Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:20]([CH3:21])=[C:19]([F:22])[C:18]([F:23])=[CH:17][C:3]=1[C:4]([CH:6](C(OCC)=O)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[F:1][C:2]1[C:20]([CH3:21])=[C:19]([F:22])[C:18]([F:23])=[CH:17][C:3]=1[C:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)c1cc(F)c(F)c(C)c1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCOC(=O)CC(=O)c1cc(F)c(F)c(C)c1F
Reaction time: 48 h
Yield: 8 %

Procedure:
A mixture of diethyl 2-(2,4,5-trifluoro-3-methylbenzoyl)malonate (8.10 g) and p-toluenesulfonic acid (9.6 mg) in water (9.6 ml) was refluxed for 3 hours with stirring vigorously. After cooling, the reacting mixture was extracted with dichloromethane. The organic layer was washed with 7% aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was allowed to stand in a refrigerator for 2 days, the resulting precipitate was collected by filtration and recrystallized from n-hexane to give the title compound (0.51 g) as colorless prisms, mp 38°-39° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH2:8][C:9]([C:12]([OH:14])=O)=[N:10][N:11]=2)=[CH:3][CH:2]=1.[NH2:15][C@H:16]([CH3:32])[CH2:17][N:18]1[CH:22]=[CH:21][C:20]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([CH3:31])[CH:24]=2)=[N:19]1>>[C:27]([C:26]1[CH:29]=[CH:30][C:23]([C:20]2[CH:21]=[CH:22][N:18]([CH2:17][C@H:16]([NH:15][C:12]([C:9]3[NH:10][N:11]=[C:7]([C:4]4[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=4)[CH:8]=3)=[O:14])[CH3:32])[N:19]=2)=[CH:24][C:25]=1[CH3:31])#[N:28]
Reactant: Cc1cc(-c2ccn(C[C@@H](C)N)n2)ccc1C#N
Reactant: O=C(O)C1=NN=C(c2ccncc2)C1
Product: Cc1cc(-c2ccn(C[C@@H](C)NC(=O)c3cc(-c4ccncc4)n[nH]3)n2)ccc1C#N
Yield: 66.9 %

Procedure:
The title compound was synthesized from 5-pyridin-4-yl-4H-pyrazole-3-carboxylic acid (13 mg, 0.069 mmol) and (R)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-methylbenzonitrile (17 mg, 0.071 mmol) using the method of Example 34(d). Crude product was purified by chromatography (CombiFlash, silica column, eluent: 0-20% MeOH/DCM) to obtain 19 mg (67%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 1.17 (d, 3H), 2.48 (s, 3H), 4.31 (m, 2H), 4.47 (m, 1H), 6.82 (d, 1H), 7.31 (s, 1H), 7.75 (m, 4H), 7.81 (d, 1H), 7.85 (s, 1H), 8.40 (d, 1H), 8.63 (m, 2H), 13.92 (br s, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].[CH2:6]([O:8][C:9]([C:11]1[C:16]([Br:17])=[CH:15][N:14]=[C:13](S(C)(=O)=O)[N:12]=1)=[O:10])[CH3:7]>ClCCl>[CH2:6]([O:8][C:9]([C:11]1[C:16]([Br:17])=[CH:15][N:14]=[C:13]([NH:5][CH2:4][CH2:3][O:2][CH3:1])[N:12]=1)=[O:10])[CH3:7]
Reactant: COCCN
Reactant: CCOC(=O)c1nc(S(C)(=O)=O)ncc1Br
Solvent: ClCCl
Product: CCOC(=O)c1nc(NCCOC)ncc1Br
Reaction time: 2 h
Yield: 88.5 %

