Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:13])=[C:4]([S:9]([NH2:12])(=[O:11])=[O:10])[C:5]([Cl:8])=[CH:6][CH:7]=1.[CH2:14]([N:16]=[C:17]=[O:18])[CH3:15]>CN(C)C=O.C(OCC)(=O)C>[NH2:12][S:9]([C:4]1[C:3]([OH:13])=[C:2]([NH:1][C:17]([NH:16][CH2:14][CH3:15])=[O:18])[CH:7]=[CH:6][C:5]=1[Cl:8])(=[O:11])=[O:10]
Reactant: CCN=C=O
Reactant: Nc1ccc(Cl)c(S(N)(=O)=O)c1O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCNC(=O)Nc1ccc(Cl)c(S(N)(=O)=O)c1O
Yield: 44.7 %

Procedure:
A solution of 3-amino-6-chloro-2-hydroxybenzenesulfonamide (150 mg, 0.67 mmol) and ethyl isocyanate (64 μL, 0.81 mmol) in 1 mL of N,N-dimethyl-formamide was stirred at room temperature for 20 hours. The mixture was diluted with ethyl acetate and washed with water to give the crude. Purification upon column chromatograph on silica gel, eluting with ethyl acetate/hexane (50/50, v/v), followed by recrystallization from acetone and hexane, gave the desired product (88 mg, 44%). LC-MS (m/z) 294.0 (M+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.Cl.[N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15]Cl)[CH:10]=1>>[N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:1]2[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]2)[CH:10]=1
Reactant: O=C1CCNCC1
Reactant: ClCc1cccnc1
Agent: Cl
Product: O=C1CCN(Cc2cccnc2)CC1

Procedure:
1-(3-Pyridinylmethyl)-4-piperidone is prepared from 4-piperidone and 3-picolyl chloride hydrochloride essentially as described above in Example 38, Scheme C, step a.
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:13]([OH:15])=[O:14])[CH2:6][CH:7]([C:9]([F:12])([F:11])[F:10])[CH3:8])(=[O:3])[CH3:2].[OH-].[Na+]>O>[C:1]([NH:4][C@@H:5]([C:13]([OH:15])=[O:14])[CH2:6][CH:7]([C:9]([F:11])([F:12])[F:10])[CH3:8])(=[O:3])[CH3:2]
Reactant: CC(=O)N[C@@H](CC(C)C(F)(F)F)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)N[C@H](CC(C)C(F)(F)F)C(=O)O
Reaction time: 0.38 h

Procedure:
To a suspension of N-acetyl-5,5,5-trifluoroleucine (4.2 g, 18.5 mmol) in H2O (35 mL) was added 1 M aqueous NaOH (18.5 mL, 18.5 mmol) and the mixture was stirred for 15 to 30 min to give a homogenous solution. Acylase I (EC 3.5.1.14, from Sigma, Cat. #A 3010; 55 mg) was added and the mixture was stirred at room temperature overnight. Crude NMR of a small aliquot (evaporated under vacuum) showed a ratio of 53:47 for starting material and product. The mixture was then acidified with 6M aqueous HCl (˜3.5 mL) and extracted with EtOAc (4×, each EtOAc extraction was washed with a small amount of H2O). The combined EtOAc extracts were washed with brine, dried (MgSO4) and concentrated to afford the crude N-acetyl-5,5,5-trifluoro-D-leucine as a pale yellow solid, [α]D=+27.6° (c 1.5, EtOH). The aqueous layer was concentrated under vacuum and dried under vacuum overnight to afford 5,5,5-trifluoro-L-leucine, probably contaminated with NaCl and HCl salts, [α]D=−−4.1° (c 0.77, H2O).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:5][N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH:7]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH2:22]([N:24]([CH2:27]CCl)[CH2:25]C)[CH3:23].CN(CCCl)C>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([CH2:23][CH2:22][N:24]([CH3:27])[CH3:25])[CH2:8][CH:7]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Clc1ccc(CN2CCNCC2c2ccccc2)cc1Cl
Reactant: CCN(CC)CCCl
Agent: CN(C)CCCl
Product: CN(C)CCN1CCN(Cc2ccc(Cl)c(Cl)c2)C(c2ccccc2)C1

