Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:7][CH:6]=1)[CH2:3][OH:4].C(N(CC)CC)C.[Cl:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:24]=1[C:25](Cl)=O>O1CCCC1>[Cl:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:24]=1[C:25]1[O:4][CH2:3][CH:2]([C:5]2[CH:10]=[CH:9][C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:7][CH:6]=2)[N:1]=1
Reactant: O=C(Cl)c1c(F)cccc1Cl
Reactant: CC(C)(C)c1ccc(C(N)CO)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(C2COC(c3c(F)cccc3Cl)=N2)cc1
Temperature: 60 °C

Procedure:
A 100 ml eggplant-shaped flask was charged with 1.4 g (7.25 millimoles) of 2-amino-2-(4-t-butylphenyl)-1-ethanol and 0.73 g (7.25 millimoles) of triethylamine and 30 ml of tetrahydrofuran, and a solution of 1.4 g (7.25 millimoles) of 2-chloro-6-fluorobenzoyl chloride in 10 ml of tetrahydrofuran was added over 30 minutes to the flask with ice cooling and stirring. The mixture was stirred further for 3 hours at room temperature. The resulting triethylamine hydrochloride was removed by a glass filter, and the filtrate was concentrated under reduced pressure. The concentrate, thionylchloride (2.6 g; 21.8 and 50 ml of benzene were put in a 200 ml egg-plant-shaped flask, and refluxed for 5 hours. The reaction mixture was concentrated under reduced pressure. Fifty milliliters of methanol was added to the remaining oil, and the mixture was heated to 60° C. To the mixture was added dropwise 5 ml of a 15 % aqueous solution of sodium hydroxide. After the addition, the mixture was stirred at the same temperature for 1 hour, transferred into water, and extracted with ethyl acetate. The extract was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate=8/2) to give 2-(2-chloro-6-fluorophenyl)-4-(4-t-butylphenyl)-2-oxazoline (compound No. 45) as a colorless oil. Yield 1.8 g (74.9 %).
Reaction SMILES: I[CH2:2][CH3:3].[CH3:4][C@@:5]12[C:22]([CH3:24])([CH3:23])[C@@H:8]([C:9]3[C:10](=[O:21])[N:11]([C:14]4[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=4)[NH:12][C:13]=31)[CH2:7][CH2:6]2.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH2:2]([N:12]1[C:13]2[C@@:5]3([CH3:4])[C:22]([CH3:24])([CH3:23])[C@H:8]([CH2:7][CH2:6]3)[C:9]=2[C:10](=[O:21])[N:11]1[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)[CH3:3].[CH2:2]([O:21][C:10]1[N:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[N:12]=[C:13]2[C:9]=1[C@@H:8]1[C:22]([CH3:24])([CH3:23])[C@@:5]2([CH3:4])[CH2:6][CH2:7]1)[CH3:3]
Reactant: CCI
Reactant: Cc1ccc(-n2[nH]c3c(c2=O)[C@H]2CC[C@]3(C)C2(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1c2c(nn1-c1ccc(C)cc1)[C@]1(C)CC[C@H]2C1(C)C
Product: CCn1c2c(c(=O)n1-c1ccc(C)cc1)[C@H]1CC[C@]2(C)C1(C)C
Yield: 60 %
Yield: 7 %

Procedure:
Iodoethane (0.12 mL, 1.5 mmol) was added to (4S,7R)-7,8,8-trimethyl-2-p-tolyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 9; 400 mg, 1.4 mmol) and potassium carbonate (400 mg, 2.8 mmol) in dimethylformamide (5 mL). The mixture was heated at 60 degrees under argon overnight. The reaction mixture was diluted with water and extracted three times with ethyl acetate. The combined organic layers were washed with water and brine, dried (magnesium sulfate), filtered, evaporated, and purified using an Analogix Intelliflash 280 system (Analogix, Inc., Burlington, Wis.) with an RS-12 column, eluting with 0-75% ethyl acetate/hexanes to give (4S,7R)-1-ethyl-7,8,8-trimethyl-2-p-tolyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (30 mg, 7%) as a white solid and (4S,7R)-3-ethoxy-7,8,8-trimethyl-2-p-tolyl-4,5,6,7-tetrahydro-2H-4,7-methano-indazole (266 mg, 60%) as a light yellow solid. ES(+)-MS (M+H) 311.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][N:6]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:12]2=[O:23])=[N:7]1.[OH-].[Na+]>C(OC(=O)C)(=O)C.O>[CH3:5][N:6]1[CH:10]=[C:9]([N+:1]([O-:4])=[O:2])[C:8]([N:11]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[C:12]2=[O:23])=[N:7]1
Reactant: O=[N+]([O-])O
Reactant: Cn1ccc(N2CCN(C(=O)OC(C)(C)C)C2=O)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: Cn1cc([N+](=O)[O-])c(N2CCN(C(=O)OC(C)(C)C)C2=O)n1
Reaction time: 0.08 h

