Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1([CH3:31])[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]#[C:19][C:20]3[CH:30]=[CH:29][C:23]([C:24](OCC)=[O:25])=[CH:22][N:21]=3)[CH:16]=2)[S:11][CH2:10][CH2:9]1.O>C1COCC1>[CH3:7][C:8]1([CH3:31])[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]#[C:19][C:20]3[N:21]=[CH:22][C:23]([CH2:24][OH:25])=[CH:29][CH:30]=3)[CH:16]=2)[S:11][CH2:10][CH2:9]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCS3)nc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)CCSc2ccc(C#Cc3ccc(CO)cn3)cc21
Temperature: -78 °C
Reaction time: 0.67 h

Procedure:
To 3.0 ml of 1M lithium aluminum hydride (3.0 mmol) in THF, cooled to -78° C., was added dropwise over 5 min a solution of 2.0 g (5.9 mmol) of ethyl 6-(2-(4,4-dimethylthiochroman-6-yl)-ethynyl)nicotinate in 5 ml of THF. The reaction mixture was stirred at -78° C. for 40 min and then treated with 2 ml of water. The mixture was warmed to room temperature and the organic layer was separated. The aqueous layer was extracted with 3×10 ml of ether. The organic extracts were combined and washed successively with 1×10 ml of dilute HCl, 3×10 ml of water and 1×15 ml of saturated NaCl solution and then dried (MgSO4). The solvent was removed in vacuo and the residue purified by flash chromatography (silica; 50% ethyl acetate in hexanes) to give the title compound as a pale yellow solid.
Reaction SMILES: [C:1]1([C:7](=[N:14][CH2:15][C:16]#[N:17])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[F:23][CH2:24][CH2:25][CH2:26]I>C1COCC1>[C:1]1([C:7](=[N:14][CH:15]([CH2:26][CH2:25][CH2:24][F:23])[C:16]#[N:17])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#CCN=C(c1ccccc1)c1ccccc1
Reactant: FCCCI
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#CC(CCCF)N=C(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 73 %

Procedure:
18 g (81.72 mmol) of [(diphenylmethylene)amino]acetonitrile were initially charged in 500 ml of abs. THF, and 39.22 ml (98.06 mmol) of n-butyllithium (2.5 N in hexane) were added at −78° C. under argon, and the mixture was stirred at −78° C. for a further 15 min. Subsequently, the reaction solution was warmed up to 0° C. and 16.9 g (89.89 mmol) of 1-fluoro-3-iodopropane were added dropwise to the reaction solution, which was stirred at 0° C. for a further 15 min. The reaction solution was quenched with water at 0° C., ethyl acetate was added and the mixture was washed with saturated aqueous sodium chloride solution. The aqueous phase was reextracted twice with ethyl acetate. The combined organic phases were dried over sodium sulphate, filtered and concentrated by rotary evaporation. The residue was purified by means of silica gel chromatography (eluent: 100% toluene, post-purification with dichloromethane/cyclohexane=1/1 to 2/1). A total of 16.73 g of the target compound (73% of theory) were obtained.
Reaction SMILES: I[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][CH:3]=1.[CH2:15]([OH:19])[CH2:16][C:17]#[CH:18]>C(N(CC)CC)C.ClCCl.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[OH:19][CH2:15][CH2:16][C:17]#[C:18][C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)c1ccc(I)cc1
Reactant: C#CCCO
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(C#CCCO)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 145.8 %