Procedure:
2-Methoxyethylamine (0.278 ml, 3.2 mmol) was added at room temperature to a solution of 5-bromo-2-methanesulfonyl-pyrimidine-4-carboxylic acid ethyl ester (0.2 g, 0.65 mmol) in dichloromethane (5 ml). Stirring was continued at 45° C. for 2 hours. The solvent was evaporated and the crude product was purified by silica gel chromatography using an ethyl acetate/heptane eluent to yield the title compound as colorless oil (0.175 g, 89%).
Reaction SMILES: [BrH:1].C(OC(=O)C)(=O)C.Cl.[CH:10]1([NH:16][CH:17]2[CH2:26][CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([O:29]C)[C:23]=3[O:27]C)[C:18]2=[O:31])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>>[BrH:1].[CH:10]1([NH:16][CH:17]2[CH2:26][CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([OH:29])[C:23]=3[OH:27])[C:18]2=[O:31])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: COc1ccc2c(c1OC)CCC(NC1CCCCC1)C2=O
Agent: Br
Agent: Cl
Solvent: CC(=O)OC(C)=O
Product: O=C1c2ccc(O)c(O)c2CCC1NC1CCCCC1

Procedure:
In a mixture of 50 volume parts 48% hydrobromic acid and 15 volume parts acetic anhydride is dissolved 5 parts of 2-cyclohexylamino-5,6-dimethoxy-3,4-dihydro-1(2H)-naphthalenone hydrochloride, and the solution is heated at 140°-160° C for about 3 hours. After cooling, the solvent is removed under reduced pressure and the residue is treated with activated carbon in ethanol. Following the addition of ethyl acetate, the filtrate is allowed to stand, whereby 2-cyclohexylamino-5,6-dihydroxy-3,4-dihydro-1(2H)-naphthalenone hydrobromide is obtained as colorless prisms. Yield 4.1 parts; melting point: 225°-237° C (decomposition). Nuclear magnetic resonance spectrum
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[O:11][N:10]=[C:9]([CH2:12][N:13]3[C:17]([CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH3:26])=[CH:16][C:15]([C:27](O)=[O:28])=[N:14]3)[CH:8]=2)=[CH:4][CH:3]=1.Cl.[CH:31]([N:34]1[CH2:39][CH2:38][CH:37]([NH2:40])[CH2:36][CH2:35]1)([CH3:33])[CH3:32].C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1>C(Cl)Cl.CCN(CC)CC>[CH:31]([N:34]1[CH2:39][CH2:38][CH:37]([NH:40][C:27]([C:15]2[CH:16]=[C:17]([CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH3:26])[N:13]([CH2:12][C:9]3[CH:8]=[C:7]([C:5]4[S:6][C:2]([Cl:1])=[CH:3][CH:4]=4)[O:11][N:10]=3)[N:14]=2)=[O:28])[CH2:36][CH2:35]1)([CH3:33])[CH3:32]
Reactant: COCCOCCOCc1cc(C(=O)O)nn1Cc1cc(-c2ccc(Cl)s2)on1
Reactant: CC(C)N1CCC(N)CC1
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCOCCOCc1cc(C(=O)NC2CCN(C(C)C)CC2)nn1Cc1cc(-c2ccc(Cl)s2)on1
Reaction time: 16 h

Procedure:
To 60 mg 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-5-[2-(2-methoxy-ethoxy)-ethoxymethyl]-1H-pyrazole-3-carboxylic acid in 2 ml DCM and 0.1 ml NEt3, 30 mg 1-Isopropyl-piperidin-4-ylamine hydrochloride and 34 mg BOP-Cl were added at RT and the mixture was stirred for 16 h. The mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC (C18 reverse phase column, elution with a H2O/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid. Yield: 19 mg MS (ES+): m/e=566, chloro pattern.
Reaction SMILES: [CH2:1]([N:6]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:7]([CH:9]([CH2:16][S:17]([C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1)=[O:18])[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[O:8])[CH2:2][CH2:3][CH2:4][CH3:5].ClC1C=CC=C(C(OO)=[O:39])C=1.S([O-])([O-])=O.[Na+].[Na+]>ClCCl>[CH2:26]([N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:7]([CH:9]([CH2:16][S:17]([C:19]1[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=1)(=[O:39])=[O:18])[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[O:8])[CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCCN(CCCCC)C(=O)C(CCC(=O)OC)CS(=O)c1ccc(C)cc1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCCCCN(CCCCC)C(=O)C(CCC(=O)OC)CS(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Yield: 83.6 %

