Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:7]=[C:6](C(O)=O)[N:5]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:4]=1>[Cu]=O.CN(C)C=O>[Cl:2][C:3]1[CH:7]=[CH:6][N:5]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:4]=1
Reactant: O=C(O)c1cc(Cl)nn1-c1cccnc1
Agent: O=[Cu]
Agent: Cl
Solvent: CN(C)C=O
Product: Clc1ccn(-c2cccnc2)n1

Procedure:
In step e of Scheme 4, 3-chloro-1-(pyridin-3-yl)-1H-pyrazole-5-carboxylic acid hydrochloride (6e) is decarboxylated in the presence of copper (II) oxide in polar solvents such as N,N-dimethylformamide at temperatures from about 80° C. to about 140° C. to yield 3-(3-chloro-1H-pyrazol-1-yl)pyridine (5b). It was surprisingly discovered that this decarboxylation only occurs in the presence of copper (II) oxide. Several known decarboxylation agents from the literature such as, for example, hydrochloric acid (See alternate synthetic route, Example 14), sulfuric acid, and palladium (II) trifluoroacetate/trifluoroacetic acid (See “CE-5”) did not yield the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([CH2:9][CH3:10])[CH:6]=[CH:5][C:3]=1[NH2:4].O[CH2:12][CH:13]([CH2:15]O)O>>[CH2:9]([C:7]1[CH:6]=[C:5]2[C:3](=[C:2]([Br:1])[CH:8]=1)[N:4]=[CH:15][CH:13]=[CH:12]2)[CH3:10]
Reactant: CCc1ccc(N)c(Br)c1
Reactant: OCC(O)CO
Product: CCc1cc(Br)c2ncccc2c1

Procedure:
2-bromo-4-ethylaniline and glycerol can be combined to form 6-ethyl-8-bromoquinoline,
Reaction SMILES: [NH2:1][C:2]1[C:11]([Cl:12])=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[C:4]([O:13][CH:14]([C:16]#[C:17][CH3:18])[CH3:15])[CH:3]=1.O.Cl>CO>[NH2:1][C:2]1[C:11]([Cl:12])=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:13][CH:14]([C:16]#[C:17][CH3:18])[CH3:15])[CH:3]=1
Reactant: CC#CC(C)Oc1cc(N)c(Cl)cc1C(=O)OC
Agent: Cl
Solvent: O
Solvent: CO
Product: CC#CC(C)Oc1cc(N)c(Cl)cc1C(=O)O
Temperature: 50 °C
Reaction time: 6 h
Yield: 97 %

Procedure:
To the suspension of methyl 4-amino-5-chloro-2-{(3-pentyn-2-yl)oxy}benzoate (56.0 g) in methanol (1.3 l) aqueous sodium hydroxide (SN) solution (140 ml) was added. -The resultant mixture was stirred for 6 hours at 50° C., and then 3 days at room temperature. To the obtained mixture, water (1 l) was added, followed by acidification with 2N hydrochloric acid. Crystal thus precipitated was recovered by filtration, washed with water and dried to obtain 51.5 g of the title compound as colorless crystal.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH3:12]>>[NH2:12][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Reactant: N
Product: Nc1nc(Cl)ccc1C(=O)O
Temperature: 135 °C
Reaction time: 10 h
Yield: 49 %

Procedure:
A mixture of 2,6-dichloro-nicotinic acid (31 g, 0.14 mol) and 28% aqueous ammonia solution (200 mL) was stirred in a sealed tube for 10 hours at 135° C. This reaction solution was cooled to room temperature, and the excess ammonia gas was removed under a reduced pressure. Water was added to the residue to a total of 1000 mL, the mixture was cooled to 0° C., and citric acid was added to a pH being about 6. The precipitated solids were filtered out to obtain the title compound (12 g, 49%).
Reaction SMILES: Cl.[CH:2]([C:5]1[S:6][CH:7]=[C:8]([C:10]([N:12]2[CH2:17][C:16]3([CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[O:15][CH2:14][CH2:13]2)=[O:11])[N:9]=1)([CH3:4])[CH3:3].Br[CH2:24][CH2:25][C:26]1[CH:27]=[C:28]([CH2:32][CH2:33][OH:34])[CH:29]=[CH:30][CH:31]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C.CCOC(C)=O>[OH:34][CH2:33][CH2:32][C:28]1[CH:27]=[C:26]([CH:31]=[CH:30][CH:29]=1)[CH2:25][CH2:24][N:20]1[CH2:19][CH2:18][C:16]2([O:15][CH2:14][CH2:13][N:12]([C:10]([C:8]3[N:9]=[C:5]([CH:2]([CH3:4])[CH3:3])[S:6][CH:7]=3)=[O:11])[CH2:17]2)[CH2:22][CH2:21]1
Reactant: OCCc1cccc(CCBr)c1
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(CCc4cccc(CCO)c4)CC3)C2)cs1
Temperature: 60 °C
Reaction time: 66 h
Yield: 88 %

