Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.C[Si](C)(C)O[Si](C)(C)C>ClCCCl>[F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]#[N:6]
Reactant: NC(=O)c1ccc([N+](=O)[O-])cc1F
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: C[Si](C)(C)O[Si](C)(C)C
Solvent: ClCCCl
Product: N#Cc1ccc([N+](=O)[O-])cc1F
Temperature: 100 °C
Yield: 92.9 %

Procedure:
A mixture of 2-fluoro-4-nitrobenzamide (0.83 g, 4.6 mmol) and phosphorus pentoxide/hexamethyl disiloxane in 1,2-dichloroethane (20 mL) was heated under nitrogen at 100° C. for 4 hours. Upon cooling, the solution was poured onto a plug of silica gel and washed with hexane (200 mL) followed by 5% methanol/chloroform (400 mL). The methanol/chloroform washes were collected and concentrated under reduced pressure to give 2-fluoro-4-nitrobenzonitrile (0.71 g, 95%) as a beige solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12](/[CH:13]=[CH:14]\[C:15]3[CH:16]=[C:17]([C:21]([OH:23])=O)[N:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.[OH:25][CH2:26][CH:27]([NH2:29])[CH3:28]>>[OH:25][CH2:26][CH:27]([NH:29][C:21]([C:17]1[N:18]([CH3:20])[N:19]=[C:15](/[CH:14]=[CH:13]\[C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[N:9][O:10][C:11]=2[CH3:24])[CH:16]=1)=[O:23])[CH3:28]
Reactant: CC(N)CO
Reactant: Cc1onc(-c2ccc(F)cc2)c1/C=C\c1cc(C(=O)O)n(C)n1
Product: Cc1onc(-c2ccc(F)cc2)c1/C=C\c1cc(C(=O)NC(C)CO)n(C)n1
Yield: 3 %

Procedure:
As described for example 120 (step 4), 5-{(Z)-2-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-vinyl}-2-methyl-2H-pyrazole-3-carboxylic acid (0.3 mmol), was converted, using 2-hydroxy-1-methylethylamine instead of isopropylamine, to the title compound (2.9 mg, 3%) which was obtained as an off white solid. MS: m/e=385.2 [M+H]+.
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][C:4]=1[O:10][CH2:11][C:12]#[CH:13].C[O-].[Na+].[Cl:17][C:18](OC(Cl)(Cl)Cl)=[O:19]>O.C(Cl)(Cl)Cl.CO>[Cl:17][C:18]([O:9][C:6]1[CH:7]=[CH:8][C:3]([Cl:2])=[C:4]([O:10][CH2:11][C:12]#[CH:13])[CH:5]=1)=[O:19]
Reactant: C#CCOc1cc(O)ccc1Cl
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: C#CCOc1cc(OC(=O)Cl)ccc1Cl

Procedure:
The sodium salt of 4-chloro-3-propargyloxyphenol as prepared from 14 g of 4-chloro-3-propargyloxyphenol and 28% methanol solution of sodium methylate was dissolved in 300 ml of distilled water and the solution was added dropwise to a solution of 5 ml of trichloromethyl chloroformate in 100 ml of chloroform at a temperature of 10° C. or below. The resulting reaction mixture was allowed to stand for phase separation. The chloroform layer was separated and dried over anhydrous magnesium sulfate, and the solvent was then distilled off. There was obtained 15.5 g of 4-chloro-3-propargyloxyphenyl chloroformate.
Reaction SMILES: [C:1](=[S:3])=S.[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:7][CH:6]=1.C(N(CC)CC)C.II.Cl.S([O-])([O-])=O.[Na+].[Na+]>C(OCC)(=O)C.O1CCCC1.O>[N:4]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:9][CH:10]=1)=[C:1]=[S:3]
Reactant: S=C=S
Reactant: Nc1ccc(CCCC(=O)O)cc1
Agent: Cl
Agent: II
Agent: O=S([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(O)CCCc1ccc(N=C=S)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 69 %