Procedure:
1-(3',4'-Dichloro benzyl)-2-phenyl piperazine prepared according to Example 3b, is alkylated by following the procedure described in Example 3c, whereby, in place of diethylamino ethylchloride, the equimolecular amount of dimethylamino ethylchloride is used. The resulting reaction product is obtained in the form of a light yellow oil boiling at 190° C./0.01 mm. Hg.
Reaction SMILES: [CH3:1][Si:2]([CH3:12])([CH3:11])[C:3]#[C:4][CH2:5][C:6]1([CH2:9][OH:10])[CH2:8][CH2:7]1.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>>[CH3:12][Si:2]([CH3:1])([CH3:11])[C:3]#[C:4][CH2:5][C:6]1([CH2:9][O:10][S:14]([CH3:13])(=[O:16])=[O:15])[CH2:8][CH2:7]1
Reactant: C[Si](C)(C)C#CCC1(CO)CC1
Reactant: CS(=O)(=O)Cl
Product: C[Si](C)(C)C#CCC1(COS(C)(=O)=O)CC1

Procedure:
In analogy to the procedure described in example 1G], [1-(3-trimethylsilanyl-prop-2-ynyl)-cyclopropyl]-methanol and methanesulfonyl chloride gave the title compound as yellow oil.
Reaction SMILES: Cl.[O:2]1[C:10]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=2[CH:4]=[CH:3]1.[C:11]([C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22](O)=[O:23])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>ClCCl.O>[C:11]([C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([N:7]1[CH2:8][CH2:9][C:10]2[O:2][CH:3]=[CH:4][C:5]=2[CH2:6]1)=[O:23])(=[O:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: c1cc2c(o1)CCNC2
Reactant: O=C(O)c1cccc(C(=O)c2ccccc2)c1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccccc1)c1cccc(C(=O)N2CCc3occc3C2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.160 g (1.000 mmol) of 4,5,6,7-tetrahydrofuro[3,2-c]pyridine hydrochloride, 0.27 g (1.2 mmol) of 3-benzoylbenzoic acid and 0.55 ml (4.0 mmol) of triethylamine in 30 ml of dichloromethane, 0.24 g (1.5 mmol) of diethyl cyanophosphonate was added dropwise under ice-cooling, followed by overnight stirring at room temperature. The reaction mixture was poured into water and extracted with dichloromethane 2 times. The combined organic layer was washed with water and dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=3/1) to yield the desired product.
Reaction SMILES: [BH4-].[C:2]([O:6][C:7]([N:9]1[CH2:14][CH2:13][C:12](=[N:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:11][CH2:10]1)=[O:8])([CH3:5])([CH3:4])[CH3:3].O>O1CCCC1>[C:2]([O:6][C:7]([N:9]1[CH2:14][CH2:13][CH:12]([NH:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:11][CH2:10]1)=[O:8])([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)NN=C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [BH4-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NNC1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
150 ml of a solution of borohydride in tertahydrofurane (1.0 mol/l) is slowly added to a solution of 0.12 mole of 4-(tert-Butoxycarbonyl-hydrazono)-piperddine-1-carboxylic acid tert-butyl ester (starting compound A7) in 100 ml of dry tetrahydrofurane. After complete addition, the mixture is stirred for another 30 min after which a 100 ml of water is added to destroy the excess of borohydride. Subsequently the tetrahydrofurane is evaporated and the resulting aqeous solution extracted with diethyl ether. After drying the solvent over magnesium sulfate, the ether is evaporated. M. p. 112-115° C.
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH:14]([CH3:16])[CH3:15])[CH:8]=1)[CH2:3][C:4]([OH:6])=O.[C:17](O)([C:19]([F:22])([F:21])[F:20])=[O:18].C(OC(C(F)(F)F)=O)(C(F)(F)F)=O.CCOC(C)=O>O>[F:20][C:19]([F:22])([F:21])[C:17]([NH:1][CH:2]1[C:7]2[C:12](=[CH:11][CH:10]=[C:9]([O:13][CH:14]([CH3:16])[CH3:15])[CH:8]=2)[C:4](=[O:6])[CH2:3]1)=[O:18]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)Oc1cccc(C(N)CC(=O)O)c1
Solvent: CCOC(C)=O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Product: CC(C)Oc1ccc2c(c1)C(NC(=O)C(F)(F)F)CC2=O
Temperature: 95 °C
Yield: 23 %