Procedure:
To a suspension of (2-isopropylthiazol-4-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone hydrochloride in a solution of 2-(3-(2-bromoethyl)phenyl)ethanol (1.15 molar equivalents) in acetonitrile (10 volumes) at room temp was added potassium carbonate (4 molar equivalents) followed by water (0.167 volumes. The mixture was stirred at 60° C. for 66 hours, cooled to room temp, filtered, washed with MeCN and concentrated in vacuo to leave a crude orange gum. This gum was dissolved in EtOAc (3 volumes) and washed with 2N HCl (1.1 molar equivalents). The aqueous layer was basified using 2N NaOH (1.5 molar equivalents) and extracted with TBME (2×2 volumes) [an oil appeared at the interface which would not dissolve in TBME]. The combined organics and oil were diluted with EtOAc (1 volume) [oil dissolved], dried (Na2SO4), filtered and concentrated in vacuo to leave an orange gum. Yield: 88% of theoretical.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[S:9][C:10](Br)=[CH:11][C:12]=1[NH:13][S:14]([C:17]1[C:18]([CH3:23])=[CH:19][CH:20]=[CH:21][CH:22]=1)(=[O:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[S:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[CH:27]=[C:26]1B(O)O.C1(C)C(S(NC2C=C(C3C=CC(C)=CC=3)SC=2C(O)=O)(=O)=O)=CC=CC=1>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>[C:1]([O:5][C:6]([C:8]1[S:9][C:10]([C:26]2[S:25][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[CH:27]=2)=[CH:11][C:12]=1[NH:13][S:14]([C:17]1[C:18]([CH3:23])=[CH:19][CH:20]=[CH:21][CH:22]=1)(=[O:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccccc1S(=O)(=O)Nc1cc(Br)sc1C(=O)OC(C)(C)C
Reactant: OB(O)c1cc2ccccc2s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1ccc(-c2cc(NS(=O)(=O)c3ccccc3C)c(C(=O)O)s2)cc1
Product: Cc1ccccc1S(=O)(=O)Nc1cc(-c2cc3ccccc3s2)sc1C(=O)OC(C)(C)C
Yield: 55.6 %

Procedure:
Suzuki coupling of 5-Bromo-3-(toluene-2-sulfonylamino)-thiophene-2-carboxylic acid tert-butyl ester (43 mg, 0.1 mmol) and bezothiophene-2-boronic acid (53.4 mg, 0.3 mmol) was carried out using Pd(PPh3)4 and Na2CO3 (as described in example 2) resulted in 5-Benzo[b]thiophen-2-yl-3-(toluene-2-sulfonylamino)-thiophene-2-carboxylic acid tert-butyl ester (27 mg, 55% yield). 1H NMR (CDCl3, 400 MHz) 9.92 (s, 1H), 8.07 (d, J=7.8 Hz, 1H), 7.79-7.71 (m, 2H), 7.45-7.24 (m, 7H), 2.7 (s, 3H), 1.56 (s, 9H).
Reaction SMILES: [F:1][C:2]([F:11])([CH:5]([F:10])[C:6]([F:9])([F:8])[F:7])[CH2:3][OH:4].[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](O)=[O:24]>CS(O)(=O)=O.C1C=CC=CC=1>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:4][CH2:3][C:2]([F:11])([F:1])[CH:5]([F:10])[C:6]([F:9])([F:7])[F:8])=[O:24]
Reactant: OCC(F)(F)C(F)C(F)(F)F
Reactant: O=C(O)CCCCCCCCCCBr
Agent: CS(=O)(=O)O
Solvent: c1ccccc1
Product: O=C(CCCCCCCCCCBr)OCC(F)(F)C(F)C(F)(F)F