Procedure:
To acetic anhydride (30 mL) was added fuming nitric acid (3.77 mL) under ice-cooling, and the mixture was stirred for 5 min. The obtained solution was added dropwise to a solution of tert-butyl 3-(1-methyl-1H-pyrazol-3-yl)-2-oxoimidazolidine-1-carboxylate (12.1 g) in acetic anhydride (60 mL) under ice-cooling, and the mixture was stirred at 0° C. for 30 min. The reaction mixture was diluted with water, and the mixture was neutralized with 8M aqueous sodium hydroxide solution, and extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (11.3 g).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]2[CH:8]([N:25]([CH3:27])[CH3:26])[CH2:9][O:10][C:11]3[CH:18]=[CH:17][C:16]([C:19]#[C:20][C:21]([OH:24])([CH3:23])[CH3:22])=[CH:15][C:12]=3[C:13]=2[N:14]=1)=O.CO.[NH3:30]>>[CH3:27][N:25]([CH3:26])[CH:8]1[C:7]2[S:6][C:5]([C:3]([NH2:30])=[O:2])=[N:14][C:13]=2[C:12]2[CH:15]=[C:16]([C:19]#[C:20][C:21]([OH:24])([CH3:23])[CH3:22])[CH:17]=[CH:18][C:11]=2[O:10][CH2:9]1
Reactant: COC(=O)c1nc2c(s1)C(N(C)C)COc1ccc(C#CC(C)(C)O)cc1-2
Reactant: N
Solvent: CO
Product: CN(C)C1COc2ccc(C#CC(C)(C)O)cc2-c2nc(C(N)=O)sc21
Yield: 87 %

Procedure:
A solution of 4-Dimethylamino-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 (50 mg, 0.130 mmol), in methanol-ammonia (5 mL) was stirred at room temperature for 0.5 h. Then the mixture was filtered to afford compound 4-Dimethylamino-9-(3-hydroxy-3-methyl-but-1-ynyl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid amide (42 mg, 87%) as a white solid. LC-MS (ESI & APCI): 372.4 (M+1). 1H NMR (400 MHz, DMSO-d6): δ 8.54 (d, J=1.9 Hz, 1H), 8.43 (s, 1H), 7.88 (s, 1H), 7.30 (dd, H1=8.4 Hz, J2=1.9 Hz, 1H), 7.05 (d, J=8.3 Hz, 1H), 5.46 (s, 1H), 4.40 (m, 3H), 2.36 (s, 6H), 1.49 (s, 6H).
Reaction SMILES: C(OC([O:11][C:12]1([CH2:51][CH3:52])[C:17]2[CH:18]=[C:19]3[N:27]([C:28](=[O:29])[C:16]=2[CH2:15][O:14][C:13]1=[O:50])[CH2:26][C:25]1[C:24]([CH2:30][CH2:31][Si:32]([CH3:45])([CH3:44])[CH2:33][CH2:34][CH2:35][O:36][C:37]([C:39]2[O:40][CH:41]=[CH:42][CH:43]=2)=[O:38])=[C:23]2[CH:46]=[CH:47][CH:48]=[CH:49][C:22]2=[N:21][C:20]3=1)=O)C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[CH2:51]([C:12]1([OH:11])[C:17]2[CH:18]=[C:19]3[N:27]([C:28](=[O:29])[C:16]=2[CH2:15][O:14][C:13]1=[O:50])[CH2:26][C:25]1[C:24]([CH2:30][CH2:31][Si:32]([CH3:45])([CH3:44])[CH2:33][CH2:34][CH2:35][O:36][C:37]([C:39]2[O:40][CH:41]=[CH:42][CH:43]=2)=[O:38])=[C:23]2[CH:46]=[CH:47][CH:48]=[CH:49][C:22]2=[N:21][C:20]3=1)[CH3:52]
Reactant: CCC1(OC(=O)OCc2ccccc2)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CCCOC(=O)c1ccco1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCC1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CCCOC(=O)c1ccco1