Procedure:
Step AU (3). To a solution of 3-amino-3-(3-isopropoxyphenyl)propanoic acid (65 g, 291 mmol) and TFA (100 mL) was added TFAA (100 mL). The mixture was warmed up to 95° C. for 2 h. The solvent was evaporated under high vacuum to afford a sticky oil which was taken into EtOAc (500 mL) and water (300 mL). The organic layer was separated, dried over Na2SO4, and concentrated in vacuo. The residue was purified using silica-gel chromatography (10-30% EtOAc/Hexane) to afford 20 g (23% yield) of 2,2,2-trifluoro-N-(6-isopropoxy-3-oxo-2,3-dihydro-1H-inden-1-yl)acetamide as a white solid.
Reaction SMILES: [N:1]#[C:2][NH2:3].[N:4]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH:20]3[CH2:22][CH2:21]3)[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)=[C:5]=[S:6].Br[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH:34]([F:36])[F:35])[CH:28]=1)=[O:26]>>[NH2:1][C:2]1[N:3]=[C:5]([NH:4][C:7]2[CH:8]=[CH:9][C:10]([N:13]3[CH2:14][CH2:15][N:16]([CH2:19][CH:20]4[CH2:22][CH2:21]4)[CH2:17][CH2:18]3)=[CH:11][CH:12]=2)[S:6][C:24]=1[C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH:34]([F:35])[F:36])[CH:28]=1)=[O:26]
Reactant: S=C=Nc1ccc(N2CCN(CC3CC3)CC2)cc1
Reactant: O=C(CBr)c1cccc(OC(F)F)c1
Reactant: N#CN
Product: Nc1nc(Nc2ccc(N3CCN(CC4CC4)CC3)cc2)sc1C(=O)c1cccc(OC(F)F)c1

Procedure:
This compound was prepared from cyanamide, 1-(4-isothiocyanato-phenyl)-4-cyclopropylmethylpiperazine (of Example 14G) and 2-bromo-1-(3-difluoro-methoxyphenyl)ethanone (of Example 14L) following the procedure used in Example 24. Mass spectrum (ES) MH+=500.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[CH:10]=[C:9]([CH:11]=O)[S:8][C:6]=2[N:7]=1.[CH3:19][NH2:20]>C1(C)C=CC=CC=1.C1COCC1.O>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[CH:10]=[C:9]([CH2:11][NH:20][CH3:19])[S:8][C:6]=2[N:7]=1
Reactant: CN
Reactant: O=Cc1cc2c(N3CCOCC3)nc(Cl)nc2s1
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: CNCc1cc2c(N3CCOCC3)nc(Cl)nc2s1
Temperature: 25 °C
Reaction time: 24 h
Yield: 53 %

