Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])[N:9]=1)[CH3:3].C(O)(C)C.CS(O)(=O)=O.[CH3:24][N:25]=[C:26](SC)[S:27][CH3:28]>O>[CH3:24][NH:25][C:26](=[N:14][CH2:13][CH2:12][S:11][CH2:10][C:8]1[N:9]=[C:5]([CH2:4][N:2]([CH3:1])[CH3:3])[S:6][CH:7]=1)[S:27][CH3:28]
Reactant: CN=C(SC)SC
Reactant: CN(C)Cc1nc(CSCCN)cs1
Agent: CS(=O)(=O)O
Solvent: O
Solvent: CC(C)O
Product: CNC(=NCCSCc1csc(CN(C)C)n1)SC

Procedure:
Ten g. of 2-dimethylaminomethyl-4-(2-aminoethyl)thiomethylthiazole was dissolved in 100 ml. of isopropanol, and 2.8 ml. of methanesulfonic acid was added, followed by 6.5 g. of methylcarbonimidodithioic acid, dimethyl ester. The mixture was stirred under reflux for 16 hours, and was evaporated under vacuum to obtain a residue, which was taken up in 100 ml. of water. The solution was extracted with two 25 ml. portions of dichloromethane, and the aqueous layer was cooled. Fifty ml. of dichloromethane and 15 ml. of 50% aqueous sodium hydroxide were added. The layers were separated, and the solution was extracted again with 50 ml. of dichloromethane. The organic layers were combined, dried over potassium carbonate and evaporated under vacuum to obtain 10.3 g. of product, substantially identical to that of Example 1, which was 96.7% pure by HPLC analysis.
Reaction SMILES: [CH3:1][C:2]1([C:21](O)=[O:22])[CH2:17][C:10]2([N+:18]([O-:20])=[O:19])[C:11]3[C:16]([CH:3]1[C:4]1[C:9]2=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH:15][CH:14]=[CH:13][CH:12]=3.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C.CCN=C=NCCCN(C)C.[CH3:54][O:55][C:56]1[CH:68]=[CH:67][C:59]([CH2:60][C:61]2[NH:65][N:64]=[C:63]([NH2:66])[N:62]=2)=[CH:58][CH:57]=1>C(#N)C>[CH3:54][O:55][C:56]1[CH:57]=[CH:58][C:59]([CH2:60][C:61]2[N:62]=[C:63]([NH2:66])[N:64]([C:21]([C:2]3([CH3:1])[CH2:17][C:10]4([N+:18]([O-:20])=[O:19])[C:11]5[C:16]([CH:3]3[C:4]3[C:9]4=[CH:8][CH:7]=[CH:6][CH:5]=3)=[CH:15][CH:14]=[CH:13][CH:12]=5)=[O:22])[N:65]=2)=[CH:67][CH:68]=1
Reactant: COc1ccc(Cc2nc(N)n[nH]2)cc1
Reactant: CC1(C(=O)O)CC2([N+](=O)[O-])c3ccccc3C1c1ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Cc2nc(N)n(C(=O)C3(C)CC4([N+](=O)[O-])c5ccccc5C3c3ccccc34)n2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 88.3 %

Procedure:
To a stirred solution of 15-methyl-8-nitrotetracyclo[6.6.2.02,7.09,14]hexadeca-2,4,6,9,11,13-hexaene-15-carboxylic acid (25 mg, 0.08 mmol, prepared according to WO04009017), 1-hydroxybenzotriazole (16 mg, 0.12 mmol), and N-ethyl-N,N-diisopropylamine (0.1 mL) in anhydrous acetonitrile (1 mL) was added EDCI (38 mg, 0.2 mmol) at RT under argon. After the mixture was stirred at RT for 5 min, 5-(4-methoxybenzyl)-1H-1,2,4-triazol-3-amine (21 mg, 0.1 mmol) was added. The reaction mixture was stirred at RT overnight and at 80° C. for 1 h. After the solvents were removed, the residue was partitioned between methylene chloride and saturated aqueous sodium bicarbonate solution. The aqueous solution was extracted with methylene chloride. The combined organic solutions were dried (Na2SO4), concentrated and purified by silica gel chromatography to give 35 mg (87% yield) of the title compound as a white solid. (M+H)+=496.20
