Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.C1COCC1.[C:14]1(C)[CH:19]=[CH:18]C=[CH:16][CH:15]=1>O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([CH2:18][CH2:19][C:14]#[C:15][CH3:16])=[CH:3][CH:4]=1
Reactant: Brc1ccc(Br)cc1
Reactant: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: CC#CCCc1ccc(Br)cc1
Temperature: 25 °C

Procedure:
This reagent was gradually (for about one hour), dropwise added to a mixture consisting of p-dibromobenzene (150 mmol), bis(triphenylphosphine) Ni(II) dichloride (7.5 mmol) and THF (150 ml), at 0° C. or lower, followed by heating the mixture under reflux with stirring, allowing the mixture to cool down to room temperature, adding toluene (200 ml) and water (200 ml) to the reaction solution, sufficiently stirring the mixture, three times washing the organic layer with a brine (200 ml), drying over anhydrous magnesium sulfate, distilling off the solvent under reduced pressure at 30° C. or lower, purifying the residue subjecting to silica gel column chromatography (eluent solvent: heptane/toluene mixture) and further distilling under reduced pressure to obtain oily 4-bromo-1-(3pentynyl)benzene (61 mmol).
Reaction SMILES: S(Cl)(Cl)=O.[CH2:5]([O:7][C:8]([NH:10][C@@H:11]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C@H:12]([OH:16])[C:13]([OH:15])=[O:14])=[O:9])[CH3:6].S(=O)(O)O.Cl.[CH3:29]O>C1(C)C=CC=CC=1>[CH3:29][O:14][C:13](=[O:15])[C@@H:12]([OH:16])[C@@H:11]([NH:10][C:8]([O:7][CH2:5][CH3:6])=[O:9])[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CO
Reactant: CCOC(=O)N[C@@H](Cc1ccccc1)[C@H](O)C(=O)O
Agent: Cl
Agent: O=S(O)O
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)N[C@@H](Cc1ccccc1)[C@H](O)C(=O)OC
Temperature: 25 °C

Procedure:
Thionyl chloride (596 mg) was added to methanol (1.39 g) over 10 minutes under ice-cooling, and the mixture was reacted at the same temperature for 1 hour. The resultant solution was added to a solution of (2S,3S)-3-(ethoxycarbonyl)amino-2-hydroxy-4-phenylbutyric acid (HPLC area ratio of erythro-isomer/threo-isomer=99/1) (1.04 g) and toluene (10 ml) over 10 minutes under ice-cooling. The mixture was reacted at the same temperature for 2 hours and then warmed to room temperature. From the resultant reaction solution, methanol and thionyl chloride as well as components secondarily produced from these reagents and having a low boiling point such as sulfurous acid, hydrogen chloride or the like were distilled off under reduced pressure. Tetrahydrofuran was added to the resultant residue to obtain a tetrahydrofuran solution (10.12 g) of (2S,3S)-3-(ethoxycarbonyl)amino-2-hydroxy-4-phenylbutyric acid methyl ester. The HPLC area ratio of erythro-isomer/threo-isomer was 99/1, and the diastereomer excess was 99% d.e.
Reaction SMILES: [NH3:1].CO.[Cl:4][C:5]1[C:10]([CH:11]=[O:12])=[C:9](Cl)[N:8]=[CH:7][N:6]=1>C1(C)C=CC=CC=1>[NH2:1][C:9]1[C:10]([CH:11]=[O:12])=[C:5]([Cl:4])[N:6]=[CH:7][N:8]=1
Reactant: O=Cc1c(Cl)ncnc1Cl
Reactant: N
Solvent: CO
Solvent: Cc1ccccc1
Product: Nc1ncnc(Cl)c1C=O
Temperature: 23 °C
Reaction time: 3.5 h

