Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[C:11]([NH:13]C(OC(C)(C)C)=O)=[O:12].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:21])[C:4]1[C:5](=[CH:6][CH:7]=[C:8]([F:10])[CH:9]=1)[C:11]([NH2:13])=[O:12]
Reactant: COC(=O)c1cc(F)ccc1C(=O)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(F)ccc1C(N)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-tert-butoxycarbonylaminocarbonyl-5-fluoro-benzoic acid methyl ester (4.5 g, 15.13 mmol) plus regioisomer in CH2Cl2 (25 mL) is added TFA (2.0 mL, 25.96 mmol). The reaction mixture is stirred at room temperature for 3 hours and concentrated under reduced pressure to afford 5-fluoro-phthalamic acid methyl ester plus regioisomer (2.24 g, 75%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]([C:14]#[N:15])([CH3:13])[CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.CN(C)C=O.[NH2:27][C:28]1[CH:29]=[C:30]([CH:47]=[CH:48][CH:49]=1)[O:31][C:32]1[CH:44]=[CH:43][C:35]2[N:36]=[C:37]([NH:39][C:40](=[O:42])[CH3:41])[S:38][C:34]=2[C:33]=1[C:45]#[N:46]>O1CCCC1.C(OCC)(=O)C>[C:40]([NH:39][C:37]1[S:38][C:34]2[C:33]([C:45]#[N:46])=[C:32]([O:31][C:30]3[CH:29]=[C:28]([NH:27][C:4](=[O:6])[C:3]4[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([C:14]#[N:15])([CH3:13])[CH3:12])[C:2]=4[Cl:1])[CH:49]=[CH:48][CH:47]=3)[CH:44]=[CH:43][C:35]=2[N:36]=1)(=[O:42])[CH3:41]
Reactant: CC(=O)Nc1nc2ccc(Oc3cccc(N)c3)c(C#N)c2s1
Reactant: CC(C)(C#N)c1cccc(C(=O)O)c1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)Nc1nc2ccc(Oc3cccc(NC(=O)c4cccc(C(C)(C)C#N)c4Cl)c3)c(C#N)c2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.3 %

Procedure:
To a solution of 2-chloro-3-(1-cyano-1-methylethyl)benzoic acid (165 mg, 0.74 mmol) in tetrahydrofuran (2 mL) were added oxalyl chloride (79 μL, 0.93 mmol) and N,N-dimethylformamide (10 μL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in N,N-dimethylacetamide (1.2 mL). N-[6-(3-Aminophenoxy)-7-cyano-1,3-benzothiazol-2-yl]acetamide (200 mg, 0.62 mmol) was added to the solution, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate (12 mL), washed successively with 5% aqueous sodium hydrogen carbonate solution (10 mL) and saturated brine (10 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=30/70→80/20), and the obtained solution was concentrated under reduced pressure. The residue was recrystallized from ethanol to give the title compound (264 mg, 81%) as a white powder.
Reaction SMILES: [C:1]([NH:18][C@H:19]([CH2:23][OH:24])[CH2:20][CH2:21][CH3:22])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].C(N(CC)CC)C.C(OC(=O)C)C>ClCCl.CS(C)=O>[CH:7]1[C:6]2[CH:5]([CH2:4][O:3][C:1]([NH:18][C@H:19]([CH:23]=[O:24])[CH2:20][CH2:21][CH3:22])=[O:2])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: CCC[C@@H](CO)NC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCC[C@@H](C=O)NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of Fmoc-norValinol (21.70 g, 66.77 mmol) in dichloromethane (668 ml) was added triethylamine (37.23 ml, 267 mmol) and the solution was cooled to 0° C. A suspension of pyridine sulfur trioxide complex (42.51 g, 267 mmol) in dimethylsulfoxide (96 ml) was added to the chilled solution. After one hour, TLC in 2:3 ethylacetate:hexanes confirmed the completion of the reaction. The dichloromethane was removed under reduced pressure and the remaining residue was dissolved in ethylacetate and washed with water (2×50 ml), 1 N saturated sodium bisulfate (2×50 ml), saturated sodium bicarbonate (2×50 ml) and brine (50 ml). The organic layer was concentrated to yield a white solid. Theoretical yield (21.57 g) was assumed and the reaction was taken to the next step without further purification.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][OH:13])[CH3:6]>N1C=CC=CC=1>[Cl-:3].[CH2:5]([O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][OH:13])[CH3:6]
Reactant: O=S(Cl)Cl
Solvent: CCOCCOCCO
Solvent: c1ccncc1
Product: [Cl-]
Reaction time: 3 h