Procedure:
The process of producing the surfactant of claim 1 comprising (a) reacting at reflux 2,2,3,4,4,4-hexafluorobutanol and 11-bromoundecanoic acid in presence of methane sulfonic acid as a catalyst and benzene as a solvent to obtain 2,2,3,4,4,4-hexafluorobutyl 11-bromoundecylate and then (b) reacting at reflux 2,2,3,4,4,4-hexafluorobutyl 11-bromoundecylate with pyridine in presence of methanol as a solvent to obtain 2,2,3,4,4,4-hexafluorobutyl 11-pyridylundecylate bromide.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:6][CH:5]=1)([O-])=O.[NH4+].[Cl-].CC1C=CC([N+]([O-])=O)=CC=1O>C(O)C.O>[NH2:1][C:4]1[CH:17]=[CH:16][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(OCc2ccccn2)cc1
Agent: Cc1ccc([N+](=O)[O-])cc1O
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1ccc(OCc2ccccn2)cc1
Temperature: 75 °C
Reaction time: 2 h
Yield: 86.6 %

Procedure:
2-[(4-Nitrophenoxy)methyl]pyridine (2.30 g, 10 mmol) was dissolved in ethanol (160 mL) and water (40 mL). NH4Cl (5.30 g) was added to the above mixture and heated to 70-80° C. To this reaction mixture was added iron powder (5:50 g) in portion wise manner under a vigorous stirring and the stirring was continued for 2 h. The reaction mixture was filtered through a Celite pad when hot and washed the filter bed with MeOH. The filtrate was concentrated, diluted with water, extracted with CH2Cl2 (3×75 mL), dried and concentrated to provide 2-[(4-aminophenoxy)methyl]pyridine as brown solid (1.735 g) in 86% yield. 1H NMR (CDCl3): δ 8.56 (m, 1H), 7.67 (m, 1H), 7.49 (d, 1H, J=7.8 Hz), 7.18 (m, 1H), 6.80 (d, 2H, J=8.7 Hz), 6.62 (d, 2H, J=8.7 Hz), 5.12 (s, 2H), 3.43 (br s, 2H); LCMS (m/z): 201 (MH+).
Reaction SMILES: [C:1]1(=[O:6])[CH2:5][CH2:4][CH:3]=[CH:2]1.[C:7]([O:13][CH3:14])(=[O:12])[CH2:8][C:9]([CH3:11])=[O:10]>C1(C)C=CC=CC=1>[C:9]([CH:8]([C:7]([O:13][CH3:14])=[O:12])[CH:3]1[CH2:4][CH2:5][C:1](=[O:6])[CH2:2]1)(=[O:10])[CH3:11]
Reactant: COC(=O)CC(C)=O
Reactant: O=C1C=CCC1
Solvent: Cc1ccccc1
Product: COC(=O)C(C(C)=O)C1CCC(=O)C1
Temperature: 40 °C
Reaction time: 24 h
Yield: 98.9 %

Procedure:
Under an atmosphere of argon, 12.6 mg (0.02 mmol, S/C=50) of Ru[(S,S)-Tsdpen] (hexamethylbenzene), 84 μL (1.0 mmol) of 2-cyclopentenone, 108 μL (1.0 mmol) of methyl acetoacetate, and 1 mL of dry toluene were placed in a 20 mL Schlenk tube and stirred at 40° C. for 24 hours. This solution was purified by flash column chromatography (hexane/acetone=90/10, SiO2) to give 196 mg (99% yield) of the title compound. The optical rotation [α]D25 was +83.5 (c 1.35, CHCl3). The percentage diastereomeric excess and the percentage enantiomeric excess were measured by 1H NMR and HPLC (CHIRALCEL OD manufactured by Daicel Chemical Industries, Ltd., hexane:2-propanol=80:20, flow rate 1.0 mL/min, detection at 210 nm), and the results were that the product was a 1:1 diastereomeric mixture and each diastereomer was present in 91% ee.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[C:9](Cl)(=[O:13])[CH2:10][CH2:11][CH3:12]>[OH-].[Na+].O>[C:5]([OH:13])(=[O:6])[CH2:7][CH2:8][CH3:1].[C:9]([OH:13])(=[O:2])[CH2:10][CH2:11][CH3:12].[C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2]
Reactant: CCCC(=O)Cl
Agent: Oc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCC(=O)O
Reaction time: 4 h