Procedure:
Into a solution of methyl 4-(N,N-dipentylcarbamoyl)-5-(4-methylphenylsulfinyl)pentanoate (0.15 g) in dry dichloromethane (5 ml) were added portions of m-chloroperbenzoic acid (80%, 0.09 g) with stirring at 0° C. After stirring at room temperature for 4 hours, sodium sulfite was added. The reaction mixture was washed with a saturated sodium bicarbonate solution and water, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica by eluting with dichloromethane/diethyl ether (2:1) to give 0.13 g of methyl 4-(N,N-dipentylcarbamoyl)-5-(4-methylphenylsulfonyl)pentanoate as an oil.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH:6]([NH:9][C:10]1[N:15]=[C:14](O)[C:13]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12][N:11]=1)([CH3:8])[CH3:7]>>[CH:6]([NH:9][C:10]1[N:15]=[C:14]([Cl:3])[C:13]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12][N:11]=1)([CH3:8])[CH3:7]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)Cc1cnc(NC(C)C)nc1O
Product: CCOC(=O)Cc1cnc(NC(C)C)nc1Cl
Yield: 73.9 %

Procedure:
Phosphorus oxychloride (26.2 g) was added to 2.26 g (9.45 mmoles) of ethyl 2-isopropylamino-4-hydroxypyrimidine-5-acetate, and the mixture was heated under reflux for 3 hours. The reaction mixture was concentrated under reduced pressure, and chloroform and ice water were added. It was then neutralized with sodium hydrogen carbonate. The chloroform layer was separated, and the solvent was evaporated. The residue was purified by silica gel column chromatography to give 1.80 g (yield 74%; melting point 67°-71° C.) of ethyl 2-isopropylamino-4-chloropyrimidine-5-acetate. To the product were added 1.05 g (13.5 mmoles) of a 40% methanol solution of methylamine and 10 ml of ethanol were added, and the mixture was reacted at 120 ° C. for 7 hours in an autoclave. Water was added, and the mixture was extracted with chloroform. The solvent was evaporated. The residue was purified by silica gel column chromatography to give 0.50 g (yield 35%) of the desired compound.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][NH:11][C@H:10]([CH3:14])[CH2:9]1)=O)(C)(C)C.CCN(CC)CC.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl>[CH3:22][S:23]([N:11]1[CH2:12][CH2:13][NH:8][CH2:9][C@H:10]1[CH3:14])(=[O:25])=[O:24]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H]1CNCCN1S(C)(=O)=O
Reaction time: 8 h
Yield: 33.5 %