Procedure:
A solution of 7M NH3 in MeOH (265 mL, 1.8602 mol, 2.0 equiv) was added over 1.25 hr to a solution of 4,6-dichloropyrimidine-5-carbaldehyde (9, 163.7 g, 0.9301 mol) in toluene (3 L). The reaction temperature slowly increased from 20 to 26° C. and a yellow suspension formed. Mild cooling was applied to maintain the reaction temperature at ≦26° C. The suspension was stirred 3.5 hr at room temperature before the solids were collected by filtration. The solids were washed with EtOAc (1 L). The filtrate was concentrated under reduced pressure, and the solids were triturated with toluene/heptane (2:1 v/v, 600 mL), filtered and dried to give 71.1 g of 4-amino-6-chloropyrimidine-5-carbaldehyde (10) as a yellow solid. The original solid filtered from the reaction mixture contained additional 10. The product was extracted from the filtered solid by stirring in EtOAc (1.25 L) for 1.5 hr, filtering, then stirring in THF (750 mL) for 1 hr and filtering. Both EtOAc and THF filtrates were concentrated under reduced pressure, and the resulting solids were triturated with toluene/heptane (2:1 v/v, 450 mL), filtered and dried to give an additional 44.1 g of 4-amino-6-chloropyrimidine-5-carbaldehyde (10) as yellow solids. The combined yield of 4-amino-6-chloropyrimidine-5-carbaldehyde (10, 115.2 g, 146.5 g theoretical) was 78.6%. For 10: 1H NMR (DMSO-d6, 300 MHz) δ ppm 10.23 (s, 1H), 8.71 (bs, 1H), 8.55 (bs, 1H), 8.39 (s, 1H); C5H4ClN3O (MW, 157.56), LCMS (EI) m/e 158 (M++H).
Reaction SMILES: N[C@H]1C[CH2:5][CH2:4][C@@H:3]1[C:7]([OH:9])=[O:8].C([N:12](CC)CC)C.[C:17]([O:21][C:22]([O:24]C(OC(C)(C)C)=O)=O)([CH3:20])([CH3:19])[CH3:18]>CO>[CH3:18][C:17]([O:21][C:22]([NH:12][C:3]1([C:7]([OH:9])=[O:8])[CH2:4][CH2:5]1)=[O:24])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: N[C@H]1CCC[C@@H]1C(=O)O
Reactant: CCN(CC)CC
Solvent: CO
Product: CC(C)(C)OC(=O)NC1(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(1S,2S)-2-Amino-cyclopentanecarboxylic acid (NH2-ACPC-OH, JKMI91, 5.18 g, 40.1 mmol) (See LePlae, Umezawa, Lee & Gellman (2001) J. Org. Chem. 66:5629-5632) was dissolved in methanol (409 mL). Triethylamine (11.16 mL, 80.2 mmol) was added via syringe followed by di-tert-butyl-dicarbonate (8.74 g, 40.1 mmol). The reaction mixture was stirred at room temperature for 2 h. The solvent was removed by rotary evaporation. The residue was diluted with ethyl acetate (250 mL), washed with 0.5 M NaHSO4 (1×100), and saturated aqueous NaCl solution (1×100). The organic layer was dried over MgSO4, filtered, and concentrated to give a white solid. The crude product was purified by column chromatography (7:3:0.3) hexane:ethyl acetate:acetic acid). Acetic acid was removed on the high-vacuum rotary evaporator. Benzene (2×100 mL) was added and removed on the rotary evaporator. The residue was dried under high vacuum overnight to give a white solid (Boc-ACPC-OH, JKMI103, 7.65 g, 83%). 1H NMR (250 MHz, CDCl3): δ=11.22 (br. s, 1H), 4.93 (br. s, 1H), 4.02 (br. s, 1H), 2.69 (br. s, 1H), 2.14-1.89 (m, 3H), 1.68 (quin., J=6.7 Hz, 2H), 1.51-1.35 (m, 10H) ppm.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[S:10][C:11]3[CH2:17][CH2:16][CH2:15][CH:14]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:12]=3[N:13]=2)=[CH:4][C:3]=1[O:24][CH3:25].[C:26]([OH:32])([C:28]([F:31])([F:30])[F:29])=[O:27].[CH3:33][C:34]1[CH:39]=[C:38](B(O)O)[CH:37]=[CH:36][N:35]=1.C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC.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.O>[F:29][C:28]([F:31])([F:30])[C:26]([OH:32])=[O:27].[CH3:25][O:24][C:3]1[CH:4]=[C:5]([NH:8][C:9]2[S:10][C:11]3[CH2:17][CH2:16][CH2:15][CH:14]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:12]=3[N:13]=2)[CH:6]=[CH:7][C:2]=1[C:38]1[CH:37]=[CH:36][N:35]=[C:34]([CH3:33])[CH:39]=1
Reactant: COc1cc(Nc2nc3c(s2)CCCC3c2ccccc2)ccc1Br
Reactant: Cc1cc(B(O)O)ccn1
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: [Cs+]
Solvent: COCCOC
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(Nc2nc3c(s2)CCCC3c2ccccc2)ccc1-c1ccnc(C)c1
Temperature: 100 °C
Yield: 35 %