Procedure:
Hydroquinone (55 g) was dissolved in a solution of sodium hydroxide (40 g) in water (300 ml) and to the resulting solution was added dropwise butyryl chloride (100 g), while maintaining the temperature at 3° to 6° C. The reaction was allowed to proceed at 10° to 13° C. for 4 hours. After reaction, the mixture was extracted with benzene and the benzene extract was washed with dil. sodium hydroxide solution. The solvent was removed from the extract and the residue was dissolved in ethanol (300 ml). Recrystallization was effected by addition of water (80 ml) to the solution to give hydroquinone dibutyrate (108 g). m.p. 42°-43° C.
Reaction SMILES: [CH2:1]([N:4]([C@@H:17]1[CH2:26][CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][C:23]=2[OH:27])[CH2:18]1)[CH2:5][CH2:6][C@H:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=O)[O:8]1)[CH2:2][CH3:3].CCOC(C)=O.Cl>C1COCC1>[CH:7]1([CH2:6][CH2:5][N:4]([CH2:1][CH2:2][CH3:3])[CH:17]2[CH2:26][CH2:25][C:24]3[C:23]([OH:27])=[CH:22][CH:21]=[CH:20][C:19]=3[CH2:18]2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][O:8]1
Reactant: CCCN(CC[C@@H]1OC(=O)c2ccccc21)[C@@H]1CCc2c(O)cccc2C1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCN(CCC1OCc2ccccc21)C1CCc2c(O)cccc2C1

Procedure:
A racemic mixture of the product of Example 36 (66 mg, 0.180 mmol) was dissolved in THF and added dropwise to a solution of BH3 in THF (2 mL) and the mixture was refluxed overnight. After workup the crude mixture was subjected to flash chromatography (Silica: EtOAc) and the product showed characteristic peaks at: NMR (300 MHz, CDCl3) δ7.3-6.5(m, 7H), 5.4-5.0(m, 3H), 0.9(t, 3H). Anal. calc. for C22H29NO2. HCl: Theor. C; 71.21; H; 7.79; N, 3.61. Observed: C, 71.16, H, 7.61; N, 3.55.
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[C:6]([F:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[F:12].[CH2:13]([O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][C:31]([C:34](O)=[O:35])=[CH:30][CH:29]=2)=[CH:24][CH:23]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)(=O)C>[CH2:13]([O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([O:8][C:7]3[C:2]([F:1])=[C:3]([F:12])[C:4]([F:11])=[C:5]([F:10])[C:6]=3[F:9])=[O:35])=[CH:30][CH:29]=2)=[CH:24][CH:23]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: CCCCCCCCOc1ccc(-c2ccc(C(=O)O)cc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Product: CCCCCCCCOc1ccc(-c2ccc(C(=O)Oc3c(F)c(F)c(F)c(F)c3F)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Pentafluorophenol (11.5 mmol) is added at 0° C. to a mixture of 10.5 mmol 4'-n-octyloxy-[1,1'-biphenyl]-4-ylcarboxylic acid and 10.5 mmol of dicyclohexylcarbodiimide in ethyl acetate. The mixture is stirred at 25° C. for a period of 18 hours whereupon a precipitate is formed. The reaction mixture is filtered, the filtrate washed with water and brine and dried, the solvent removed in vacuo to obtain pentafluorophenyl 4'-n-octyloxy[1,1'-biphenyl]-4-ylcarboxylate, C27H25F5O3, M.W. 492.5.
Reaction SMILES: N[C@@H](CC(C)C)C(C1C=CC=CC=1)(C1C=CC=CC=1)O.B.O1CCCC1.[Cl:27][C:28]1[CH:33]=[CH:32][C:31](/[CH:34]=[C:35](/[N:42]2[CH:46]=[N:45][CH:44]=[N:43]2)\[C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:30][CH:29]=1>C(Cl)(Cl)Cl>[Cl:27][C:28]1[CH:33]=[CH:32][C:31](/[CH:34]=[C:35](/[N:42]2[CH:46]=[N:45][CH:44]=[N:43]2)\[CH:36]([OH:41])[C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:30][CH:29]=1
Reactant: CC(C)(C)C(=O)/C(=C\c1ccc(Cl)cc1)n1cncn1
Agent: B
Agent: CC(C)C[C@H](N)C(O)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CC(C)(C)C(O)/C(=C\c1ccc(Cl)cc1)n1cncn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 98.6 %

