Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH3:7])=[C:4]([CH:8]=[O:9])[CH:3]=1.[CH3:10][C:11]1[C:15](B(O)O)=[C:14]([CH3:19])[O:13][N:12]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.O>[CH3:10][C:11]1[C:15]([C:2]2[O:6][C:5]([CH3:7])=[C:4]([CH:8]=[O:9])[CH:3]=2)=[C:14]([CH3:19])[O:13][N:12]=1
Reactant: Cc1noc(C)c1B(O)O
Reactant: Cc1oc(Br)cc1C=O
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: Cc1noc(C)c1-c1cc(C=O)c(C)o1
Reaction time: 8 h
Yield: 67.9 %

Procedure:
A mixture of 5-bromo-2-methylfuran-3-carbaldehyde (1.9 g), 3,5-dimethylisoxazole-4-boronic acid (1.7 g), tetrakis(triphenylphosphine)palladium(0) (0.6 g), 2N aqueous sodium carbonate solution (9 mL) and 1,2-dimethoxyethane (20 mL) was stirred overnight with refluxing under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 30% ethyl acetate/hexane), and crystallized from ethyl acetate/hexane to give the title compound (1.4 g, 69%) as a yellow crystal.
Reaction SMILES: [OH:1][C@H:2]([CH2:6][OH:7])[CH2:3][C:4]#[N:5].[S:8](Cl)([CH3:11])(=[O:10])=[O:9].Cl>N1C=CC=CC=1.C(Cl)Cl>[OH:1][C@H:2]([CH2:6][O:7][S:8]([CH3:11])(=[O:10])=[O:9])[CH2:3][C:4]#[N:5]
Reactant: N#CC[C@H](O)CO
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)OC[C@@H](O)CC#N
Temperature: 0 °C
Reaction time: 6 h

Procedure:
(3S)-3,4-Dihydroxybutyronitrile (16.2 g, 160 mmol) was dissolved in pyridine (26.0 ml). To the resulting solution, a solution of mesyl chloride (14.8 ml) in methylene chloride (160 ml) was added at 0° C. and stirred at 0° C. for 6 hours. Then, the pH of the mixture was adjusted at 2 with 6N hydrochloric acid, and the mixture was extracted with methylene chloride. After the organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated off. The residue was purified with silica gel column chromatography (acetone:chloroform=5:95) to obtain (3S)-3-hydroxy-4-methanesulfonyloxybutyronitrile (15.2 g). Yield, 53 %.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([CH3:13])([CH3:12])[CH2:6][C:5]2=[O:14].[B:15]1(B2OC(C)(C)C(C)(C)O2)[O:19]C(C)(C)C(C)(C)[O:16]1.C([O-])(=O)C.[K+].O>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:12][C:7]1([CH3:13])[CH2:6][C:5](=[O:14])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([B:15]([OH:19])[OH:16])[CH:3]=2)[O:8]1
Reactant: CC1(C)CC(=O)c2cc(Br)ccc2O1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)CC(=O)c2cc(B(O)O)ccc2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.8 %

Procedure:
A solution of 6-bromo-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one (21 g), pinacol diborane (25 g), palladium acetate (0.92 g) and potassium acetate (2.4 g) in N,N-dimethylformamide (250 mL) was stirred at 90° C. for 2 hr under an argon atmosphere. Water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (80 mL), and 0.5 M hydrochloric acid (40 mL) and sodium periodate (7.0 g) were added at 0° C. The reaction mixture was stirred at room temperature for 2 hr and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was crystallized from ethyl acetate and hexane to give the title compound (15 g, 84%) as a colorless solid.
Reaction SMILES: [F:1][C:2]1[C:18]([C:19]#[C:20][C:21]([C:24]2[CH:28]=[C:27]([CH:29]=O)[O:26][N:25]=2)([OH:23])[CH3:22])=[CH:17][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]([NH2:16])=[O:15])[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.Cl.NO.C([N:36](CC)CC)C.CCN(CC)CC.CC(O)=O>CN(C)C=O.C(Cl)Cl>[C:29]([C:27]1[O:26][N:25]=[C:24]([C:21]([OH:23])([CH3:22])[C:20]#[C:19][C:18]2[C:2]([F:1])=[CH:3][C:4]3[O:10][CH2:9][CH2:8][N:7]4[CH:11]=[C:12]([C:14]([NH2:16])=[O:15])[N:13]=[C:6]4[C:5]=3[CH:17]=2)[CH:28]=1)#[N:36]
Reactant: CC(O)(C#Cc1cc2c(cc1F)OCCn1cc(C(N)=O)nc1-2)c1cc(C=O)on1
Reactant: CCN(CC)CC
Agent: Cl
Agent: NO
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC(O)(C#Cc1cc2c(cc1F)OCCn1cc(C(N)=O)nc1-2)c1cc(C#N)on1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 6 %

