Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[F:14][C:15]([F:24])([F:23])[C:16]([F:22])([F:21])[CH2:17][CH2:18][CH2:19]I>O1CCCC1>[F:21][C:16]([F:22])([C:15]([F:24])([F:23])[F:14])[CH2:17][CH2:18][CH2:19][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: FC(F)(F)C(F)(F)CCCI
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CCCC(F)(F)C(F)(F)F)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 0.1 %

Procedure:
To a solution of sodium hydride (60%) (3.90 g, 96.07 mol) in tetrahydrofuran (160 ml) was added dropwise a solution of diethyl malonate (16.6 ml, 110.85 mol) under ice-cooling, which was then stirred for 30 minutes. Then, 1,1,1,2,2-Pentafluoro-5-iodopentane (21 g, 73.9 mol) was added dropwise thereto, and reaction mixture was warmed to room temperature, with stirring, for overnight. After the reaction was completed, the reaction was quenched with water, extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and removed by evaporation under reduced pressure. This product was purified by column chromatography on silica gel, eluting with dichloromethane:n-hexane=1:3 to afford 18.3 g of the title compound as a colorless oil. (yield: 78.4%)
Reaction SMILES: [OH-].[K+].C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[N:15]=2)[CH2:10][CH2:9]1)=O)C.COC(O)C>O>[F:29][C:26]1[CH:25]=[CH:24][C:23]([N:16]2[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[N:15]2)=[CH:28][CH:27]=1
Reactant: CCOC(=O)N1CCN(c2nn(-c3ccc(F)cc3)c3ccccc23)CC1
Agent: COC(C)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Fc1ccc(-n2nc(N3CCNCC3)c3ccccc32)cc1
Yield: 74.6 %

Procedure:
A stirred solution of 9.2 g of potassium hydroxide in 90 ml of distilled water, 10.0 g of 4-[1-(4-fluorophenyl)-1H-indazol-3-yl]-1-piperazine carboxylic acid ethyl ester, and 180 ml of methoxyethanol was refluxed for 16 hours and then poured into water. The aqueous mixture was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and concentrated to give 6.0 g (75%) of 1-(4-fluorophenyl)-3-(1-piperazinyl)-1H-indazole. Recrystallization from isopropyl ether gave the analytical sample, mp 85°-87°.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[C:17]([O:21][C:22](=[O:33])[NH:23][C@H:24]1[CH2:29][CH2:28][C@H:27]([CH2:30][CH:31]=O)[CH2:26][CH2:25]1)([CH3:20])([CH3:19])[CH3:18].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:17]([O:21][C:22](=[O:33])[NH:23][C@H:24]1[CH2:25][CH2:26][C@H:27]([CH2:30][CH2:31][N:12]2[CH2:11][CH2:10][CH:9]([C:6]3[C:5]4[CH:15]=[CH:16][C:2]([F:1])=[CH:3][C:4]=4[O:8][N:7]=3)[CH2:14][CH2:13]2)[CH2:28][CH2:29]1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CC=O)CC1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCN2CCC(c3noc4cc(F)ccc34)CC2)CC1
Reaction time: 12 h

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (4 g, 18.1 mmol), trans-[4-(2-oxo-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester (5.4 g, 22.7 mmol), in 1,2 dichloroethane (55 mL) was stirred for 4 h at room temperature and sodium triacetoxyborohydride (6.9 g, 32.7 mmol) was added slowly and the resulting solution was stirred for 12 hours until the TLC indicated completion of the reaction. The mixture was filtrated and concentrated to dryness and purified with column chromatography on silica gel using CH2Cl2—CH2Cl2/MeOH (1-9:1). The product fractions were concentrated to give 9.4 g (21 mmol, 100% yield) of a light brown solid. MS (m/e): 446.3 (M+H+).
Reaction SMILES: O[C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[OH:15])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:16][C:17]([OH:19])=[O:18].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[OH:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][C:7]1[C:2]2[O:19][C:17](=[O:18])[CH2:16][C:3]=2[CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)Cc1cccc(Oc2ccccc2O)c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: O=C1Cc2cccc(Oc3ccccc3O)c2O1
Yield: 70.9 %