Procedure:
487 ml of thionyl chloride are added dropwise to a stirred solution of 805 g of diethylene glycol monoethyl ether in 10 ml of pyridine. After all has been added, the mixture is heated to 80°. The initially vigorous evolution of gas ceases after about 3 hours. The reaction mixture is then degassed in vacuo, affording as residue 843 g of diethylene glycol monoethyl ether chloride which is taken up in 1 l of ethanol and stirred with 750 ml of ammonia in an autoclave at 130° for 15 hours. After cooling, 240 g of sodium hydroxide are cautiously added. The mixture is filtered and the residue is washed with alcohol. The filtrate is concentrated by evaporation and the residue is dried by azeotropic distillation with toluene and then purified by fractional distillation through a Vigreux column. The main fraction, diethylene glycolamine ethyl ether, distills at 73°-76°/17 mbar. Yield: 382 g (48% of theory).
Reaction SMILES: [Cl:1][C:2]1[C:13]2[CH2:12][CH2:11][N:10]([CH3:14])[CH2:9][CH2:8][N:7](N)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:16]1(=O)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)CC.C(OCC)(=O)C>[Cl:1][C:2]1[C:13]2[CH2:12][CH2:11][N:10]([CH3:14])[CH2:9][CH2:8][N:7]3[C:6]=2[C:5]([C:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=23)=[CH:4][CH:3]=1
Reactant: O=C1CCCCC1
Reactant: CN1CCc2c(Cl)cccc2N(N)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCCO
Product: CN1CCc2c(Cl)ccc3c4c(n(c23)CC1)CCCC4
Temperature: 25 °C
Yield: 33.8 %

Procedure:
To a solution of 7-chloro-4-methyl-3,4,5,6-tetrahydro-2H-benzo[e][1,4]diazocin-1-ylamine (1.20 g, 5.32 mmole) in 1-propanol (100 mL) was added cyclohexanone (4.73 g, 48.2 mmole) followed by p-toluenesulfonic acid monohydrate (3.2 g, 16.8 mmole) and the resulting reaction mixture was refluxed for 24 hours. The reaction mixture was cooled to room temperature and solvent removed in vacuo to produce a brown residue. The residue was diluted with ethyl acetate (300 mL) and washed with saturated sodium bicarbonate (150 mL), saturated sodium chloride (150 mL), dried (sodium sulfate) and concentrated. Purification by flash column chromatography (silica gel, ethyl acetate:hexanes 1:1) provided 0.52 g of the title compound as a white solid, mp 128-130° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[NH:16][CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[H-].[Na+].CN([CH:26]=[O:27])C>>[CH2:11]([O:12][C:26](=[O:27])[C:2]([CH2:3][N:16]1[C:17](=[O:20])[CH2:18][CH2:19][N:13]([C:11](=[O:12])/[CH:10]=[CH:9]/[C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:14][CH2:15]1)=[CH2:7])[CH3:10]
Reactant: CN(C)C=O
Reactant: O=C1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCN1
Agent: [H-]
Agent: [Na+]
Product: C=C(CN1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCC1=O)C(=O)OCC
Temperature: 18 °C