Procedure:
A solution of 9-fluoro-10-(3-(5-formylisoxazol-3-yl)-3-hydroxybut-1-yn-1-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide (90 mg, 0.22 mmol, 1.00 equiv), hydroxylamine hydrochloride (15 mg, 0.22 mmol, 1.00 equiv) in N,N-dimethylformamide (3 mL) was heated at 140° C. for 1 h. To this was added triethylamine (90 mg, 0.89 mmol, 4.00 equiv) at 0° C. To the mixture was added TEAA (70 mg, 1.50 equiv) dropwise with stirring at 0° C. The resulting solution was stirred for 12 h at 120° C. The reaction solution was diluted with DCM and washed with water. The crude product was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-005(Waters)): Column, XBridge Shield RP18 OBD Column, 5 um, 19*150 mm; mobile phase, Water with 10 mmolNH4HCO3 and CH3CN (15% CH3CN up to 70% in 10 min, up to 95% in 1 min, hold 95% in 1 min, down to 15% in 2 min); Detector, UV 254/220 nm. This gave the titled compound (5.4 mg, 6%).
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][CH:10]=[C:9]([CH3:12])[C:8]=2[CH:13]=1)N.[CH2:14]([N:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1)[CH2:15][CH3:16]>>[CH3:12][C:9]1[C:8]2=[C:13]3[C:4](=[CH:5][CH:6]=[C:7]2[S:11][CH:10]=1)[NH:2][C:20]1[CH2:21][CH2:22][N:17]([CH2:14][CH2:15][CH3:16])[CH2:18][C:19]3=1
Reactant: CCCN1CCC(=O)CC1
Reactant: Cc1csc2ccc(NN)cc12
Agent: Cl
Product: CCCN1CCc2[nH]c3ccc4scc(C)c4c3c2C1

Procedure:
The compound is formed analogously to that described in Example 5, from 2.15 g of 5-hydrazino-3-methylbenzothiophene hydrochloride and 1.9 g of 1-propyl-4-piperidone. Melting point: 169° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[C:4]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[CH:3]=1.C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1.[CH3:56][N:57]1[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]1>O1CCCC1>[Cl:1][C:2]1[C:7]([C:8]([N:60]2[CH2:61][CH2:62][N:57]([CH3:56])[CH2:58][CH2:59]2)=[O:10])=[CH:6][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[C:4]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)[CH:3]=1
Reactant: CN1CCNCC1
Reactant: COc1ccc(COc2cc(Cl)c(C(=O)O)cc2OCc2ccc(OC)cc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: COc1ccc(COc2cc(Cl)c(C(=O)N3CCN(C)CC3)cc2OCc2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97 %