Procedure:
To 2-chloro-4-morpholinothieno[2,3-d]pyrimidine-6-carbaldehyde (2.0 g) in 50 mL toluene and 50 mL THF was added 20 mL of 40% methylamine in H2O. The reaction mixture was stirred at room temp under N2 for 24 hours. The solvents were removed in vacuo and the residue was dissolved in 50 mL MeOH and 50 mL THF and the NaBH4 added portion-wise. This reaction mixture was stirred at room temp under N2 for 24 hours and complete reaction was confirmed by LCMS. The solvents were removed in vacuo and the crude product purified by flash chromatography (EtOAc/EtOH) to give 1.12 g (2-chloro-4-morpholinothieno[2,3-d]pyrimidin-6-yl)-N-methylmethanamine (53% yield). MS (Q1) 300 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH2:14][CH:13]([CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH2:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:18][CH2:17]3)[C:11](=[O:12])[C:6]2=[CH:7][C:8]=1[O:9][CH3:10].[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]\[C:32]([OH:34])=[O:33]>CC(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH2:14][CH:13]([CH2:15][CH:16]3[CH2:17][CH2:18][N:19]([CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:20][CH2:21]3)[C:11](=[O:12])[C:6]2=[CH:7][C:8]=1[O:9][CH3:10].[C:29]([O-:36])(=[O:35])/[CH:30]=[CH:31]\[C:32]([O-:34])=[O:33]
Reactant: O=C(O)/C=C\C(=O)O
Agent: COc1cc2c(cc1OC)C(=O)C(CC1CCN(Cc3ccccc3)CC1)C2
Solvent: CC(C)O
Product: O=C([O-])/C=C\C(=O)[O-]
Temperature: 25 °C

Procedure:
Donepezil (3.79 g, dissolved in 20 ml of ethyl acetate) is slowly added to a solution of maleic acid (0.58 g) in 2-propanol (5 ml) with stirring at room temperature. The solid precipitated is filtered and dried at 55° C. under vacuum to give the title compound. Melting point: 129.5° C.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:9][CH2:8][S:7][CH:6]1[CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19])=[O:4].[I-:20].[Na+]>CC(C)=O.O>[I:20][CH2:2][C:3]([N:5]1[CH2:9][CH2:8][S:7][CH:6]1[CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19])=[O:4]
Reactant: COc1ccccc1OCC1SCCN1C(=O)CCl
Reactant: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: COc1ccccc1OCC1SCCN1C(=O)CI
Yield: 75.7 %

Procedure:
A solution of 3-α-chloroacetyl-2-(o-methoxyphenoxy)methyl-thiazolidine (6 g) in acetone (80 ml) is heated to reflux temperature in the presence of sodium iodide (5 g) for 3 hours and then poured in ice and water (400 ml). The precipitate is collected, dissolved in methylene dichloride and washed with water, 5% aqueous NaHCO3, 2N sodium thiosulphate, water and dried on Na2SO4. After the usual work-up, the residue is crystallized from acetone and isopropanol to give 5.92 g of 3-α-iodoacetyl-2-(o-methoxyphenoxy)methyl-thiazolidine m.p. 81°-83° C. Using this procedure sodium bromide, the 3-α-bromoacetyl-2-(o-methoxyphenoxy)methyl-thiazolidine is obtained, m.p. 82°-84° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([S:8]([NH2:11])(=[O:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:12]1(C)C=CC(S(O)(=O)=O)=C[CH:13]=1>C([O-])([O-])(OCC)C>[CH3:12][C:13]1[NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[N:4][C:3]=2[S:8](=[O:10])(=[O:9])[N:11]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Nc1cccnc1S(N)(=O)=O
Agent: CCOC(C)([O-])[O-]
Product: CC1=NS(=O)(=O)c2ncccc2N1
Reaction time: 0.17 h

Procedure:
1 g of 3-aminopyridine-2-sulfonamide (Preparation 1) and 1 g of p-toluenesulfonic acid are dissolved in 6 cm3 of ethyl orthoacetate. After 10 minutes at room temperature, the precipitate obtained is collected on a filter, washed with diethyl ether and dried. It is recrystallized from hot water.
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH2:20][CH3:21])[C:3](=[O:19])[C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][NH:8][N:7]1CC1C=CC=CC=1)=[O:5]>CCO.[Pd]>[CH3:1][C:2]([CH3:22])([CH2:20][CH3:21])[C:3](=[O:19])[C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][NH:8][NH:7]1)=[O:5]
Reactant: CCC(C)(C)C(=O)C(=O)C1CCCNN1Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCC(C)(C)C(=O)C(=O)C1CCCNN1