Procedure:
A mixture of N-(4-bromo-3-methoxyphenyl)-4-phenyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine, TFA (70 mg, 0.13 mmol), 2-methylpyridin-4-ylboronic acid (36 mg, 0.26 mmol), tetrakis(triphenylphosphine)palladium(0) (7.6 mg, 6.6 μmol) and Cs2CO3 (172 mg, 0.529 mmol) in DME (994 μL)/water (328 μL) was heated at 100° C. for 18 h. The crude reaction products were purified using preparatory HPLC (Solvent A=10% MeOH-90% water-0.1% TFA, Solvent B=90% MeOH-10% water-0.1% TFA. Column: Phenomenex Luna 30×100 mm, S10, flow rate: 40 ml/min, 40-100% B, 40 min) to afford 30 mg (35% yield) of the titled compound as a yellow oil. LC-MS (M+H)+ 428.2.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[F:22][C:23]([F:35])([F:34])[O:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>O.C(O)C.C1(C)C=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>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([C:28]4[CH:27]=[CH:26][C:25]([O:24][C:23]([F:22])([F:34])[F:35])=[CH:30][CH:29]=4)[CH:10]=3)[CH:6]=[CH:7]2)=[CH:13][CH:14]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)c1ccc(Cn2ccc3ccc(Br)cc32)cc1
Reactant: OB(O)c1ccc(OC(F)(F)F)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: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)c1ccc(Cn2ccc3ccc(-c4ccc(OC(F)(F)F)cc4)cc32)cc1
Yield: 61.4 %

Procedure:
Following the procedure described in Step 2 of Example 5, 6-bromo-1-[4-(tert-butyl)benzyl]-1H-indole (0.488 g, 1.43 mmol) was coupled to 4-trifluoromethoxybenzene boronic acid (0.329 g, 1.60 mmol), using tetrakis(triphenylphosphine)palladium (0.0574 g, 0.0496 mmol) and sodium carbonate (0.617 g, 5.82 mmol) in water (2.8 mL), ethanol (1.4 mL) and toluene (10 mL). Purification by flash chromatography using hexane as an eluant yielded 1-[4-(tert-butyl)benzyl]-6-[4-(trifluoromethoxy)phenyl]-1H-indole as a white solid (0.372 g, 61%), mp 100-102° C. 1HNMR (200 MHz, DMSO-d6): δ 7.8 (d, 3H, J=8.5 Hz), 7.65 (d, 1H, J=8.5 Hz), 7.55 (d, 1H, J=3.5 Hz), 7.3-7.5 (m, 5H), 7.15 (d, 2H, J=7.5 Hz), 6.5 (d, 1H, J=3.5 Hz), 5.45 (s, 2H), and 1.2 ppm (s, 9H).
Reaction SMILES: [CH2:1]([N:3]([CH3:14])[C:4]1[N:13]=[C:7]2[CH:8]=[C:9]([NH2:12])[CH:10]=[CH:11][N:6]2[N:5]=1)[CH3:2].[CH2:15]([O:17][C:18]([C:20]1[CH:21]=[N:22][N:23]([CH3:28])[C:24]=1[C:25](O)=[O:26])=[O:19])[CH3:16].CCCP(=O)=O.C(N(CC)C(C)C)(C)C>O1CCCC1>[CH2:15]([O:17][C:18]([C:20]1[CH:21]=[N:22][N:23]([CH3:28])[C:24]=1[C:25](=[O:26])[NH:12][C:9]1[CH:10]=[CH:11][N:6]2[N:5]=[C:4]([N:3]([CH2:1][CH3:2])[CH3:14])[N:13]=[C:7]2[CH:8]=1)=[O:19])[CH3:16]
Reactant: CCN(C)c1nc2cc(N)ccn2n1
Reactant: CCOC(=O)c1cnn(C)c1C(=O)O
Agent: CCCP(=O)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnn(C)c1C(=O)Nc1ccn2nc(N(C)CC)nc2c1
Yield: 90.2 %

