution of THF:H2O (3:1, 12 mL). The reaction mixture was stirred at ambient temperature for 5 hours. The pH value of the reaction mixture was adjusted to between pH 3 and pH 4 with 1 N HCl solution. The reaction mixture was evaporated in vacuo to afford a crude product, which was dissolved in ethyl acetate, washed with H2O and brine. The solvent was evaporated to give 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-(1,1-dimethylethoxycarbonyl)propyl]aminocarbonyl-4-[(1-carboxy-3-(1,1-dimethylethoxycarbonyl)propyl)aminocarbonyl]quinoline (150 mg); NMR (CD3 OD) 1.30 (t, 3), 1.40 (s, 9), 1.50 (s, 9), 1.90 (m, 1), 2.15 (m, 2), 2.30-2.50 (m, 5), 3.45-3.90 (m, 8), 4.18 (q, 2), 4.75 (m, 1), 5.25 (m, 1), 7.75 (m, 1), 7.90 (m, 1), 8.25 (m, 3) ppm.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C:11]([CH2:22][OH:23])([C:17](OCC)=[O:18])[C:12](OCC)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].O.C(O)C>CO>[CH2:1]([O:8][CH2:9][CH2:10][C:11]([CH2:17][OH:18])([CH2:22][OH:23])[CH2:12][OH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(CO)(CCOCc1ccccc1)C(=O)OCC
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CO
Product: OCC(CO)(CO)CCOCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.7 %

Procedure:
1.03 g (3.24 mmol equivalents) of diethyl 2-(2-benzyloxyethyl)-2-hydroxymethylmalonate was dissolved in 10 mL of methanol, and this was added dropwise to 1.69 g (44.6 mmol equivalents) of sodium borohydride over 20 minutes. This was refluxed while heating overnight and then cooled to room temperature (25° C.). Water was added to the reaction liquid, and a reaction was carried out for 30 minutes. The reaction liquid was washed with chloroform, and the aqueous phase was concentrated under vacuum. 100 mL of ethanol was added to the obtained residue, and the mixture was refluxed while heating for 2 hours. Immediately after completion of the reaction, the mixture was subjected to silica gel column chromatography (eluent: ethanol) to give 543 mg of 4-benzyloxy-2,2-dihydroxymethylbutanol as an crude product.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].Br[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:24]=[C:23]([C:25]([NH2:27])=[O:26])[O:22][N:21]=2)=[CH:16][CH:15]=1.O>CN(C=O)C>[N:1]1([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:24]=[C:23]([C:25]([NH2:27])=[O:26])[O:22][N:21]=3)=[CH:18][CH:19]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: NC(=O)c1cc(-c2ccc(CBr)cc2)no1
Reactant: c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1cc(-c2ccc(Cn3ccc4ccccc43)cc2)no1
Reaction time: 0.33 h
Yield: 17.7 %

Procedure:
To a mixture of indole (13 mg, 0.11 mmol) in DMF (1 mL) was added NaH (60% dispersion; 5 mg, 0.125 mmol). The mixture was stirred for 20 min and then a solution of 3-(4-bromomethyl-phenyl)-isoxazole-5-carboxylic acid amide (which may be prepared as described in Preparation of Intermediate 14; 30 mg, 0.107 mmol) in DMF (1 mL) was added. The reaction mixture was stirred at room temperature overnight. H2O was added and the mixture was extracted with EtOAc (3×25 mL). The combined organic layers were washed three times with H2O/brine, dried (Na2SO4), evaporated, and purified by chromatography (10-25% acetone/CH2Cl2) to give 3-(4-indol-1-ylmethyl-phenyl)-isoxazole-5-carboxylic acid amide (6 mg, 18%) as an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.34 (br. s., 1H), 7.97 (br. s., 1H), 7.82 (d, J=8.2 Hz, 2H), 7.48-7.61 (m, 3H), 7.43 (d, J=7.8 Hz, 1H), 7.30 (d, J=8.2 Hz, 2H), 6.94-7.14 (m, 2H), 6.49 (d, J=3.0 Hz, 1H), 5.49 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:29])[C:5]2[CH2:6][CH:7]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=3)[CH2:8][C:9]=2[C:10](=[O:14])[C:11]=1[O:12][CH3:13].Cl.[C:31]1([CH:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>O.C1COCC1.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[C:4](=[O:29])[C:5]2[CH2:6][CH:7]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:21]=[CH:22][C:23]([C:24]([N:40]4[CH2:41][CH2:42][CH:37]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)[CH2:38][CH2:39]4)=[O:25])=[CH:27][CH:28]=3)[CH2:8][C:9]=2[C:10](=[O:14])[C:11]=1[O:12][CH3:13]
Reactant: COC1=C(OC)C(=O)C2=C(CC(CCCCOc3ccc(C(=O)O)cc3)C2)C1=O
Reactant: c1ccc(C2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: COC1=C(OC)C(=O)C2=C(CC(CCCCOc3ccc(C(=O)N4CCC(c5ccccc5)CC4)cc3)C2)C1=O
Yield: 56.7 %