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3](=[O:11])[CH2:2]1.[OH:12][C:13]1[C:20]([Br:21])=[CH:19][C:16]([CH:17]=O)=[CH:15][C:14]=1[Br:22].[C:23](OC(=O)C)(=[O:25])[CH3:24].C(N(CC)CC)C>>[C:23]([O:12][C:13]1[C:20]([Br:21])=[CH:19][C:16](/[CH:17]=[C:2]2/[C:3](=[O:11])[NH:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[O:1]/2)=[CH:15][C:14]=1[Br:22])(=[O:25])[CH3:24]
Reactant: O=C1COc2ccccc2N1
Reactant: O=Cc1cc(Br)c(O)c(Br)c1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)Oc1c(Br)cc(/C=C2\Oc3ccccc3NC2=O)cc1Br
Reaction time: 8 h

Procedure:
A stirred mixture of (0.5 g, 3.35 mmol) of 2H-1,4-benzoxazin-3(4H)-one, 1.4 g of 4-hydroxy-3,5-dibromo benzaldehyde, 1.68 mL (17.729 mmol) of acetic anhydride and 0.7 mL (5 mmol) of triethyl amine was refluxed for 7 h, left overnight at room temperature and poured into crushed ice. The precipitated solid was collected by filtration and washed with acetonitrile. The crude product was purified by recrystallization from DMF: ethanol.
Reaction SMILES: [CH2:1]([C:3]1([CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][N+:19]([O-])=[C:18]([CH3:23])[C:17]=2[CH3:24])[O:12][CH2:11][C:6]2([O:10][CH2:9][CH2:8][O:7]2)[CH2:5][O:4]1)[CH3:2].C(N(CC)CC)C.C(OC(=O)C)(=[O:34])C>>[CH2:1]([C:3]1([CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([CH2:23][OH:34])[C:17]=2[CH3:24])[O:12][CH2:11][C:6]2([O:10][CH2:9][CH2:8][O:7]2)[CH2:5][O:4]1)[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCC1(CCOc2cc[n+]([O-])c(C)c2C)OCC2(CO1)OCCO2
Solvent: CCN(CC)CC
Product: CCC1(CCOc2ccnc(CO)c2C)OCC2(CO1)OCCO2
Temperature: 50 °C
Reaction time: 2 h
Yield: 59.6 %

Procedure:
The 4-(2-(8-ethyl-1,4,7,9-tetraoxaspiro[4.5]dec-8-yl)ethoxy)-2,3-dimethylpyridine 1-oxide (947 mg, 2.79 mmol) obtained in the step (4f) was mixed with acetic anhydride (10 ml). To the mixture, triethylamine (0.6 ml, 4.3 mmol) was added and stirred at 50° C. for 2 hours. The reaction mixture was concentrated and methanol (10 ml) was added to the residue and thereafter, a 5N aqueous sodium hydroxide solution (7 ml) was added and stirred at room temperature for one hour. To the mixture, a saturated aqueous ammonium chloride solution (7 ml) was added and the pH of the resultant solution was adjusted to about 10. The reaction mixture was diluted with ethyl acetate and the organic layer was washed with a 2N aqueous sodium hydroxide solution, water, and a saline solution, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: ethyl acetate/methanol=1/0-4/1 gradient) and a desired fraction(s) was concentrated to obtain the title compound (564 mg, yield: 59.6%) as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][C:3]=1[N:17]=[C:18]=S.[Cl:20][C:21]1[C:22]([N:30]2[CH2:35][CH2:34][CH2:33][CH:32]([C:36]([F:39])([F:38])[F:37])[CH2:31]2)=[CH:23][C:24]([NH:28][CH3:29])=[C:25]([CH:27]=1)[NH2:26].C(Cl)CCl>CC#N>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][C:3]=1[NH:17][C:18]1[N:28]([CH3:29])[C:24]2[CH:23]=[C:22]([N:30]3[CH2:35][CH2:34][CH2:33][CH:32]([C:36]([F:38])([F:39])[F:37])[CH2:31]3)[C:21]([Cl:20])=[CH:27][C:25]=2[N:26]=1