Procedure:
A mixture of Compound 56 (180 mg, 0.25 mmol), 10% palladium on carbon (36 mg, 20%) in 6 mL of ethanol was hydrogenated for 18 hours at a balloon pressure of hydrogen at 21° C. The catalyst was removed by filtration over celite and the filtrate was evaporated to give a crude product, which was chromatographed to give the desired product.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:18]([CH3:19])=[C:17]2[N:8]([C:9](=[O:20])[NH:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=32)[N:7]=1)=[O:5])C.[OH-].[K+]>>[CH3:19][C:18]1[C:6]([C:4]([OH:5])=[O:3])=[N:7][N:8]2[C:17]=1[C:16]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:10][C:9]2=[O:20]
Reactant: CCOC(=O)c1nn2c(=O)[nH]c3ccccc3c2c1C
Agent: [K+]
Agent: [OH-]
Product: Cc1c(C(=O)O)nn2c(=O)[nH]c3ccccc3c12
Temperature: 25 °C

Procedure:
A suspension of 25.7 g (0.10 mole) of 1-methyl-pyrazolo[1,5-c]quinazolin-5(6H)-one-2-carboxylic acid ethyl ester in 2.5 l. of 10% alcoholic potassium hydroxide is refluxed for 3 hours, cooled to room temperature and filtered. The solid is dissolved in water extracted with chloroform, treated with Norit-A and filtered. The filtrate is cooled in an ice bath and acidified (Congo red) with 25 ml of concentrated hydrochloric acid. The white precipitate is filtered, digested with 1 l. of hot water and filtered, and dried to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]([NH2:7])=[N:4][CH:3]=1.[C:8]1([CH:14]([C:20](OCC)=[O:21])[C:15](OCC)=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.N12CCCN=C1CCCCC2>CN(C=O)C>[CH3:1][C:2]1[N:6]=[C:5]2[N:7]=[C:20]([OH:21])[C:14]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[C:15]([OH:16])[N:4]2[CH:3]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccccc1
Reactant: Cc1cnc(N)[nH]1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: Cc1cn2c(O)c(-c3ccccc3)c(O)nc2n1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
18 g (135 mmol) 5-Methyl-1H-imidazol-2-ylamine are dissolved in 155 mL DMF and 31.8 g (135 mmol) diethyl phenylmalonate are added. After dropwise addition of 61.5 g (404 mmol) 1,8-diazabicyclo[5.4.0]undec-7-ene the reaction mixture is stirred at 100° C. for 16 h. The DMF has been removed and the darkbrown oily residue treated with 150 mL water (complete dissolution). 2M HCl (250 mL) is added at room temperature until a pH of 1. After stirring for 1 h at ice bath cooling the formed crystals are collected by filtration to yield the product (10.2 g=31%), which is used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:23])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[C:15]#[C:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]([N:34]=[C:35]=[O:36])=[O:33])=[CH:27][CH:26]=1.COC1C=CC(CNC2N=CN=C(OC3C=CC(NC(NC(=O)CC4C=CC(F)=CC=4)=O)=CC=3F)C=2)=CC=1.[ClH:75]>>[ClH:75].[ClH:75].[F:1][C:2]1[CH:3]=[C:4]([NH:23][C:35]([NH:34][C:32](=[O:33])[CH2:31][C:28]2[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=2)=[O:36])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[C:15]#[C:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1
Reactant: Nc1ccc(Oc2ccncc2C#Cc2ccccn2)c(F)c1
Reactant: O=C=NC(=O)Cc1ccc(F)cc1
Agent: COc1ccc(CNc2cc(Oc3ccc(NC(=O)NC(=O)Cc4ccc(F)cc4)cc3F)ncn2)cc1
Agent: Cl
Product: O=C(Cc1ccc(F)cc1)NC(=O)Nc1ccc(Oc2ccncc2C#Cc2ccccn2)c(F)c1
Yield: 60 %