Procedure:
A mixture of N2-ethyl-N2-methyl-[1,2,4]triazolo[1,5-a]pyridine-2,7-diamine (215 mg, 1.12 mmol), 4-(ethoxycarbonyl)-1-methyl-1H-pyrazole-5-carboxylic acid (267 mg, 1.35 mmol), propylphosphonic anhydride (50% in ethyl acetate, 1.66 ml, 2.81 mmol) and N,N-diisopropylethylamine (574 μl, 3.37 mmol) in tetrahydrofuran (10 ml) was refluxed for 18 hours. The crude material was applied on silicagel and purified by flash chromatography over a 20 g silicagel column using ethyl acetate 100% as eluent affording 5-[2-(ethyl-methyl-amino)-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl]-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (375 mg, 89.8%) as a light yellow solid. mp: 167° C., MS: m/z=372.5 (M+H+)
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]([CH3:8])[C:6]2[CH:9]=[CH:10][C:11]([C:20]3[C:21]4[CH:30]=[CH:29][N:28]([S:31]([C:34]5[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=5)(=[O:33])=[O:32])[C:22]=4[C:23](=[O:27])[N:24]([CH3:26])[CH:25]=3)=[C:12]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:5]=2[N:4]=1.[CH:41]1([C:45](Cl)=[O:46])[CH2:44][CH2:43][CH2:42]1>>[CH3:8][N:7]1[C:6]2[CH:9]=[CH:10][C:11]([C:20]3[C:21]4[CH:30]=[CH:29][N:28]([S:31]([C:34]5[CH:35]=[CH:36][C:37]([CH3:40])=[CH:38][CH:39]=5)(=[O:32])=[O:33])[C:22]=4[C:23](=[O:27])[N:24]([CH3:26])[CH:25]=3)=[C:12]([O:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:5]=2[N:4]=[C:3]1[CH2:2][NH:1][C:45]([CH:41]1[CH2:44][CH2:43][CH2:42]1)=[O:46]
Reactant: O=C(Cl)C1CCC1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(-c4ccc5c(nc(CN)n5C)c4Oc4ccccc4)cn(C)c(=O)c32)cc1
Product: Cc1ccc(S(=O)(=O)n2ccc3c(-c4ccc5c(nc(CNC(=O)C6CCC6)n5C)c4Oc4ccccc4)cn(C)c(=O)c32)cc1

Procedure:
This compound was synthesized according to the procedure of Example 66, Step 2, using 4-[2-(aminomethyl)-1-methyl-4-phenoxy-1H-benzimidazol-5-yl]-6-methyl-1-[(4-methylphenyl)sulfonyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one and cyclobutanecarboxylic acid chloride as the starting materials. LCMS calculated for C35H34N5O5S (M+H)+: m/z=636.2. found: 636.2.
Reaction SMILES: [O:1]1CCCC1.S(=O)(=O)(O)O.[OH:11][C:12]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH:15]([CH3:17])[CH3:16])[C:13]#[CH:14]>O>[OH:11][C:12]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([CH:15]([CH3:17])[CH3:16])[C:13](=[O:1])[CH3:14]
Reactant: C#CC(O)(c1ccccc1)C(C)C
Reactant: C1CCOC1
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)C(O)(c1ccccc1)C(C)C
Temperature: 60 °C
Reaction time: 0.08 h