Reactant: CNc1cc(N2CCCC(C(F)(F)F)C2)c(Cl)cc1N
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)c(N=C=S)c1
Solvent: CC#N
Solvent: ClCCCl
Product: Cn1c(Nc2cc(CNC(=O)OC(C)(C)C)ccc2Cl)nc2cc(Cl)c(N3CCCC(C(F)(F)F)C3)cc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Tert-butyl 4-chloro-3-isothiocyanatobenzylcarbamate (938 mg, 3.1 mmol) was added to 5-chloro-2-methylamino-4-(3-(trifluoromethyl)piperidin-1-yl)aniline (920 mg, 3.0 mmol) in MeCN (20 mL). The mixture was stirred for 4 h at rt, then EDC (582 μL, 3.3 mmol) was added and it was stirred overnight. The reaction mixture was purified by chromatography to give the sub-title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11]C)[CH:6]=[O:7].S(=O)(=O)(O)O>>[CH:6](=[O:7])[C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:10]([OH:11])=[C:9]([O:13][CH3:14])[CH:8]=1
Reactant: COc1cc(C=O)cc(OC)c1OC
Agent: O=S(=O)(O)O
Product: COc1cc(C=O)cc(OC)c1O

Procedure:
Monodemethylation of 3,4,5-trimethoxybenzaldehyde using sulphuric acid at 40° C. for 8 hours as described above in Example 1 yields syringaldehyde. Condensation of 3,5-Dimethoxy-4-hydroxy benzaldehyde (Syringaldehyde) with diethyl malonate in the presence of piperidine—acetic acid and benzene as the reaction medium at reflux temperature under continuous azeotropic water removal yields the title product. The reaction takes about 7.5 hours for completion.
Reaction SMILES: [CH3:1]/[C:2](=[CH:6]\[CH3:7])/[C:3](=[O:5])[CH3:4].CCN(CC)CC.[Si:15](OS(C(F)(F)F)(=O)=O)([CH2:20][CH3:21])([CH2:18][CH3:19])[CH2:16][CH3:17].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:16]([Si:15]([CH2:20][CH3:21])([CH2:18][CH3:19])[O:5][C:3](/[C:2](/[CH3:1])=[CH:6]/[CH3:7])=[CH2:4])[CH3:17]
Reactant: CC[Si](CC)(CC)OS(=O)(=O)C(F)(F)F
Reactant: C/C=C(\C)C(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(O[Si](CC)(CC)CC)/C(C)=C/C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (E)-3-methylpent-3-en-2-one (2.69 mL, 24.1 mmol) in DCM (200 mL) cooled to 0° C. was added Et3N (10.5 mL, 79.5 mmol) followed by TESOTf (6.0 mL, 26.5 mmol). The mixture was warmed to room temperature and stirred for 18 hr. Saturated aqueous NaHCO3 solution (100 mL) and DCM (200 mL) were added. The aqueous layer was extracted with DCM (3×200 mL) and the combined organic layers were washed with brine (100 mL), separated, dried over MgSO4 and concentrated under reduced pressure to give (E)-triethyl((3-methylpenta-1,3-dien-2-yl)oxy)silane. To a solution of 2-methyl-4-nitro-pyrazole-3-carbaldehyde (1.0 g, 8 mmol, intermediate 3) in CDCl3 (28 mL) was added (E)-triethyl((3-methylpenta-1,3-dien-2-yl)oxy)silane (1.6 g, 7.55 mmol) followed by EuFOD (220 mg, 0.50 mmol). The reaction mixture was heated at 65° C. behind a blast shield for 18 hr in a pressure tube. The mixture was cooled to room temperature and concentrated under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) gave 5-(5,6-dimethyl-4-((triethylsilyl)oxy)-3,6-dihydro-2H-pyran-2-yl)-1-methyl-4-nitro-1H-pyrazole as a colourless oil (2.92 g, quantitative). 