Procedure:
A mixture of 2-[2-hydroxy-3-(2-hydroxyphenoxy)phenyl]acetic acid (9.4 g) and p-toluene sulfonic acid (0.2 g) in benzene (100 ml) was refluxed under heating for 3 hrs. Benzene (20 ml) was distilled off from the reaction mixture, and benzene (20 ml) was newly added and refluxed again under heating for 3 hrs. The reaction mixture was washed with water, aqueous sodium bicarbonate and saline successively, dried over magnesium sulfate and then evaporated. The precipitates were recrystallized from ethanol (10 ml) to give 7-(2-hydroxyphenoxy)-2,3-dihydrobenzofuran-2-one (6.2 g). mp 150°-152.5° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:26]=[CH:25][C:11]([N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[C:27]1([N:33]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[C:34]2[CH:39]=[CH:38][C:37]([C:40]3[CH:45]=[CH:44][C:43](B4OC(C)(C)C(C)(C)O4)=[CH:42][N:41]=3)=[CH:36][CH:35]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+].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.C1COCC1>[N:6]1[C:5]([C:8]2[CH:26]=[CH:25][C:11]([N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=[C:2]([C:43]2[CH:42]=[N:41][C:40]([C:37]3[CH:38]=[CH:39][C:34]([N:33]([C:55]4[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=4)[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:35][CH:36]=3)=[CH:45][CH:44]=2)[CH:7]=1
Reactant: Brc1ccc(-c2ccc(N(c3ccccc3)c3ccccc3)cc2)nc1
Reactant: CC1(C)OB(c2ccc(-c3ccc(N(c4ccccc4)c4ccccc4)cc3)nc2)OC1(C)C
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: C1CCOC1
Solvent: O
Product: c1ccc(N(c2ccccc2)c2ccc(-c3ccc(-c4ccc(-c5ccc(N(c6ccccc6)c6ccccc6)cc5)nc4)cn3)cc2)cc1
Temperature: 80 °C
Yield: 81.6 %

Procedure:
A mixture of 1 (3.05 g, 7.59 mmol), 2 (3.40 g, 7.59 mmol), tetrakis(triphenylphosphine)palladium(0) (0.438 g, 0.379 mmol), Na2CO3 (7.42 g, 70.0 mmol), H2O (70 mL) and THF (115 mL) was degassed with argon for about 1.25 h while stirring. The stirring reaction mixture was then maintained under argon at 80° C. for about 65 h. Upon confirming consumption of the starting materials by TLC (SiO2, CH2Cl2), the reaction was cooled to room temperature (RT) and poured over CH2Cl2 (400 mL). The organics were then washed with sat. NaHCO3, H2O and brine, dried over MgSO4, filter and concentrated in vacuo. Purification of the crude product via flash chromatography (SiO2, 100% CH2Cl2 to 49:1 CH2Cl2-acetone) provided 3 (3.98 g, 82% yield) as a yellow solid.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:21][CH2:20][C:9]2([O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:10]2)[CH2:8][CH2:7]1)=[O:5])C.O.[OH-].[Li+]>CO.O>[C:14]1([C:11]2[CH2:10][C:9]3([CH2:20][CH2:21][CH:6]([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]3)[O:13][N:12]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)C1CCC2(CC1)CC(c1ccccc1)=NO2
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C1CCC2(CC1)CC(c1ccccc1)=NO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-phenyl-1-oxa-2-azaspiro[4.5]dec-2-ene-8-carboxylic acid ethyl ester (190 mg, 0.67 mmol) in MeOH (5 ml) and lithium hydroxide monohydrate (74 mg, 1.0 mmol) in H2O (1 ml) was stirred overnight at RT. After removal of the solvent under vacuum, the residue was taken up in 10% aq. citric acid solution and EtOAc and the phases were separated. The aqueous phase was extracted several times with EtOAc, dried over magnesium sulphate and desolventised under vacuum. 150 g (87% of the theoretical amount) of the free acid 3-phenyl-1-oxa-2-azaspiro[4.5]dec-2-ene-8-carboxylic acid was obtained in the form of a colourless solid.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[O:16][C:15]([Br:17])=[CH:14][CH:13]=2)[CH:7]=1)(=O)C.[OH-].[K+]>CO.O.[Cl-].[Na+]>[Br:17][C:15]1[O:16][C:12]([C:8]2[CH:7]=[C:6]([CH2:5][OH:4])[CH:11]=[CH:10][CH:9]=2)=[CH:13][CH:14]=1
Reactant: CC(=O)OCc1cccc(-c2ccc(Br)o2)c1
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OCc1cccc(-c2ccc(Br)o2)c1
Yield: 88.1 %