Procedure:
A suspension of 2.50 g (7.98 mmol) of 1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-[1,4]diazepan-5-one (intermediate 1A) and 1.15 ml (7.98 mmol) of ethyl 2-(bromomethylacrylate) in 80 ml of DMF was treated at −20° C. with 0.38 g (8.78 mmol) of NaH (55% in oil) and warmed up naturally to 18° C. (2.5 h). After cooling (0° C.) additionally 0.12 ml (0.80 mmol) of ethyl 2-(bromomethylacrylate) was added and after 30 min no starting material was left, based on TLC. The reaction was extracted with aqueous 10% KHSO4/ether (3×), the organic phases were washed with a aqueous 10% NaCl solution, dried (Na2SO4) and evaporated to give 3.51 g (quantitative, 90% purity) of the crude title compound as light yellow viscous oil, which was used directly in the next step. MS: 425.1 (MH+, 2Cl).
Reaction SMILES: Br[CH:2]([O:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH2:5][F:6].[NH:18]1[CH:22]=[N:21][CH:20]=[N:19]1>CC(C)=O>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([O:10][CH:2]([N:18]2[CH:22]=[N:21][CH:20]=[N:19]2)[C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH2:5][F:6])=[CH:12][CH:13]=1
Reactant: CC(C)(CF)C(=O)C(Br)Oc1ccc(Cl)cc1
Reactant: c1nc[nH]n1
Solvent: CC(C)=O
Product: CC(C)(CF)C(=O)C(Oc1ccc(Cl)cc1)n1cncn1
Yield: 89.1 %

Procedure:
87 g (0.27 mol) of 1-bromo-1-(4-chlorophenoxy)-3,3-dimethyl-4-fluoro-butan-2-one were dissolved in 200 ml of acetone and the solution was added dropwise to a boiling solution of 46 g (0.66 mol) of 1,2,4-triazole in 200 ml of acetone. After heating the mixture under reflux for one hour, the solvent was removed in vacuo, the residue was taken up in methylene chloride, the methylene chloride mixture was washed several times with water and the organic phase was dried over sodium sulphate. After removing the solvent in vacuo, the residue was crystallized with petroleum ether. 75 g (89% of theory) of 1-(4-chlorophenoxy)-3,3-dimethyl-4-fluoro-1-(1,2,4-triazol-1-yl)-butan-2-one of melting point 60°-63° C. were obtained.
Reaction SMILES: [OH-].[K+].[C:3]([O:7][OH:8])([CH3:6])([CH3:5])[CH3:4].[CH2:9](Cl)/[CH:10]=[C:11](/[CH2:13][CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17])\[CH3:12]>S1(CCCC1)(=O)=O>[C:3]([O:7][O:8][CH2:9]/[CH:10]=[C:11](/[CH2:13][CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17])\[CH3:12])([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)=CCC/C(C)=C/CCl
Reactant: CC(C)(C)OO
Agent: [K+]
Agent: [OH-]
Solvent: O=S1(=O)CCCC1
Product: CC(C)=CCC/C(C)=C/COOC(C)(C)C
Temperature: 10 °C
Reaction time: 16 h
Yield: 53 %

Procedure:
Sulpholane (40 cc) and potassium hydroxide pellets (6.5 g) are introduced into a 250-cc three-necked round-bottomed flask. After cooling to 10° C., a 70% strength aqueous solution of tert-butyl hydroperoxide (12.9 g) is added dropwise. The temperature is maintained at 20° C. for two hours and geranyl chloride (17.2 g, 0.1 mole) is then added dropwise at a temperature of between 10° and 20° C. The solution is kept at 20° C. for 16 hours. After extraction with pentane and purification of the product obtained by flash chromatography, geranyl tert-butyl peroxide (12 g) is obtained, and its structure is confirmed by the infrared spectrum, the mass spectrum and the proton nuclear magnetic resonance spectrum.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][CH:17]=[CH:18][CH2:19][CH2:20][CH:21]([C:26](=[O:29])[CH2:27][CH3:28])[C:22](=[O:25])[CH2:23][CH3:24])[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1>[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]([C:22](=[O:25])[CH2:23][CH3:24])[C:26](=[O:29])[CH2:27][CH3:28])[CH:12]=[CH:13][CH:14]=1
Reactant: CCC(=O)C(CCC=CCCc1cccc(OCc2ccccc2)c1)C(=O)CC
Agent: [Pd]
Product: CCC(=O)C(CCCCCCc1cccc(O)c1)C(=O)CC