Procedure:
A mixture of 1,1-dimethylethyl 4-iodobenzoate (1.1 g, 3.62 mmol, e.g. which can be preparable e.g. according to E. C. Taylor, J. Org. Chem., 1995, 60(24), 7947), 3-butyn-1-ol (0.36 ml, 4.70 mmol, 1.3 equivalents), bis(triphenylphosphine)palladium(II)dichloride [(PPh3)2PdCl2] (0.13 g, 018 mmol, 5 mol %) and copper(I)iodide (0.014 g, 0.07 mmol, 2 mol %) in triethylamine (5 ml) was stirred at room temperature for 18 hours. The mixture was diluted with dichloromethane (50 ml) and washed with water (50 ml). The organic phase was collected by passing through a hydrophobic frit and evaporated to give a dark brown oil (1.3 g). This was purified by flash chromatography on silica gel (100 g silica cartridge, FlashMaster II), eluting with a gradient of 0 to 100% ethyl acetate in cyclohexane over 20 minutes. Fractions containing product (obtained from 4:1 cyclohexane:ethyl acetate eluant) were pooled and evaporated to dryness to give the title compound as a brown gummy oil (0.9 g). 1H NMR (400 MHz, chloroform-d) δ (delta) ppm 1.60 (9H, s), 1.85 (1H, t, J=6.27 Hz), 2.73 (2H, t, J=6.27 Hz), 3.85 (2H, q, J=6.27 Hz), 7.45 (2H, d, J=8.53 Hz), 7.92 (2H, d, J=8.53 Hz).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]2[O:11][C:12]([C:14]3[S:18][C:17]([C:19]4[O:23][C:22]5[CH:24]=[CH:25][C:26]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:27][C:21]=5[N:20]=4)=[CH:16][CH:15]=3)=[N:13][C:7]=2[CH:6]=1)([CH3:4])[CH3:3].[S:32](=[O:36])(=[O:35])([OH:34])O>>[S:18]1[C:14]([C:12]2[O:11][C:8]3[C:9]([S:32]([OH:34])(=[O:36])=[O:35])=[CH:10][C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])=[CH:6][C:7]=3[N:13]=2)=[CH:15][CH:16]=[C:17]1[C:19]1[O:23][C:22]2[C:24]([S:32]([OH:36])(=[O:35])=[O:34])=[CH:25][C:26]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:27][C:21]=2[N:20]=1
Reactant: CC(C)(C)c1ccc2oc(-c3ccc(-c4nc5cc(C(C)(C)C)ccc5o4)s3)nc2c1
Reactant: O=S(=O)(O)O
Product: CC(C)(C)c1cc(S(=O)(=O)O)c2oc(-c3ccc(-c4nc5cc(C(C)(C)C)cc(S(=O)(=O)O)c5o4)s3)nc2c1

Procedure:
One hundred milliliters of 20% fuming sulfuric acid is charged into a 500 mL Erlenmeyer flask. With magnetic stirring, 60 g of BBOT is added in small portions. The reaction is exothermic. After the addition is complete, the reaction mixture is heated to 90°-100° C. for two hours. The reaction is then quenched by pouring the reaction mixture onto 500 g of crushed ice. A brown product precipitates as a fine powder. The product is collected on a fritted-glass Buchner funnel. The product is then washed by stirring it in 200 mL of 1N hydrochloric acid. Washing is prepared several times. The product is then dried in a vacuum oven at 60°-70° C. Typical yields are 75-80 g (89-93%).
Reaction SMILES: Cl[C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])=[CH:6][N:5]=[C:4]([CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])[N:3]=1.[CH3:22][N:23]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]1=[O:42]>>[F:16][C:10]1[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:9]=1[O:8][C:7]1[C:2]([C:31]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24](=[O:42])[N:23]([CH3:22])[CH:32]=2)=[N:3][C:4]([CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])=[N:5][CH:6]=1
Reactant: CS(=O)(=O)Cc1ncc(Oc2ccc(F)cc2F)c(Cl)n1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)c2ccccc2c1=O
Product: Cn1cc(-c2nc(CS(C)(=O)=O)ncc2Oc2ccc(F)cc2F)c2ccccc2c1=O

Procedure:
The title compound of Example 146, step 2 was reacted with the title compound of Example 89, step 1 in a manner similar to Example 143, step 3 to give the title compound. 1H NMR (DMSO-d6, 400 MHz) δ 8.62 (s, 1H), 8.28 (d, J=8.0 Hz, 1H), 7.91 (s, 1H), 7.69-7.68 (m, 2H), 7.58-7.54 (m, 1H), 7.45-7.34 (m, 2H), 7.07-7.03 (m, 1H), 4.83 (s, 2H), 3.58 (s, 3H), 3.17 (s, 3H). LCMS: 458.1 (M+1)+
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][C@@H:10]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH2:9]1)C1C=CC=CC=1.[Cl:21]C(OC(Cl)C)=O.CCOC(C)=O.CCOC(C)=O.CO>ClCCCl.CO>[ClH:21].[F:20][C:17]1[CH:16]=[CH:15][C:14]([C@@H:10]2[O:11][CH2:12][CH2:13][NH:8][CH2:9]2)=[CH:19][CH:18]=1
Reactant: Fc1ccc([C@H]2CN(Cc3ccccc3)CCO2)cc1
Reactant: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CO
Product: Cl
Product: Fc1ccc([C@H]2CNCCO2)cc1
Temperature: 70 °C
Reaction time: 3 h
Yield: 39.4 %