Procedure:
First step: To a stirred solution of commercially available (R)-3-methyl-piperazine-1-carboxylic acid tert-butyl ester (8.78 g, 44 mmol) in CH2Cl2 (80 mL) at 0° C. were added Et3N (12.15 mL, 88 mmol) and methanesulfonyl chloride (5.09 mL, 66 mmol). Stirring was continued at RT overnight, the reaction was poured onto water and extracted with CH2Cl2. The combined organic phases were dried on Na2SO4 and concentrated under vacuo. The crude product was dissolved in CH2Cl2 (50 mL) and TFA (15 mL) was added. After 2 hours at RT, the volatiles were removed under vacuo, the crude was dissolved in CH2Cl2 and washed with aq. NaHCO3 (until pH=8). The organic phase was dried on Na2SO4 and concentrated under vacuo to yield 2.63 g (34%) of (R)-1-methanesulfonyl-2-methyl-piperazine as a light yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[C:7]([CH:10]=O)[C:6]=2[CH:12]=1.[S:13]([NH2:17])([NH2:16])(=[O:15])=[O:14].[BH4-].[Na+].O>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[C:7]([CH2:10][NH:16][S:13]([NH2:17])(=[O:15])=[O:14])[C:6]=2[CH:12]=1
Reactant: NS(N)(=O)=O
Reactant: O=Cc1csc2ccc(Br)cc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: NS(=O)(=O)NCc1csc2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
5-Bromobenzothiophene (1.60 g, 7.51 mmol) and dichloromethyl methyl ether (1.29 g, 11.3 mmol) were dissolved in anhydrous 1,2-dichloroethane (75 mL). Titanium tetrachloride (2.14 g, 11.3 mmol) was added, turning the solution dark. After one hour at room temperature, the reaction was poured into a mixture of saturated aqueous NaHCO3 and ice. The mixture was stirred for about 30 minutes and then was extracted with DCM (2×100 mL). The extracts were concentrated and chromatographed (0 to 5% ethyl acetate in hexane) to yield 5-bromo-benzo[b]thiophene-3-carbaldehyde (1.32 g). The 5-bromobenzothiophene-3-carboxaldehyde (1.20 g, 4.98 mmol) and sulfamide (4.0 g, 42 mmol) were combined in anhydrous ethanol (25 mL) and heated to reflux for three days. The reaction was cooled to room temperature and sodium borohydride (0.207 g, 5.47 mmol) was added. After five hours, water (50 ml) was added and the solution was extracted with chloroform (3×50 mL). The extracts were concentrated, suspended in a minimal amount of DCM, and filtered to provide the title compound as a yellow solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][NH2:5].CN([CH:9]=[C:10]1[C:15](=[O:16])[CH2:14][CH2:13][CH2:12][C:11]1=O)C>CO>[OH:1][CH2:2][CH2:3][N:4]1[C:11]2[CH2:12][CH2:13][CH2:14][C:15](=[O:16])[C:10]=2[CH:9]=[N:5]1
Reactant: CN(C)C=C1C(=O)CCCC1=O
Reactant: NNCCO
Solvent: CO
Product: O=C1CCCc2c1cnn2CCO
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
2-hydroxyethyl hydrazine (1.36 mL, 20 mmol) was slowly added to an ice-cooled solution of 2-((dimethylamino)methylene)cyclohexane-1,3-dione (3.34 g) in methanol (50 mL). After stirring at room temperature for 20 min, the solvent was evaporated. Flash chromatography (SiO2, EtOAc/MeOH=100:5 to 100:7 to 100:10) gave the title compound as a white solid. B. Preparation of 1-(2-(tert-butyldimethylsilyloxy)ethyl)-6,7-dihydro-1H-indazol-4(5H)-one.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:28])[C:16]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH2:25][C:26]#[N:27])[CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-:30].[K+].[K+].OO>CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:28])[C:16]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH2:25][C:26](=[O:30])[NH2:27])[CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: COc1cc(OCC#N)cc(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: COc1cc(OCC(N)=O)cc(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)c1
Reaction time: 24 h
Yield: 504.2 %

Procedure:
2.10 g (5.4 mmol) of 4-(3-cyanomethoxy-5-methoxy-benzoylamino)-piperidine-1-carboxylic acid tert-butyl ester (example 245) and 0.15 g (1.1 mmol) of potassium carbonate were suspended under argon in 10 mL of DMSO at rt; while stirring, 0.93 mL (1.05 g=2.0 eq.) of hydrogen peroxide solution (35% in water) was added below 25° C. and stirring continued at ambient temperature for 24 hours. Then, the reaction mixture was poured into crashed ice and extracted three times with MeCl2 /2-propanol (4:1); the organic phases were evaporated i.V. to yield 2.26 g of the crude title compound as colorless solid. MS: 408.1 (MH+).
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[C:3](Cl)=[O:4].[Br:7][C:8]1[CH:14]=[C:13]([O:15][C:16]([F:19])([F:18])[F:17])[CH:12]=[CH:11][C:9]=1[NH2:10]>>[Br:7][C:8]1[CH:14]=[C:13]([O:15][C:16]([F:18])([F:19])[F:17])[CH:12]=[CH:11][C:9]=1[NH:10][C:3](=[O:4])[CH:2]([CH3:6])[CH3:1]
Reactant: CC(C)C(=O)Cl
Reactant: Nc1ccc(OC(F)(F)F)cc1Br
Product: CC(C)C(=O)Nc1ccc(OC(F)(F)F)cc1Br

Procedure:
Prepared by Procedure Q1 using 2-methylpropanoyl chloride and 2-bromo-4-(trifluoromethoxy)aniline: ESMS m/e: 325.9 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH2:12][CH2:13][CH2:14][CH2:15][C:16](O)=O>>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:16]2[CH2:15][CH2:14][CH2:13][N:12]=2)=[CH:8][CH:7]=1
Reactant: NCCCC(=O)O
Reactant: ClCCCOc1ccccc1
Product: ClCCCOc1ccc(C2=NCCC2)cc1
Yield: 9.3 %

