Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8](I)[C:7]([CH:11]([F:13])[CH3:12])=[CH:6][C:5]=1[NH2:14].[CH3:16][N:17]1[C:21]([Sn](CCCC)(CCCC)CCCC)=[CH:20][CH:19]=[N:18]1>O1CCOCC1.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>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([C:21]2[N:17]([CH3:16])[N:18]=[CH:19][CH:20]=2)[C:7]([CH:11]([F:13])[CH3:12])=[CH:6][C:5]=1[NH2:14]
Reactant: COC(=O)c1cc(I)c(C(C)F)cc1N
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnn1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2ccnn2C)c(C(C)F)cc1N
Temperature: 90 °C
Reaction time: 24 h
Yield: 93.5 %

Procedure:
To a solution of 2-amino-4-(1-fluoro-ethyl)-5-iodo-benzoic acid methyl ester (0.339 g, 1.05 mmol) in dioxane (5 mL) were added 1-methyl-5-tributylstannanyl-1H-pyrazole (0.842 g, 2.14 mmol) and Pd(PPh3)2Cl2 (75.1 mg, 0.105 mmol) and the resulting mixture was stirred at 90° C. for 24 h. The solvent was removed in vacuo to afford a dark oil. The crude product was purified by flash chromatography (silica gel, EtOAc/hexanes (0:10 to 4:6)) to give 2-amino-4-(1-fluoro-ethyl)-5-(2-methyl-2H-pyrazol-3-yl)-benzoic acid methyl ester (280 mg, 0.982 mmol, 93%). ES-MS: m/z 278 [M+H]+, rt 4.66 min.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[CH:10][C:9]2[C:8]([F:14])([F:13])[CH:7]([C:15]3[N:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:17][N:16]=3)[CH2:6][CH2:5][C:4]=2[C:3]=1[OH:28].[CH2:29]([CH:32]1[O:34][CH:33]1[CH2:35]O)[CH2:30][CH3:31]>>[CH2:22]([O:21][C:18]1[CH:19]=[N:20][C:15]([CH:7]2[CH2:6][CH2:5][C:4]3[C:9](=[CH:10][C:11]([F:12])=[C:2]([F:1])[C:3]=3[O:28][CH2:35][CH:33]3[CH:32]([CH2:29][CH2:30][CH3:31])[O:34]3)[C:8]2([F:13])[F:14])=[N:16][CH:17]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCC1OC1CO
Reactant: CCCCCCOc1cnc(C2CCc3c(cc(F)c(F)c3O)C2(F)F)nc1
Product: CCCCCCOc1cnc(C2CCc3c(cc(F)c(F)c3OCC3OC3CCC)C2(F)F)nc1

Procedure:
From 2,3,5,5-tetrafluoro-6-(5-hexyloxypyrimidin-2-yl)-5,6,7,8-tetrahydronaphthalen-1-ol and (3-propyloxiranyl)methanol by means of the Mitsunobu reaction.
Reaction SMILES: [CH2:1]([C:5]1([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]#[N:24])[CH:6]1[OH:25])[CH2:2][CH2:3][CH3:4].[OH-:30].[Na+].OO>C(O)C.C(OCC)(=O)C>[CH2:1]([C:5]1([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23](=[O:30])[NH2:24])[CH:6]1[OH:25])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1(CCCC)CCc2c(OCc3ccccc3C#N)cccc2C1O
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCCCC1(CCCC)CCc2c(OCc3ccccc3C(N)=O)cccc2C1O
Temperature: 50 °C
Reaction time: 5 h

