Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(P(C(C)(C)C)C1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][CH:9]=[CH:8][CH:7]=1)(C)C.C(N(CC)CC)C.[C:29]1([C:35]#[C:36][P:37](=[O:42])([OH:41])[O:38][CH2:39][CH3:40])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(C1C=CC=CC=1)CCC#C>[Au].ClC(Cl)C>[C:29]1([C:35]#[C:36][P:37](=[O:41])([O:42][C:8]([CH2:9][CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH2:7])[O:38][CH2:39][CH3:40])[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CCOP(=O)(O)C#Cc1ccccc1
Reactant: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: [Au]
Agent: C#CCCCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: C=C(CCCc1ccccc1)OP(=O)(C#Cc1ccccc1)OCC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 74 %

Procedure:
A gold (Ag(I)) catalyst {[Au(JohnPhos)NCCH3]|SbF6—} [JohnPhos:(2-biphenyl)di-tert-butylphosphine] (11.3 mg, 0.015 mmol) and triethylamine (Et3N) (3.0 mg, 0.03 mmol) were put into a reaction container, and dichloroethane (0.4 mL) was put thereinto. After stirring at room temperature for 5 minutes, ethyl hydrogen phenylethynylphosphonate) (63.0 mg, 0.3 mmol) diluted with 0.5 mL of dichloroethane was added thereto, and finally, pent-4-ynylbenzene (86.5 mg, 0.6 mmol) was put thereinto. Then, when all of the starting materials disappeared in the TLC, the reaction was allowed to be completed. After the solvent was removed under low atmospheric pressure, the product was separated by chromatography to obtain ethyl 5-phenylpent-1-en-2-yl phenylethynylphosphonate (78.7 mg, 74%) which is a title compound.
Reaction SMILES: C[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:27]4[N:31](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[N:30]=[N:29][N:28]=4)=[CH:17][CH:16]=3)[C:9]([CH2:11][CH2:12][CH3:13])=[CH:10][C:3]=12.C(Cl)Cl>CO.Cl.[NH4+].[OH-]>[CH2:11]([C:9]1[N:8]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[NH:31][N:30]=[N:29][N:28]=3)=[CH:19][CH:20]=2)[C:4]2=[N:5][CH:6]=[CH:7][CH:2]=[C:3]2[CH:10]=1)[CH2:12][CH3:13]
Reactant: CCCc1cc2c(C)ccnc2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CCCc1cc2cccnc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
To a stirred solution of 4-methyl-2-propyl-1-[[2'-(1-triphenylmethyl-1H-tetrazol-5-yl)[1,1']-biphenyl-4-yl]methyl]-1H-pyrrolo[2,3-b]pyridine (68 mg, 0.11 mmol) in 30 mL of 2:1 MeOH--CH2Cl2 at rt was added 2 drops of conc HCl. After 30 min 3 drops of conc NH4OH were added. Concentration and purification by flash chromatography (SiO2, 25% EtOAc/hexanes) gave 2-propyl-1-[[2'-(1H-tetrazol-5-yl)-[1,1']-biphenyl-4-yl]methyl]-1H-pyrrolo[2,3-b]-pyridine as a solid. FAB MS M+ +1=395.
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][N:6]=2.[H-].[Na+].[CH3:14]I>CN(C)C=O>[OH:1][CH2:2][C:3]1[N:11]([CH3:14])[C:10]2[C:5]([N:4]=1)=[N:6][CH:7]=[CH:8][CH:9]=2
Reactant: CI
Reactant: OCc1nc2cccnc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(CO)nc2ncccc21

Procedure:
A procedure similar to that described in Preparation 15 was repeated, except that 45 g of 2-hydroxymethyl-3H-imidazo[5,4-b]pyridine, 13.17 g of sodium hydride (as a 55% by weight dispersion in mineral oil), 20.7 ml of methyl iodide and 1.43 liter of dimethylformamide were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of ethyl acetate and methanol in ratios ranging from 1:0 to 1:1 by volume as the eluent, to give 3.24 g of the title compound, melting at 130-132° C.
Reaction SMILES: [C:1]([C:4]1[CH:23]=[CH:22][CH:21]=[CH:20][C:5]=1[C:6](C1C2C(=CC=CC=2)N(CC)C=1C)=[O:7])(O)=[O:2].C(C1C=CC=CC=1C(C1C2C(=CC=CC=2)N(CCCCCCCC)C=1C)=O)(O)=O>>[C:1]1([C:4]2[C:5](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:6][O:7]1)=[O:2]
Reactant: CCn1c(C)c(C(=O)c2ccccc2C(=O)O)c2ccccc21
Agent: CCCCCCCCn1c(C)c(C(=O)c2ccccc2C(=O)O)c2ccccc21
Product: O=C1OCc2ccccc21