Procedure:
To a solution of 4-[4-(5,6-dimethoxy-4,7-dioxoindan-2-yl)butoxy]benzoic acid (626 mg), 4-phenylpiperidinehydrochloride (617 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (598 mg), 1-hydroxybenzotriazole monohydrate (478 mg), triethylamine (1.30 ml), and THF (12 ml) was stirred at room temperature for 6 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water, 1N hydrochloric acid, water, saturated aqueous sodium bicarbonate, water, and saturated aqueous sodium chloride and dried. The solvent was removed in vacuo. The residue was recrystallized from ethyl acetate-diethyl ether to yield the entitled compound (482 mg) as crystals.
Reaction SMILES: [C:1]([C:4]1([CH3:18])[CH2:13][CH2:12][C:11]2[CH2:10][C:9]([OH:15])(C)[C:8]([CH3:16])=[C:7]([CH3:17])[C:6]=2[O:5]1)([OH:3])=[O:2].[C:19](OC(=O)C)(=[O:21])[CH3:20].N1C=CC=C[CH:27]=1>>[C:19]([O:15][C:9]1[C:10]([CH3:27])=[C:11]2[C:6](=[C:7]([CH3:17])[C:8]=1[CH3:16])[O:5][C:4]([C:1]([OH:3])=[O:2])([CH3:18])[CH2:13][CH2:12]2)(=[O:21])[CH3:20]
Reactant: c1ccncc1
Reactant: CC1=C(C)C(C)(O)CC2=C1OC(C)(C(=O)O)CC2
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(C(=O)O)O2
Reaction time: 16 h

Procedure:
To a partial solution of 5.0 g. (20 mmol) of (±)-2-carboxy-6-hydroxy-2,6,7,8-tetramethylchroman in 8.0 ml. of pyridine was added, dropwise over 10 minutes, 12.0 ml. of acetic anhydride. The solution was allowed to stand for 16 hours and was then worked up and dried by the procedure of Example 2 utilizing dichloromethane as a solvent to give a white solid. Crystallization from a mixture of ether-petroleum ether (b.p. 30°-60° centigrade) gave (±)-6-acetoxy-2-carboxy-2,5,7,8-tetramethylchroman.
Reaction SMILES: [CH2:1]([O:3][P:4]([NH:9][NH2:10])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].C(N(CC)CC)C.[C:18](Cl)(=[O:20])[CH3:19]>ClCCl>[C:18]([NH:10][NH:9][P:4]([O:5][CH2:6][CH3:7])([O:3][CH2:1][CH3:2])=[O:8])(=[O:20])[CH3:19]
Reactant: CC(=O)Cl
Reactant: CCOP(=O)(NN)OCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOP(=O)(NNC(C)=O)OCC