Procedure:
A solution of 3.8 g (0.013 mol) of 3-(2-bromo-5-furanyl)-phenylmethyl acetate and 0.85 g (0.019 mol) of potassium hydroxide in 100 mL of methanol was stirred for 75 minutes at ambient temperature. The reaction mixture was diluted with 200 mL of water, saturated with solid sodium chloride, and extracted with three portions of 150 mL each of chloroform. The combined extracts were dried with magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure to give 2.9 g of 3-(2-bromo-5-furanyl)phenylmethanol.
Reaction SMILES: N#N.[Si:3]([O:10][CH2:11][C:12]1[N:13]=[C:14]([C:17]([OH:20])([CH3:19])[CH3:18])[O:15][CH:16]=1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].[CH3:21]I>C(Cl)Cl>[Si:3]([O:10][CH2:11][C:12]1[N:13]=[C:14]([C:17]([O:20][CH3:21])([CH3:19])[CH3:18])[O:15][CH:16]=1)([C:6]([CH3:9])([CH3:7])[CH3:8])([CH3:5])[CH3:4]
Reactant: CC(C)(O)c1nc(CO[Si](C)(C)C(C)(C)C)co1
Reactant: CI
Agent: N#N
Solvent: ClCCl
Product: COC(C)(C)c1nc(CO[Si](C)(C)C(C)(C)C)co1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 2-(4-(((tert-butyldimethylsilyl)oxy)methyl)oxazol-2-yl)propan-2-ol (153 mg, 0.56 mmol) in CH2Cl2 (0.4 mL) was treated with MeI (0.08 mL, 1.35 mmol) followed by Ag2O (196 mg, 0.85 mmol). The resulting mixture (protected form light) was stirred overnight at 40° C. The reaction mixture was filtered and the solvent was removed under reduced pressure. Purification of the residue by FC (7:3 hept-EA) gave the title compound as an orange oil. TLC: rf (7:3 hept-EA)=0.40. LC-MS-conditions 07: tR=0.99 min, [M+H]+=286.20.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([NH2:12])=[O:11])=[CH:4][CH:3]=1.[Cl:13][CH2:14][C:15]([CH2:17]Cl)=O>>[Cl:13][CH2:14][C:15]1[N:12]=[C:10](/[CH:9]=[CH:8]/[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[O:11][CH:17]=1
Reactant: O=C(CCl)CCl
Reactant: NC(=O)/C=C/c1ccc(F)cc1
Product: Fc1ccc(/C=C/c2nc(CCl)co2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 43.7 %