Procedure:
The title compound was prepared from 3-fluoro-4-(3-(2-(pyridin-2-yl)ethynyl)pyridin-4-yloxy)benzenamine (19 mg, 0.062 mmol) and 0.3 M solution of 2-(4-fluorophenyl)acetyl isocyanate in toluene (Compound D of Example 11, 0.50 mL, 0.15 mmol) in a manner similar to that of Step D of Example 33. Purification of the reaction mixture by flash chromatography on SiO2 eluting with 0-100% EtOAc/CH2Cl2 gave a white solid which was converted to the hydrochloride in a manner similar to Step D of Example 33 to give the title compound (19 mg, 60%) as a white solid. 1H NMR (DMSO-d6) δ 11.07 (s, 1H), 10.61 (s, 1H), 8.79 (s, 1H), 8.63 (d, 1H, J=5.6 Hz), 8.47 (d, 1H, J=5.6 Hz), 7.89-7.86 (m, 1H), 7.83 (dd, 1H, J=1.5, 12.7 Hz), 7.67 (d, 1H, J=7.6 Hz), 7.47-7.43 (m, 2H), 7.39-7.35 (m, 1H), 7.30-7.27 (m, 1H), 7.20-7.16 (m, 2H), 7.14-7.10 (m, 1H), 6.77 (d, 1H, J=5.6 Hz), 3.75 (s, 2H); MS(ESI+): m/z 485.17 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CCC(N=C=NC2CCCCC2)CC1.CS(O[C:40]1[CH:49]=[CH:48][C:47]2[C:42](=[CH:43][CH:44]=[C:45]([C:50](=[NH:52])[NH2:51])[CH:46]=2)[CH:41]=1)(=O)=O>N1C=CC=CC=1>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][C:40]1[CH:49]=[CH:48][C:47]2[C:42](=[CH:43][CH:44]=[C:45]([C:50](=[NH:51])[NH2:52])[CH:46]=2)[CH:41]=1)=[O:18])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Oc1ccc2cc(C(=N)N)ccc2c1
Reactant: O=C(O)CCCCCNC(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Product: N=C(N)c1ccc2cc(OC(=O)CCCCCNC(=O)OCc3ccccc3)ccc2c1
Reaction time: 0.5 h
Yield: 80.7 %

Procedure:
To a solution of 4.7 g of ε-benzyloxycarbonylaminocaproic acid in 50 ml of anhydrous pyridine, while being cooled in ice, was added 4.4 g of DCC. After stirring for 30 minutes, 5.0 g of 6-amidino-2-naphthol methanesulfonate was added to the mixture and stirred overnight at room temperature. The precipitate was separated by filtration and washed with a small volume of pyridine. The filtrate and the washings were added to stirred ethyl ether. The precipitated crystals were collected by filtration, recrystallized from an ethanol-ether mixture, and washed with acetone to obtain 6.2 g of white crystals of 6-amidino-2-naphthyl ε-benzyloxycarbonylaminocaproate methanesulfonate.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=1.[CH2:9]([Mg]Br)[CH:10]([CH3:12])[CH3:11]>C1C=CC=CC=1.O1CCCC1.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>[Br:8][C:4]1[CH:3]=[C:2]([CH2:9][CH:10]([CH3:12])[CH3:11])[CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)C[Mg]Br
Reactant: Brc1cccc(I)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)Cc1cccc(Br)c1
Reaction time: 2 h