Procedure:
To a refluxing mixture of tetrahydrofuran (70 ml), water (5 ml), and conc. sulfuric acid (1.5 g) is added 1 g of red mercuric oxide and the reflux is continued for 5 min. Then, the inside temperature is adjusted to 60°-62° C. and 10 g of 3-hydroxy-4-methyl-3-phenyl-1-pentyne (described in Example 1) is added. The reaction is exothermic (spontaneous mild reflux) and there is a noticeable clearing of the mixture. Another 1 g of mercuric oxide is added, and the solution is refluxed for 30 min. The reaction mixture is stirred at 60° C. for an additional 3 hr, during which time the precipitation of a mercury sludge occurred. After cooling, the slurry is diluted with 100 ml of diethyl ether and filtered through diatomaceous earth. The filter cake is washed with 200 ml of diethyl ether, and the combined filtrates are washed repeatedly with water, dried over magnesium sulfate, filtered, and evaporated to give 10.6 g of the title product, ir (CDCl3) 3470 and 1715-1710 cm-1 and nmr (CDCl3) δ 0.91(d), 2.15(s), 2.79(heptuplet), 4.39(s) and 7.20-7.65(m).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8](F)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[N+:15]([O-:17])=[O:16].[CH3:19][NH2:20]>O1CCOCC1>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([NH:20][CH3:19])[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[N+:15]([O-:17])=[O:16]
Reactant: CN
Reactant: COC(=O)c1cc(F)c(C(F)(F)F)cc1[N+](=O)[O-]
Solvent: C1COCCO1
Product: CNc1cc(C(=O)OC)c([N+](=O)[O-])cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 48 h
Yield: 95.4 %

Procedure:
5-Fluoro-2-nitro-4-trifluoromethyl-benzoic acid methyl ester (300 mg, 1.12 mmoles) is dissolved in dioxane and after addition of methylamine (0.490 ml, 3.5 eq.) the yellow mixture is stirred at room temperature for 2 days. The mixture is evaporated to dryness. Dichloromethane is added and the suspension is filtrated. Evaporation of the filtrate yielded 2-nitro-5-methylamino-4-trifluoromethyl-benzoic acid methyl ester as a yellow solid (291.3 mg, 95.4% yield). The product is used in the next step without further purification.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][C:8](O)=[O:9].B>C1COCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][CH2:8][OH:9]
Reactant: O=C(O)CCc1ccco1
Agent: B
Solvent: C1CCOC1
Product: OCCCc1ccco1
Temperature: 25 °C
Reaction time: 12 h
Yield: 79.3 %

Procedure:
To 3-(furan-2-yl)propanoic acid (1.4 g, 10 mmol) in THF (50 mL) was added dropwise borane (1M) (20 mL, 20 mmol). The mixture was stirred at rt for 12 hrs, quenched with MeOH, and the mixture was concentrated. The resulting residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-50% Hexane in ethyl acetate) to afford 1.0 g (79%) of the title compound. 1H NMR (500 MHz, CDCl3) δ ppm 1.87-1.94 (m, 2 H) 2.74 (t, J=7.32 Hz, 2 H) 3.69 (t, J=6.10 Hz, 2 H) 6.28 (dd, J=3.05, 1.83 Hz, 1 H) 7.30 (d, J=0.92 Hz, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH2:23][CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][CH:11]=1)[NH2:5].C(N(CC)CC)C.ClC(Cl)(O[C:43](=[O:49])OC(Cl)(Cl)Cl)Cl.[F:51][C:52]1[CH:57]=[CH:56][C:55]([CH:58]([NH2:60])[CH3:59])=[CH:54][CH:53]=1>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:43]([NH:60][CH:58]([C:55]2[CH:56]=[CH:57][C:52]([F:51])=[CH:53][CH:54]=2)[CH3:59])=[O:49])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH2:23][CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][CH:11]=1
Reactant: CC(N)c1ccc(F)cc1
Reactant: COc1cc2c(Oc3ccc(N)cc3F)ccnc2cc1OCCCN1CCOCC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc2c(Oc3ccc(NC(=O)NC(C)c4ccc(F)cc4)cc3F)ccnc2cc1OCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 64.8 %

Procedure:
3-Fluoro-4-{[6-methoxy-7-(3-morpholinopropoxy)-4-quinolyl]oxy}-aniline (30 mg) was dissolved in chloroform (3 ml) and triethylamine (0.3 ml) to prepare a solution. A solution of triphosgene (17 mg) in chloroform (0.2 ml) was then added to the solution, and the mixture was stirred at room temperature for 25 min. Next, a solution of 1-(4-fluorophenyl)ethylamine (12 mg) in chloroform (0.2 ml) was added thereto, and the mixture was stirred at room temperature for 5 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (22 mg, yield 52%).
Reaction SMILES: Cl[C:2]1[C:3]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:20])[F:19])(=[O:11])=[O:10])=[N:4][CH:5]=[CH:6][N:7]=1.[CH2:22]([OH:25])[C:23]#[CH:24].CC(O[K])=O>CN(C=O)C.[Cu]I.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>[OH:25][CH2:22][C:23]#[C:24][C:2]1[C:3]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:20])[F:19])(=[O:11])=[O:10])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: O=S(=O)(Nc1nccnc1Cl)c1ccccc1C(F)(F)F
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: CC(=O)O[K]
Solvent: CN(C)C=O
Product: O=S(=O)(Nc1nccnc1C#CCO)c1ccccc1C(F)(F)F
Temperature: 100 °C
Yield: 50 %