Procedure:
1 g 10% Pd/C was added to a solution of 3,3-dimethyl-1-[2-benzylperhydropyridazinyl] pentane-1,2-dione (7.0 g, 20.2 mmol) in 70 ml EtOH. The mixture was under hydrogenation at room pressure (1 atm) overnight. The product was obtained as white solid after filtering Pd catalyst and concentration (3.8 g, 89%). 1H NMR (CDCl3, 400 MHz): δ 0.88 (t, 3H, J=7.0); 1.19 (s, 6H); 1.65 (m, 4H); 1.79 (m, 2H); 2.85 (m, 2H); 3.42 (m, 1H); 3.56 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:12][CH2:13][O:14][CH3:15])[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:16][C:17]([CH3:24])([CH3:23])[CH2:18][S:19](Cl)(=[O:21])=[O:20]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([O:3][C:4]([C:6]1([CH2:12][CH2:13][O:14][CH3:15])[CH2:7][CH2:8][N:9]([S:19]([CH2:18][C:17]([CH3:24])([CH3:23])[CH3:16])(=[O:21])=[O:20])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CC(C)(C)CS(=O)(=O)Cl
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C1(CCOC)CCN(S(=O)(=O)CC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (0.72 g) in methylene chloride (40 ml) was added at RT under an argon atmosphere DMAP (0.75 g) and then dropwise 2,2-dimethyl-propane-1-sulfonyl chloride (0.57 ml). The reaction mixture was stirred 12 h at RT then partitioned between AcOEt and aqueous 1M HCl, the layers were separated and the aqueous layer washed with 2M aqueous KHCO3 then dried over Na2SO4. The solvent was evaporated off, the residue purified by flash chromatography (AcOEt/heptane, gradient from 0 to 40%) to give the desired 1-(2,2-dimethyl-propane-1-sulfonyl)-4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (0.34 g) as a light yellow viscous oil.
Reaction SMILES: I[C:2]1[C:7]2[O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:15]1(B(O)O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O.C1(C)C=CC=CC=1>[C:15]1([C:2]2[C:7]3[O:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Ic1cccc2c1oc1ccccc12
Reactant: OB(O)c1ccccc1
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: c1ccc(-c2cccc3c2oc2ccccc23)cc1
Temperature: 25 °C

Procedure:
4-iododibenzo[b,d]furan (4 g, 13.60 mmol), phenylboronic acid (1.99 g, 16.32 mmol), dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (0.447 g, 1.08 mmol), Pd2(dba)2 (0.250 g, 0.272 mmol), K3PO4 (10.1 g, 47.6 mmol), 150 mL toluene and 15 mL water were charged in a 250 mL flask. The reaction mixture was degassed by bubbling N2 for 30 minutes and then heated to reflux under N2 overnight. The reaction was cooled to room temperature and the crude product was purified by silica gel column to yield 3.3 g (99%), which was confirmed by GC-MS.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:15][CH:14]=2)[N:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCN(CC)CC.[C:54]([C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=1[CH2:62][C:63]([O:65][CH3:66])=[O:64])#[CH:55]>CN(C=O)C.C1(C)C=CC=CC=1.[Cu]I.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>[C:21]([O:20][C:19]([NH:18][CH2:17][C:16]1[CH:26]=[CH:27][C:13]([NH:12][C:4]2[N:3]=[C:2]([C:55]#[C:54][C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=3[CH2:62][C:63]([O:65][CH3:66])=[O:64])[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)=[CH:14][CH:15]=1)=[O:25])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)NCc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1
Reactant: C#Cc1ccccc1CC(=O)OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccccc1C#Cc1nc(Nc2ccc(CNC(=O)OC(C)(C)C)cc2)ncc1C(F)(F)F
Temperature: 120 °C