Procedure:
Diethylphosphorohydrazidate (5.3 g) and triethylamine (13 ml) were dissolved in dichloromethane (15 ml). To this solution was added dropwise with stirring and cooling a solution of acetyl chloride (7.4 g) in dichloromethane (15 ml). The mixture was then stirred at ambient temperature and then filtered to remove the triethylamine hydrochloride after the addition of 50 ml of anhydrous diethylether. The filtrates were stripped on a rotary evaporator to yield a red-brown oil which was distilled under high vacuum to give a pale yellow liquid, b.p. 180° C./1 mm, identified as the product.
Reaction SMILES: [N:1]([O-])=O.[Na+].[C:5]([O:9][C:10](=[O:37])[NH:11][C@H:12]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18]2[C:23]([NH2:24])=[CH:22][N:21]=[C:20]3[N:25]([S:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)(=[O:30])=[O:29])[CH:26]=[CH:27][C:19]=23)[CH2:13]1)([CH3:8])([CH3:7])[CH3:6]>C(O)(=O)C>[C:5]([O:9][C:10](=[O:37])[NH:11][C@H:12]1[CH2:16][CH2:15][C@H:14]([N:17]2[C:18]3[C:23](=[CH:22][N:21]=[C:20]4[C:19]=3[CH:27]=[CH:26][N:25]4[S:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)(=[O:30])=[O:29])[N:24]=[N:1]2)[CH2:13]1)([CH3:8])([CH3:6])[CH3:7]
Reactant: O=N[O-]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2c(N)cnc3c2ccn3S(=O)(=O)c2ccccc2)C1
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](n2nnc3cnc4c(ccn4S(=O)(=O)c4ccccc4)c32)C1
Reaction time: 0.75 h
Yield: 87.2 %

Procedure:
Sodium nitrite (612 mg, 8.87 mmol) was added to a stirred solution of racemic trans [3-(5-amino-1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl amino)-cyclopentyl]-carb amic acid tert-butyl ester (3.80 g, 8.06 mmol) in acetic acid (50 mL). Stirring was continued for 45 minutes at room temperature and then the solvent removed in vacuo. The residue was dissolved in ethyl acetate, washed (saturated sodium hydrogen carbonate (3×) and brine) and concentrated to dryness. Purification by column chromatography on silica gel (gradient: DCM to ethyl acetate) gave 3.39 g (87%) of racemic trans [3-(6-benzenesulfonyl-6H-1,2,3,5,6-pentaaza-as-indacen-1-yl)-cyclopentyl]-carbamic acid tert-butyl ester as a beige solid. LCMS (Method B, ESI): RT=4.00 min, m+H=483.3; 1H NMR (400 MHz, DMSO) δ: 9.20 (s, 1H), 8.15 (m, 3H), 7.73 (t, 1H), 7.63 (t, 2H), 7.45 (d, 1H), 7.15 (d, 1H), 5.65 (m, 1H), 4.21 (m, 1H), 2.44 (m, 2H, partially obscured by DMSO), 2.16 (m, 3H), 1.65 (m, 1H), 1.40 (s, 9H).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:15]1[N:16]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:17](=[O:39])[C:18]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[C:32]([C:37]#[N:38])=[CH:33][CH:34]=[CH:35][CH:36]=3)=[CH:27][CH:26]=2)=[C:19]([CH2:21][CH2:22][CH3:23])[N:20]=1)[CH3:14]>C(OCC)(=O)C>[CH2:13]([C:15]1[N:16]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:17](=[O:39])[C:18]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]3[NH:3][C:4](=[O:7])[O:5][N:38]=3)=[CH:27][CH:26]=2)=[C:19]([CH2:21][CH2:22][CH3:23])[N:20]=1)[CH3:14]
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCCc1nc(CC)n(-c2ccccc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1nc(CC)n(-c2ccccc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 41.6 %