Procedure:
To a solution of 1-iodo-3-bromobenzene (6.0 g, 21.2 mmol) in 100 mL of benzene at room temperature under argon, 1.2 g (1.06 mmol) of tetrakis(triphenylphosphine)palladium(0) was added and to this mixture a 2M solution in tetrahydrofuran of isobutyl magnesium bromide (10.6 mL) was added dropwise over 15 minutes. The mixture was stirred 2 hours, diluted with 100 mL of water, the organic layer was separated and the aqueous layer was extracted with 2×100 mL of ether. The combined organic extracts were dried and evaporated to provide 4.3 g of a colorless liquid, which upon distillation in vacuo provided 1.95 g (43%) of compound A as a colorless liquid; b.p. 124-125° C. (15-20 mm).
Reaction SMILES: [CH3:1][O-:2].[Mg+2].C[O-].[CH2:6]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C=O.S(=O)(=O)(O)O>CO.C1(C)C=CC=CC=1.O>[OH:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:20][C:19]=1[CH:1]=[O:2]
Reactant: C[O-]
Reactant: CCCCCCCCCc1ccc(O)cc1
Agent: C=O
Agent: O=S(=O)(O)O
Agent: [Mg+2]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CO
Product: CCCCCCCCCc1ccc(O)c(C=O)c1
Temperature: 90 °C
Yield: 94.2 %

Procedure:
A solution of magnesium methoxide (292 g of 8% solution in methanol, 0.275 mol) was added over 10 minutes to a stirred solution of p-nonylphenol (55 g, 0.25 mol) in methanol (50 ml). The stirred mixture was heated to reflux temperature, the bulk of the methanol was removed by distillation, toluene (500 ml) was added and toluene:methanol azeotrope was removed by fractional distillation until the temperature of the reaction mixture rose to 100° C. The mixture was cooled to 90° C. and an agitated slurry of paraformaldehyde fine powder (26.25 g, 0.875 mol) in toluene (100 ml) was added evenly over 1 hour to the reaction mixture at 90°-100° C. with removal of volatile by-products by distillation. Stirring was continued at 100° C. for a further hour, the mixture was cooled to 45° C. and was added to a premixed solution of concentrated sulphuric acid (62.5 g, 0.875 mol) in water (1 liter). The resulting mixture was stirred at ambient temperature for 1 hour, the phases were separated and the aqueous phase was extracted with toluene (200 ml). The toluene extract was combined with the original organic phase and toluene was removed by distillation under reduced pressure to give the crude 2-hydroxy-5-nonyl benzaldehyde as a yellow oil (58.5 g).
Reaction SMILES: [CH3:1][CH:2]([CH3:13])[C:3]([NH:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1I)=[O:4].[C:14](=O)([O-])[O-].[Na+].[Na+].[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)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>[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:11]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[NH:5][C:3](=[O:4])[C:2]([CH3:13])([CH3:14])[CH3:1]
Reactant: OB(O)c1ccccc1Cl
Reactant: O=C([O-])[O-]
Reactant: CC(C)C(=O)Nc1cnccc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)C(=O)Nc1cnccc1-c1ccccc1Cl
Temperature: 80 °C
Yield: 65 %

Procedure:
A mixture of 35 g (115 mmol) 2,2-dimethyl-N-(4-iodo-pyridin-3-yl)-acetamide, 400 ml toluene, 120 ml 2 N sodium carbonate solution, 4.0 g (3.5 mmol) tetrakis(triphenylphosphine)palladium(0) and 20.0 g (128 mmol) o-chlorophenylboronic acid was heated under argon at 80° C. for 12 h. After cooling to room temperature, the aqueous phase was separated and washed twice with toluene. The combined organic layers were washed with 50 ml brine, dried (magnesium sulfate) and evaporated. The residue was purified by flash chromatography to yield 21.6 g (65%) of the title compound as white crystals.
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]([CH3:13])[CH3:12])[C:5]=1[NH2:6])([CH3:3])[CH3:2].C1([O-])C=CC=CC=1.[CH:21]1[C:34]2[C:25](=[CH:26][C:27]3[C:32]([C:33]=2[C:35]2[CH:40]=[C:39]([CH3:41])[CH:38]=[CH:37][C:36]=2[OH:42])=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:24]=[CH:23][CH:22]=1.[OH-].[Na+].[N:45]1C=CC=CC=1>C1C=CC=CC=1.O>[CH:11]([C:7]1[CH:8]=[CH:9][CH:10]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]=1[N:6]=[N:45][C:37]1[CH:38]=[C:39]([CH3:41])[CH:40]=[C:35]([C:33]2[C:34]3[C:25]([CH:26]=[C:27]4[C:32]=2[CH:31]=[CH:30][CH:29]=[CH:28]4)=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:36]=1[OH:42])([CH3:13])[CH3:12]
Reactant: Cc1ccc(O)c(-c2c3ccccc3cc3ccccc23)c1
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: c1ccncc1
Agent: [Na+]
Agent: [O-]c1ccccc1
Agent: [OH-]
Solvent: O
Solvent: c1ccccc1
Product: Cc1cc(N=Nc2c(C(C)C)cccc2C(C)C)c(O)c(-c2c3ccccc3cc3ccccc23)c1