Procedure:
A suspension of tert-butyl 4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzylcarbamate (A12) (500 mg, 1.24 mmol), CuI (12 mg, 0.06 mmol), PPh3 (16 mg, 0.06 mmol), and Et3N (346 μL, 2.28 mmol) in DMF (3 mL) was sonicated for 5 minutes before the addition of PdCl2(PPh3)2 (44 mg, 0.06 mmol) and methyl 2-(2-ethynylphenyl)acetate (K1) (324 mg, 1.86 mmol). The resulting mixture was heated under microwave irradiation at 120° C. for 20 minutes then adsorbed onto silica gel and purified by column chromatography (Biotage Isolera, SiO2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.) to yield a yellow solid. The solid was suspended in toluene and the resulting suspension sonicated for 10 minutes. The resulting suspension was filtered and the filter cake dried to give the title compound A13 as a yellow solid (412 mg, 61%); 1H NMR (400 MHz, d6-DMSO) δ 10.44 (s, 1H), 8.82 (s, 1H), 7.68 (d, J=8.4 Hz, 2H), 7.63 (d, J=7.6 Hz, 1H), 7.58-7.52 (m, 1H), 7.50-7.40 (m, 2H), 7.36 (t, J=6.0 Hz, 1H), 7.22 (d, J=8.5 Hz, 2H), 4.10 (d, J=6.0 Hz, 2H), 3.96 (s, 2H), 3.62 (s, 3H), 1.40 (s, 9H). LCMS-A: rt 6.497 min; m/z 539 [M−1]−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[S:9]([CH3:12])(=[O:11])=[O:10].[CH3:13][O:14][C:15]([C:17]1[CH:27]=[C:26]([OH:28])[C:20]2[CH2:21][C:22]([CH3:25])([CH3:24])[O:23][C:19]=2[CH:18]=1)=[O:16].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:13][O:14][C:15]([C:17]1[CH:27]=[C:26]([O:28][C:6]2[CH:5]=[CH:4][C:3]([S:9]([CH3:12])(=[O:11])=[O:10])=[C:2]([Cl:1])[CH:7]=2)[C:20]2[CH2:21][C:22]([CH3:25])([CH3:24])[O:23][C:19]=2[CH:18]=1)=[O:16]
Reactant: COC(=O)c1cc(O)c2c(c1)OC(C)(C)C2
Reactant: CS(=O)(=O)c1ccc(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Oc2ccc(S(C)(=O)=O)c(Cl)c2)c2c(c1)OC(C)(C)C2
Temperature: 80 °C
Yield: 91.9 %

Procedure:
A mixture of 2-chloro-4-fluoro-1-(methylsulfonyl)benzene (939 mg, 4.50 mmol), 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (3e) (1.00 g, 4.50 mmol) and Cs2CO3 (2.93 g, 9.00 mmol) in DMF (5 mL) was heated to 80° C. for 1.5 h, cooled to room temperature, quenched with H2O and extracted with 3×EtOAc. The organic layers were washed with 2×H2O, dried over Na2SO4 and concentrated. The residue was purified by Biotage column chromatography with 25-50% EtOAc in hexanes to give a white solid (1.70 g, 92% yield). 1H NMR (400 MHz, CDCl3) δ 8.11 (d, J=8.84 Hz, 1H) 7.31 (d, J=1.26 Hz, 1 H) 7.25 (d, J=1.26 Hz, 1 H) 7.10 (d, J=2.27 Hz, 1 H) 6.88-7.03 (m, 1 H) 3.89 (s, 3 H) 3.28 (s, 3 H) 2.88 (s, 2 H) 1.50 (s, 6 H); LCMS for C19H19ClO6S m/z 411.00 and 413.00 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[CH2:7][CH2:8][NH:9]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:19][C:20]1[S:21][CH:22]=[CH:23][C:24]=1[C:25](Cl)=[O:26]>ClCCl.O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[CH2:7][CH2:8][N:9]2[C:25]([C:24]2[CH:23]=[CH:22][S:21][C:20]=2[CH3:19])=[O:26])=[CH:4][CH:3]=1
Reactant: O=C1CCNc2cc(Cl)ccc21
Reactant: Cc1sccc1C(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1sccc1C(=O)N1CCC(=O)c2ccc(Cl)cc21
Yield: 83.2 %