1H NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 5.64 (dd, J=10.9, 3.6 Hz, 1H), 4.33-4.28 (m, 1H), 4.25-3.94 (m, 3H), 2.50-2.41 (m, 1H), 2.31 (m, 1H), 1.61 (s, 3H), 1.31 (d, J=6.4 Hz, 3H), 1.05-0.97 (m, 6H), 0.73-0.61 (m, 9H).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5][C@H:4]([C:15]([O:17][CH3:18])=[O:16])[CH2:3]1.[CH:19](=O)[CH:20]([CH3:22])[CH3:21].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH3:19][CH:20]([CH3:22])[CH2:21][NH:1][C@@H:2]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:5][C@H:4]([C:15]([O:17][CH3:18])=[O:16])[CH2:3]1
Reactant: COC(=O)[C@@H]1C[C@H](N)CN(C(=O)OC(C)(C)C)C1
Reactant: CC(C)C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)[C@@H]1C[C@H](NCC(C)C)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-tert-Butyl 3-methyl (3R,5S)-5-aminopiperidine-1,3-dicarboxylate (1.83 g), isobutyraldehyde (0.78 ml) and acetic acid (0.49 ml) were dissolved in methanol (50 ml), and the mixture was stirred at room temperature for 30 min. Sodium triacetoxyborohydride (3.80 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 7 hr. The reaction mixture was concentrated under reduced pressure, the concentrate was basified with aqueous sodium bicarbonate, and extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (1:1)-ethyl acetate 100%-ethyl acetate-methanol (9:1) was concentrated under reduced pressure to give the object product (1.42 g) as an oil.
Reaction SMILES: O[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.C(N(CC)CC)C.P(Cl)(Cl)([Cl:21])=O>C(#N)C>[Cl:21][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1ccc(O)nc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)c1ccc(Cl)nc1
Reaction time: 0.25 h

Procedure:
In 100 ml of acetonitrile was dissolved 4.0 g (0.026 mole) of methyl 6-hydroxynicotinate followed by addition of 0.9 ml of triethylamine. The mixture was refluxed and 3.7 ml of phosphorus oxychloride was added dropwise with stirring over a period of 15 minutes. The mixture was further refluxed for 3 hours. After cooling, the acetonitrile was distilled off and the residue was diluted with 20 ml of water and adjusted to pH about 8 with a saturated aqueous solution of sodium hydrogen carbonate. The resulting crystals are collected by filtration, rinsed with water and dried to give 3.6 g of methyl 6-chloronicotinate as pale yellow needles.
Reaction SMILES: [CH:1]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:2]=1[C:3](=[O:18])[N:4]1[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][C:5]1=[N:6]2.Cl[C:20]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:21]>>[C:27]([CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][C:20]([N:11]1[C:5]2=[N:6][C:7]3[C:2]([C:3](=[O:18])[N:4]2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]1=2)=[CH:1][CH:10]=[CH:9][CH:8]=3)=[O:21])([O:29][CH2:30][CH3:31])=[O:28]
Reactant: CCOC(=O)CCCCCC(=O)Cl
Reactant: O=c1c2ccccc2nc2[nH]c3ccccc3n12
Product: CCOC(=O)CCCCCC(=O)n1c2ccccc2n2c(=O)c3ccccc3nc12

Procedure:
6-(6-Carboethoxyhexanoyl)benzimidazo[2,1-b]quinazolin-12(6H)one is prepared with benzimidazo[2,1-b]quinazolin-12(6H)one and ethyl 6-(chloroformyl)hexanoate.