Procedure:
Carbon disulfide (0.26 mL, 4.4 mmol) was added to a mixture comprising 4-(4-aminophenyl)butyric acid (0.27 g, 1.5 mmol), tetrahydrofuran (1.0 mL), water (1.0 mL) and triethylamine (0.51 mL, 3.6 mmol), followed by stirring at room temperature for 24 hours. To the obtained reaction mixture, a tetrahydrofuran (1.0 mL) solution of iodine (0.41 g, 1.6 mmol) was dropwise added over a period of 5 minutes at 0° C., followed by stirring at 0° C. for further 1.5 hours. Thereafter, 1M hydrochloric acid (1.5 mL) and sodium sulfite (38 mg, 0.30 mmol) were added and mixed. Then, ethyl acetate (6 mL) was added, and the organic layer was separated, and the aqueous layer was extracted once with a solvent mixture of ethyl acetate (3 mL) and tetrahydrofuran (1 mL). The organic layers were combined and concentrated under reduced pressure to dryness. To the obtained residue, water (8.0 mL) and saturated sodium hydrogencarbonate aqueous solution (2.0 mL) were added and thoroughly mixed. Thereafter, the insoluble matter was filtered off, and to the filtrate, water (8.0 mL) and saturated sodium hydrogencarbonate aqueous solution (2.0 mL) were added and thoroughly mixed, and an insoluble matter was filtered off. The filtrates were combined, and 1M hydrochloric acid (5.0 mL) was added thereto. The precipitated solid was collected by filtration to obtain 4-(4-isothiocyanatophenyl)butyric acid as a colorless solid (0.23 g, yield: 69%, HPLC purity: 97%, HPLC retention time: 3.9 min). LC-MS ES-220(retention time: 4.3 min, condition 2).
Reaction SMILES: CC(C)([O-])C.[K+].[NH2:7][C:8]1[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][C:11]([CH:12]=O)=[CH:10][C:9]=1[Cl:20].[CH3:21][O:22][CH2:23][C:24]([O:26]C)=[O:25].[OH-].[Na+].Cl>C1COCC1.O>[NH2:7][C:8]1[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][C:11](/[CH:12]=[C:23](\[O:22][CH3:21])/[C:24]([OH:26])=[O:25])=[CH:10][C:9]=1[Cl:20]
Reactant: Nc1c(Cl)cc(C=O)cc1C(F)(F)F
Reactant: COCC(=O)OC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CO/C(=C\c1cc(Cl)c(N)c(C(F)(F)F)c1)C(=O)O
Temperature: 20 °C
Reaction time: 24 h

Procedure:
26.14 kg (55.91 mol) potassium tert.butoxide solution in THF were metered into a mixture of 10.00 kg (44.73 mol) 4-amino-3-chloro-5-trifluoromethylbenzaldehyde (A), 9.31 kg (89.45 mol) methyl methoxyacetate (B) and 30.0 L tetrahydrofuran and the mixture was stirred for 24 hours at 20° C. Then 7.16 kg (89.45 mol) sodium hydroxide solution (50%) were metered in and the mixture was heated to 30° C. for 1 hour, before 16.31 kg (134.18 mol) hydrochloric acid (30%) and 15.0 L water were added. After the aqueous phase has been separated off, 40 L of the solvent were distilled off and the residue was combined with 25.0 L toluene, before another 40 L solvent were distilled off. The organic phase was combined with 20.0 L water and cooled to 23° C. After the addition of 10.0 L toluene the suspension was stirred for a further 30 minutes, the product was separated off and dried.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][CH2:6][CH2:7][NH:8][C:9]([C:11]12[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2)=[O:10])C.C(O)(=O)C.Cl>C(O)C>[O:3]=[CH:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]([C:11]12[CH2:18][CH:17]3[CH2:19][CH:13]([CH2:14][CH:15]([CH2:16]3)[CH2:20]1)[CH2:12]2)=[O:10]
Reactant: CCOC(CCCNC(=O)C12CC3CC(CC(C3)C1)C2)OCC
Agent: Cl
Solvent: CC(=O)O
Solvent: CCO
Product: O=CCCCNC(=O)C12CC3CC(CC(C3)C1)C2
Reaction time: 16 h