Procedure:
If the 3-(2'-carboxybenzoyl)-1-ethyl-2-methyl-indole in Example 1 is replaced by an equimolar amount of 3-(2'-carboxybenzoyl)-1-n-octyl-2-methyl-indole, with the procedure otherwise being as described in Example 1, there is obtained 3.8 g of a phthalide compound of the formula ##STR14## which melts at 123°-125° C. This colour former develops on silton clay a blue colour of λmax. 600 nm.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:24]=[CH:25][C:26]=1[C:27]#[N:28])[NH:12][CH:13]=[C:14]1[C:19](=[O:20])OC(C)(C)OC1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:24]([C:19](=[O:20])[CH:14]=[CH:13][NH:12]2)=[CH:25][C:26]=1[C:27]#[N:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)OC(=O)C(=CNc2ccc(C#N)c(OCc3ccccc3)c2)C(=O)O1
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: N#Cc1cc2c(=O)cc[nH]c2cc1OCc1ccccc1
Temperature: 190 °C
Reaction time: 1 h
Yield: 79.7 %

Procedure:
5-((3-Benzyloxy-4-cyanoanilino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (6 g, 15.9 mmol) was suspended in DOWTHERM A, (trade mark of Fluka Chemie AG), (100 ml) and heated to 190° C. The mixture was stirred for 1 hour at 190° C. Upon cooling to ambient temperature the product precipitated out. Ether (125 ml) was added and the suspension was stirred for 30 minutes. The product was collected by filtration, washed with ether and dried under vacuum to give 7-benzyloxy-6-cyano-1,4-dihydroquinolin-4-one (3.5 g) which was used without further purification in the next step.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:15]1[N:16]=[C:17]([CH2:47][CH2:48][CH3:49])[N:18]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]3[C:40]([C:45]#[N:46])=[CH:41][CH:42]=[CH:43][CH:44]=3)=[CH:35][CH:34]=2)[C:19](=[O:31])[C:20]=1[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH3:30])=[CH:23][CH:22]=1)[CH3:14]>O>[CH2:13]([C:15]1[N:16]=[C:17]([CH2:47][CH2:48][CH3:49])[N:18]([CH2:32][C:33]2[CH:34]=[CH:35][C:36]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[C:45]3[NH:3][C:4](=[O:7])[O:5][N:46]=3)=[CH:37][CH:38]=2)[C:19](=[O:31])[C:20]=1[C:21]1[CH:22]=[CH:23][C:24]([O:27][CH2:28][CH2:29][CH3:30])=[CH:25][CH:26]=1)[CH3:14]
Reactant: O=C([O-])O
Reactant: [NH3+]O
Reactant: CCCOc1ccc(-c2c(CC)nc(CCC)n(Cc3ccc(-c4ccccc4C#N)cc3)c2=O)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCCOc1ccc(-c2c(CC)nc(CCC)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2=O)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
A mixture of hydroxylammonium chloride (1.3 g), sodium hydrogen carbonate (1.8 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[4-ethyl-6-oxo-5-(4-propoxyphenyl)-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile (0.52 g) was added, and the mixture was stirred at 90° C. for 24 hr. The reaction mixture was allowed to cool to room temperature, water was added to the reaction mixture, and the precipitated solid was collected by filtration. The obtained solid was dissolved in ethyl acetate. The solution was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.26 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.24 mL) were added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.39 g, 66%).
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:14]=[C:13]2[C:8]([NH:9][C:10](=[O:17])[C:11](=[O:16])[N:12]2[OH:15])=[CH:7][CH:6]=1)([OH:3])=[O:2].S(=O)(=O)(O)O.[CH3:23]O>>[OH:15][N:12]1[C:13]2[C:8](=[CH:7][CH:6]=[C:5]([CH2:4][C:1]([O:3][CH3:23])=[O:2])[CH:14]=2)[NH:9][C:10](=[O:17])[C:11]1=[O:16]
Reactant: O=C(O)Cc1ccc2[nH]c(=O)c(=O)n(O)c2c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc2[nH]c(=O)c(=O)n(O)c2c1
Temperature: 25 °C
Yield: 76 %