Procedure:
[I; Ar is 3-HOC6H4, R0 is H, R' and R" are CH3CH2CO, Y is CH2CH2CH2CH2 ] was prepared by catalytic hydrogenation of 4-[6-(3-benzyloxyphenyl)-3-hexenyl]-3,5-heptanedione with palladium-on-carbon. The product was chromatographed on silica gel and eluted with ethyl acetate-chloroform 1:9 to give 4-[6-(3-hydroxyphenyl)hexyl]-3,5-heptanedione as a colorless oil.
Reaction SMILES: [CH2:1]([C@H:3]1[C:20](=O)[CH2:19][CH2:18][C@@:17]2([CH3:22])[CH:4]1[C:5](=[O:24])[CH2:6][C@@H:7]1[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]1[CH2:9][CH2:10][C:11]2=[O:23])[CH3:2].[ClH:25].Cl.[NH2:27][CH2:28][CH2:29][O:30][NH2:31]>C1COCC1.O>[ClH:25].[NH2:27][CH2:28][CH2:29][O:30]/[N:31]=[C:20]1/[C@H:3]([CH2:1][CH3:2])[CH:4]2[C@:17]([CH3:22])([CH2:18][CH2:19]/1)[C@@H:16]1[C@H:7]([C@H:8]3[C@@:12]([CH2:14][CH2:15]1)([CH3:13])[C:11](=[O:23])[CH2:10][CH2:9]3)[CH2:6][C:5]2=[O:24]
Reactant: CC[C@H]1C(=O)CC[C@@]2(C)C1C(=O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: NCCON
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CC[C@H]1/C(=N/OCCN)CC[C@@]2(C)C1C(=O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reaction time: 3.5 h

Procedure:
To a stirred solution of 4β-ethylandrostan-3,6,17-trione (Preparation 11, 67 mg) in THF (1.1 ml), a solution of 2-aminoethoxyamine dihydrochloride (31 mg) and Na2HPO4.12H2O (15 mg) in H2O (0.55 ml) was added in portions over 45 minutes. After 3.5 h, the solution was evaporated, water was added and the aqueous phase was extracted with THF. The combined organic extracts were washed with brine, dried over Na2SO4 and evaporated to dryness. The crude product was triturated with Et2O and the precipitate was filtered to give the title compound I-bd (34 mg, 42%).
Reaction SMILES: [CH3:1][C:2]([S:28]([CH3:31])(=[O:30])=[O:29])([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:17][C:16]=1[CH3:27])[C:3]([NH:5][O:6]C1CCCCO1)=[O:4].Cl.O1CCOCC1.CO>ClCCl>[OH:6][NH:5][C:3](=[O:4])[C:2]([CH3:1])([S:28]([CH3:31])(=[O:29])=[O:30])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:17][C:16]=1[CH3:27]
Reactant: Cc1cc(-c2ccccc2)ccc1CCC(C)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1cc(-c2ccccc2)ccc1CCC(C)(C(=O)NO)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 5.8 %