Procedure:
Following the procedure described in example 1§A, but starting from O-(3-chloropropyl)phenol (3.41 g), 4-aminobutanoic acid (2.06 g) and polyphosphoric acid (36 g) gives 0.44 g of 2-[4-(3-chloropropoxy)phenyl]-4,5-dihydro-3H-pyrrole.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[C:11]([CH2:14][N:15]3[CH:19]=[C:18]([C:20]([O:22]CC)=[O:21])[CH:17]=[N:16]3)[S:12][CH:13]=2)[CH:6]=[CH:7][CH:8]=1.C(O)C.[OH-].[Na+]>O1CCCC1>[F:26][C:2]([F:1])([F:25])[C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[C:11]([CH2:14][N:15]3[CH:19]=[C:18]([C:20]([OH:22])=[O:21])[CH:17]=[N:16]3)[S:12][CH:13]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1cnn(Cc2nc(-c3cccc(C(F)(F)F)c3)cs2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)c1cnn(Cc2nc(-c3cccc(C(F)(F)F)c3)cs2)c1
Reaction time: 8 h
Yield: 67.4 %

Procedure:
To the compound (4.80 g, 12.6 mmol) obtained in Example 1c were added ethanol (40 mL), tetrahydrofuran (10 mL) and 2N aqueous sodium hydroxide solution (12.6 mL, 25.2 mmol), and the mixture was stirred overnight. The reaction mixture was concentrated under reduced pressure, and the residue was extracted with water, and washed with ether. The aqueous layer was acidified with 6N hydrochloric acid, extracted with ethyl acetate, washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (3.0 g, 67%) as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[S:6][CH:5]=[C:4]([C:7]([OH:9])=[O:8])[CH:3]=1.C1C[O:13][CH2:12]C1.[Li+].CC([N-]C(C)C)C.CN(C=O)C>O>[Br:1][C:2]1[S:6][C:5]([CH:12]=[O:13])=[C:4]([C:7]([OH:9])=[O:8])[CH:3]=1
Reactant: C1CCOC1
Reactant: O=C(O)c1csc(Br)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1sc(Br)cc1C(=O)O
Temperature: -30 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
Under a nitrogen atmosphere, 5-bromo-3-thiophenecarboxylic acid (12 g, 58 mmol) was added to THF (300 ml), and LDA (174 mmol, 232 ml, 0.75 M) was slowly dropped at −78° C. Then, the mixture was stirred for two hours at −30° C., and DMF was slowly dropped at −78° C. Then, water was added to the reaction solution. The reaction solution was then extracted with ethyl acetate, and an organic layer was washed with a saturated saline solution and water. The organic layer was dried with anhydrous magnesium sulfate, and, after filtration, the solvent was distilled off under reduced pressure. With this, a target substance was obtained as a solid (95% yield, crude product). 1H-NMR (400 MHZ, CDCl3, TMS) δ 10.44 (s, 1 H), 7.63 (s, 1 H)
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[C:11]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]([Br:20])=[CH:9][N:8]=1)(=O)=O.[CH:23]#[C:24][CH:25]([OH:27])[CH3:26].C(N(CC)CC)C.N>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.CN(C)C=O>[CH2:13]([C:11]1[C:10]([Br:20])=[CH:9][N:8]=[C:7]([C:23]#[C:24][CH:25]([OH:27])[CH3:26])[CH:12]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=S(=O)(Oc1cc(Cc2ccccc2)c(Br)cn1)C(F)(F)F
Reactant: C#CC(C)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(O)C#Cc1cc(Cc2ccccc2)c(Br)cn1
Reaction time: 1 h
Yield: 79 %