Procedure:
In a nitrogen atmosphere, 3.5 ml of a chloroform solution containing 0.233 g (0.86 mmole) of (S)-2-amino-1,1-diphenyl-4-methylpentan-1-ol was added at -60° C. to 0.87 ml (0.87 mmole) of a 1.0M borane-tetrahydrofuran solution, and the temperature of the resulting solution was raised to room temperature over 2 hours. Thereafter, 2 ml of a chloroform solution containing 0.164 g (0.57 mmole) of (E)-1-(4-chlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-one was added to this solution at room temperature, and stirring was carried out for 24 hours. After-treatment was carried out in the same manner as in Example 1 to obtain 0.164 g of (+)-(E)-1-(4-chlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-ol. The conversion was 87.0%, and the composition of the product was: E-form alcohol, 97.3% and Z-form alcohol, 2.7%. The enantiomer ratio of the E-form alcohol was: (+)-isomer, 87.2% and (-)-isomer 12.8%.
Reaction SMILES: [CH3:1][C:2]1([O:5][CH2:6][CH2:7][OH:8])[CH2:4][CH2:3]1.[OH-].[Na+].[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>O1CCCC1>[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([O:8][CH2:7][CH2:6][O:5][C:2]2([CH3:1])[CH2:4][CH2:3]2)(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: CC1(OCCO)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)OCCOC2(C)CC2)cc1
Temperature: 2.5 °C
Reaction time: 3 h

Procedure:
To the crude 2-(1-methylcyclopropoxy)ethanol from the previous step (0.32 g) in a mixture of 4.6N sodium hydroxide (6.3 mL, 2.52 mmol) and tetrahydrofuran (3 mL) was added 4-methylbenzene-1-sulfonyl chloride (2.1 g, 11.2 mmol) dichloromethane (6 mL) at 0-5° C. The solution was stirred for 3 h at 0-5° C., and then extracted with dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, and concentrated to obtain crude product (100 mg), which was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:19])[C:5]([C:8]2([OH:18])[CH2:17][CH2:16][C:11]3(OCC[O:12]3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.C(=O)([O-])O.[Na+]>Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH3:19])[C:5]([C:8]2([OH:18])[CH2:9][CH2:10][C:11](=[O:12])[CH2:16][CH2:17]2)=[N:6][CH:7]=1
Reactant: Cc1cc(Br)cnc1C1(O)CCC2(CC1)OCCO2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(Br)cnc1C1(O)CCC(=O)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.1 %

Procedure:
To 8-(5-bromo-3-methylpyridin-2-yl)-1,4-dioxaspiro[4.5]decan-8-ol (23.2 g) described in Reference Example 105 (1) was added 3 N hydrochloric acid aqueous solution (140 ml), and stirred at room temperature for 16 hours. After completion of the reaction, a saturated aqueous solution of sodium hydrogen carbonate was added thereto, the precipitated solid was collected by filtration, and then washed with ethanol to give 4-(5-bromo-3-methylpyridin-2-yl)-4-hydroxycyclohexanone (18.3 g) as a pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.Br[C:10]([CH3:19])([CH3:18])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].[OH-].[K+]>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:10]([CH3:19])([CH3:18])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:4][CH:3]=1
Reactant: Sc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)C(C)(C)Sc1ccc(Br)cc1

Procedure:
4-Bromothiophenol (100 g) and tert-butyl 2-bromoisobutyrate (118 g) are dissolved in 1 l of ethanol and treated with 29 g of KOH. The mixture is stirred under reflux for 2 h and cooled, and the KBr is filtered off. The filtrate is concentrated and the residue is recrystallized from n-hexane. This gives 93.6 g of a colourless solid.
Reaction SMILES: C(OC([N:8]([C:26]1[CH:30]=[C:29]([CH3:31])[N:28](C(OC(C)(C)C)=O)[N:27]=1)[C:9]1[C:18]2[C:13](=[CH:14][C:15]([C:19]([OH:21])=[O:20])=[CH:16][CH:17]=2)[C:12](=[O:22])[N:11]([CH:23]([CH3:25])[CH3:24])[N:10]=1)=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH:23]([N:11]1[C:12](=[O:22])[C:13]2[C:18](=[CH:17][CH:16]=[C:15]([C:19]([OH:21])=[O:20])[CH:14]=2)[C:9]([NH:8][C:26]2[CH:30]=[C:29]([CH3:31])[NH:28][N:27]=2)=[N:10]1)([CH3:25])[CH3:24]
Reactant: Cc1cc(N(C(=O)OC(C)(C)C)c2nn(C(C)C)c(=O)c3cc(C(=O)O)ccc23)nn1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(Nc2nn(C(C)C)c(=O)c3cc(C(=O)O)ccc23)n[nH]1
Reaction time: 48 h