Procedure:
Dissolve (2S)-4-benzyl-2-(4-fluorophenyl)morpholine (948 g, 3.5 mol) in 1,2-dichloroethane (17 L). Heat the mixture to 70° C. and add 1-chloroethyl chloroformate (1500 g, 10.5 mol) drop-wise while heating. Stir the mixture at 70° C. for 3 h and then concentrate the mixture to give a residue. Dissolve the residue in MeOH (10 L) and heat to 70° C. while stirring for 1 h. Concentrate the solution under reduced pressure to give a residue. Slurry the residue with EtOAc (5 L); filter; and wash the solid with EtOAc (1 L) to provide an off white solid. Slurry the solid with 10:1 EtOAc/MeOH (10:1. 3 L); filter; collect the solid to provide the title compound as a white solid (300 g). Concentrate the mother liquor to provide additional material. Slurry the this material with a mixture of EtOAc/MeOH (2:1; 1 L) and filter to give an additional 105 g of the title compound as a white solid. Mix the product batches to give the title compound (405 g, 53%). MS (m/z): 182 (M-Cl). ee value 100% (AD-H 250 mm×4.6 mm×5 um column using 90:10 hexanes (with 0.02% DEA):ethyl alcohol at 25° C. with a flow rate of 1.0 mL/min).
Reaction SMILES: CC(C)=O.O[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18].OCCCCCCCCCC[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([OH:38])=[O:37]>C(Cl)(Cl)Cl>[CH2:35]([C:36]([OH:38])=[O:37])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18]
Reactant: O=C(O)CCCCCCCCCCCCCCCO
Reactant: O=C(O)CCCCCCCCCCCO
Solvent: CC(C)=O
Solvent: ClC(Cl)Cl
Product: O=C(O)CCCCCCCCCCCCCCCCC(=O)O
Reaction time: 15 h

Procedure:
In Example 3, acetone solution of 12-hydroxydodecanoic acid was replaced by 16-hydroxy hexadecanoic acid (100 mg) dissolved in chloroform (10 ml) and reaction time was set for 15 hours. 72 mg of 1,16-hexadecane dicarboxylic acid was produced.
Reaction SMILES: C(N)CC.[CH2:5]([NH:8][C:9](=[NH:11])[NH2:10])[CH2:6]C.[CH3:12][N:13](C)[CH2:14]CN>>[CH3:12][N:13]([CH3:14])[CH2:6][CH2:5][NH:8][C:9](=[NH:11])[NH2:10]
Reactant: CCCNC(=N)N
Reactant: CN(C)CCN
Solvent: CCCN
Product: CN(C)CCNC(=N)N

Procedure:
By the same procedure, using propylamine the corresponding N'-propyl guanidine is prepared. Using 2-(dimethylamino)ethylamine the corresponding N'-(2-dimethylaminoethyl) guanidine is prepared.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])[CH:10]=2)[CH:5]=[CH:4]1.[CH3:22]I>O1CCCC1>[CH3:22][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:13])[CH:10]=2)[CH:5]=[CH:4]1
Reactant: O=C(OCc1ccccc1)c1ccc2cc[nH]c2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1ccc2ccc(C(=O)OCc3ccccc3)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.4 %

Procedure:
Sodium hydride (1.03 g of a 60% dispersion in paraffin oil) was added portionwise to a stirred solution of benzyl 1H-indole-6-carboxylate (from (a), 5.4 g, 21.5 mmol) in tetrahydrofuran (80 ml) at 0° C. under a nitrogen atmosphere. The mixture was stirred for 2 h, then methyl iodide (2.04 ml, 32.6 mmol) was added dropwise. The solution was allowed to warm to room temperature over 12 h. The reaction was quenched by the slow addition of ice cold water and the tetrahydrofuran was removed in vacuo. The product was extracted from saturated sodium chloride solution (300 ml) with dichloromethane (2×300 ml) and the organics were dried (MgSO4). The dried organics were filtered through a 5 cm plug of silica in a sintered funnel and concentrated in vacuo to give the subtitle compound as a white solid (5.1 g).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)=O.[NH2:9][N:10]1[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[NH:12][C:11]1=[O:19]>Cl.C(O)C>[O:19]=[C:11]1[NH:12][C:13]([C:15]([CH3:17])([CH3:16])[CH3:18])=[CH:14][N:10]1[N:9]=[CH:1][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)c1cn(N)c(=O)[nH]1
Reactant: O=Cc1cccnc1
Agent: Cl
Solvent: CCO
Product: CC(C)(C)c1cn(N=Cc2cccnc2)c(=O)[nH]1
Temperature: 25 °C