Procedure:
This phenol was prepared, as described above, from a theoretical yield of 3.9 mmol of diazotized 2,6-diisopropylaniline and a phenolate solution comprised of 2-(9-Anthracenyl)-4-methylphenol (0.63 g), water (20 mL), NaOH (20 mmol), pyridine (2 mL), and benzene (4 mL). In this case, the product was eluted with ether:hexanes (1:10). Yield=0.30 g (29%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:14]([OH:16])=O)[C:5]2[CH:6]=[N:7][N:8]([CH:11]3[CH2:13][CH2:12]3)[C:9]=2[CH:10]=1.[NH2:17][CH2:18][C:19]1[C:20](=[O:27])[NH:21][C:22]([CH3:26])=[CH:23][C:24]=1[CH3:25]>>[Br:1][C:2]1[CH:3]=[C:4]([C:14]([NH:17][CH2:18][C:19]2[C:20](=[O:27])[NH:21][C:22]([CH3:26])=[CH:23][C:24]=2[CH3:25])=[O:16])[C:5]2[CH:6]=[N:7][N:8]([CH:11]3[CH2:12][CH2:13]3)[C:9]=2[CH:10]=1
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: O=C(O)c1cc(Br)cc2c1cnn2C1CC1
Product: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2cnn3C2CC2)c(=O)[nH]1
Reaction time: 12 h

Procedure:
The title compound was prepared in the same manner as described for example 3 (step c) from 6-bromo-1-cyclopropyl-1H-indazole-4-carboxylic acid (0.22 g, 0.783 mmol) and 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone (0.221 g, 1.174 mmol), wherein the reaction stir time was 12 h. The title compound was collected as a white solid (0.27 g, 81%); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.06-1.17 (m, 4H), 2.12 (s, 3H), 2.20 (s, 3H), 3.76-3.85 (m, 1H), 4.33 (d, J=5.05 Hz, 2H), 5.88 (s, 1H), 7.76 (d, J=1.52 Hz, 1H), 8.10 (s, 1H), 8.30 (d, J=1.01 Hz, 1H), 8.64 (t, J=4.93 Hz, 1H), 11.54 (s, 1H); LC-MS (ES) m/z=414.8 [M+H].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([C:14]([OH:16])=O)[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.C1(C(O)=O)(C(O)=O)CC1.FC1C=CC([NH2:31])=CC=1.[F:34][C:35]1[CH:36]=[C:37](N)[CH:38]=[CH:39][C:40]=1[O:41][C:42]1[CH:47]=[CH:46][N:45]=[C:44]2[CH:48]=[C:49]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[S:50][C:43]=12>>[F:34][C:35]1[CH:36]=[C:37]([N:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:9]([C:11]2([C:14]([NH2:31])=[O:16])[CH2:12][CH2:13]2)=[O:10])[CH:38]=[CH:39][C:40]=1[O:41][C:42]1[CH:47]=[CH:46][N:45]=[C:44]2[CH:48]=[C:49]([C:51]3[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=3)[S:50][C:43]=12
Reactant: Nc1ccc(F)cc1
Reactant: Nc1ccc(Oc2ccnc3cc(-c4ccccc4)sc23)c(F)c1
Reactant: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CC1
Agent: O=C(O)C1(C(=O)O)CC1
Product: NC(=O)C1(C(=O)N(c2ccc(F)cc2)c2ccc(Oc3ccnc4cc(-c5ccccc5)sc34)c(F)c2)CC1