Procedure:
A mixture of 0.5 g (2.1 mmol) 7-carboxymethyl-1-hydroxyquinoxaline-2,3(1H,4H)-dione, 5 dr. sulfuric acid (97%) and 50 ml methanol was refluxed for 1 h. After cooling to 25° C. the precipitate was filtered off and washed with ether to give 0.4 g (76%) of 1-hydroxy-7-methoxycarbonylmethyl-quinoxaline-2,3(1H,4H)-dione. M.p. decomp. 1H-NMR (DMSO-d6): 12.2 (1H, broad s), 7.5-7.1 (3H, m), 3.9 (2H, s), 3.7 (3H,s).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[C:19]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][C:22](C(Cl)=O)=[CH:21][CH:20]=1.O[N:35]=[C:36]([NH2:41])[CH:37]([OH:40])[CH2:38][CH3:39].NC(=NO)C1CCN(C(OC(C)(C)C)=O)CC1>>[CH3:15][O:14][N:13]=[C:11]1[CH2:10][C@@H:9]([C:16]2[O:18][N:41]=[C:36]([CH:37]([OH:40])[CH2:38][CH3:39])[N:35]=2)[N:8]([C:6]([C:31]2[CH:30]=[CH:29][C:28]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:33][CH:32]=2)=[O:7])[CH2:12]1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: CCC(O)C(N)=NO
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Agent: CC(C)(C)OC(=O)N1CCC(C(N)=NO)CC1
Product: CCC(O)c1noc([C@@H]2CC(=NOC)CN2C(=O)c2ccc(-c3ccccc3)cc2)n1

Procedure:
Following the general method as outlined in Example 59, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidine-carboxylic acid (Intermediate 2), [1,1′-biphenyl]-4-carbonyl chloride, and (2RS)-N′,2-dihydroxybutanimidamide (an Intermediate 7), the title compound was obtained in 79% purity by HPLC. MS(ESI+): m/z=421.2.
Reaction SMILES: Cl[CH2:2][CH2:3]CCC/C=C\CC/C=C\C=C\CC.[CH2:17]([OH:29])[CH2:18]/C=C\CC/C=C\C=C\CC.ClCC/C=C\CC/C=C\C=C\CC.BrCCCCl.[CH:48](=[O:64])[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53]/[CH:54]=[CH:55]\[CH2:56][CH2:57]/[CH:58]=[CH:59]\[CH:60]=[CH:61]\[CH2:62][CH3:63].C([O-])([O-])OCC>>[CH2:2]([O:64][CH:48]([O:29][CH2:17][CH3:18])[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53]/[CH:54]=[CH:55]\[CH2:56][CH2:57]/[CH:58]=[CH:59]\[CH:60]=[CH:61]\[CH2:62][CH3:63])[CH3:3]
Reactant: CC/C=C/C=C\CC/C=C\CCO
Reactant: CC/C=C/C=C\CC/C=C\CCCCCC=O
Reactant: CC/C=C/C=C\CC/C=C\CCCCCCl
Agent: CC/C=C/C=C\CC/C=C\CCCl
Agent: CCOC([O-])[O-]
Agent: ClCCCBr
Product: CC/C=C/C=C\CC/C=C\CCCCCC(OCC)OCC

Procedure:
In one aspect of the invention, there is provided (Z,Z,E)-1-chloro-6,10,12-pentadecatriene. In another aspect of the invention, there is also provided a method for preparing (Z,Z,E)-1-chloro-6,10,12-pentadecatriene comprising a step of chlorinating (Z,Z,E)-3,7,9-dodecatrien-1-ol into (Z,Z,E)-1-chloro-3,7,9-dodecatriene and a step of reacting a Grignard reagent into which the (Z,Z,E)-1-chloro-3,7,9-dodecatriene is converted with 1-bromo-3-chloropropane. In a further aspect of the invention, there is also provided a method for preparing (Z,Z,E)-7,11,13-hexadecatrienal comprising a step of reacting a Grignard reagent into which (Z,Z,E)-1-chloro-6,10,12-pentadecatriene is converted with ethyl orthoformate to obtain (Z,Z,E)-1,1-diethoxy-7,11,13-hexadecatriene, and a step of treating the (Z,Z,E)-1,1-diethoxy-7,11,13-hexadecatriene with an acid to obtain (Z,Z,E)-7,11,13-hexadecatrienal.
Reaction SMILES: [CH:1](=[CH:8][C:9](=[O:11])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:12]1([CH3:20])[CH:17]=[CH:16][C:15]([CH:18]=O)=[CH:14][CH:13]=1.[OH-].[Na+]>C(O)C.O>[C:2]1([CH:1]=[CH:8][C:9](=[O:11])[CH:10]=[CH:20][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)C=Cc1ccccc1
Reactant: Cc1ccc(C=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ccc(C=CC(=O)C=Cc2ccccc2)cc1
Temperature: 25 °C
Yield: 72.5 %