Procedure:
1.94 g (6 mmol) N-(4,4-diethoxybutyl)adamantylcarboxamide, 7.5 mL of acetic acid, 3.75 mL of 1N aqueous hydrochloric acid and 30 mL ethanol are put together and stirred for 16 hours under argon atmosphere. Ethanol is evaporated. Then the resulting residue is dispersed in dichloromethane and extracted with saturated sodium bicarbonate solution. The organic phase is dried with sodium sulfate and the solvent evaporated in vacuum.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]#[N:8])=[O:5])[CH3:2].[CH3:9]OS(OC)(=O)=O>>[CH2:1]([O:3][C:4]([N:6]([CH3:9])[C:7]#[N:8])=[O:5])[CH3:2]
Reactant: CCOC(=O)NC#N
Reactant: COS(=O)(=O)OC
Product: CCOC(=O)N(C)C#N

Procedure:
Berichte, 62, 1393-1394 (1929) discloses the reaction of the ethoxycarbonylcyanamide with dimethylsulfate to produce N-ethoxycarbonyl-N-methylcyanamide.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7](B2OC(C)(C)C(C)(C)O2)[CH:6]=1)[OH:4].[C:22]([O:26][C:27](=[O:48])[NH:28][C:29]([C:31]1[S:32][C:33]([S:46][CH3:47])=[C:34]([S:36]([C:39]2[CH:44]=[CH:43][CH:42]=[C:41](Br)[CH:40]=2)(=[O:38])=[O:37])[CH:35]=1)=[NH:30])([CH3:25])([CH3:24])[CH3:23].C([O-])([O-])=O.[Na+].[Na+]>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.C1(C)C=CC=CC=1.CCO>[C:22]([O:26][C:27](=[O:48])[NH:28][C:29](=[NH:30])[C:31]1[S:32][C:33]([S:46][CH3:47])=[C:34]([S:36]([C:39]2[CH:44]=[C:43]([C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([CH:3]([OH:4])[C:2]([F:1])([F:20])[F:21])[CH:6]=3)[CH:42]=[CH:41][CH:40]=2)(=[O:38])=[O:37])[CH:35]=1)([CH3:25])([CH3:23])[CH3:24]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(Br)c1
Reactant: CC1(C)OB(c2cccc(C(O)C(F)(F)F)c2)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: Cc1ccccc1
Solvent: CCO
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2cccc(C(O)C(F)(F)F)c2)c1

Procedure:
Following the same procedure in Example 1, step c, reaction of 2,2,2-trifluoro-1-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-ethanol (123 mg, 416 mmol, as prepared in Example 28, step b), {[4-(3-bromo-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (100 mg, 0.2 mmol, as prepared in Example 27, step c), tetrakis(triphenylphosphine)palladium(0) (59 mg, 0.05 mmol, Strem Chemicals Inc, Newburyport, Mass.), Na2CO3 (800 μL, 2M aqueous), and toluene/EtOH mixture (2:1, 2.4 mL) afforded 100 mg (85%) after purification (SiO2, flash elution: 30% EtOAc in hexanes) of the title compound as a white foam. 1H-NMR (CDCl3; 400 MHz) δ 8.20 (t, 1H, J=1.7 Hz), 7.94–7.99 (m, 2H), 7.77–7.81 (m, 1H), 7.67 (br s, 1H), 7.57 (m, 1H), 7.27–7.34 (m, 1H), 7.15–7.21 (m, 2H), 5.11 (q, 1H, J=6.8 Hz), 2.51 (s, 3H), 1.49 (s, 9H). 19F-NMR (CDCl3; 400 MHz) δ −78.51 (d, J=6.9 Hz). ESI-MS (m/z): Calcd. for C25H25F3N2O5S3: 586.7; found: 586.7.
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([NH2:15])[CH:10]=1>CO.[Pd]>[C:1]1([CH3:16])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([NH2:15])[CH:10]=1
Reactant: Cc1ccccc1C=Cc1ccnc(N)c1
Agent: [Pd]
Solvent: CO
Product: Cc1ccccc1CCc1ccnc(N)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.2 %