Procedure:
To a solution of 2,2-dibutyl-5-(2-cyanobenzyloxy)-1,2,3,4-tetrahydro-1-naphthol (500 mg) in a mixture of ethanol (3.5 ml) and aqueous 6N-sodium hydroxide solution (0.275 ml) was added aqueous 30% hydrogen peroxide (2.62 ml) in one portion at ambient temperature. The mixture was stirred for 5 hours at 50° C. and allowed to stand overnight at ambient temperature. The reaction mixture was diluted with ethyl acetate (40 ml). The separated organic layer was washed with aqueous hydrochloric acid, aqueous sodium bicarbonate solution, and brine, and then dried, and evaporated under reduced pressure. The residue was crystallized from aqueous ethanol to yield 2,2-dibutyl-5-(2-carbamoylbenzyloxy)-1,2,3,4-tetrahydro-1-naphthol (425 mg).
Reaction SMILES: C(O[C@H:15]1[O:62][C@H:61]([CH2:63][O:64][C:65](=[O:77])[CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH3:76])[C@H:46]([O:47][C:48](=[O:60])[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])[C@H:31]([O:32][C:33](=[O:45])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[C@H:16]1[O:17][C:18](=[O:30])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])(=O)CCCCCCCCCCC.[C:78]([OH:81])(=[S:80])[CH3:79].FC(F)(F)S(O[Si](C)(C)C)(=O)=O>ClCCl>[C:78]([S:80][C@H:15]1[O:62][C@H:61]([CH2:63][O:64][C:65](=[O:77])[CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH3:76])[C@H:46]([O:47][C:48](=[O:60])[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])[C@H:31]([O:32][C:33](=[O:45])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[C@H:16]1[O:17][C:18](=[O:30])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])(=[O:81])[CH3:79]
Reactant: CC(O)=S
Reactant: CCCCCCCCCCCC(=O)OC[C@H]1O[C@H](OC(=O)CCCCCCCCCCC)[C@H](OC(=O)CCCCCCCCCCC)[C@@H](OC(=O)CCCCCCCCCCC)[C@H]1OC(=O)CCCCCCCCCCC
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCCCCCC(=O)OC[C@H]1O[C@H](SC(C)=O)[C@H](OC(=O)CCCCCCCCCCC)[C@@H](OC(=O)CCCCCCCCCCC)[C@H]1OC(=O)CCCCCCCCCCC
Reaction time: 20 h
Yield: 7.2 %

Procedure:
To compound 1 (25.0 g, 22.9 mmol) and thioacetic acid (8.5 mL, 114.5 mmol) in dry dichloromethane (100 mL) under argon, was added trimethylsilyl trifluoromethanesulfonate (5.6 mL, 45.8 mmol) at room temperature. After 20 h, the mixture was diluted with dichloromethane (600 mL), washed with saturated sodium hydrogen carbonate (250 mL) and water (2×200 mL), dried with Na2SO4 and concentrated. The residue was purified by column chromatography three times (SiO2, pentane/EtOAc 20:1, 30:1, 40:1) to give 1-S-acetyl-2,3,4,6tetra-O-lauroyl-1-thio-α-D-galactopyranose (1.59 g, 7.2%).
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([OH:10])[C:5]([Br:11])=[CH:4][C:3]=1[CH2:12][C:13]([CH3:18])([CH3:17])[CH2:14][CH:15]=[O:16].[OH-].[Na+].[CH2:21]([OH:23])[CH3:22]>O.[N+]([O-])([O-])=O.[Ag+]>[Br:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([OH:10])[C:5]([Br:11])=[CH:4][C:3]=1[CH2:12][C:13]([CH3:18])([CH3:17])[CH2:14][C:15]([O:23][CH2:21][CH3:22])=[O:16]
Reactant: COc1c(O)c(Br)cc(CC(C)(C)CC=O)c1Br
Reactant: CCO
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)CC(C)(C)Cc1cc(Br)c(O)c(OC)c1Br
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of Silver Nitrate (0.722 g, 4.25 mmol) in 2.0 ml H2O was added to a solution of the product of STEP 4 (0.775 g, 2.04 mmol) in 20 ml ethanol. A solution of sodium hydroxide (2.71 g, 67.7 mmol) in 3.0 ml H2O was added dropwise at room temperature. After 6 h, the reaction was filtered through a short column of Celite® and washed with H2O. The filtrate was extracted with ether (3×30 ml). The aqueous layer was acidified with concentrated HCl and extracted with chloroform. The organic layer was dried with MgSO4, concentrated and dried in vacuo. The residue (0.75 g) was dissolved in 15 ml ethanol and 15 ml 4N HCl in dioxane. The reaction was stirred at room temperature for 18 h and concentrated. The residue was purified by chromatography (on silica gel, ethyl acetate/hexane=3/7) to afford a pale brown oil in 0.536 g. NMR spectra of the product were consistent for the proposed structure.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=2)[N:8]=1)=O.[C:26]1([NH:36]N)[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1>>[C:26]1([N:36]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(OC(F)(F)F)c2)ccc1=O
Reactant: NNc1cccc2ccccc12
Product: O=c1ccn(-c2cccc(OC(F)(F)F)c2)nc1-c1ccnn1-c1cccc2ccccc12