Procedure:
Prepared from 1-((4-fluorophenyl)carbamoyl)cyclopropanecarboxylic acid (34.84 mg, 0.1561 mmol; prepared from cyclopropane-1,1-dicarboxylic acid and 4-fluoroaniline using the methods described in WO 2005/030140 and by Shih and Rankin, Synth. Comm. 1996, 26(4), 833-836), and 3-fluoro-4-(2-phenylthieno[3,2-b]pyridin-7-yloxy)benzenamine (Example 76, Step A; 35 mg, 0.1040 mmol) according to the procedure for Example 73. The product was purified by preparative TLC eluting with EtOAc/MeOH (9:1). Isolated the product as a light yellow oil, which solidified upon standing (4.3 mg, 8%). 1H NMR (CDCl3, 400 MHz) δ 10.03 (s, 1H), 8.47 (d, J=5.5 Hz, 1H), 8.27 (s, 1H), 7.77 (m, 3H), 7.46 (m, 5H), 7.24 (m, 2H), 7.06 (d, J=9.0 Hz, 2H), 6.49 (m, 2H) 1.80, (m, 2H), 1.62 (m, 2H). LRMS (APCI pos) m/e 542 (M+1).
Reaction SMILES: [K].[O:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:5][NH:4][C:3]1=[S:12].[CH2:13](I)[CH2:14][CH3:15]>[Hg]>[CH2:13]([S:12][C:3]1[O:2][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:5][N:4]=1)[CH2:14][CH3:15]
Reactant: CCCI
Reactant: CCOC(=O)c1n[nH]c(=S)o1
Agent: [Hg]
Agent: [K]
Product: CCCSc1nnc(C(=O)OCC)o1

Procedure:
The title compound was prepared from ethyl 1,3,4-oxadiazole-2-thione-5-carboxylate potassium salt dimethylsulfoxide solvate (10 g., 28.5 mmole) and n-propyliodide (4.17 ml., 42.8 mmole) analogously to the procedure described in Experiment A. The yield was 4.99 g. (81%). The product had a B.P. of 108°-118° C. at 0.65 mm. of mercury.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH:4]=C.[CH2:7]=[CH:8][CH:9]1[O:11][CH2:10]1.B(CC)(CC)[CH2:13]C>CN(C1C=CN=CC=1)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(Cl)(Cl)Cl.C1COCC1.C(Cl)Cl>[CH3:13][CH:10]([O:11][C@H:2]([CH:3]=[CH2:4])[CH2:1][OH:6])[CH2:9][CH:8]=[CH2:7]
Reactant: C=CC1CO1
Reactant: C=CCCCO
Reactant: CCB(CC)CC
Agent: [Pd]
Agent: CN(C)c1ccncc1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: C=CCC(C)O[C@H](C=C)CO
Reaction time: 4 h
Yield: 84 %

Procedure:
Following the general procedure in Example 13A, 4-pentenol was added to butadiene monoepoxide, using the following quantities of reagents and solvents: Pd2dba3.CHCl3 (5.2 mg, 5.0 μmol), (S,S)-9 (11.8 mg, 15 μmol), DMAP (6.2 mg, 50 μmol), a 1.0 M solution of Et3B in THF (5.0 μL, 5.0 μmol), 4-pentenol (207 μL, 2.0 mmol), butadiene monoepoxide (81 μL, 1.0 mmol), CH2Cl2 (10 mL). The reaction time in this case was 4 h. Flash chromatography of the crude material (silica gel, 4:1 pentane-ether) afforded 131 mg (84%) of a colorless oil in 90% ee (separated by chiral GLC, Cyclosil B column, isothermal 120° C., (S)-(+)-isomerrt=9.33 min, (R)-(−)-isomerrt=9.68 min). [α]D=−33.2° (c 2.86, CHCl3); 1H NMR (300 MHz) δ 1.66 (quint 2H, J=7 Hz), 2.07-2.26 (m, 3H), 3.28-3.61 (m, 4H), 3.75-3.81 (m, 1H), 4.94 (d, 1H, J=11 Hz), 5.00 (d, 1H, J=17 Hz), 5.24 (d, 1H, J=9 Hz), 5.28 (d, 1H, J=17 Hz), 5.60-5.83 (m, 2H). 13C NMR (75.5 MHz) δ 28.9, 30.4, 65.2, 68.2, 81.6, 114.8, 118.7, 135.4, 138.2. Anal. Calc'd. for C9H16O2: C, 69.19; H, 10.32. Found: C, 69.23; H, 10.14.