Procedure:
To the solution of mixture of E and Z 4-(2-o-Tolyl-vinyl)-pyridin-2-ylamine (200 mg, 0.95 mmol) in methanol (10 mL) is added 5% palladium on carbon (20 mg). The mixture is purged and back filled with hydrogen three times using a hydrogen balloon. The reaction is then stirred at room temperature for 3 hours under the hydrogen atmosphere. The palladium on carbon is filtered and the filtrate is concentrated to give the desired product (198 mg).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6](=[O:8])[CH:5]=[N:4][NH:3]1.C(O[CH:14]1[CH2:18][CH2:17][CH2:16][O:15]1)(C)(C)C>CN(C)C=O>[O:15]1[CH2:16][CH2:17][CH2:18][CH:14]1[N:3]1[C:2](=[O:1])[N:7]([CH:16]2[CH2:17][CH2:18][CH2:14][O:15]2)[C:6](=[O:8])[CH:5]=[N:4]1
Reactant: O=c1cn[nH]c(=O)[nH]1
Reactant: CC(C)(C)OC1CCCO1
Solvent: CN(C)C=O
Product: O=c1cnn(C2CCCO2)c(=O)n1C1CCCO1
Reaction time: 5 h
Yield: 12 %

Procedure:
3,5-Dioxo-2,3,4,5-tetrahydro-1,2,4-triazine (1 g) and 2-t-butoxytetrahydrofuran (1.9 g) are dissolved in dimethylformamide (3 ml), and the mixture is stirred at 160°-165° C. for 5 hours. The dimethylformamide is removed in vacuo from the reaction mixture to give the residue. The residue is column-chromatographed over silica gel using a mixture of acetone/n-hexane (1/3) as an eluent. The first major fraction gives 2,4-bis(tetrahydro-2-furanyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine (Compound No. 85) (yield, 0.2 g; 12%), the second gives 3,5-dioxo-4-(tetrahydro-2-furanyl)-2,3,4,5-tetrahydro-1,2,4-triazine (Compound No. 86) (yield, 0.6 g; 36%) and the third gives 2-(tetrahydro-2-furanyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine (Compound No. 101) (yield, 0.4 g; 24%). Compound Nos. 85 and 86 melt at 67°-68° C. and 87° C., respectively.
Reaction SMILES: [CH:1]([C:4]1[CH:41]=[CH:40][C:7]([O:8][CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][NH:25][C:26](=[O:39])[C:27]3[CH:32]=[CH:31][C:30]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=4)=[CH:29][CH:28]=3)=[CH:18][CH:17]=2)[C:10]([O:12]CC)=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[OH-].[Na+]>>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:8][CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][NH:25][C:26](=[O:39])[C:27]3[CH:28]=[CH:29][C:30]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=4)=[CH:31][CH:32]=3)=[CH:18][CH:17]=2)[C:10]([OH:12])=[O:11])=[CH:40][CH:41]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(OCCNC(=O)c2ccc(-c3ccccn3)cc2)cc1)Oc1ccc(C(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Product: CC(C)c1ccc(OC(Cc2ccc(OCCNC(=O)c3ccc(-c4ccccn4)cc3)cc2)C(=O)O)cc1
Yield: 99.9 %

Procedure:
In a similar manner to that described in Example 2, ethyl 2-(4-isopropylphenoxy)-3-[4-[2-(4-pyridine-2-ylbenzoylamino)ethoxy]phenyl]propionate (8.38 g), which is the product of Example 9, was reacted with aqueous sodium hydroxide solution (1N, 30.32 ml) and the reaction mixture was treated to give the title compound (7.95 g) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[C:8](Br)[CH:7]=[C:6]([CH3:11])[C:5]=1[N:12]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.[CH2:32]([N:34]([C:41](=[O:44])[CH:42]=[CH2:43])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH3:33]>>[CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[C:8]([CH:43]=[CH:42][C:41](=[O:44])[N:34]([CH2:32][CH3:33])[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:7]=[C:6]([CH3:11])[C:5]=1[N:12]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)c1cc(Br)cc(C)c1N(Cc1cccnc1)S(=O)(=O)c1ccc(OC)cc1
Reactant: C=CC(=O)N(CC)c1ccccc1
Product: CCN(C(=O)C=Cc1cc(C)c(N(Cc2cccnc2)S(=O)(=O)c2ccc(OC)cc2)c(C(=O)OC)c1)c1ccccc1
Yield: 65.4 %