Procedure:
5.4 g of 3-formylpyridine and three drops of concentrated hydrochloric acid are added to a solution of 7.8 g of 1-amino-2,3-dihydro-2-oxo4-tert-butyl-1H-imidazole in 50 ml of ethanol. The reaction mixture is refluxed for 30 minutes with stirring and then cooled to room temperature, upon which the mixture starts to crystallize. To complete the crystal precipitation process, 100 ml of diethyl ether are added to the mixture. The crystallizate is filtered off with suction, triturated with acetonitrile, again filtered off with suction and then dried. This gives the title compound which melts at 255°-256°.
Reaction SMILES: [ClH:1].O1CCOCC1.OC(C(F)(F)F)=O.[CH3:15][N:16]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:17]([N:19]1[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH:20]1[CH2:32][O:33][C:34]1[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=1)=[O:18]>CO>[ClH:1].[ClH:1].[CH3:15][N:16]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:17]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH:20]1[CH2:32][O:33][C:34]1[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=1)=[O:18]
Reactant: CN(C(=O)N1CCN(C(=O)OC(C)(C)C)CC1COc1cccnc1)c1ccccc1
Agent: Cl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: CN(C(=O)N1CCNCC1COc1cccnc1)c1ccccc1
Reaction time: 12 h
Yield: 81 %

Procedure:
4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution of tert-butyl 4-(N-methyl-N-phenylcarbamoyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate TFA salt (28.1 mg, 0.052 mmol) in MeOH (1 mL). After 12 h, the reaction mixture was concentrated under reduced pressure, yielding 16.9 mg (81%) of the desired product as a yellow solid. LC-MS: RT=3.83 min, [M+H]+=327.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([C:7](=O)[CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[C:22]1([NH:28][NH2:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Cl.[OH-].[Na+]>C(O)C.O>[CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([C:7]2[CH2:8][CH:9]([C:10]3[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=3)[N:28]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:29]=2)=[CH:5][CH:4]=1
Reactant: NNc1ccccc1
Reactant: COc1ccc(C(=O)C=Cc2ccc([N+](=O)[O-])cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(C2=NN(c3ccccc3)C(c3ccc([N+](=O)[O-])cc3)C2)cc1
Yield: 78.8 %

Procedure:
14.2 g of 4'-methoxy-4-nitrochalcone was reacted with 5.4 g of phenylhydrazine in 100 ml of ethanol in the presence of 5 ml of hydrochloric acid by refluxing while heating for 6 hours. After neutralizing the reaction mixture with 50 ml of 1N NaOH, 400 ml of water was added thereto. Decantation-water washing was repeated three times. Crystals formed were recrystallized from 200 ml of acetone to obtain 14.7 g of the desired compound. m.p. 168°-173° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19]([NH2:21])=[O:20])=[N:4][C:5]([C:9]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([CH:16]([CH3:18])[CH3:17])[CH:10]=2)=[C:6](Cl)[N:7]=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.O.CCOC(C)=O>C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1.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>[NH2:1][C:2]1[C:3]([C:19]([NH2:21])=[O:20])=[N:4][C:5]([C:9]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([CH:16]([CH3:18])[CH3:17])[CH:10]=2)=[C:6]([C:27]2[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=2)[N:7]=1
Reactant: CC(C)n1cc(-c2nc(C(N)=O)c(N)nc2Cl)ccc1=O
Reactant: COc1ccc(B(O)O)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: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1ccc(-c2nc(N)c(C(N)=O)nc2-c2ccc(=O)n(C(C)C)c2)cc1
Yield: 83.1 %