Procedure:
Reaction of 3-((E)-3-dimethylamino-acryloyl)-1-(3-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-6) and naphthalen-1-yl-hydrazine according to example 43 gave the desired product. MS: M=449.0 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([F:12])[CH:3]=1.[CH2:13]([C:20]1[CH:25]=[C:24]([CH3:26])[N:23]=[C:22](Cl)[N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([C:20]1[CH:25]=[C:24]([CH3:26])[N:23]=[C:22]([NH:1][C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([F:12])[CH:3]=2)[N:21]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Cc1cc(Cc2ccccc2)nc(Cl)n1
Reactant: COC(=O)c1ccc(N)cc1F
Product: COC(=O)c1ccc(Nc2nc(C)cc(Cc3ccccc3)n2)cc1F

Procedure:
The title compound was prepared from methyl 4-amino-2-fluoro-benzoate (480 mg, 2.84 mmol) and 4-benzyl-2-chloro-6-methyl-pyrimidine (620 mg, 2.84 mmol) in the same manner as described for example 1e). Obtained as white solid (840 mg, 84%). Mp 148-151° C.
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[CH3:6][C:7]1[N:8]([CH2:20][CH2:21][C:22]([O:24]CC)=O)[C:9]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[CH:11][C:10]=2[N:19]=1>O>[CH3:6][C:7]1[N:8]([CH2:20][CH2:21][C:22]([NH2:5])=[O:24])[C:9]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[CH:11][C:10]=2[N:19]=1
Reactant: [NH4+]
Reactant: CCOC(=O)CCn1c(C)nc2cnc3ccccc3c21
Agent: CC(=O)[O-]
Solvent: O
Product: Cc1nc2cnc3ccccc3c2n1CCC(N)=O
Temperature: 130 °C

Procedure:
Ammonium acetate (4.0 g) and ethyl 3-(2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)propanoate (4.5 g, 17 mmol, prepared as described in Parts A through C of Example 22) were heated for three days at 130° C. in a sealed vessel. The reaction was allowed to cool to ambient temperature, and water was added. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluting with dichloromethane:methanol in a gradient from 90:10 to 85:15) to provide 2.20 g of 3-(2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)propanamide as a tan solid.
Reaction SMILES: [NH:1]([C:8]1[CH:16]=[C:15]([C:17](O)=[O:18])[C:14]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:13][C:9]=1[C:10](O)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(=O)(O)(O)O.CO>O.C1C=C2C3N=C(C2=CC=1)N=C1C2C(C(=N1)N=C1C4C(C(=N1)N=C1C5C(C(=N1)N=3)=CC=CC=5)=CC=CC=4)=CC=CC=2.[Cu]>[CH:24]1[CH:25]=[C:26]2[C:17]([C:15]3[C:14]([NH:20][C:21]2=[CH:22][CH:23]=1)=[CH:13][C:9]1[C:10]([C:7]2[C:2]([NH:1][C:8]=1[CH:16]=3)=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:11])=[O:18]
Reactant: O=C(O)c1cc(Nc2ccccc2)c(C(=O)O)cc1Nc1ccccc1
Agent: [Cu]
Agent: O=P(O)(O)O
Agent: c1ccc2c(c1)C1=NC2=NC2=NC(=NC3=NC(=NC4=NC(=N1)c1ccccc14)c1ccccc13)c1ccccc12
Solvent: CO
Solvent: O
Product: O=c1c2ccccc2[nH]c2cc3c(=O)c4ccccc4[nH]c3cc12
Temperature: 95 °C
Reaction time: 0.25 h
Yield: 88.3 %