Procedure:
In the same manner as described in Example 203, 550.4 mg (1.0 mmol) of the product of Example 89 and 425 mg (2.43 mniol) of N-ethylacryianilide provided 392 mg (65%) of the desired product as a brown solid. Electrospray Mass Spec 600(M+H).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].O.Br[C:9]1[C:13]2=[C:14]3[C:19](=[CH:20][CH:21]=[C:12]2[S:11][C:10]=1[CH:22]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[C:23]([O:25][CH3:26])=[O:24])[N:18]=[CH:17][CH:16]=[CH:15]3.CC1(C)C(C)(C)OB([C:40]2[CH:41]=[C:42]3[C:47](=[CH:48][CH:49]=2)[O:46][CH2:45][CH2:44][CH2:43]3)O1>CN(C)C=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[C:28]([O:27][CH:22]([C:10]1[S:11][C:12]2[C:13](=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]=[CH:17][CH:16]=[CH:15]3)[C:9]=1[C:40]1[CH:49]=[CH:48][C:47]2[O:46][CH2:45][CH2:44][CH2:43][C:42]=2[CH:41]=1)[C:23]([O:25][CH3:26])=[O:24])([CH3:31])([CH3:30])[CH3:29]
Reactant: COC(=O)C(OC(C)(C)C)c1sc2ccc3ncccc3c2c1Br
Reactant: CC1(C)OB(c2ccc3c(c2)CCCO3)OC1(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(OC(C)(C)C)c1sc2ccc3ncccc3c2c1-c1ccc2c(c1)CCCO2
Temperature: 100 °C
Yield: 28.6 %

Procedure:
Under argon atmosphere, sodium carbonate (15.7 mg, 0.15 mmol), water (0.8 mL), and methyl 2-{1-bromothieno[3,2-f]quinolin-2-yl}-2-(tert-butoxy)acetate (16i) (55 mg, 0.14 mmol) were added to a solution of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chroman (38.5 mg, 0.15 mmol) in N,N-dimethylformamide (3 mL). The solution was degassed under argon and palladium tetrakis(triphenylphosphine) (47 mg, 0.04 mmol) was added. The mixture was heated at 100° C. for 4 hours. The mixture was then cooled at room temperature, water was added and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by preparative TLC (cyclohexane/ethyl acetate 70/30) to afford the desired product (16j) (19 mg, 0.04 mmol, 31%).
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:15]([F:16])=[CH:14][N:13]=[C:12]([C:17]4[S:21][C:20]([C:22](=[O:24])[CH3:23])=[CH:19][CH:18]=4)[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.CB1N2CCC[C@H]2C(C2C=CC=CC=2)(C2C=CC=CC=2)O1.B.C1COCC1>C1COCC1>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:15]([F:16])=[CH:14][N:13]=[C:12]([C:17]4[S:21][C:20]([C@H:22]([OH:24])[CH3:23])=[CH:19][CH:18]=4)[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: CC(=O)c1ccc(-c2ncc(F)c(Nc3cc(C4CC4)[nH]n3)n2)s1
Agent: B
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@@H]2CCCN12
Solvent: C1CCOC1
Product: C[C@@H](O)c1ccc(-c2ncc(F)c(Nc3cc(C4CC4)[nH]n3)n2)s1
Reaction time: 3 h
Yield: 40.5 %

Procedure:
A solution of compound 1-(5-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoropyrimidin-2-yl)thiophen-2-yl)ethanone (50 mg, 0.15 mmol, 1.0 eq) in dry THF (5 mL) was added dropwise to the mixture of (S)-1-methyl-3,3-diphenyl-hexahydropyrrolo[1,2-c][1,3,2] oxazaborole (0.22 mL, 0.22 mmol, 1.5 eq) and BH3.THF (0.44 mL, 0.44 mmol, 3.0 eq) in dry THF (2 mL) at 0° C. The mixture was stirred for 3 h, quenched with isopropylalcohol and concentrated. The residue was purified by silica gel column chromatography, then, recrystallized with THF/CH2Cl2/Petroleum ether to afford (R)-1-(5-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoropyrimidin-2-yl)thiophen-2-yl)ethanol (Compound 147) (21 mg, 42%).
Reaction SMILES: C([N:4](C(C)C)[C:5](=[O:21])[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:8][C:7]=1[CH:19]=O)(C)C.[NH2:25]N>C(O)(=O)C>[C:13]1([CH3:18])[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:9]1[CH:8]=[C:7]2[C:6](=[CH:11][CH:10]=1)[C:5]([OH:21])=[N:4][N:25]=[CH:19]2
Reactant: NN
Reactant: Cc1ccccc1-c1ccc(C(=O)N(C(C)C)C(C)C)c(C=O)c1
Solvent: CC(=O)O
Product: Cc1ccccc1-c1ccc2c(O)nncc2c1
Temperature: 110 °C