Reaction SMILES: [F:1][C:2]1[C:38]([F:39])=[CH:37][CH:36]=[CH:35][C:3]=1[CH2:4][S:5][C:6]1[N:11]=[C:10]([NH:12][S:13]([N:16]2[CH2:21][CH2:20][N:19]([C:22](=[O:32])[CH2:23][NH:24]C(=O)OC(C)(C)C)[CH2:18][CH2:17]2)(=[O:15])=[O:14])[CH:9]=[C:8]([O:33][CH3:34])[N:7]=1.C(O)(C(F)(F)F)=O.C(Cl)[Cl:48]>>[ClH:48].[F:1][C:2]1[C:38]([F:39])=[CH:37][CH:36]=[CH:35][C:3]=1[CH2:4][S:5][C:6]1[N:11]=[C:10]([NH:12][S:13]([N:16]2[CH2:17][CH2:18][N:19]([C:22](=[O:32])[CH2:23][NH2:24])[CH2:20][CH2:21]2)(=[O:14])=[O:15])[CH:9]=[C:8]([O:33][CH3:34])[N:7]=1
Reactant: COc1cc(NS(=O)(=O)N2CCN(C(=O)CNC(=O)OC(C)(C)C)CC2)nc(SCc2cccc(F)c2F)n1
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(NS(=O)(=O)N2CCN(C(=O)CN)CC2)nc(SCc2cccc(F)c2F)n1
Product: Cl

Procedure:
A solution of tert-butyl (2-{4-[({2-[(2,3-difluorobenzyl)thio]-6-methoxypyrimidin-4-yl}amino)sulfonyl]piperazin-1-yl}-2-oxoethyl)carbamate (the product of step ii, 0.19 g) in 10% TFA/DCM (5 mL) was stirred at room temperature for 3 h. The solution was evaporated, and then redissolved in 4N HCl in dioxane (2 mL) and MeOH (8 mL). Evaporation gave a crude residue that was triturated in Et2O, filtered and dried in a vacuum oven at 40° C. overnight to give the title compound as a white solid. Yield: 140 mg.
Reaction SMILES: CN(C)[CH:3]=[C:4]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)[C:5](OCC)=[O:6].[C:17]([O:21][CH2:22][C:23]1[CH:24]=[CH:25][C:26]([NH:29][NH2:30])=[N:27][CH:28]=1)([CH3:20])([CH3:19])[CH3:18].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[C:17]([O:21][CH2:22][C:23]1[CH:24]=[CH:25][C:26]([N:29]2[C:5](=[O:6])[C:4]([C:10]3[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=3)=[CH:3][NH:30]2)=[N:27][CH:28]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OCc1ccc(NN)nc1
Reactant: CCOC(=O)C(=CN(C)C)c1cccnc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CC(C)(C)OCc1ccc(-n2[nH]cc(-c3cccnc3)c2=O)nc1
Temperature: 25 °C

Procedure:
661 mg (3.0 mmol) of the compound from Example 2A and 586 mg (3.0 mmol) of the compound from Example 17A are initially charged in 10 ml of ethanol. 114 mg (0.6 mmol) of p-toluenesulfonic acid are added, and the mixture is stirred under reflux for 16 h. The mixture is then allowed to cool to RT, and the solid formed is filtered off, washed once with ethanol and dried under high vacuum. The solid is then stirred in tert-butyl methyl ether for 30 min, filtered off again and dried under high vacuum (batch 1). The filtrates and wash solutions obtained beforehand are combined and concentrated, and the residue is stirred in saturated sodium bicarbonate solution. The solid obtained is filtered off and washed once with water, and the filter residue is then purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% TFA to the water). The product fractions are combined and concentrated (batch 2).