Procedure:
1-[tert-Butoxycarbonyl-(1-tert-butoxycarbonyl-5-methyl-1H-pyrazol-3-yl)-amino]-3-isopropyl-4-oxo-3,4-dihydro-phthalazine-6-carboxylic acid (13.0 mg, 0.02 mmol) was dissolved in a 20% TFA/DCM solution (2 ml) and the reaction mixture was stirred for 48 hours. After this time, the reaction mixture was concentrated and the resulting residue was triturated with diethyl ether to give the title compound (Example M-1) as a white solid. 1H-NMR: (400 MHz, D6- DMSO), 9.34(1H, s), 8.73 (1H, s), 8.47 (1H, d), 8.26 (1H, d), 6.28 (1H, s), 5.20-5.17 (1H, m), 2.19 (3H, s), 1.26 (6H, d) MS (ESI+)=(M+H)+ 328.31.
Reaction SMILES: C([N:8]([C@@H:10]([C:20]#[CH:21])[CH2:11][O:12][Si](C(C)(C)C)(C)C)[CH3:9])(OC(C)(C)C)=O.[F:22][C:23]1[C:24](I)=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27](=[O:32])/[C:26]/2=[CH:33]\[C:34]1[NH:35][CH:36]=[CH:37][C:38]=1[O:39][CH3:40]>CN(C=O)C.CCN(CC)CC.CCOC(C)=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>[F:22][C:23]1[C:24]([C:21]#[C:20][C@H:10]([NH:8][CH3:9])[CH2:11][OH:12])=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27](=[O:32])/[C:26]/2=[CH:33]\[C:34]1[NH:35][CH:36]=[CH:37][C:38]=1[O:39][CH3:40]
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Reactant: C#C[C@@H](CO[Si](C)(C)C(C)(C)C)N(C)C(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN[C@@H](C#Cc1c(F)ccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2)CO
Reaction time: 2 h

Procedure:
Using Method C above, (S)-2-(N-Boc-N-methylamino)-1-(tert-butyldimethylsilyloxy)-but-3-yne (190 mg, 0.61 mmol) (Example 115C above) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (80 mg, 0.21 mmol) (Starting Material 6) using (Ph3P)4Pd (24 mg, 0.02 mmol) and a catalytic amount of Cul in a mixture of DMF (5 mL) and Et3N (5 mL) as solvent at 80 IC for 5.5 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with H2O. The organic layer was dried over Na2SO4, concentrated and the residue was chromatographed on a silica gel column with a 40-100% EtOAc in hexanes gradient. The resulting intermediate was dissolved directly in 6 mL of a 50% trifluoroacetic acid in CH2Cl2 solution that contained 0.5 mL of H2O at 0 °C. and stirred for 2 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with ammonium hydroxide. The organic layer was dried over Na2SO4 and concentrated. (S)-(Z)-1,3-Dihydro-5-fluoro-4-[3-methylamino-4-hydroxy-1-butynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one was obtained after silica gel column chromatography with a 0-10% MeOH in CH2Cl2 gradient and precipitation out of THF with excess of pentane. (Yield 32 mg, 42%).
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[O-2].[Zn+2:22]>C(O)(=O)C>[C:1]([O-:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[Zn+2:22].[C:1]([O-:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Agent: [O-2]
Agent: [Zn+2]
Solvent: CC(=O)O
Product: CCCCCCCCCCCCCCCCCC(=O)[O-]
Reaction time: 0.08 h

Procedure:
118.1 g of stearic acid and 36.3 g of zinc oxide were stirred at 45° C., and 1.5% of 30% acetic acid was added. During stirring, caking initially occurred on the walls of the reactor, but could be removed. After 5 minutes, the mixture was readily stirrable. A dusty, whitish, slightly voluminous powder having a zinc content of 18.8%, a melting temperature of 128° C., and an acid value of 4.1 was obtained after 10 minutes.