Procedure:
To a mixture of 7-chloro-2,3-dihydro-4(lH)-quinolinone (20.0 g), pyridine (26 g) and dichloromethane (200 ml) was added dropwise 2-methyl-3-thienylcarbonyl chloride (26 g) at room temperature with stirring. The mixture was stirred under reflux for 4 hours. The reaction mixture was poured into 500 ml of water, then shaken with additional dichloromethane (1000 ml). The organic layer was washed once with 1 N HCl (100 ml), twice with water (200 ml each) and once with saturated aqueous NaCl solution, then dried over anhydrous sodium sulfate. Solvent was removed in vacuo and 7-chloro-2,3-dihydro-l-(2-methyl-3-thienylcarbonyl)-4(lH)-quinolinone (yield 28 g) was obtained as colorless oil.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[N:6][C:7]([OH:10])=[N:8][CH:9]=1.[C:11]([O:15][C:16](=[O:19])[CH2:17]Br)([CH3:14])([CH3:13])[CH3:12].O>CN(C=O)C>[C:11]([O:15][C:16](=[O:19])[CH2:17][O:10][C:7]1[N:8]=[CH:9][C:4]([Br:3])=[CH:5][N:6]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: Oc1ncc(Br)cn1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1ncc(Br)cn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
137 mg of sodium hydride (55% in mineral oil) were added to 500 mg (2.86 mmol) of 5-bromo-pyrimidin-2-ol in 20 ml of DMF, and the mixture was stirred at room temperature for 15 min. Then 613 mg (3.14 mmol) of bromoacetic acid tert-butyl ester were added and the reaction mixture was stirred for 1 h. After addition of water, the mixture was extracted with ethyl acetate. The combined extracts were dried and evaporated to give the crude product. Yield: 868 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([C:8](C)(C)[C:9](OCC)=[O:10])=O)=[CH:4][CH:3]=1.O.[NH2:19][NH2:20]>C(O)C>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]2[CH2:8][C:9](=[O:10])[NH:20][N:19]=2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: CCOC(=O)C(C)(C)C(=O)c1ccc(Cl)cc1
Solvent: O
Solvent: CCO
Product: O=C1CC(c2ccc(Cl)cc2)=NN1
Yield: 82212.5 %

Procedure:
A mixture of 26 g (0.10 mmol) of ethyl α-(4-chlorobenzoyl)isobutyrate, 10 g (0.20 mmol) of hydrazine monohydrate and 200 ml of ethanol was heated under reflux for 18 hours. The reaction solution was concentrated under reduced pressure. The obtained crude product was washed successively with water, methanol-water and diethyl ether-n-hexane, and then air dried to give 16 g of the object compound as white crystals (yield 84%).
Reaction SMILES: [C:1]([CH:6]([CH2:10][CH3:11])[C:7]([OH:9])=[O:8])([O:3]CC)=[O:2].C(N[CH2:15][CH3:16])C.[CH2:17]=O.S(=O)(=O)(O)O>>[CH2:11]([CH:10]=[C:6]([CH2:15][CH3:16])[C:7]([OH:9])=[O:8])[CH3:17].[CH2:10]([C:6](=[CH2:7])[C:1]([OH:3])=[O:2])[CH3:11]
Reactant: CCOC(=O)C(CC)C(=O)O
Reactant: CCNCC
Reactant: C=O
Agent: O=S(=O)(O)O
Product: C=C(CC)C(=O)O
Product: CCC=C(CC)C(=O)O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The 2-carboethoxybutyric acid obtained in step (a) was cooled to −5° C. and diethylamine was added. A solution of formalin was added dropwise into the cooled reaction mixture which was then allowed to warm to room temperature. After stirring for 24 h the reaction mixture was warmed to 60° C. and stirred for 8 h more. The mixture consisted of two layers, which were cooled to 0° C. Concentrated sulfuric acid was added and the mixture is extracted with three 200 ml portions of diethyl ether. The ether extracts were combined, dried over magnesium sulfate and filtered. The ether was removed under reduced pressure to produce ethyl 2-ethylacrylate as a yellow oil.