Procedure:
N-(3-chloropyrazin-2-yl)-2-(trifluoromethyl)benzenesulfonamide (1.35 g; 4.0 mmol; 1.00 eq.) and 2-propyn-1-ol (336 mg 6.0 mmol; 1.5 eq.) were dissolved in 10 mL of DMF under nitrogen atmosphere. To the reaction mixture was added CH3COOK (588 mg; 6.0 mmol; 1.5 eq.) CuI (40 mg; 0.2 mmol; 0.05 eq.) and Pd(PPh3)2Cl2 (28 mg; 0.04 mmol) under nitrogen. The reaction mixture was then heated at 100° C. under nitrogen for 2 hours. After removal of the solvent by distillation in vacuo, the residue was triturated with water (40 mL) and extracted with diethyl ether (3×30 mL). The organic layer was dried over MgSO4 and evaporated down. The crude product was purified by silica gel column chromatography using a mixture of hexane and AcOEt to give pure N-[3-(3-hydroxyprop-1-yn-1-yl)pyrazin-2-yl]-2-(trifluoromethyl)benzenesulfonamide as a yellowish solid (702 mg, 50% yield, 98% HPLC purity).
Reaction SMILES: Cl[S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH:14]1([NH2:17])[CH2:16][CH2:15]1>ClCCl>[CH:14]1([NH:17][S:2]([C:5]2[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=2)(=[O:4])=[O:3])[CH2:16][CH2:15]1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: NC1CC1
Solvent: ClCCl
Product: O=C(O)c1ccc(S(=O)(=O)NC2CC2)cc1
Temperature: 25 °C
Yield: 91.5 %

Procedure:
To 4-chlorosulfonylbenzoic acid (10.0 g, 45.3 mmol) in dichloromethane (350 mL) at 0° C. was added cyclopropanamine (15.5 g, 19 mL, 271.9 mmol). The reaction mixture was allowed to warm to room temperature over 16 hours. The solvent was evaporated under reduced pressure. The residue was dissolved in water (150 mL) and acidified using hydrochloric acid. The aqueous layer was extracted with EtOAc (2×200 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give 4-(cyclopropylsulfamoyl)benzoic acid (10.0 g, 92%) as a white solid. ESI-MS m/z calc. 241.0. Found 242.5 (M+1)+; Retention time: 0.84 minutes (3 min run); 1H NMR (400 MHz, DMSO) δ 13.27 (s, 1H), 7.97 (d, J=8.3 Hz, 2H), 7.91 (d, J=2.5 Hz, 1H), 7.75 (d, J=8.3 Hz, 2H), 2.03-1.90 (m, 1H), 0.38-0.28 (m, 2H), 0.23-0.15 (m, 2H).
Reaction SMILES: [C:1](=O)([O-])[O-].[Cs+].[Cs+].[CH3:7][CH2:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:10].[CH3:18][O:19][CH2:20]Br.O>CN(C)C=O>[CH3:18][O:19][CH2:20][CH2:1][O:17][C:14]1[CH:13]=[CH:12][C:11]([C:9](=[O:10])[CH2:8][CH3:7])=[CH:16][CH:15]=1
Reactant: O=C([O-])[O-]
Reactant: COCBr
Reactant: CCC(=O)c1ccc(O)cc1
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(=O)c1ccc(OCCOC)cc1