Procedure:
The (E)-3-(4-fluorophenyl)-2-propenamide (17.55 g) thus obtained and 1,3-dichloroacetone (12.85 g) were molten at 130° C. and stirred for 1.5 hours. After the reaction mixture was cooled to room temperature and extracted with ethyl acetate, it was washed with ice water, saturated aqueous sodium bicarbonate, and saturated saline. After drying with anhydrous sodium sulfate, the solvent was distilled off; the residue was purified by column chromatography (eluent: diethyl ether-hexane=1:9→3:17) to yield the titled compound (10.5 g) as colorless crystals.
Reaction SMILES: [NH2:1][C@H:2]([CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:3]O.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23].O>O1CCCC1>[CH2:7]([O:6][CH2:5][C@@H:2]1[CH2:3][CH2:21][S:22](=[O:24])(=[O:23])[NH:1]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CS(=O)(=O)Cl
Reactant: N[C@@H](CO)COCc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: O=S1(=O)CC[C@@H](COCc2ccccc2)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (S)-2-amino-3-benzyloxy-1-propanol (5.0 g) and triethylamine (7.9 mL) was dissolved in tetrahydrofuran (40 mL), methanesulfonyl chloride (4.4 mL) was added under ice-cooling, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, the organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was dissolved in N,N-dimethylformamide (10 mL), sodium chloride (3.2 g) was added, and the mixture was stirred at 80° C. for 5 hr. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. A mixture of the obtained residue and 1,10-phenanthroline (28 mg) was dissolved in tetrahydrofuran (80 mL), diisopropylamine (3.9 mL) was added at −70° C., and n-butyllithium (38 mL) was further added. The reaction mixture was heated to room temperature, and stirred overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, the organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate) to give the title compound (4.49 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1OS(C(F)(F)F)(=O)=O)=[CH:13][CH:12]=[C:11]([C:24]([F:27])([F:26])[F:25])[CH:10]=2)=[O:5])[CH3:2].[C:28]1(B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C(OCC)(=O)C.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>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[CH:13][CH:12]=[C:11]([C:24]([F:27])([F:26])[F:25])[CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1OS(=O)(=O)C(F)(F)F
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1-c1ccccc1

Procedure:
4-Trifluoromethanesulfonyloxy-7-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester (208 mg, 0.5 mmol), phenylboronic acid (65 mg, 0.55 mmol), tetrakis(triphenylphosphine)palladium(0) (29 mg) and potassium phosphate (159 mg, 0.75 mmol) were heated together in dioxane (5 mL) to 80° C. overnight. The reaction mixture was then diluted with ethyl acetate and washed with brine twice. The organic layer was dried over sodium sulfate, concentrated, and the residue purified by flash column eluted with 30% ethyl acetate in hexane to yield 4-phenyl-7-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]([SH:7])=[N:5][N:4]=[N:3]1.[CH3:8][N:9]1[C:13]([S:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]Cl)=[N:12][N:11]=[N:10]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][N:2]1[C:6]([S:7][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][S:14][C:13]2[N:9]([CH3:8])[N:10]=[N:11][N:12]=2)=[N:5][N:4]=[N:3]1
Reactant: Cn1nnnc1S
Reactant: Cn1nnnc1SCCCCCCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cn1nnnc1SCCCCCCCCSc1nnnn1C
Yield: 56.5 %

Procedure:
1-Methyl-5-mercapto-1,2,3,4-tetrazole (1.2 g) is dissolved in acetone (50 ml). To the solution are added 1-methyl-5-(8-chlorooctyl)thio-1,2,3,4-tetrazole (4.1 g) and potassium carbonate (1.5 g) and the mixture is refluxed for 4 hours. Acetone is distilled off and water is added to the residue. The mixture is extracted with chloroform. The chloroform solution is washed with saturated aqueous sodium chloride and dried over magnesium sulfate. Chloroform is distilled off and the residue is recrystallized from ethyl acetate-hexane to obtain 1-methyl-5-[8-(1-methyl-1,2,3,4-tetrazol-5-yl)thiooctyl]thio-1,2,3,4-tetrazole (2.0 g) as colorless needles, m.p. 52°-54° C.
Reaction SMILES: [C:1]([C:5]1[C:10]([F:11])=[C:9](S(C)=O)[N:8]=[C:7]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[C:21]([Cl:24])[CH:22]=3)[NH:17][CH:16]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:25][C@H:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C@@H:27]1[C:32]([OH:34])=[O:33].C([O-])([O-])=O.[Na+].[Na+].CCN(C(C)C)C(C)C.Cl>C1COCC1.CC#N>[C:1]([C:5]1[N:6]=[C:7]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[C:21]([Cl:24])[CH:22]=3)[NH:17][CH:16]=2)[N:8]=[C:9]([NH:25][C@H:26]2[CH2:31][CH2:30][CH2:29][CH2:28][C@@H:27]2[C:32]([OH:34])=[O:33])[C:10]=1[F:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: N[C@H]1CCCC[C@@H]1C(=O)O
Reactant: CS(=O)c1nc(-c2c[nH]c3ncc(Cl)cc23)nc(C(C)(C)C)c1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: C1CCOC1
Product: CC(C)(C)c1nc(-c2c[nH]c3ncc(Cl)cc23)nc(N[C@H]2CCCC[C@@H]2C(=O)O)c1F
Temperature: 140 °C