Procedure:
A mixture of 146.0 g (1.0 mole) of benzalacetone and 122.0 g (1.02 mole) 4-tolualdehyde (Compound II-A) was dissolved in 750 ml ethanol, and the solution was diluted with 200 ml water. With stirring, at room temperature, all at once, 100 ml of 10% NaOH solution were added. After 1.5 hours the thick, cream precipitate was filtered off, resuspended in 1 liter 20% ethanol in water, refiltered, sucked dry and recrystallized from ethanol/ethyl acetate to give 180 g of 1-phenyl-5-(4-tolyl)-1,4-pentadiene-3-one (Compound IV-A). The product structure was confirmed by field desorption mass spectrometry (FDMS) and infrared (IR) spectrometry.
Reaction SMILES: [CH3:1][CH:2]([CH2:9][CH:10]([CH3:12])[CH3:11])[CH2:3][CH:4]=[CH:5][C:6](=[O:8])[CH3:7].O.[BH4-].[Na+].C(O)(=O)C(C(C(O)=O)O)O>CCOCC.C(O)C>[CH3:1][CH:2]([CH2:9][CH:10]([CH3:12])[CH3:11])[CH2:3][CH:4]=[CH:5][CH:6]([OH:8])[CH3:7]
Reactant: CC(=O)C=CCC(C)CC(C)C
Agent: O=C(O)C(O)C(O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CCO
Product: CC(O)C=CCC(C)CC(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 494.1 %

Procedure:
58, 9 g of 6,8-dimethyl-3-nonen-2-one, 25 ml of water and 70 ml of ethanol are added to a 250 ml round flask which is provided with a stirrer and a thermometer. 8 g of sodium borohydride are added slowly while maintaining the temperature below 25° C. by cooling with a cold water bath. The mixture is now stirred at 25° C. for 3 hours. 50 ml of a saturated solution of tartaric acid and 100 ml of ether are added to the reaction mixture. The organic layer is then washed with brine until neutral. The solvent is evaporated. There are obtained 58 g of crude product, distillation of which yields 45 g (76,2%) of 6,8-dimethyl-3-nonen-2-ol of boiling point 88°-90° C./5 mm; nD20 =1,4435; d420 =0,8330.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9]([O:16][CH:17]([CH3:19])[CH3:18])(=[O:15])/[CH:10]=[CH:11]\[C:12]([OH:14])=[O:13].[C:20]1(=[O:26])[O:25][C:23](=[O:24])[CH:22]=[CH:21]1.Cl.N1C=CC=C[CH:29]=1>O1C=CCCC1>[CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9]([O:16][CH:17]([CH3:19])[CH3:18])(=[O:15])/[CH:10]=[CH:11]\[C:12]([O:14][CH:23]1[CH2:22][CH2:21][CH2:29][CH2:20][O:25]1)=[O:13].[C:23]1(=[O:24])[O:25][C:20](=[O:26])[CH:21]=[CH:22]1
Reactant: CC(C)OC(=O)/C=C\C(=O)O
Reactant: c1ccncc1
Agent: C1=COCCC1
Agent: Cl
Agent: O=C1C=CC(=O)O1
Solvent: C=Cc1ccccc1
Product: CC(C)OC(=O)/C=C\C(=O)OC1CCCCO1
Temperature: 25 °C