Procedure:
2-Methyl-4-(3-methylbiphenyl-4-yl)-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (170 mg, 0.382 mmol) was dissolved in 5 mL of dichloromethane at ambient temperature. To this was added a 4M HCl solution in dioxane (2.86 mL, 11.5 mmol) and the reaction was stirred at ambient temperature for 5 minutes. 0.5 mL of methanol was then added followed by silica gel and the mixture was concentrated to dryness. Silica chromatography (100% dichloromethane to 96% DCM 4% MeOH over 60 minutes) yielded product that contained impurities and was further triturated with a solution of 4:1 heptane:isopropanol afforded the title compound as a white solid (8 mg, 6%).
Reaction SMILES: [CH2:1]([N:5]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH:7]=[N:6]1)[CH2:2][C:3]#[CH:4].Br[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1>>[F:16][C:13]1[CH:12]=[CH:11][C:10]([C:8]2[CH:7]=[N:6][N:5]([CH2:1][CH2:2][C:3]#[C:4][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[N:9]=2)=[CH:15][CH:14]=1
Reactant: C#CCCn1ncc(-c2ccc(F)cc2)n1
Reactant: Brc1ccccn1
Product: Fc1ccc(-c2cnn(CCC#Cc3ccccn3)n2)cc1
Yield: 41.4 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-(but-3-ynyl)-4-(4-fluorophenyl)-2H-1,2,3-triazole (150 mg, 0.70 mmol, Example 254(B)) and 2-bromopyridine (122 mg, 0.77 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 84 mg (0.29 mmol, 41%) of 2-(4-(4-(4-fluorophenyl)-2H-1,2,3-triazol-2-yl)but-1-ynyl)pyridine as a yellow solid (M.P.=83.5-84.5° C.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:11]([C:19]([OH:21])=O)=[N:12][N:13]([CH3:18])[C:14](=[O:17])[C:15]=1[CH3:16].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH:43]([O:45][CH2:46][CH2:47][O:48][NH2:49])=[CH2:44]>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:11]([C:19]([NH:49][O:48][CH2:47][CH2:46][O:45][CH:43]=[CH2:44])=[O:21])=[N:12][N:13]([CH3:18])[C:14](=[O:17])[C:15]=1[CH3:16]
Reactant: Cc1c(Nc2ccc(I)cc2F)c(C(=O)O)nn(C)c1=O
Reactant: C=COCCON
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=COCCONC(=O)c1nn(C)c(=O)c(C)c1Nc1ccc(I)cc1F
Reaction time: 1.5 h

Procedure:
To a suspension of 4-(2-fluoro-4-iodophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridazine-3-carboxylic acid (41 mg, 0.10 mmol) and HOBt (28 mg, 0.21 mmol) in DMF (1.5 mL) was added EDCI (40 mg, 0.21 mmol) at room temperature. The resulting mixture was stirred for 1.5 hours. O-(2-Vinyloxy-ethyl)-hydroxylamine (21 mg, 0.20 mmol) and TEA (0.030 mL, 0.22 mmol) was added to the activated ester at room temperature. After stirring for 1.5 hours, the reaction mixture was diluted with EtOAc and washed with saturated aqueous NH4Cl, brine, saturated aqueous NaHCO3 (2×), and brine. The organic layer was separated, dried over MgSO4, filtered, and concentrated under reduced pressure to give 4-(2-fluoro-4-iodophenylamino)-1,5-dimethyl-6-oxo-N-(2-(vinyloxy)ethoxy) 1,6-dihydropyridazine-3-carboxamide that was used directly without further purification. The title compound was prepared by the procedure previously described in Example 1 (step J) using the crude 4-(2-fluoro-4-iodophenylamino)-1,5-dimethyl-6-oxo-N-(2-(vinyloxy)ethoxy)-1,6-dihydropyridazine-3-carboxamide (40% yield over two steps). MS APCI (−) m/z 461 (M−1) detected; 1H NMR (400 MHz, CD3OD) δ 7.52 (dd, 1H), 7.44 (d, 1H), 6.63 (t, 1H), 3.98 (t, 2H), 3.80 (s, 3H), 3.74 (t, 2H), 1.78 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:21])[CH2:5][CH:6]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)[C:7]=1[C:8]([OH:10])=O.[NH2:22][C:23]1[CH:24]=[C:25]2[C:29](=[C:30]([CH3:32])[CH:31]=1)[NH:28][N:27]=[CH:26]2.C(Cl)CCl.CCN(CC)CC>CN(C=O)C.CCOC(C)=O.Cl>[CH3:1][C:2]1[NH:3][C:4](=[O:21])[CH2:5][CH:6]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)[C:7]=1[C:8]([NH:22][C:23]1[CH:24]=[C:25]2[C:29](=[C:30]([CH3:32])[CH:31]=1)[NH:28][N:27]=[CH:26]2)=[O:10]
Reactant: CC1=C(C(=O)O)C(c2ccc3ccccc3c2)CC(=O)N1
Reactant: Cc1cc(N)cc2cn[nH]c12
Agent: Cl
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC1=C(C(=O)Nc2cc(C)c3[nH]ncc3c2)C(c2ccc3ccccc3c2)CC(=O)N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 13.3 %