Procedure:
To a solution of N,N-diisopropyl 2-formyl-4-(2-methylphenyl)benzamide (5.45 g, 12 mmol) in acetic acid (15 mL) was added anhydrous hydrazine (0.56 mL, 18 mmol). The resulting solution was then heated at 110° C. for 16 h. The reaction mixture was cooled to RT, and the volatiles removed in vacuo. The residue was diluted with ethyl acetate (150 mL) and washed with saturated aqueous solution of sodium bicarbonate, and brine. The resulting organic solution was then dried over magnesium sulfate and concentrated under reduced pressure to give 6-o-tolylphthalazin-1-ol as a yellow solid. MS (ESI, pos.ion) m/z: 237.2 (M+1)
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([C@@H:9]([NH:11][C:12]([C:14]2[CH:15]=[N:16][NH:17][C:18]=2[CH3:19])=[O:13])[CH3:10])[CH:6]=[CH:7][CH:8]=1.[Cl:22][C:23]1[CH:24]=[CH:25][C:26](I)=[N:27][CH:28]=1.C(=O)([O-])[O-].[K+].[K+].CN[C@@H]1CCCC[C@H]1NC>[Cl-].[NH4+].[Cu]I.CN(C=O)C>[F:21][C:2]([F:1])([F:20])[C:3]1[CH:4]=[C:5]([C@@H:9]([NH:11][C:12]([C:14]2[CH:15]=[N:16][N:17]([C:26]3[CH:25]=[CH:24][C:23]([Cl:22])=[CH:28][N:27]=3)[C:18]=2[CH3:19])=[O:13])[CH3:10])[CH:6]=[CH:7][CH:8]=1
Reactant: Cc1[nH]ncc1C(=O)N[C@@H](C)c1cccc(C(F)(F)F)c1
Reactant: Clc1ccc(I)nc1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: Cc1c(C(=O)N[C@@H](C)c2cccc(C(F)(F)F)c2)cnn1-c1ccc(Cl)cn1
Temperature: 120 °C
Yield: 38.7 %

Procedure:
5-Methyl-1H-pyrazole-4-carboxylic acid [(S)-1-(3-trifluoromethyl-phenyl)-ethyl]-amide (70 mg, 0.24 mmol), copper(I) iodide (10 mg, 0.05 mmol), 5-chloro-2-iodopyridine (75 mg, 0.31 mmol) and potassium carbonate (75 mg, 0.54 mmol) are added to a reaction vial with a septum top which is then evacuated and filled with argon for 3 cycles. DMF (2 mL, degassed) and racemic trans-N,N′-dimethylcyclohexane-1,2-diamine (15 μL, 0.10 mmol) are added and the reaction is heated at 120° C. for 17 hours. The resultant mixture is cooled to room temperature, diluted with saturated aqueous ammonium chloride (15 mL) and extracted with EtOAc (3×20 mL). The combined organic layers is washed with saturated aqueous sodium bicarbonate (15 mL) followed by brine (15 mL), dried over sodium sulfate, filtered and concentrated in vacuo to provide a crude solid. Recrystallization from ether/hexanes provides 1-(5-chloro-pyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid [(S)-1-(3-trifluoromethyl-phenyl)-ethyl]-amide as a colorless solid (38 mg, 40%). (For references, see Buchwald, et al., J. Org. Chem. 2004, 69, 5578; Buchwald, et al., J. Am. Chem. Soc. 2002, 124, 11684).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][CH2:19][O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Cl-].[NH4+]>CN(C=O)C.C(OCC)(=O)C>[CH2:21]([O:20][CH2:19][CH2:18][O:10][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[OH:1])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCCOCc1ccccc1
Reactant: O=Cc1ccc(O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCCOCc2ccccc2)c(O)c1
Yield: 22.2 %