Procedure:
To 300 g of polyphosphoric acid (117% phosphoric acid) heated at 90° C. was added 0.7 g of copper phthalocyanine followed by 68.2 g of 2,5-dianilinoterephthalic acid. The mixture was heated at 120°-125° C. for two hours. After the melt was cooled to 95° C., the acid strength was adjusted to 112% by the dropwise addition of phosphoric acid. The resultant melt was stirred for 15 minutes and then slowly poured into 453 g of methanol at 24° C. During the drown, the temperature was allowed to increase to 55° C., with the temperature being controlled by external cooling and adjustment of melt addition rate. The slurry was heated at reflux (68°-72° C.) for one hour, diluted with water, and stirred at 60° C. for 30 minutes. The solid component was collected by filtration and washed with water until acid free. The resultant presscake was reslurried in water. After adjustment of the pH to greater than 7, 7.5 g of 50% sodium hydroxide was added and the resultant slurry was heated at 90° C. for one hour. The slurry was cooled, filtered, and washed with water until alkali free, then reslurried in water. After adjustment of the pH to greater than 8.5, 3.2 g of a cycloaliphatic carboxylic acid was added. The resultant slurry was heated at about 140°-145° C. for two hours in a closed system, cooled, acidified with phosphoric acid, and stirred. The solid component was collected by filtration and washed with water. The wet cake can be dried or used as is for specific applications. Here, the wet cake was dried in an oven at 60° C. to give approximately 54.0 g of quinacridone as a brilliant violet pigment.
Reaction SMILES: [NH2:1][C:2]1[C:14]([N:15]2[CH2:20][CH2:19][N:18]([S:21]([CH3:24])(=[O:23])=[O:22])[CH2:17][CH2:16]2)=[CH:13][C:5]2[N:6]=[C:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[S:8][C:4]=2[CH:3]=1.C(=O)(O)[O-].[Na+].[C:30](Cl)(Cl)=[S:31]>C(Cl)(Cl)Cl>[C:9]([C:7]1[S:8][C:4]2[CH:3]=[C:2]([N:1]=[C:30]=[S:31])[C:14]([N:15]3[CH2:16][CH2:17][N:18]([S:21]([CH3:24])(=[O:23])=[O:22])[CH2:19][CH2:20]3)=[CH:13][C:5]=2[N:6]=1)([CH3:11])([CH3:12])[CH3:10]
Reactant: CC(C)(C)c1nc2cc(N3CCN(S(C)(=O)=O)CC3)c(N)cc2s1
Reactant: S=C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)c1nc2cc(N3CCN(S(C)(=O)=O)CC3)c(N=C=S)cc2s1

Procedure:
A mixture of 1 g of 6-amino-2-tert-butyl-5-[4-methanesulphonylpiperazin-1-yl]benzothiazole and 500 g of sodium bicarbonate in 100 ml of chloroform is cooled in an ice-bath and 2 ml of thiophosgene in 10 ml of chloroform is added to it under stirring. The mixture is stirred over-night at ambient temperature. After filtering off the solid the filtrate is evaporated and the residue is subjected to silica gel column chromatography. Elution with 1% methanol in chloroform gives 2-tert-butyl-6-isothiocyanato-5-[4-methanesulphonylpiperazin-1-yl]benzothiazole melting at 128°-130°.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:21]([O:23]CC3C=CC=CC=3)=[O:22])[N:11]([CH3:20])[C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1>CO.[Pd]>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([C:21]([OH:23])=[O:22])[N:11]([CH3:20])[C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2nc(C(=O)OCc3ccccc3)n(C)c2-c2ccc(C)cc2)cc1
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(-c2nc(C(=O)O)n(C)c2-c2ccc(C)cc2)cc1
Reaction time: 1 h