Procedure:
To a solution of 6-chloro-3,4-bis(p-methoxybenzyloxy)benzoic acid (94 g: 218 mMol.) in tetrahydrofuran (1 liter) are added dicyclohexylcarbodiimide (50 g: 1.1 Eq.) and N-hydroxybenzotriazole (33 g: 1.1 Eq.), and the mixture is stirred at room temperature for 90 minutes. To the reaction mixture is added N-methylpiperazine (48 ml: 2 Eq.) and the resulting precipitate is filtered off. The filtrate is concentrated under reduced pressure, diluted with ethyl acetate, washed with aqueous sodium hydroxide and water, dried and concentrated in vacuum. The residue is treated in dichloromethane and ether to remove a small amount of insoluble material and concentrated under reduced pressure to give 1-(6-chloro-3,4-bis(p-methoxybenzyloxy)benzoyl-4-methylpiperazine (108 g). Yield: 97%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][OH:16])[C:10]=1[CH3:17])([CH3:4])([CH3:3])[CH3:2].C([N-]C(C)C)(C)C.[Li+].C(NC(C)C)(C)C.C([Li])CCC.[C:39]1([N:45]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:46](Cl)=[O:47])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>O1CCCC1>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][C:46](=[O:47])[N:45]([C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:10]=1[CH3:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)N(c1ccccc1)c1ccccc1
Reactant: Cc1c(CO)cccc1OCC(=O)OC(C)(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Cc1c(COC(=O)N(c2ccccc2)c2ccccc2)cccc1OCC(=O)OC(C)(C)C
Temperature: -50 °C
Reaction time: 0.17 h
Yield: 73.1 %

Procedure:
A solution of (3-hydroxymethyl-2-methylphenoxy)acetic acid te/t-butyl ester (80.1 g, 318 mmol) dissolved in tetrahydrofuran (400 mL) was cooled to −50° C. and treated with lithium diisopropylamide (325 mmol) freshly prepared from diisopropylamine (49 mL) and 2.5M n-butyllithium (130 mL) in tetrahydrofuran (100 mL). After about 10 minutes at −50° C., a solution of diphenylcarbamyl chloride (80.8 g, 350 mmol) dissolved in tetrahydrofuran (100 mL) was added. The entire reaction mixture was stirred for an additional 30 minutes and then allowed to warm to room temperature over a period of 3 hours. The solution was evaporated in vacuo, poured into dilute hydrochloric acid, and extracted with diethyl ether. The organic layer was dried over brine, evaporated, and purified by silica gel chromatography, eluting with acetone/hexane (1:5→1:3), to give {3-[(diphenylcarbamoyloxy)-methyl]-2-methylphenoxy}acetic acid tert-butyl ester as a white solid (104.1 g, 73%).
Reaction SMILES: [CH2:1]([N:3]1[CH:8]=[C:7]([C:9]([O:11]C)=[O:10])[CH:6]=[CH:5][C:4]1=[O:13])[CH3:2].O.[OH-].[Li+].Cl>O.CO>[CH2:1]([N:3]1[CH:8]=[C:7]([C:9]([OH:11])=[O:10])[CH:6]=[CH:5][C:4]1=[O:13])[CH3:2]
Reactant: CCn1cc(C(=O)OC)ccc1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCn1cc(C(=O)O)ccc1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.7 %