Procedure:
A solution of commercially available 3,4-dihydroxybenzaldehyde (17.04 g, 123.7 mmol) in 150 ml DMF and 14.9 g (107.5 mmol) potassium carbonate was stirred at 60° C. for 4 hours. 30.8 g (14.2 mmol) [(2-bromoethoxy)methyl]benzene was added at room temperature. The reaction mixture was stirred over night. The volume of the reaction mixture is reduced to half volume in vacuo. Aqueous saturated ammonium chloride solution and ethyl acetate is added to the reaction mixture. The organic phase is separated, washed twice with saturated aqueous sodium chloride solution, dried with magnesium sulfate filtered and concentrated in vacuo. The crude product is purified by column chromatography (silica gel, hexane/ethylacetate gradient: 7:1→1:2). The desired product was obtained in 22.2% yield (8.27 g, 27.3 mmol).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([CH3:14])[C:6]([CH3:13])=[C:7]([OH:12])[CH:8]=2)[O:3]1.B(F)(F)F.[CH3:20][C:21](O)([CH:23]=[CH2:24])[CH3:22]>O1CCOCC1>[CH3:1][C:2]1([CH3:15])[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([CH3:14])[C:6]([CH3:13])=[C:7]([OH:12])[C:8]=2[CH2:24][CH:23]=[C:21]([CH3:22])[CH3:20])[O:3]1
Reactant: C=CC(C)(C)O
Reactant: Cc1c(O)cc2c(c1C)OC(C)(C)CC2
Agent: FB(F)F
Solvent: C1COCCO1
Product: CC(C)=CCc1c(O)c(C)c(C)c2c1CCC(C)(C)O2
Reaction time: 0.05 h
Yield: 60 %

Procedure:
To a solution of 2,2,7,8-tetramethyl-chroman-6-ol (305 mg, 1.39 mmol), in 5 mL dry dioxane was added boron trifluoride (296 mg, 2.1 mmol). It was stirred for 3 min followed by dropwise addition of 2-methyl-but-3-en-2-ol solution (143 mg, 1.66 mmol, in 3 mL of dioxane). The reaction was allowed to stir for 5 h at RT before quenching on to ice (80 g). The mixture was extracted with DCM (3×50 mL) and the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by chromatography (hexane) to afford 2,2,7,8-tetramethyl-5-(3-methyl-but-2-enyl)-chroman-6-ol as a light brown oil (229 mg). 1H-NMR (300 MHz, CDCl3) δ (ppm): 5.16 (m, 1H), 4.70 (s, 1H), 3.34 (d, J=6.8 (2H), 2.18 (s, 3H), 2.14 (s, 3H), 1.86 (s, 3H), 1.81 (t, J=13.8, 2H), 1.77 (s, 3H), 1.32 (s, 6H); 13C-NMR δ (ppm): 145.7, 145.4, 134.1, 123.5, 122.2, 122.0, 121.8, 116.3, 72.5, 33.1, 26.7, 25.8, 20.8, 17.9, 12.1, 11.9; (ESI) m/z: 275 (M+H+, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][O:6][CH2:7][C:8]1[N:13]=[C:12]([NH2:14])[CH:11]=[CH:10][CH:9]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][C:20]=1[C:29]([F:32])([F:31])[F:30]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][O:6][CH2:7][C:8]1[N:13]=[C:12]([NH:14][S:25]([C:22]2[CH:23]=[CH:24][C:19]([F:18])=[C:20]([C:29]([F:32])([F:30])[F:31])[CH:21]=2)(=[O:27])=[O:26])[CH:11]=[CH:10][CH:9]=1
Reactant: Nc1cccc(COCc2cccc(Cl)c2)n1
Reactant: O=S(=O)(Cl)c1ccc(F)c(C(F)(F)F)c1
Product: O=S(=O)(Nc1cccc(COCc2cccc(Cl)c2)n1)c1ccc(F)c(C(F)(F)F)c1

Procedure:
This material was prepared in analogy to example 1 from 6-(3-chloro-benzyloxymethyl)-pyridin-2-ylamine (0.08 g) and 4-fluoro-3-(trifluoromethyl)-benzenesulfonyl chloride (0.092g) as a light yellow gum (0.088 g). MS (ESI−): 472.8 ([M−H]−).