Procedure:
To a suspension of benzyl 4,5-di-(4-methylphenyl)-1-methylimidazole-2-carboxylate (0.35 g, 0.9 mmol) from Example 2, Step C in methanol (10 mL) was added 20% palladium on carbon (50% w/w water, 100 mg) and the mixture was hydrogenated at 40 psi for 1 hr. The reaction was filtered and the filtrate was evaporated to dryness to afford the title compound as a white solid. (Note: The title compound readily decarboxylates as the acid.)
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13]CS([O-])(=O)=O)=[CH:8][CH:7]=1)(=[O:4])=[O:3].[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C>CN(C)C=O>[CH2:19]([NH:26][CH2:13][CH2:12][C:9]1[CH:8]=[CH:7][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:11][CH:10]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CS(=O)(=O)Nc1ccc(CCCS(=O)(=O)[O-])cc1
Reactant: NCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1ccc(CCNCc2ccccc2)cc1

Procedure:
2-(4-Methanesulfonamidophenyl)ethylmethanesulfonate (XXXII) (20 g), benzylamine (7.0 g) and triethylamine (15 ml) were combined in dimethylformamide (75 ml) and heated 18 hours at 100°. The solvent was evaporated and the residue was dissolved in EtOAc, which was washed with saturated NaHCO3, dried (MgSO4) and evaporated to give a dark oil. This was chromatographed on a silica column, eluting 8.0 g of solid product with CHCl3 /MeOH/concentrated NH4OH (15:1:0.1). This solid was treated with MeOH/concentrated HCl (10:1), causing precipitation of 4'-(2-benzylaminoethyl)methanesulfonanilide.HCl (XXIX.HCl), m.p. 244°-245°, whose NMR was consistent with the proposed structure.
Reaction SMILES: C([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11](=[O:14])(=[O:13])[NH2:12])C.Br[CH2:17][CH2:18][CH2:19][CH2:20][N:21]1[C:30](=[O:31])[C:29]2[CH:32]=[CH:33][CH:34]=[C:27]3[C:28]=2[C:23](=[CH:24][CH:25]=[CH:26]3)[C:22]1=[O:35]>>[O:35]=[C:22]1[C:23]2[C:28]3[C:27](=[CH:34][CH:33]=[CH:32][C:29]=3[C:30](=[O:31])[N:21]1[CH2:20][CH2:19][CH2:18][CH2:17][NH:12][S:11]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:4]([OH:3])=[O:15])(=[O:13])=[O:14])[CH:26]=[CH:25][CH:24]=2
Reactant: O=C1c2cccc3cccc(c23)C(=O)N1CCCCBr
Reactant: CCOC(=O)c1ccccc1S(N)(=O)=O
Product: O=C(O)c1ccccc1S(=O)(=O)NCCCCN1C(=O)c2cccc3cccc(c23)C1=O

Procedure:
The compound was prepared according to GP-2 using 2-sulfamoylbenzoic acid ethyl ester 4 and compound 3b. The crude product was purified by flash column chromatography using MeOH—CHCl3 to obtain 5b. 1H NMR (500 MHz, DMSO-d6) δ 9.27 (bs, 2H), 8.49-8.45 (m, 4H), 7.87 (t, J=8.0 Hz, 2H), 7.69 (d, J=8.0 Hz 1H), 7.63 (d, J=8.0 Hz 1H), 7.44 (t, J=7.5 Hz, 1H), 7.32 (t, J=7.5 Hz, 1H), 3.99 (t, J=7.0, 2H), 2.71 (q, J=7.0 Hz, 2H), 1.64-1.56 (m, 2H), 1.46-1.38 (m, 2H). MS (ES−) m/z 451 (M−H)−.
Reaction SMILES: C([O:5][C:6](=[O:35])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]2[N:18]=[N:17][C:16]([C:19]3[CH:20]=[N:21][CH:22]=[C:23]([C:25]#[C:26][CH2:27][C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[CH:24]=3)=[N:15]2)=[CH:9][CH:8]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:34][C:31]1[CH:32]=[CH:33][C:28]([CH2:27][C:26]#[C:25][C:23]2[CH:24]=[C:19]([C:16]3[N:17]=[N:18][N:14]([CH2:13][C:10]4[CH:9]=[CH:8][C:7]([C:6]([OH:35])=[O:5])=[CH:12][CH:11]=4)[N:15]=3)[CH:20]=[N:21][CH:22]=2)=[CH:29][CH:30]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Cn2nnc(-c3cncc(C#CCc4ccc(F)cc4)c3)n2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(Cn2nnc(-c3cncc(C#CCc4ccc(F)cc4)c3)n2)cc1
Yield: 78 %