Procedure:
650 mg of 4-benzyl-5-bromo-2-pyridyl trifluoromethanesulfonate (Production Example 1), 115 mg of 1-butyne-3-ol, 100 mg of tetrakis(triphenylphosphine)palladium(0), 30 mg of cuprous iodide and 1 ml of triethylamine were mixed with 5 ml of N,N-dimethylformamide, followed by stirring for one hour in an oil bath kept at 60° C. After cooling as it was, aqueous ammonia was added thereto and the mixture was extracted with ethyl acetate. The extract was washed with brine and then evaporated. The residue was subjected to silica gel column chromatography and eluted with 30% ethyl acetate/hexane, to give 410 mg of the target compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([C:16]3[CH:26]=[CH:25][C:19]([C:20]([O:22]CC)=[O:21])=[CH:18][CH:17]=3)=[O:15])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[OH-].[Na+:28]>CO>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:8][CH2:9][N:10]([CH2:13][C:14]([C:16]3[CH:26]=[CH:25][C:19]([C:20]([O-:22])=[O:21])=[CH:18][CH:17]=3)=[O:15])[CH2:11][CH2:12]2)=[CH:3][CH:2]=1.[Na+:28]
Reactant: CCOC(=O)c1ccc(C(=O)CN2CCN(c3ccncc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C([O-])c1ccc(C(=O)CN2CCN(c3ccncc3)CC2)cc1
Reaction time: 2 h

Procedure:
A stirred suspension of the product of Example 131 (353 mg) in methanol (5 ml) was treated with a 1 molar sodium hydroxide solution (3 ml). After 2 hours, the cream coloured solid was collected, washed with a little methanol and dried to give the title compound, 240 mg, m.p. >300° C.; NMR (d6DMSO) δ 8.15 (2H, d), 8.05 (4H, t, AB pattern), 6.85 (2H, d), 3.97 (2H, s), 3.38 (4H, t), 2.65 (4H, t), m/e 348 (M+H)+ ; calculated for C18H8N3NaO3. 0.25H2O: C, 61.4; H, 5.3; N, 11.9. found: C, 61.3; H, 5.2; N, 11.7%.
Reaction SMILES: Cl[C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][C:8]([O:10]C(C)(C)C)=[O:9])=[C:4]([CH2:17][OH:18])[CH:3]=1.O[C:20]1C=CC(C)=CC=1C=O>>[CH:17]([C:4]1[CH:3]=[C:2]([CH3:20])[CH:16]=[CH:15][C:5]=1[O:6][CH2:7][C:8]([OH:10])=[O:9])=[O:18]
Reactant: CC(C)(C)OC(=O)COc1ccc(Cl)cc1CO
Reactant: Cc1ccc(O)c(C=O)c1
Product: Cc1ccc(OCC(=O)O)c(C=O)c1

Procedure:
Prepared by the method of example 1 part (d) using 2-hydroxy-5-methyl-benzaldehyde to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH:14]([OH:15])[CH2:13][CH2:12][N:11](C(OCC2C=CC=CC=2)=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]1[C@@H:14]([OH:15])[CH2:13][CH2:12][NH:11][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CN(C(=O)OCc2ccccc2)CCC1O
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H]1CNCC[C@@H]1O
Yield: 97.8 %

Procedure:
A solution of benzyl 3-((tert-butoxycarbonyl)amino)-4-hydroxypiperidine-1-carboxylate (141 mg, 0.402 mmol) in methanol (8.05 mL) was hydrogenated using the H-cube (settings: 25° C., full H2 mode, 1 mL/min flow rate) and 10% Pd/C CatCart 30 as the catalyst. The eluent was evaporated in vacuo to give the required tert-butyl(4-hydroxypiperidin-3-yl)carbamate (85.1 mg, 0.393 mmol, 98% yield) as a clear oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[F:29])[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:24][CH3:25])=[CH:13][C:14]=2[O:16][CH2:17][C@H:18]2[NH:22][CH2:21][C@H:20]([OH:23])[CH2:19]2)[N:9]=[CH:8][N:7]=1.[C:30](O)(=[O:32])[CH3:31]>>[C:30]([N:22]1[C@H:18]([CH2:17][O:16][C:14]2[CH:13]=[C:12]([O:24][CH3:25])[CH:11]=[C:10]3[C:15]=2[C:6]([NH:5][C:4]2[CH:26]=[CH:27][C:28]([F:29])=[C:2]([Cl:1])[CH:3]=2)=[N:7][CH:8]=[N:9]3)[CH2:19][C@@H:20]([OH:23])[CH2:21]1)(=[O:32])[CH3:31]
Reactant: CC(=O)O
Reactant: COc1cc(OC[C@@H]2C[C@@H](O)CN2)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Product: COc1cc(OC[C@@H]2C[C@@H](O)CN2C(C)=O)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Yield: 92 %