Procedure:
The product of Example 1, Step 2 (180 mg, 0.64 mmol, 1.00 equiv), 5-amino-7-methylindazole (94 mg, 0.64 mmol, 1.0 equiv), and EDC (147 mg, 0.768 mmol, 1.20 equiv) were suspended in 1.5 mL DMF. Et3N (0.107 mL, 0.768 mmol, 1.2 equiv) was added and the solution was stirred at room temperature for 18 hrs. The reaction mixture was diluted with EtOAc and 1N HCl. The phases were separated, and the organic phase was washed twice with 1N HCl, once with satd. NaHCO3, and once with satd. NaCl. The organic phase was dried over Na2SO4, filtered, and concentrated en vacuo. The residue was triturated with EtOAc and CH2Cl2, filtered, and washed with CH2Cl2 to provide 35 mg (13%) of the title compound as an off white solid. MS (ES+) m/e 434 [M+H]+
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][OH:9].[NH:10]1[CH:14]=[CH:13][N:12]=[N:11]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.[Cu]I.CN[C@@H]1CCCC[C@H]1NC>[N:10]1[N:11]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][OH:9])[N:12]=[CH:13][CH:14]=1
Reactant: OCc1ccccc1I
Reactant: c1c[nH]nn1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: OCc1ccccc1-n1nccn1
Temperature: 160 °C
Reaction time: 0.25 h
Yield: 130 %

Procedure:
To a mixture of (2-iodophenyl)methanol [5159-41-1] (1.50 g, 6.41 mmol), 1H-1,2,3-triazole (0.797 g, 11.54 mmol), trans-N,N′-dimethylcyclohexane-1,2-diamine [68737-65-5] (0.091 g, 0.641 mmol) and Cs2CO3 (3.76 g, 11.54 mmol) in DMF (15 mL), CuI (0.61 g, 3.20 mmol) was added and the reaction mixture was stirred for 20 min at 120° C. and 15 min at 160° C. in the microwave. The reaction mixture was cooled to rt and filtered to remove the solids. The filtrate was concentrated under reduced pressure. The residue was purified by flash-column chromatography over silicagel (eluent: gradient 10%-100% ethyl acetate/heptane) to yield the title compound (1.46 g, 64%). [1H NMR (400 MHz, DMSO-d6) ♀ ppm 8.10 (s, 2H), 7.74 (d, J=7.53 Hz, 1H), 7.61 (dd, J=8.03, 1.25 Hz, 1H), 7.52 (td, J=7.53, 1.25 Hz, 1H), 7.44 (m, 1H), 5.26 (t, J=5.40 Hz, 1H), 4.59 (d, J=5.02 Hz, 2H); LCMS RtA=0.68, [M+H]+=176.1].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7](O)=[O:8].C(Cl)(Cl)(Cl)[Cl:14].S(Cl)(Cl)=O>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([Cl:14])=[O:8]
Reactant: ClC(Cl)(Cl)Cl
Reactant: COc1ncc(Cl)cc1C(=O)O
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: COc1ncc(Cl)cc1C(=O)Cl