Procedure:
A 5 g sample of poly(styrene [50 mol %], isopropyl hydrogen maleate [32 mol %], maleic anhydride [18 mol %]) was suspended in 75 mL of 3,4-dihydro-2H-pyran and treated with 0.1 g of pyridine hydrochloride. The mixture was stirred at reflux for 18 hours, during which time a homogeneous solution was formed. After cooling to room temperature, the solution was stirred for 1 hour with crosslinked poly(dimethylaminomethylstyrene) to remove the catalyst. After filtration, the product was isolated from the filtrate by precipitation in methanol and dried to give 3 g of poly(styrene, isopropyl tetrahydropyranyl maleate, maleic anhydride). Titration of the starting material with 0.1N sodium hydroxide shows 4.32 meq/g of anhydride and acid. Titration of the product shows 2.49 meq/g of anhydride. IR analysis of the product shows absorption characteristic of anhydride (1855 and 1780 cm-1), but no absorption characteristic of carboxylic acid. Differential scanning calorimetry (DSC) of the product shows a sharp decomposition endotherm peaking at 153.9° C. (104.1 J/g) which is absent from the starting material. Thermal gravimetric analysis (TGA) shows a 13.36% weight loss centered at 154.54° C. which is not seen in the TGA of the starting material. The thermal event at 154° C. is the thermal loss of dihydropyran to form polymeric carboxylic acid groups.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[CH3:11][CH:12]([CH2:16][CH3:17])[C:13](Cl)=[O:14].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[Cl:8][C:7]1[C:2]([Cl:1])=[C:3]([O:9][CH3:10])[CH:4]=[CH:5][C:6]=1[C:13](=[O:14])[CH:12]([CH3:11])[CH2:16][CH3:17]
Reactant: COc1cccc(Cl)c1Cl
Reactant: CCC(C)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCC(C)C(=O)c1ccc(OC)c(Cl)c1Cl

Procedure:
By following the procedure described in Example 5, Step A, using as the reactants 2,3-dichloroanisole (100 g., 0.565 mole), 2-methylbutyryl chloride (.75 g., 0.62 mole), aluminum chloride (84 g., 0.62 mole) and methylene chloride (400 ml.), there is obtained 2',3'-dichloro-4'-methoxy-2-methylbutyrophenone.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH:7]([C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=1)=[O:8].[Cl:18][C:19]1[CH:20]=[C:21]([CH2:26][OH:27])[CH:22]=[N:23][C:24]=1Cl>COCCOC.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>[Cl:18][C:19]1[C:24]([C:12]2[CH:13]=[CH:14][C:9]([CH:7]=[O:8])=[CH:10][CH:11]=2)=[N:23][CH:22]=[C:21]([CH2:26][OH:27])[CH:20]=1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: OCc1cnc(Cl)c(Cl)c1
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: COCCOC
Solvent: O
Product: O=Cc1ccc(-c2ncc(CO)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.8 %

Procedure:
2.68 g of sodium carbonate (25.3 mmol), 1.15 g of 4-formylphenylboronic acid (7.66 mmol), and 0.27 g of Pd(PPh3)4 were added to 1.5 g of (5,6-dichloropyridin-3-yl)methanol (8.43 mmol) dissolved in 30 mL of 1,2-dimethoxyethane and 30 mL of distilled water, and refluxed under heating and stirring for 18 hours. The mixture was cooled to room temperature, and concentrated under about 50% reduced pressure to extract the aqueous layer with ethyl acetate. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography (eluting solvent: chloroform/methanol=10/1) to obtain 1.40 g of 4-(3-chloro-5-(hydroxymethyl)pyridin-2-yl)benzaldehyde (yield 74%).
Reaction SMILES: [CH3:1][CH:2]1[S:7][C:6](=[O:8])[NH:5][N:4]=[C:3]1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[C:12]2=[N:19]C1C=CC=CC=1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34]N)=[CH:30][CH:29]=1>>[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][N:19]=[C:12]2[C:11]3[C:15](=[CH:16][CH:17]=[C:9]([C:3]4[CH:2]([CH3:1])[S:7][C:6](=[O:8])[NH:5][N:4]=4)[CH:10]=3)[NH:14][C:13]2=[O:18])=[CH:30][CH:29]=1
Reactant: CC1SC(=O)NN=C1c1ccc2c(c1)C(=Nc1ccccc1)C(=O)N2
Reactant: COc1ccc(NN)cc1
Product: COc1ccc(NN=C2C(=O)Nc3ccc(C4=NNC(=O)SC4C)cc32)cc1
Yield: 90 %

Procedure:
Starting from 1,3-dihydro-5-(3,6-dihydro-6-methyl-2-oxo -2H-1,3,4-thiadiazin-5-yl)-3-phenylimino-2H-indol-2-one, and 4-methoxyphenyl hydrazine and following the method described in Example 21, the desired compound was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:19])([CH3:18])[CH2:13][C:14]([O:16]C)=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:19])([CH3:18])[CH2:13][C:14]([OH:16])=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CC(C)(C)NC(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(CC(=O)O)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.7 %