Reaction SMILES: Cl.[C:2](=[N:10][OH:11])([Cl:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.[CH2:12]=[CH:13][CH:14]=[CH2:15].C(N(CC)CC)C>C(O)C>[ClH:9].[CH:13]([CH:14]1[O:11][N:10]=[C:2]([C:3]2[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=2)[CH2:15]1)=[CH2:12]
Reactant: ON=C(Cl)c1cccnc1
Reactant: C=CC=C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: C=CC1CC(c2cccnc2)=NO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of 27.0 g. of nicotinoyl chloride oxime hydrochloride and 30.2 g. of 1,3-butadiene in 500 ml. of absolute ethanol was added dropwise, over a one hour period, a solution of 29.3 g. of triethylamine in 200 ml. of ethanol. The reaction was stirred at room temperature for one hour, the solvent was removed by evaporation and the residue mixed with water and filtered. The solid was dissolved in diethyl ether and washed several times with water. The ether layer was separated, dried over sodium sulfate and filtered to remove solids (drying agent). Removal of the solvent left a red orange liquid which was dissolved in diethyl ether and HCl gas was bubbled in to form a white solid which was collected by filtration and recrystallized from ethanol. Recrystallization was repeated a second time. The hydrochloride salt melts at 201°-204°C.
Reaction SMILES: [C:1]([CH:4]([CH2:9][CH2:10][CH3:11])[CH2:5][C:6](O)=[O:7])(=O)[CH3:2].[NH2:12][NH2:13].O>CCO>[CH3:2][C:1]1[CH:4]([CH2:9][CH2:10][CH3:11])[CH2:5][C:6](=[O:7])[NH:12][N:13]=1
Reactant: NN
Reactant: CCCC(CC(=O)O)C(C)=O
Solvent: CCO
Solvent: O
Product: CCCC1CC(=O)NN=C1C
Temperature: 85 °C

Procedure:
To a solution of 3-acetyl-hexanoic acid (18.8 g, 119 mmol) in EtOH (150 ml) is added NH2NH2—H2O (6.94 ml, 143 mmol) and the mixture is refluxed (oil bath 85° C.) for 4 hours. solvent is removed in vacuo and to the residue is added water (100 ml) and EtOAc (100 ml). The layers are separated and the aqueous layer is extracted with EtOAc (3×100 ml). The combined extracts are washed with brine (150 ml), dried (Na2SO4) and evaporated. The resulting light yellow oil is used without further purification in the next step.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([S:12]([NH:15][C:16]1[S:17][CH:18]=[N:19][N:20]=1)(=[O:14])=[O:13])[CH2:7]2.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[F:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][C:35]=1[F:36].Cl.O1[CH2:46][CH2:45][O:44][CH2:43]C1>O>[F:29][C:30]1[CH:31]=[C:32]([C:2]2[CH:3]=[CH:4][C:46]([C:2]3[CH:11]=[CH:10][CH:9]=[C:8]4[C:3]=3[CH2:4][CH2:5][N:6]([S:12]([NH:15][C:16]3[S:17][CH:18]=[N:19][N:20]=3)(=[O:14])=[O:13])[CH2:7]4)=[C:45]([O:44][CH3:43])[CH:11]=2)[CH:33]=[CH:34][C:35]=1[F:36]
Reactant: C1COCCO1
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: O=S(=O)(Nc1nncs1)N1CCc2c(Br)cccc2C1