Procedure:
A mixture of hydroxylammonium chloride (5.8 g), sodium hydrogen carbonate (8.5 g) and dimethyl sulfoxide (30 mL) was stirred at 50° C. for 30 min, 4′-[(2-ethyl-6-oxo-1-phenyl-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (3.6 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (30 mL), N,N′-carbonyldiimidazole (2.0 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (1.9 mL) were added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (1.7 g, 40%) as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:35](=[O:41])OC(Cl)(Cl)Cl)Cl.[CH2:43]([N:50]1[CH2:55][CH2:54][CH:53]([NH2:56])[CH2:52][CH2:51]1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>C(Cl)(Cl)Cl.O>[CH2:43]([N:50]1[CH2:55][CH2:54][CH:53]([NH:56][C:35]([NH:20][C:19]2[CH:21]=[CH:22][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:17][C:18]=2[CH3:23])=[O:41])[CH2:52][CH2:51]1)[C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3)c2cc1OC
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1cc2nccc(Oc3ccc(NC(=O)NC4CCN(Cc5ccccc5)CC4)c(C)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 51.9 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-methylaniline (100 mg) was dissolved in chloroform (10 ml) and triethylamine (1 ml) to prepare a solution. A solution of triphosgene (142 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 10 min. Next, 1-benzyl-4-piperidineamine (91 mg) was added thereto, and the mixture was further stirred at room temperature for one hr. Water was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by concentration. The residue was purified on a column using chloroform/methanol to give the title compound (88 mg, yield 52%).
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([S:11]([OH:14])(=O)=[O:12])[C:5]=2[CH:4]=[CH:3][N:2]=1.S(Cl)([Cl:17])=O>>[ClH:17].[CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([S:11]([Cl:17])(=[O:14])=[O:12])[C:5]=2[CH:4]=[CH:3][N:2]=1
Reactant: O=S(=O)(O)c1cccc2cnccc12
Reactant: O=S(Cl)Cl
Product: Cl
Product: O=S(=O)(Cl)c1cccc2cnccc12

Procedure:
To 1200 ml of thionyl chloride were added 150 g of 5-isoquinolinesulfonic acid and 0.4 ml of N,Ndimethylformamide. Then, the resulting mixture was refluxed while heating at 80° to 85 ° C for 3 hours, followed by removal of the thionyl chloride under reduced pressure. Subsequently, 300 ml of dichloromethane was added to the reaction mixture to precipitate crystals. The precipitated crystals were separated by filtration, washed with 100 ml of dichloromethane, and then dried under reduced pressure to obtain 170 g of 5-isoquinolinesulfonyl chloride hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]3[O:15][C:14]([NH:16][S:17]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)(=[O:19])=[O:18])=[N:13][N:12]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:27][C:28](OC(C)=O)=[O:29]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[F:26][C:23]1[CH:22]=[CH:21][C:20]([S:17]([NH:16][C:14]2[O:15][C:11]([C:9]3[CH:8]=[CH:7][C:5]4[N:6]=[C:2]([NH:1][C:28](=[O:29])[CH3:27])[S:3][C:4]=4[CH:10]=3)=[N:12][N:13]=2)(=[O:18])=[O:19])=[CH:25][CH:24]=1
Reactant: Nc1nc2ccc(-c3nnc(NS(=O)(=O)c4ccc(F)cc4)o3)cc2s1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)Nc1nc2ccc(-c3nnc(NS(=O)(=O)c4ccc(F)cc4)o3)cc2s1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of N-(5-(2-aminobenzo[d]thiazol-6-yl)-1,3,4-oxadiazol-2-yl)-4-fluorobenzenesulfonamide, pyridine, Ac2O, and DMAP, was stirred at rt for 4 h. The product was isolated following standard procedures. MS (ESI pos. ion) m/z: calk's for C17H12FN5O4S2: 433.0. found: 434.0 (MH+).
Reaction SMILES: O[CH2:2][CH2:3][CH:4]1[CH2:9][CH:8]2[CH2:10][CH2:11][N:5]1[CH2:6][CH2:7]2.Cl.S(Cl)([Cl:15])=O>C(Cl)(Cl)Cl>[Cl:15][CH2:2][CH2:3][CH:4]1[CH2:9][CH:8]2[CH2:10][CH2:11][N:5]1[CH2:6][CH2:7]2
Reactant: OCCC1CC2CCN1CC2
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Product: ClCCC1CC2CCN1CC2

Procedure:
A solution of 10 g of 2-hydroxyethyl-quinuclidine in 80 ml of anhydrous chloroform was cooled to 0° C and treated with anhydrous gaseous hydrogen chloride. 50 ml of thionyl chloride were then added to the solution and the reaction mixture was heated to reflux for 3 hours. The excess thionyl chloride and the chloroform were removed by evaporation under reduced pressure on a water bath at 50° C. The residue was purified by washing with anhydrous ether. The ethereal suspension was filtered and the crystals obtained were dried under reduced pressure at room temperature. 12 g of 2-chloroethyl-quinuclidine, m.p. 202° C, were obtained.