Procedure:
A mixture of 3-amino-5-chloro-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridyl)-2-pyrazinecarboxamide (500 mg), (4-methoxyphenyl)boronic acid (740 mg), and Pd(PPh3)4 (56.3 mg) in 2M aq. Na2CO3 (3.25 ml) and dioxane (20 ml) was refluxed for 3 hours. Water (40 ml) and of EtOAc (30 ml) were poured into the reaction mixture and the aqueous solution was extracted with EtOAc. The organic layer was washed with water and brine, and dried over MgSO4. After filtration, the solvent was removed under reduced pressure. The residual solid was placed on a column of silica-gel and eluted with CHCl3:MeOH (25:1). The eluent was evaporated and the residue was suspended with IPE and filtrated to give 3-amino-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridyl)-5-(4-methoxyphenyl)-2-pyrazinecarboxamide (512 mg) as a yellow powder.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Cl[C:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[S:13](=[O:21])(=[O:20])[N:12]=1.[Al+3].[Cl-].[Cl-].[Cl-]>ClCCCl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[S:13](=[O:20])(=[O:21])[N:12]=2)=[CH:2]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: O=S1(=O)N=C(Cl)c2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: O=S1(=O)N=C(c2c[nH]c3ccccc23)c2ccccc21
Temperature: 65 °C
Yield: 106.3 %

Procedure:
Indole (117 mg, 1 mmol) and 3-chloro-benzo[d]isothiazole 1,1-dioxide (201 mg, 1 mmol) were treated 5 mL of 1,2-dichloroethane followed by AlCl3 (160 mg, 1.2 mmol). The reaction mixture was heated to 65° C. overnight, then cooled and quenched with water (1 mL). The resulting solid was filtered, washed with water, and dried to give 0.3 grams of the sub-title compound. MS: ESI (negative): 281 (M−H).
Reaction SMILES: [Cl-].C[Al+]C.CCCCCC.[CH3:11][C:12]1[CH2:17][C:16]([CH3:19])([CH3:18])[CH:15]([C:20]([CH3:22])=[CH2:21])[C:14]([CH3:24])([CH3:23])[CH:13]=1.[CH:25](=[O:28])[CH2:26][CH3:27]>ClCCl>[CH2:26]([CH:25]([OH:28])[CH2:21][C:20](=[CH2:22])[CH:15]1[C:16]([CH3:18])([CH3:19])[CH2:17][C:12]([CH3:11])=[CH:13][C:14]1([CH3:24])[CH3:23])[CH3:27]
Reactant: CCC=O
Reactant: C=C(C)C1C(C)(C)C=C(C)CC1(C)C
Agent: C[Al+]C
Agent: [Cl-]
Solvent: CCCCCC
Solvent: ClCCl
Product: C=C(CC(O)CC)C1C(C)(C)C=C(C)CC1(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 22 %

Procedure:
Dimethylaluminum chloride (60 mL of a 1 M hexane solution) was added dropwise to a solution of 1,3,3,5,5-pentamethyl-4-(1-methylethenyl)-1-cyclohexene (7.70g, 0.04 mol) and propionaldehyde (2.30g, 0.04 mol) in dichloromethane (150 mL) at 25°-30° C. over a 15 min period. The mixture was stirred at 25° C. for 16h. Work-up (as described in Example 2) and chromatography provided 2.20g of α-ethyl-2,2,4,6,6-pentamethyl-γ-methylene-3-cyclohexene-1-propanol, bp (kugelrohr bath) 125° C., 0.5 mm, (GLC purity, two isomers, 40.7% and 57.9%). 1H-NMR (60 MHz, CDCl3) δ0.98 and 1.03 (12H, 2s), 1.02 (3H, t, J =4 Hz), 1.63 (3H, s), 1.1-2.6 (8H, m), 3.5-3.9 (1 H, m), 5.0-5.3 (3H, broad s); IR (film) vmax 3350, 2950, 1640, 1460, 1380, 1360 cm-1 ; MS m/e 250, 235, 217, 125, 107, 96. The mass spectra of the diastereomers were nearly identical.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:24]4[C:19](=[CH:20][C:21]([S:25](OC5C(F)=C(F)C(F)=C(F)C=5F)(=[O:27])=[O:26])=[CH:22][CH:23]=4)[CH:18]=[CH:17][N:16]=3)=[C:11]([O:40][CH3:41])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.[CH3:42][C:43]1[N:48]=[CH:47][N:46]=[C:45]([NH2:49])[CH:44]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:24]4[C:19](=[CH:20][C:21]([S:25]([NH:49][C:45]5[CH:44]=[C:43]([CH3:42])[N:48]=[CH:47][N:46]=5)(=[O:26])=[O:27])=[CH:22][CH:23]=4)[CH:18]=[CH:17][N:16]=3)=[C:11]([O:40][CH3:41])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: COc1cc(-c2cc(F)cc(F)c2)ccc1-c1nccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Reactant: Cc1cc(N)ncn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(-c2cc(F)cc(F)c2)ccc1-c1nccc2cc(S(=O)(=O)Nc3cc(C)ncn3)ccc12
Reaction time: 0.33 h
Yield: 47.7 %