Procedure:
A mixture of 3-(tert-butyl-5-fluoro-6-(methylsulfinyl)pyrimidin-2-yl)-5-chloro-1H-pyrrolo[2,3-b]pyridine, 40c, (0.05 g, 0.14 mmol), (1S,2S)-2-amino-cyclohexanecarboxylic acid (0.04 g, 0.27 mmol), freshly ground Na2CO3 (0.04 g, 0.41 mmol), and iPr2NEt (0.37 mL, 0.27 mmol) in THF (1 mL) and CH3CN (0.5 mL) was heated in a sealed vessel to 140° C. for 30 minutes under microwave irradiation. The mixture was cooled to room temperature. A solution of 1N HCl (0.5 mL, 0.5 mmol) was added and the mixture was concentrated to give a yellow solid, which was purified by reverse phase HPLC (0%-50% methanol in water) to afford the desired product, 629, as off-white solid.
Reaction SMILES: N[C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.S(=O)(=O)(O)[OH:14].N([O-])=O.[Na+].COC(C)(C)C>O>[OH:14][C@@H:2]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:10]([OH:12])=[O:11]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: O=S(=O)(O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: COC(C)(C)C
Product: O=C(O)[C@@H](O)Cc1ccccc1
Temperature: 20 °C
Reaction time: 20 h
Yield: 85.5 %

Procedure:
L-Phenylalanine (10.00 g, 60.5 mmol) was added to a dilution of 8.88 g (90.5 mmol) of concentrated sulfuric acid in 110 g of water and then, at an inside temperature of 20° C., a mixture of 10.45 g (151.5 mmol) of sodium nitrite and 20 g of water was added over 5 hours. After addition, the mixture was stirred at 20° C. for 20 hours, 100 ml of t-butyl methyl ether was then added and, after 30 minutes of stirring at 20° C., the organic phase was separated (extract 1). Further, 50 ml of t-butyl methyl ether was added to the aqueous phase, the mixture was stirred at 20° C. for 30 minutes, and the organic phase was separated (extract 2). The extracts 1 and 2 were combined. The combined extract (116.5 g) contained 8.6 g of (2S)-2-hydroxy-3-phenylpropionic acid (yield 86%, optical purity 95.9% ee). The proton concentration (normality) in the reaction of this example was 1.7 mol/kg, the amount of the protonic acid was 3.0 equivalents (relative to L-phenylalanine), and the reaction temperature was 20° C.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl>[CH3:26][S:27]([N:14]1[CH2:15][CH2:16][N:11]([C:8]2[CH:7]=[CH:6][C:5]([O:4][CH2:3][C:2]([F:1])([F:17])[F:18])=[CH:10][CH:9]=2)[CH2:12][CH2:13]1)(=[O:29])=[O:28]
Reactant: FC(F)(F)COc1ccc(N2CCNCC2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CCN(c2ccc(OCC(F)(F)F)cc2)CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 19.5 %