Procedure:
The product of Step (c) was treated with trifluoroacetic acid in dichloromethane in a manner analogous to that described above in Step (c) of Example 43, then rotary evaporated in vacuo. Trituration of the resulting oil with diethyl ether gave the title product (84 mg, 78%). 1H NMR (DMSO-d6) δ 13.0 (s, 1H), 9.13 (s, 1H), 8.78 (s, 1H), 8.36 (s, 1H), 7.93 (d, J=8 Hz, 2H), 7.50 (d, J=8 Hz, 2H), 7.45 (m, 2H), 7.17 (m, 2H), 6.13 (s, 2H), 3.95 (s, 2H).
Reaction SMILES: [OH:1][C:2]1[C:3]2[O:16][N:15]=[C:14]([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[C:4]=2[C:5](I)=[N:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH:22]1(B(O)O)[CH2:24][CH2:23]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>CCOC(C)=O.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.C1(C)C=CC=CC=1>[CH:22]1([C:5]2[C:4]3[C:14]([C:17]4[S:18][CH:19]=[CH:20][CH:21]=4)=[N:15][O:16][C:3]=3[C:2]([OH:1])=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)[CH2:24][CH2:23]1
Reactant: OB(O)C1CC1
Reactant: CCOC(=O)c1nc(I)c2c(-c3cccs3)noc2c1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1nc(C2CC2)c2c(-c3cccs3)noc2c1O
Temperature: 100 °C
Yield: 19.8 %

Procedure:
Ethyl 7-hydroxy-4-iodo-3-(thiophen-2-yl)isoxazolo[4,5-c]pyridine-6-carboxylate (300 mg, 0.72 mmol), cyclopropylboronic acid (74 mg, 0.87 mmol), K3PO4 (505 mg, 2.38 mmol) and Pd(PPh3)4 (83 mg, 0.072 mmol) were added to a flask, and the flask evacuated. After refilling with nitrogen, toluene (4 mL) and water (43 μl, 2.38 mmol) were added, and the resulting suspension was heated in an oil bath (T=100° C.) for 18 h. After the mixture was cooled to room temperature, the mixture was diluted with EtOAc (50 mL) and the solid was removed by filtration. The filtrate was concentrated and the residue was purified first by flash chromatography (0-40% EtOAc/hexanes), then by preparative TLC (eluted with 40% EtOAc/hexanes), to afford 47 mg of the title compound. MS: (+) m/z 331.24 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1)#[CH:2].[Cl:11][C:12]1[CH:17]=[C:16](I)[CH:15]=[CH:14][C:13]=1[F:19].C(N(CC)CC)C>C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:11][C:12]1[CH:17]=[C:16]([C:2]#[C:1][C:3]2[CH:4]=[N:5][CH:6]=[C:7]([O:9][CH3:10])[CH:8]=2)[CH:15]=[CH:14][C:13]=1[F:19]
Reactant: Fc1ccc(I)cc1Cl
Reactant: C#Cc1cncc(OC)c1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COc1cncc(C#Cc2ccc(F)c(Cl)c2)c1
Temperature: 60 °C
Yield: 93 %