Procedure:
Methyl 1-ethyl-2-oxo-1,2-dihydropyridine-5-carboxylate (375 mg, 2.07 mmol) obtained in Step 4 was dissolved in a mixed solvent (1:1) (20 mL) of water and methanol, and lithium hydroxide monohydrate (191 mg, 4.55 mmol) was added thereto, followed by stirring at room temperature for 1 hour. The reaction mixture was neutralized with 3 mol/L hydrochloric acid added thereto, and the precipitated solid was collected by filtration to afford the entitled Compound u (224 mg, 65%).
Reaction SMILES: [NH2:1][C:2]1[C:13]([CH3:14])=[CH:12][C:11]([Br:15])=[CH:10][C:3]=1[C:4]([NH:6][CH:7]([CH3:9])[CH3:8])=[O:5].[C:16](Cl)(Cl)=[O:17].C1(C)C=CC=CC=1>O1CCOCC1>[Br:15][C:11]1[CH:10]=[C:3]2[C:2](=[C:13]([CH3:14])[CH:12]=1)[NH:1][C:16](=[O:17])[N:6]([CH:7]([CH3:9])[CH3:8])[C:4]2=[O:5]
Reactant: O=C(Cl)Cl
Reactant: Cc1cc(Br)cc(C(=O)NC(C)C)c1N
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: Cc1cc(Br)cc2c(=O)n(C(C)C)c(=O)[nH]c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the anthranilamide of Step F, (1.11 g, 4.1 mmol) in dioxane (20 mL) was added a 2.0 M solution of phosgene in toluene (2.3 mL, 4.6 mmol). The reaction was stirred at room temperature for 1 hour then heated to reflux for 4 hours and cooled to room temperature. The white solids were filtered and dried to afford the title compound (0.89 g).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH:19]([O:22][CH2:23][C:24]1[CH:25]=[C:26]([C:30]2[O:34][CH:33]=[N:32][C:31]=2[C:35](O)=[O:36])[CH:27]=[CH:28][CH:29]=1)([CH3:21])[CH3:20]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:35]([C:31]3[N:32]=[CH:33][O:34][C:30]=3[C:26]3[CH:27]=[CH:28][CH:29]=[C:24]([CH2:23][O:22][CH:19]([CH3:21])[CH3:20])[CH:25]=3)=[O:36])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC(C)OCc1cccc(-c2ocnc2C(=O)O)c1
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)c3ncoc3-c3cccc(COC(C)C)c3)n2)o1

Procedure:
Following general procedure B followed by C, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and 5-(3-isopropoxymethyl-phenyl)-oxazole-4-carboxylic acid. LC-MS-conditions 02: tR=1.03 min; [M+H]+=449.63.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][CH2:10][CH:11]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])[C:12]([OH:14])=[O:13])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:20]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[Cl:1][C:2]1[CH:3]=[C:4]([S:9][CH2:10][CH:11]([CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[C:12]([OH:14])=[O:13])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)CCC(CSc1ccc(Cl)c(Cl)c1)C(=O)O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC(=O)CCC(CSc1ccc(Cl)c(Cl)c1)C(=O)O
Temperature: 40 °C
Reaction time: 2.5 h
Yield: 1656.8 %

Procedure:
A mixture of 2-(3,4-dichlorophenylthiomethyl)glutaric acid (3.00 g), methanol (30 ml), and p-toluenesulfonic acid (0.09 g) was stirred at 40° C. for 2.5 hours. The reaction mixture was concentrated in vacuo, and the resulting residue was purified by flash column chromatography on silica by eluting with chloroform/ethanol (10:1) to give 2.92 g of 3-(3,4-dichlorophenylthio)-2-(2-methoxycarbonylethyl)propionic acid as an oil.
Reaction SMILES: NC1SC=C(C(=O)C(N[C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[N:30]4[N:31]=[C:32]([C:34](=[O:36])[NH2:35])[N:33]=[C:29]4[N:28]=[C:27]([CH3:37])[CH:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=O)N=1.NOC(C)(C)C(NNC(C1NC=C(O)C(=O)C=1)=O)=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(N(C)C)=O>[C:34]([C:32]1[N:33]=[C:29]2[N:28]=[C:27]([CH3:37])[CH:26]=[C:25]([S:24][CH2:23][C:15]3[CH2:14][S:13][CH:12]4[N:17]([C:18](=[O:19])[CH2:11]4)[C:16]=3[C:20]([OH:22])=[O:21])[N:30]2[N:31]=1)(=[O:36])[NH2:35]
Reactant: Cc1cc(SCC2=C(C(=O)O)N3C(=O)[C@@H](NC(=O)C(=O)c4csc(N)n4)[C@H]3SC2)n2nc(C(N)=O)nc2n1
Agent: CC(C)(ON)C(=O)NNC(=O)c1cc(=O)c(O)c[nH]1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1cc(SCC2=C(C(=O)O)N3C(=O)CC3SC2)n2nc(C(N)=O)nc2n1
Reaction time: 0.25 h