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Product: COc1cc(-c2ccc(F)c(F)c2)ccc1-c1cccc2c1CCN(S(=O)(=O)Nc1nncs1)C2
Temperature: 150 °C
Reaction time: 0.17 h
Yield: 35 %

Procedure:
A microwave vial charged with Pd(Amphos)2Cl2 (9.43 mg, 0.013 mmol), (4-chloro-2-methoxy)phenylboronic acid (0.050 g, 0.266 mmol), 5-bromo-N-(1,3,4-thiadiazol-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide (0.100 g, 0.266 mmol), potassium phosphate (0.339 g, 1.599 mmol), 1.5 mL of dioxane and 0.25 mL of water was heated to 150° C. in the microwave for 30 minutes. (3,4-difluorophenyl)boronic acid (0.053 g, 0.333 mmol) and an additional portion of Pd(Amphos)2Cl2 (9.43 mg, 0.013 mmol) were added, and the reaction mixture was heated to 150° C. in the microwave for an additional 30 minutes. The aqueous layer was removed, and the reaction mixture was treated with HCl (4N in dioxane) (0.266 ml, 1.066 mmol). After stirring for 10 minutes, the reaction mixture was concentrated. Purification of the crude residue by reverse phase column chromatography [RediSep Gold C18, 10-100% (0.1% NH4OH in MeOH)/(0.1% NH4OH in water)] gave 5-(3′,4′-difluoro-3-methoxy-[1,1′-biphenyl]-4-yl)-N-(1,3,4-thiadiazol-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide (0.048 g, 0.093 mmol, 35.0% yield). 1H NMR (MeCN-d3) δ: 8.31 (s, 1H), 7.65 (ddd, J=12.2, 7.8, 2.2 Hz, 1H), 7.52 (dddt, J=7.1, 4.3, 2.7, 1.2 Hz, 1H), 7.37 (dt, J=10.6, 8.5 Hz, 1H), 7.14-7.27 (m, 4H), 7.07-7.12 (m, 1H), 6.99-7.05 (m, 1H), 4.20-4.41 (m, 2H), 3.81 (s, 3H), 3.30-3.39 (m, 1H), 3.12-3.24 (m, 1H), 2.63-2.76 (m, 1H), 2.42-2.55 (m, 1H); (M+H)+=515.0.
Reaction SMILES: [C:1]([C:3]1[NH:17][C:16]2[C:18]3[C:4]=1[CH2:5][C@@H:6]1[C@@H:11]([C:12]=3[CH:13]=[CH:14][CH:15]=2)[CH2:10][C@H:9]([NH:19][C:20](=[O:26])[N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[CH2:8][N:7]1[CH3:27])#[CH:2].N1C2C(=CC=CC=2)C=CC=1>C(O)C.[Pd]>[CH3:27][N:7]1[C@H:6]2[C@@H:11]([C:12]3[CH:13]=[CH:14][CH:15]=[C:16]4[C:18]=3[C:4]([CH2:5]2)=[C:3]([CH:1]=[CH2:2])[NH:17]4)[CH2:10][C@H:9]([NH:19][C:20](=[O:26])[N:21]([CH2:22][CH3:23])[CH2:24][CH3:25])[CH2:8]1
Reactant: C#Cc1[nH]c2cccc3c2c1C[C@@H]1[C@@H]3C[C@H](NC(=O)N(CC)CC)CN1C
Agent: [Pd]
Solvent: c1ccc2ncccc2c1
Solvent: CCO
Product: C=Cc1[nH]c2cccc3c2c1C[C@@H]1[C@@H]3C[C@H](NC(=O)N(CC)CC)CN1C
Yield: 14.9 %

Procedure:
200 mg of 3-(2-ethynyl-6-methyl-8α-ergolinyl)-1,1-diethylurea is hydrogenated at room temperature and under normal pressure in 35 ml of ethanol with 200 mg of palladium/calcium carbonate (2%) and 200 mg of quinoline. After the mixture has been filtered off from the catalyst, it is evaporated. The residue is chromatographed over silica gel with methylene chloride/ethanol 6:1, thus obtaining 30 mg of 3-(6-methyl-2-vinyl-8α-ergolinyl)-1,1-diethylurea after recrystallization from ethanol/hexane, mp 145°-150° C.;