Procedure:
Add bis(triphenylphosphine)palladium (II) dichloride (110 mg, 0.15 mmol), copper (I) iodide (57 mg, 0.30 mmol), and 3-ethynyl-5-methoxypyridine, (prepared as described in PREPARATION 10), (400 mg, 3.0 mmol) to a solution of 2-chloro-1-fluoro-4-iodobenzene (0.46 mL, 3.6 mmol) in triethylamine (6.3 mL, 45.0 mmol) and heat at 60° C. for 5 h. Cool to room temperature and concentrate. Purify the residue by silica gel chromatography, eluting with a gradient of 100:0 to 80:20 dichloromethane:ethyl acetate, followed by a second silica gel chromatography, eluting with 67:33 to 60:40 hexanes:ethyl acetate, to give the title compound as a white solid (730 mg, 93%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]2[CH:8]([NH:20][C:21](=[O:23])[CH3:22])[CH2:9][O:10][C:11]3[CH:18]=[CH:17][C:16](Br)=[CH:15][C:12]=3[C:13]=2[N:14]=1)=[O:4].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH3:43][C:44]([OH:48])([C:46]#[CH:47])[CH3:45]>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2].[Cu]I>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]2[CH:8]([NH:20][C:21](=[O:23])[CH3:22])[CH2:9][O:10][C:11]3[CH:18]=[CH:17][C:16]([C:47]#[C:46][C:44]([OH:48])([CH3:45])[CH3:43])=[CH:15][C:12]=3[C:13]=2[N:14]=1)=[O:4]
Reactant: C#CC(C)(C)O
Reactant: COC(=O)c1nc2c(s1)C(NC(C)=O)COc1ccc(Br)cc1-2
Agent: [Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: COC(=O)c1nc2c(s1)C(NC(C)=O)COc1ccc(C#CC(C)(C)O)cc1-2
Temperature: 80 °C
Yield: 44.7 %

Procedure:
To a stirred mixture of 4-Acetylamino-9-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid methyl ester (180 mg, 0.453 mmol) in TEA (5 mL) and DMF (1 mL) were added Pd(OAc)2 (20.3 mg, 0.091 mmol), PPh3 (35.6 mg, 0.136 mmol), CuI (17.26 mg, 0.091 mmol) and 2-methylbut-3-yn-2-ol (190.6 mg, 2.266 mmol). The reaction mixture was degassed with N2 and heated in a microwave reactor at 80° C. for 2 h. Then the mixture was cooled to room temperature, and EtOAc was added. The mixture was filtered though Celite, and the filtrate was washed with saturated brine, dried over Na2SO4, filtered, concentrated in vacuo, and purified by flash column chromatography (silica gel, EtOAc in hexane from 10% to 20%) to afford 4-Acetylamino-9-(3-hydroxy-3-methyl-but-1-ynyl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid methyl ester (81 mg, 45%) as a light yellow solid. LC-MS (ESI & APCI): 399.1 (M−1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=O)=[N:6][CH:5]=[CH:4][N:3]=1.Cl.[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:20]1([CH:23]([NH2:25])[CH3:24])[CH2:22][CH2:21]1.Cl.C(N=C=NCCCN(C)C)C.O>CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:20]1([CH:23]([NH:25][C:8]([C:7]2[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][N:6]=2)=[O:10])[CH3:24])[CH2:21][CH2:22]1
Reactant: O=C(O)c1nccnc1Cl
Reactant: CC(N)C1(c2ccc(Cl)cc2Cl)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(NC(=O)c1nccnc1Cl)C1(c2ccc(Cl)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 68.9 %

Procedure:
To a solution of 2-chloropyrazine-3-carboxylic acid (0.15 g, 1.0 mmol), 1-[1-(2,4-dichlorophenyl)cyclopropyl]ethylamine hydrochloride (0.25 g, 0.94 mmol) and 4-dimethylaminopyridine (0.29 g, 2.4 mmol) in chloroform (10 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.22 g, 1.2 mmol) and the mixture was stirred at room temperature for 12 hrs. After adding water and chloroform, the mixture was separated, and the organic layer was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to give a desired compound (yield; 0.24 g, 69%).