Procedure:
1-[4-(2,2,2-trifluoroethoxy)phenyl]piperazine (13.48 g, 50 mmol) was dissolved in DCM (500 mL) and cooled to 0° C. Triethylamine (29 mL, 0.2 mol) was added, followed by the dropwise addition of methanesulfonyl chloride (4.2 mL, 55 mmol). The reaction was then allowed to warm to room temperature and stir overnight, before being quenched by the addition of water. The layers were separated, and the organic phase dried (MgSO4), filtered and concentrated. The residue was recrystallised from hot ethanol to give pure 1-(methylsulfonyl)-4-[4-(2,2,2-trifluoroethoxy)phenyl]piperazine (3.3 g, 18%).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH3:7][O:8][C:9](=[O:34])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]1[C:17]2[C:24]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)=[C:23](Br)[O:22][C:18]=2[N:19]=[CH:20][N:21]=1.[F:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1B(O)O>CS(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:7][O:8][C:9](=[O:34])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]1[C:17]2[C:24]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)=[C:23]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=3[F:35])[O:22][C:18]=2[N:19]=[CH:20][N:21]=1
Reactant: COC(=O)CCCCCNc1ncnc2oc(Br)c(-c3ccc(OC)cc3)c12
Reactant: OB(O)c1ccccc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)CCCCCNc1ncnc2oc(-c3ccccc3F)c(-c3ccc(OC)cc3)c12
Temperature: 80 °C
Reaction time: 15 h

Procedure:
Add 0.22 ml of a 2 M aqueous sodium carbonate solution to a mixture of 100 mg (0.22 mmol) 6-{[6-bromo-5-(4-methoxyphenyl)furo[2,3-d]pyrimidin-4-yl]amino}hexanoic acid methyl ester and 8 mg (0.01 mmol) bis(triphenylphosphine)palladium(II) chloride in 5.0 ml DMSO. Next, add 39 mg (0.28 mmol) (2-fluorophenyl)boronic acid and stir the mixture for 15 h at 80° C. Filter the reaction mixture and purify directly by preparative RP-HPLC (gradient: water/acetonitrile). 69 mg (29% of theor.) of the desired product is obtained.
Reaction SMILES: Cl[C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[CH3:16][NH2:17]>C(O)C>[CH3:16][NH:17][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2
Reactant: Cc1cc(Cl)c([N+](=O)[O-])c2cccnc12
Reactant: CN
Solvent: CCO
Product: CNc1cc(C)c2ncccc2c1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture of 6-chloro-8-methyl-5-nitroquinoline (420 mg, 1.9 mmol) in methanamine as a solution in ethyl alcohol (30 mL) was heated to 80° C. and stirred for 1 h. After concentration under reduced pressure, the reaction mixture was extracted with DCM (50 mL). The organic layer was washed with water (20 mL×2), dried over Na2SO4, and concentrated under reduced pressure to give 410 mg of N,8-dimethyl-5-nitroquinolin-6-amine as a yellow solid. MS (ESI): m/z 218 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)=O.P([Cl:31])(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O.C(N(CC)CC)C.C(#N)C>C(OCC)(=O)C>[CH3:12][C:9]1[CH:10]=[CH:11][C:6]([N:5]=[C:3]([Cl:31])[C:2]([F:14])([F:13])[F:1])=[CH:7][CH:8]=1
Reactant: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Reactant: Cc1ccc(NC(=O)C(F)(F)F)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1ccc(N=C(Cl)C(F)(F)F)cc1
Temperature: 82 °C
Yield: 88.5 %

Procedure:
Seven grams (34.5 mmol) of 2,2,2-trifluoro-N-(4-methylphenyl)acetamide, 18.49 g (68.9 mmol) of diphenyl chlorophosphate, 6.97 g (68.9 mmol) of triethylamine, and 35 ml of acetonitrile were introduced into a 100 ml flask and reacted for 18 hours while being refluxed (82° C.). After the reaction, the reaction solution was cooled to room temperature, 25 ml of ethyl acetate was added thereto, and the precipitate was then filtered off. The filtrate was subjected to solvent removal by evaporation, and the crude product thus obtained was purified by column chromatography (silica gel, ethyl acetate:hexane=3:7), resulting in 6.77 g of N-(4-methylphenyl)-2,2,2-trifluoroacetimidoyl chloride as a yellow liquid (yield: 88.6%).