Procedure:
Cesium carbonate (5.7 g, 17.5 mmol) was added to a stirred solution of 4-hydroxypropiophenone (12; 2.5 g, 16.7 mmol) in dimethylformamide (25 mL) under nitrogen at room temperature, followed by bromomethyl methyl ether (1.43 g, 17.5 mmol). After 20 hours the mixture was stirred into 200 mL of water, and then extracted 3× with dichloromethane. The combined extracts were washed with water and then sat brine, and dried over magnesium sulfate. The solvent was removed in vacuo, leaving 3.4 g of pale yellow apparently crystalline solid; mp 31-35° C.; mass spec ES+m/z=209 (m+1).
Reaction SMILES: O[C:2]1[CH:3]=[C:4]([NH:8][C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1.CN(C)C=O.[H-].[Na+].[CH3:22][CH:23]1[CH2:27][C:26]2[CH:28]=[C:29]([CH2:32][CH2:33][O:34]S(C3C=CC(C)=CC=3)(=O)=O)[CH:30]=[CH:31][C:25]=2[O:24]1>O>[CH3:22][CH:23]1[CH2:27][C:26]2[CH:28]=[C:29]([CH2:32][CH2:33][O:34][C:5]3[CH:6]=[CH:7][CH:2]=[CH:3][C:4]=3[NH:8][C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])[CH:30]=[CH:31][C:25]=2[O:24]1
Reactant: CON(C)C(=O)Nc1cccc(O)c1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc3c(c2)CC(C)O3)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CON(C)C(=O)Nc1ccccc1OCCc1ccc2c(c1)CC(C)O2
Reaction time: 0.5 h
Yield: 93.3 %

Procedure:
2.0 g of 1-(3-hydroxyphenyl)-3-methoxy-3-methylurea was dissolved into 20 ml of dried N,N-dimethylformamide, and 0.4 g of 60% sodium hydride was added thereto. After the mixture was stirred for 30 minutes, 3.3 g of 2-(2,3-dihydro-2-methyl-5-benzofuranyl)ethyl-p-toluene sulfonate was added dropwise thereto under cooling with ice. After the mixture was stirred at room temperature for 5 hours, it was poured into water and extracted with ethyl acetate. After the organic layer was washed with water, it was dried over anhydrous magnesium sulfate and ethyl acetate was distilled off. The residue was subjected to silica gel column chromatography using ethyl acetate/n-hexane (1/2) as a developer to obtain 3.3 g of Compound No. 49 shown in Table 3.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH3:12].[Li]CCCC.[Cl:18][C:19]1[CH:20]=[CH:21][C:22]2[N:23]([C:25]([C:28](=[O:30])[CH3:29])=[CH:26][N:27]=2)[N:24]=1>C1COCC1>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]2[N:23]([C:25]([C:28]([C:10]3[C:2]([F:1])=[C:3]4[C:7](=[CH:8][C:9]=3[F:11])[N:6]([CH3:12])[N:5]=[CH:4]4)([OH:30])[CH3:29])=[CH:26][N:27]=2)[N:24]=1
Reactant: CC(=O)c1cnc2ccc(Cl)nn12
Reactant: Cn1ncc2c(F)cc(F)cc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1ncc2c(F)c(C(C)(O)c3cnc4ccc(Cl)nn34)c(F)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.8 %

Procedure:
To a solution of 4,6-difluoro-1-methyl-1H-indazole (600 mg, 3.57 mmol) in 20 mL of anhydrous THF at −78° C. was added n-BuLi (1.6M solution in hexane, 2.56 mL, 4.1 mmol). The solution was stirred at this temperature for 1 hour and then a solution of 1-(6-Chloro-imidazo[1,2-b]pyridazin-3-yl)-ethanone (698 mg, 3.57 mmol) in 10 mL of anhydrous THF was added at −78° C. dropwise. The resulting solution was stirred at this temperature for 3 hours and slowly warmed up to room temperature and stirred overnight. The reaction mixture was quenched with water, extracted with EtOAc for three times. The organic layers were combined and washed with brine, dried over Na2SO4. The crude product was purified with flash chromatography (CH2Cl2:MeOH 95:5) to give the title compound as a yellow oil (530 mg, 41%). 1H-NMR (400 MHz, CDCl3) δ ppm 8.05 (d, 1H), 8.0 (s, 1H), 7.85 (s, 1H), 7.1 (d, 1H), 6.85 (d, 1H), 4.0 (s, 3H), 2.3 (s, 3H). LCMS (method B): [MH]+=363.9, tR=2.15 min.