Procedure:
A solution of 18.27 g (68.9 mmol) of methyl 3-benzyloxycarbonylamino-3-methylbutanoate (Step D) in 20 mL of methanol at room temperature was treated dropwise with 51 mL of 2N NaOH (102 mmol, 1.5 eq). The mixture was stirred at room temperature for 16 hours then transferred to a separatory funnel and washed with hexane (3×). The aqueous layer was removed, cooled to 0° and slowly acidified to pH 2 (paper) by dropwise addition of 6N HCl. This mixture was extracted with ether (6×); combined extracts were washed with 1N HCl and brine, then dried over magnesium sulfate, filtered and solvent removed under vacuum to afford 17.26 g (68.7 mmol, 99%) of the product. 1H NMR (200 MHz,CDCl3): 1.42 (s,6H), 2.77 (s,2H), 5.06 (s,2H), 5.2 (br s,1H), 7.3 (s,5H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH2:16][CH:15]([C:17]([F:20])([F:19])[F:18])[N:14]3[N:21]=[C:22]([C:24]4[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=4)[C:27]([OH:29])=O)[CH:23]=[C:13]3[NH:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH2:33][C@H:34]1[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH2:16][CH:15]([C:17]([F:20])([F:19])[F:18])[N:14]3[N:21]=[C:22]([C:24]4[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=4)[C:27]([NH:33][C@H:34]4[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35]4)=[O:29])[CH:23]=[C:13]3[NH:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2CC(C(F)(F)F)n3nc(-c4cccc(C(=O)O)c4)cc3N2)cc1OC
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Product: COc1ccc(C2CC(C(F)(F)F)n3nc(-c4cccc(C(=O)N[C@H]5CCN(C(=O)OC(C)(C)C)C5)c4)cc3N2)cc1OC
Yield: 20.4 %

Procedure:
Example ER-895811 was prepared in two steps from 3-(5-(3,4-dimethoxyphenyl)-7-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-2-yl)benzoic acid (24 mg, 0.054 mmol) and commercially available (S)-tert-butyl 3-aminopyrrolidine-1-carboxylate (40 mg, 0.215 mmol) in a manner similar to that of example D-6 to afford intermediate (3S)-tert-butyl 3-(3-(5-(3,4-dimethoxyphenyl)-7-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-2-yl)benzamido)pyrrolidine-1-carboxylate (7 mg, 0.011 mmol, 21% yield). Then, this intermediate (6 mg, 0.0097 mmol) was treated with HCl in a manner similar to that of example ER-897560 to afford the desired product ER-895811 (4.4 mg, 82% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:20])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([F:18])[C:11]=2[F:19])=O)[CH:7]=1.B(F)(F)F.CCOCC.C(OCC)(=O)C.C(=O)(O)[O-]>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:20])=[C:6]([CH2:8][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([F:18])[C:11]=2[F:19])[CH:7]=1
Reactant: COc1ccc(C(=O)c2cc(Br)ccc2Cl)c(F)c1F
Agent: FB(F)F
Agent: O=C([O-])O
Solvent: CCOCC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1ccc(Cc2cc(Br)ccc2Cl)c(F)c1F
Temperature: 25 °C
Reaction time: 15 h
Yield: 25.9 %

Procedure:
To a solution of (5-bromo-2-chloro-phenyl)-(2,3-difluoro-4-methoxy-phenyl)methanone 21e (5.42 g, 14.9 mmol) in acetonitrile (100 mL) were added triethyl silicane (4.8 mL, 29.87 mmol) at 15° C., followed by boron trifluoride diethyl ether (7.4 mL, 59.74 mmol). The mixture was warmed up to room temperature and stirred for 15 hours. To the reaction mixture was added ethyl acetate (4 mL). The mixture was adjusted with saturated aqueous bicarbonate to pH 7, and then partitioned. The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=20/1 to give the title compound 21f as pale yellow oil (1.34 g, 25.8%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 347.05 [M+H]+; and 1H NMR (400 MHz, CDCl3) δ (ppm): 7.33 (m, 1H), 7.28 (m, 2H), 6.84-6.76 (m, 1H), 6.75-6.62 (m, 1H), 4.05 (s, 2H), 3.91 (s, 3H).