Procedure:
To a suspension of 3.76 g. (0.02 mole) of 5-chloro-2-methoxynicotinic acid in 100 ml. of carbon tetrachloride, there were added 100 ml. of thionyl chloride in one portion and the resulting mixture was then refluxed on a steam bath for a period of 90 minutes. Upon completion of this step, the clear solution so obtained was cooled and then concentrated in vacuo at room temperature to afford a residual oil. The excess thionyl chloride present was next removed in the same manner as described in Preparation A for the production of 2-methoxynicotinoyl chloride, except that only 100 ml. of benzene was employed this time (i.e., during each purification step). The yield of pure 5-chloro-2-methoxynicotinoyl chloride, obtained as the residual product, was quantitative in this particular instance.
Reaction SMILES: C(=O)(O)[O-].[Na+].[CH:6]1([C:9]([N:11]2[CH2:23][CH2:22][C:21]3[C:20]4[C:15](=[CH:16][CH:17]=[C:18]([O:24][CH3:25])[CH:19]=4)[NH:14][C:13]=3[C:12]2=[CH2:26])=[O:10])[CH2:8][CH2:7]1>C(OCC)(=O)C.[Pd]>[CH:6]1([C:9]([N:11]2[CH2:23][CH2:22][C:21]3[C:20]4[C:15](=[CH:16][CH:17]=[C:18]([O:24][CH3:25])[CH:19]=4)[NH:14][C:13]=3[CH:12]2[CH3:26])=[O:10])[CH2:7][CH2:8]1
Reactant: C=C1c2[nH]c3ccc(OC)cc3c2CCN1C(=O)C1CC1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1ccc2[nH]c3c(c2c1)CCN(C(=O)C1CC1)C3C
Reaction time: 8 h
Yield: 72 %

Procedure:
Sodium bicarbonate (500 mg) and 10% palladium-on-charcoal are added to a solution of cyclopropyl (6-methoxy-1-methylene-2,3,4,9-tetrahydro-1H-β-carbolin-2-yl)-methanone (500 mg) in ethyl acetate (150 mL). The mixture is stirred overnight under a hydrogen atmosphere. After filtration and washing of the palladium with a chloroform/methanol solution, the product is recrystallized from ethyl acetate and the cyclopropyl(6-methoxy-1-methyl-2,3,4,9-tetrahydro- 1H-β-carbolin-2-yl)methanone is obtained (72% yield).
Reaction SMILES: N#N.C([Li])(C)(C)C.Br[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH:16]([CH3:18])[CH3:17])=[C:11]([O:19][CH3:20])[CH:10]=1.[C:21](=[O:23])=[O:22]>C1COCC1.O>[CH:16]([O:15][C:12]1[CH:13]=[CH:14][C:9]([C:21]([OH:23])=[O:22])=[CH:10][C:11]=1[O:19][CH3:20])([CH3:18])[CH3:17]
Reactant: O=C=O
Reactant: COc1cc(Br)ccc1OC(C)C
Agent: N#N
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C(=O)O)ccc1OC(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 90.5 %

Procedure:
Under a balloon of N2, tert-butyllithium (2.14 mL of 1.6 M, 3.43 mmol) was added drop-wise to a solution of 4-bromo-1-isopropoxy-2-methoxy-benzene (400 mg, 1.63 mmol) in THF (6.0 mL) at −78° C. The mixture was allowed to stir for 1 h at −78° C. before it was added drop-wise to a flask containing CO2 (1.80 g, 40.8 mmol)(solid, dry ice) in THF (2.0 mL). The mixture was allowed to stir for 30 min as it warmed to room temperature (caution: CO2 gas evolution). Water (20 mL) was added and the volatiles were removed under reduced pressure. The resultant aqueous layer was acidified with 1N HCl to pH ˜1-2 and the mixture was extracted with ethyl acetate (3×15 mL). The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated to give 4-isopropoxy-3-methoxy-benzoic acid (≧94% pure, 310 mg, 85%) as a white solid. ESI-MS m/z calc. 210.1, found 210.9 (M+1)+; Retention time: 1.23 min. 1H NMR (400 MHz, DMSO) δ 12.63 (s, 1H), 7.53 (dd, J=8.4, 2.0 Hz, 1H), 7.44 (d, J=2.0 Hz, 1H), 7.04 (d, J=8.7 Hz, 1H), 4.67 (dt, J=12.1, 6.0 Hz, 1H), 3.78 (s, 3H), 1.28 (d, J=6.0 Hz, 6H).