Procedure:
A vial was charged with perfluorophenyl 1-(3′,5′-difluoro-3-methoxy-[1,1′-biphenyl]-4-yl)isoquinoline-6-sulfonate (INTERMEDIATE KKKKK; 63.5 mg, 0.107 mmol), 6-methylpyrimidin-4-amine (12.26 mg, 0.112 mmol), and THF (535 μl). The vial was cooled in an ice-water bath for 10 min, then lithium bis(trimethylsilyl)amide (1M in THF) (225 μl, 0.225 mmol) was added. After 20 min of stirring, the mixture was loaded directly onto a silica gel loading column. The column was eluted onto a pre-equilibrated 12-g Redi-Sep Gold column with 0-10% MeOH/DCM to give an orange solid. This solid was resubjected to chromatography on silica gel (12-g Redi-Sep Gold column, 4.5% MeOH/DCM) to give 1-(3′,5′-difluoro-3-methoxy-[1,1′-biphenyl]-4-yl)-N-(6-methylpyrimidin-4-yl)isoquinoline-6-sulfonamide (26.22 mg, 0.051 mmol, 47.3% yield) as a light-pink solid. 1H NMR (400 MHz, DMSO-d6) δ=13.48-12.42 (m, 1H), 8.75-8.62 (m, 2H), 8.47 (s, 1H), 8.11 (d, J=5.6 Hz, 1H), 7.95 (d, J=9.1 Hz, 1H), 7.75 (d, J=8.7 Hz, 1H), 7.63 (d, J=6.9 Hz, 2H), 7.57-7.48 (m, 2H), 7.46-7.40 (m, 1H), 7.34-7.23 (m, 1H), 7.06-6.86 (m, J=17.2 Hz, 1H), 3.77 (s, 3H), 2.31 (s, 3H). m/z (ESI) 519.0 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[N:4]2[C:8]([C:9]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:11]=1)=[CH:7][CH:6]=[CH:5]2)=O.[NH2:16][OH:17].Cl.CC([O-])=O.[Na+]>C1COCC1.O>[OH:17]/[N:16]=[CH:1]/[C:3]1[N:4]2[C:8]([C:9]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:11]=1)=[CH:7][CH:6]=[CH:5]2
Reactant: NO
Reactant: COC(=O)c1ccc(C=O)n2cccc12
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(/C=N/O)n2cccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 5-formylindolizine-8-carboxylate (203 mg, 1.0 mmol) and NH2OH.HCl (105 mg, 1.5 mmol) in THF (30 mL) and H2O (8 mL) at rt was added NaOAc (164 mg, 2.0 mmol). The reaction mixture was stirred at rt for 2 h. The mixture was extracted with EA (2×40 mL). The organic layers was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was used in next step without further purification.
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:9]=[CH:8][C:7](Br)=[C:6]([CH3:11])[CH:5]=1)[CH3:2].[Mg].BrC(Br)C.[Br-].C[O:19][B:20](OC)[O:21]C>C1COCC1>[CH2:1]([S:3][C:4]1[CH:9]=[CH:8][C:7]([B:20]([OH:21])[OH:19])=[C:6]([CH3:11])[CH:5]=1)[CH3:2]
Reactant: CCSc1ccc(Br)c(C)c1
Reactant: COB(OC)OC
Agent: CC(Br)Br
Agent: [Br-]
Agent: [Mg]
Solvent: C1CCOC1
Product: CCSc1ccc(B(O)O)c(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 100 ml portion of a solution of the product from example 10 step (i) (120.7 g) in THF (500 ml) was added to a stirred mixture of magnesium turnings (13.4 g) in THF (100 ml). Dibromoethane (0.2 ml) was added, and the mixture gently refluxed on initiation. The remaining bromide solution was added dropwise maintaining the reaction at reflux. After addition the mixture was allowed to cool to RT then transferred via cannula into a stirred solution of trimethylborate (112 ml) in TIE (200 ml) at 0° C. The mixture was warmed to RT, stirred for 2 h then quenched with 2M hydrochloric acid (300 ml). After stirring at RT for 18 h the THF was removed under reduced pressure and the mixture extracted with diethylether. The organics were separated, washed with water, dried and evaporated under reduced pressure. The residue was triturated with diethylether/isohexane and filtered. Yield 53.02 g