Procedure:
The procedure described in Example 25 was repeated using (3R,5S)-5-[({4-[3-chloro-4-fluoroanilino]-7-methoxyquinazolin-5-yl}oxy)methyl]pyrrolidin-3-ol (209 mg) with acetic acid (32 μl) to give the title compound as a white solid in 92% yield; NMR spectrum (DMSO-d6) 9.98 (s, 1H), 8.47 (s, 1H), 8.16-8.14 (m, 1H), 7.73-7.70 (m, 1H) 6.84 (s, 1H), 5.10 (m, 1H), 4.67-4.63 (m, 1H), 4.47-4.38 (m, 2H), 4.26-4.21 (m, 1H), 3.94 (s, 3H), 3.59 (dd, 1H), 3.41 (dd, 1H), 2.11-2.05 (m, 2H), 2.00 (s, 3H); Mass spectrum MH+ 461.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH2:10][CH3:11])[CH3:9])[C:5]([Cl:12])=[CH:4][N:3]=1.[N+:13]([C:16]1[C:21]([CH3:22])=[CH:20][C:19]([OH:23])=[C:18]([CH3:24])[CH:17]=1)([O-:15])=[O:14].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:12][C:5]1[C:6]([N:8]([CH2:10][CH3:11])[CH3:9])=[N:7][C:2]([O:23][C:19]2[CH:20]=[C:21]([CH3:22])[C:16]([N+:13]([O-:15])=[O:14])=[CH:17][C:18]=2[CH3:24])=[N:3][CH:4]=1
Reactant: CCN(C)c1nc(Cl)ncc1Cl
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(C)c1nc(Oc2cc(C)c([N+](=O)[O-])cc2C)ncc1Cl

Procedure:
A solution of 16.8 g (40 mmol) 2,5-dichloro-N-ethyl-N-methylpyrimidin-4-amine, 7.35 g 4-nitro-2,5-dimethylphenol (44 mmol) and 8.29 g potassium carbonate (60 mmol) in 70 ml DMF were stirred for 20 hrs at 100° C. After adding the mixture to 150 ml water the resulting suspension was extracted twice with 50 ml dichloromethane. The combined organic layers were washed with aqueous solution of sodium hydroxide. The organic layer was dried over magnesium sulfate, concentrated in vacuo and column chromatography (dichloromethane) yielded 8.3 g (47%) with a purity of 76%; log P (pH=2.3)=4.07.
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([C:12]1[N:17]=[CH:16][C:15]([O:18][CH2:19][C@@H:20]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH3:21])=[CH:14][C:13]=1[F:30])=[O:11].[CH2:31](I)[CH3:32]>>[CH2:31]([O:8][C:6]1[CH:7]=[CH:2][C:3]2[N:9]=[C:10]([C:12]3[N:17]=[CH:16][C:15]([O:18][CH2:19][C@@H:20]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:26])[CH3:27])[CH3:21])=[CH:14][C:13]=3[F:30])[O:11][C:4]=2[CH:5]=1)[CH3:32]
Reactant: C[C@@H](COc1cnc(C(=O)Nc2ccc(O)cc2O)c(F)c1)NC(=O)OC(C)(C)C
Reactant: CCI
Product: CCOc1ccc2nc(-c3ncc(OC[C@H](C)NC(=O)OC(C)(C)C)cc3F)oc2c1

Procedure:
Using tert-butyl [(1S)-2-({6-[(2,4-dihydroxyphenyl)carbamoyl]-5-fluoropyridin-3-yl}oxy)-1-methylethyl]carbamate and ethyl iodide, and in the same manner as in Example 2, steps D-E, the title compound was obtained.