Procedure:
0.228 g (0.4 mmol) of (6R,7R)-7-(2-amino-4-thiazoleglyoxylamido)-3-[[(2-carbamoyl -5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo [4.2.0]oct-2-ene-2-carboxylic acid was dissolved in 2 ml of dimethylacetamide. 0.140 g (0.52 mmol) of 1-[2-(aminooxy)-2-methylpropionyl]-2-[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridyl) carbonyl]hydrazine and 0.100 g (0.52 mmol) of p-toluenesulfonic acid hydrate were added. After stirring for 20 hours at room temperature the dimethylacetamide was evaporated off at strongly reduced pressure and the residue was taken up in water and stirred for 15 minutes in order to completely precipitate the product. The product was filtered off, washed well with water and dried under strongly reduced pressure at room temperature. (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[1,4-dihydro-5-hydroxy -4-oxo-2-pyridyl)carbonyl]carbazoyl]-1-methylethoxy]imino] -acetamido]-3-[[[2-carbamoyl-5-methyl-s-triazolo[1,5-a]-pyrimidin-7-yl) thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid was obtained as beige-colored powder.
Reaction SMILES: C(NC(C)C)(C)C.[C:8]12([CH3:18])[C:15]([CH3:17])([CH3:16])[CH:12]([CH2:13][CH2:14]1)[CH2:11][C:9]2=[O:10].[CH:19](=[O:21])[CH3:20].C(=O)([O-])O.[Na+]>C1COCC1.CCCCCC>[OH:21][CH:19]([CH:11]1[CH:12]2[C:15]([CH3:17])([CH3:16])[C:8]([CH3:18])([CH2:14][CH2:13]2)[C:9]1=[O:10])[CH3:20]
Reactant: CC=O
Reactant: CC12CCC(CC1=O)C2(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(O)C1C(=O)C2(C)CCC1C2(C)C
Reaction time: 0.25 h
Yield: 80.1 %

Procedure:
2.50 ml of 2.5 M n-butylithium hexane solution was added dropwise a tetrahydrofuran solution comprising 4 ml THF and 1.00 ml diisopropylamine at -78° C. and the mixture was stirred for 15 minutes. Then, a THF solution comprising 4 ml THF and 0.91 g camphor was added dropwise to the above solution at -78° C., then the solution was further admixed with 0.27 g of acetaldehyde and stirred for 15 minutes. This reaction solution was admixed with 50 ml of a saturated sodium hydrogen carbonate aqueous solution and restored to room temperature. The reaction product was extracted with diethylether. The organic layer was washed with saturated brine, dried with anhydrous sodium sulfate and then the solvent was removed under a vacuum. The residue was purified by means of silica gel column chromatography (eluent: hexane/ethylacetate=8/2) and 0.94 g of 3-(1-hydroxyethyl)-camphor was obtained (yield: 80%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]([CH3:18])[C:10](=[O:19])[NH:9]2)=[CH:4][CH:3]=1.[Cl:20][CH2:21][C:22](Cl)=[O:23].C(N(CC)CC)C>C(O)(=O)C>[Cl:20][CH2:21][C:22]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]([CH3:18])[C:10](=[O:19])[NH:9]2)=[CH:6][CH:7]=1)=[O:23]
Reactant: CC1C(=O)NC(c2ccc(N)cc2)c2ccccc21
Reactant: O=C(Cl)CCl
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: CC1C(=O)NC(c2ccc(NC(=O)CCl)cc2)c2ccccc21

Procedure:
9.75 g. (0.0386 moles) of 1-(4'-aminophenyl)-1,4-dihydro-4-methyl-3(2H)-isoquinolinone are reacted, in 80 ml. of glacial acetic acid, with 5.64 g. (0.05 moles) of chloroacetyl chloride, in the presence of 5.06 g. (0.05 moles) of triethylamine. The reaction conditions are the same as described in Example 1. The crude product is recrystallized from butanol to yield 4.9 g. of the title compound; m.p. 238°-239°C.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CCCCCC.C([O:26][B:27]([O:32]C(C)C)[O:28]C(C)C)(C)C.Cl>C(OCC)C>[C:2]1([O:26][B:27]([OH:32])[OH:28])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Brc1cccc2ccccc12
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: OB(O)Oc1cccc2ccccc12
Temperature: -40 °C
Reaction time: 6 h