Reaction SMILES: [CH3:1]C(C)([O-])C.[Na+].BrC1[CH:9]=[C:10]([CH3:15])[CH:11]=[C:12]([CH3:14])[CH:13]=1.[C:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:19])[CH2:17][CH3:18]>CC([O-])=O.CC([O-])=O.[Pd+2].C1(C)C=CC=CC=1>[CH3:15][C:10]1[CH:9]=[C:18]([CH:17]([CH3:1])[C:16]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:19])[CH:13]=[C:12]([CH3:14])[CH:11]=1
Reactant: Cc1cc(C)cc(Br)c1
Reactant: CCC(=O)c1ccccc1
Reactant: CC(C)(C)[O-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1cc(C)cc(C(C)C(=O)c2ccccc2)c1
Temperature: 80 °C
Yield: 83.1 %

Procedure:
A dry Schlenk tube was charged with Pd(OAc)2 (2.2 mg, 0.01 mmol) and sodium tert-butoxide (125 mg, 1.3 mmol). The tube was then evacuated and filled with argon. Toluene (1 mL), 5-bromo-m-xylene (185 mg, 0.136 mL, 1.0 mmol) and propiophenone (161 mg, 0.160 mL, 1.2 mmol) were sequentially added with a syringe, and the tube was sealed and heated in an oil bath at 80° C. for 2 h 20 min. The mixture was cooled, and partitioned between ether and water. The aqueous layer was extracted twice with ether, and the combined organics were dried over Na2SO4, filtered and concentrated. Chromatography on silica gel, eluting first with hexane, then 4:1 toluene: hexane, gave 0.198 g (83%) of α-(3,5-dimethylphenyl)propiophenone, a clear oil. 1H NMR (CDCl3, 300 MHz) δ 7.96 (m, 2H); 7.48 (m, 1H); 7.38 (m, 2H); 6.89 (s, 2H); 6.83 (s, 2H); 4.60 (q, 1H, J=6.9 Hz); 2.26 (s, 6H); 1.50 (d, 3H, J=6.9 Hz).
Reaction SMILES: [Cl-].C[Al+]C.[CH3:5]CCCCC.[CH3:11][C:12]1[CH2:17][C:16]([CH3:19])([CH3:18])[CH:15]([CH2:20][C:21]2S(=C)C=CC=2)[C:14]([CH3:28])([CH3:27])[CH:13]=1.[CH:29](=[O:33])[CH:30]([CH3:32])[CH3:31]>ClCCl>[CH3:31][CH:30]([CH:29]([OH:33])[CH2:5][C:20](=[CH2:21])[CH:15]1[C:16]([CH3:18])([CH3:19])[CH2:17][C:12]([CH3:11])=[CH:13][C:14]1([CH3:27])[CH3:28])[CH3:32]
Reactant: C=S1C=CC=C1CC1C(C)(C)C=C(C)CC1(C)C
Reactant: CCCCCC
Reactant: CC(C)C=O
Agent: C[Al+]C
Agent: [Cl-]
Solvent: ClCCl
Product: C=C(CC(O)C(C)C)C1C(C)(C)C=C(C)CC1(C)C
Yield: 45 %

Procedure:
Dimethylaluminum chloride (3 mL of a 1M hexane solution) was reacted with a solution of 1,3,3,5,5-pentamethyl-4-(1-methylenethenyl)-1-cyclohexene (0.48 g, 0.0025 mol) and isobutyraldehyde (0.18 g, 0.0025 mol) in dichloromethane (10 mL) according to the procedure described in Example 3. Work-up and chromatography gave 0.300 g (45% yield) of α-(1-methylethyl)-2,2,4,6,6-pentamethyl-γ-methylene-3-cyclohexene-1-propanol, bp (kugelrohr bath) 135° C., 0.5 mm (GLC purity 94.4%, 2:1 mixture of diastereomers). 1H-NMR (60 MHz, CDCl3) δ0.88-1.07 (18H, 1d and 1 broad s), 1.4-2.4 (10H, m), 3.2-3.7 (1H, m) 4.9-5.2 (3H, m); IR (film) vmax 3450, 2950, 1640, 1465, 1380, 1360 cm-1 ; MS m/e 264, 249, 246, 221, 203, 177, 107, 96. The mass spectra of the diastereomers were nearly identical.