Procedure:
To one liter egg-plant type flask were added 55 g (0.27 mmol) of 1-bromonaphthalene and 300 ml of diethyl ether. The mixture was cooled to −70° C. on a dry ice/methanol bath, to which 170 ml (0.27 mmol) of a n-butyllithium/hexane solution (1.56 mol/l) was added dropwise. After addition was completed, the mixture was stirred for 6 hours while it was gradually brought to room temperature. The mixture was further cooled to −40° C. and to this were added dropwise 70 ml (0.30 mmol) of triisopropylborate and 100 ml of diethyl ether, and stirred overnight. To the reaction solution was added 200 ml of 2 N hydrochloric acid to cause hydrolysis. Diethyl ether (200 ml) was added to the reaction solution, which was washed with brine until it turned neutral. After drying over anhydrous sulfate, the solvent was distilled off under reduced pressure to give light yellow crystals of naphthyl boric acid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:22]=[C:23]([CH3:34])[C:24]=1[N:25]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[N:26]1)[O:5][CH:6]([CH:16]1[CH2:19][C:18]([CH3:21])([CH3:20])[CH2:17]1)[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1.Cl.[NH2:36][CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>O1CCCC1>[CH3:1][C:2]1[CH:3]=[C:4]([CH:22]=[C:23]([CH3:34])[C:24]=1[N:25]1[CH:29]=[C:28]([C:30]([F:32])([F:31])[F:33])[CH:27]=[N:26]1)[O:5][CH:6]([CH:16]1[CH2:19][C:18]([CH3:21])([CH3:20])[CH2:17]1)[C:7]1[CH:15]=[CH:14][C:10]([C:11]([NH:36][CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[O:13])=[CH:9][CH:8]=1
Reactant: CCOC(=O)CCN
Reactant: Cc1cc(OC(c2ccc(C(=O)O)cc2)C2CC(C)(C)C2)cc(C)c1-n1cc(C(F)(F)F)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)CCNC(=O)c1ccc(C(Oc2cc(C)c(-n3cc(C(F)(F)F)cn3)c(C)c2)C2CC(C)(C)C2)cc1
Reaction time: 1 h
Yield: 80.2 %

Procedure:
Tetrahydrofuran (1.2 mL) was added to a vial containing 4-((3,5-dimethyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenoxy)(3,3-dim ethylcyclobutyl)methyl)benzoic acid (115 mg, 0.240 mmol), ethyl 3-aminopropanoate hydrochloride (74.7 mg, 0.490 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (185 mg, 0.490 mmol). Diisopropylethylamine (0.210 mL, 1.22 mmol) was then added. The reaction was stirred for 1 h, and was then concentrated. Purification by column chromatography (0-50% ethyl acetate in heptane) afforded ethyl 3-(4-((3,5-dimethyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenoxy)(3,3-dimethylcyclobutyl)methyl)benzamido)propanoate (110 mg, 39% yield) as an oil. 1H NMR (400 MHz, CDCl3) δ 7.87 (s, 1H), 7.71 (d, J=8.6 Hz, 2H), 7.64 (s, 1H), 7.36 (d, J=8.2 Hz, 2H), 6.81 (t, J=4.8 Hz, 1H), 6.57 (s, 2H), 5.00 (d, J=6.8 Hz, 1H), 4.17 (q, J=7.2 Hz, 2H), 3.71 (q, J=6.1 Hz, 2H), 2.57-2.74 (m, 3H), 1.87-1.92 (m, 7H), 1.80-1.87 (m, 1H), 1.72-1.80 (m, 1H), 1.59-1.68 (m, 1H), 1.21-1.35 (m, 3H), 1.13 (s, 3H), 1.10 (s, 3H). MS (M+1): 572.3.
Reaction SMILES: C(O)=O.C([O:8][C:9](=[O:46])[CH2:10][O:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=1)[C:16]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:15]2[C:35]1[CH:40]=[CH:39][C:38]([O:41][CH2:42][CH:43]2[CH2:45][CH2:44]2)=[CH:37][CH:36]=1)(C)(C)C>ClCCl>[CH:43]1([CH2:42][O:41][C:38]2[CH:37]=[CH:36][C:35]([C:15]3[C:14]4[C:18](=[CH:19][CH:20]=[C:12]([O:11][CH2:10][C:9]([OH:46])=[O:8])[CH:13]=4)[N:17]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C:16]=3[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:40][CH:39]=2)[CH2:44][CH2:45]1
Reactant: CCOC(=O)c1c(-c2ccc(OCC3CC3)cc2)c2cc(OCC(=O)OC(C)(C)C)ccc2n1Cc1cccc(OC)c1
Solvent: O=CO
Solvent: ClCCl
Product: CCOC(=O)c1c(-c2ccc(OCC3CC3)cc2)c2cc(OCC(=O)O)ccc2n1Cc1cccc(OC)c1
Reaction time: 1 h
Yield: 53 %

Procedure:
Formic acid (1 mL) was added to a stirred solution of ethyl 5-(2-tert-butoxy-2-oxoethoxy)-3-[4-(cyclopropylmethoxy)phenyl]-1-(3-methoxybenzyl)-1H-indole-2-carboxylate (Example 150, 20 mg, 0.035 mmol) in dichloromethane (1 mL). The reaction was stirred for 1 h and then concentrated in vacuo. Flash chromatography of the residue over silica gel using (1:1 ethyl acetate/hexane) gave 10 mg (53% of the desired product. The product had: 1H NMR (300 MHz, CD3OD) δ 7.30-7.48 (m, 3 H), 6.92-7.19 (m, 4 H), 6.77 (dd, 1 H), 6.54-6.68 (m, 3 H), 5.79 (s, 2 H), 4.61 (s, 2 H), 4.13 (q, 2 H), 3.95 (d, 2 H), 3.74 (s, 3 H), 1.29-1.41 (m, 1 H), 1.25 (t, 3 H), 0.61-0.71 (m, 2 H), 0.39-0.49 (m, 2 H); mass spectroscopy gave MH+ of 530.2 (calc'd exact mass for C31H31NO7=529.21).
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][S:10][C:6]=2[CH2:5][CH2:4][CH:3]1[C:11]([O:13][CH3:14])=[O:12].[Br:15]Br.O>CCOCC.C(Cl)(Cl)(Cl)Cl>[Br:15][C:3]1([C:11]([O:13][CH3:14])=[O:12])[C:2](=[O:1])[C:7]2[CH:8]=[CH:9][S:10][C:6]=2[CH2:5][CH2:4]1
Reactant: BrBr
Reactant: COC(=O)C1CCc2sccc2C1=O
Solvent: CCOCC
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: COC(=O)C1(Br)CCc2sccc2C1=O
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 99.7 %

Procedure:
Methyl 4-oxo4,5,6,7-tetrahydro-1-benzothiophene-5-carboxylate (Preparation 11, 3.50 g) is dissolved in anhydrous ether (30 mL) and carbon tetrachloride (20 mL). This solution is cooled to −10° C. and a solution of bromine (2.66 g) in carbon tetrachloride (5 mL) with 3 drops of ether. Each drop of the bromine solution is added only after the orange color dissipated from the prior drop. After completion of addition, the solution is allowed to stir for 15 minutes at −10° C., 15 minutes at 0° C., and then overnight at rt. This reaction mixture is poured into water (100 mL) and extracted with ether (100 mL). The ether phase is washed with brine, dried over Na2SO4, filtered, and concentrated to give 4.80 g (99%) of the title compound as a yellow oil. Physical characteristics: MS (ESI+) m/z 289.0/291.0 (M+H)+.