Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C:7](=[O:13])[CH2:6][CH2:5]2.[F:14][C:15]([F:26])([F:25])[S:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C:7](=[O:13])/[C:6](=[CH:21]/[C:20]1[CH:23]=[CH:24][C:17]([S:16][C:15]([F:26])([F:14])[F:25])=[CH:18][CH:19]=1)/[CH2:5]2
Reactant: COc1cc2c(cc1Br)CCC2=O
Reactant: O=Cc1ccc(SC(F)(F)F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: COc1cc2c(cc1Br)C/C(=C\c1ccc(SC(F)(F)F)cc1)C2=O
Temperature: 120 °C
Reaction time: 6 h

Procedure:
To a solution of 5-bromo-6-methoxy-2,3-dihydro-1H-inden-1-one 11 (250 mg, 0.1037 mmol) in benzene was added 4-((trifluoromethyl)thio)benzaldehyde 72 (213 mg, 0.103 mmol). PTSA (395 mg, 0.207 mmol) was added, the reaction mass was stirred at 120° C. for 6 h, then diluted with ethyl acetate and washed with water (3×25 mL). The organic layer was dried over sodium sulphate and concentrated to get the crude compound 104 and was purified through flash chromatography by using 100-200 mesh silica gel. The compound 104 was eluted at 30% ethyl acetate in hexane to afford yellow coloured solid.
Reaction SMILES: [CH3:1][C:2]1[C:3](=O)[NH:4][N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1.P(Cl)(Cl)([Cl:17])=O.[Cl-].[Cl-].[Ca+2].Cl.OP(O)(O)=O.[OH-].[Na+]>C(#N)C>[Cl:17][C:3]1[N:4]=[N:5][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:7][C:2]=1[CH3:1]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(-c2ccccc2)n[nH]c1=O
Agent: Cl
Agent: O=P(O)(O)O
Agent: [Ca+2]
Solvent: CC#N
Product: Cc1cc(-c2ccccc2)nnc1Cl
Temperature: 25 °C
Yield: 96 %

Procedure:
6.0 g (32 mmole) of 3 is placed in a 250 mL single neck round bottom flask and 30 mL of acetonitrile is added to create a pale yellow slurry. 6.0 ml (64 mmole, 2 equiv.) of phosphorus oxychloride is added changing the slurry to a darker color. The flask is fitted with a reflux condenser and a dry tube filled with anhydrous CaCl2 is fitted to the top of the condenser. The reaction mixture is heated at reflux and becomes a dark red liquid. After the reaction is completed (2.5 h), the mixture is cooled to ambient temperature and placed in an ice water bath. Ice water (150 mL) is slowly poured into the reaction mixture with stirring to decompose the phosphorus oxychloride into HCl and H3PO4, resulting in formation of a pink solid. The solid is collected by filtration and washed three times with 50 mL of Milli-Q water. The solid is transferred to a 250 mL beaker, followed by addition of 100 mL of water to form a suspension. Subsequently, 1N NaOH is added until the aqueous suspension is at pH=8, and the mixture is stirred for 5 minutes to remove all trace starting material contaminants. The solid is filtered and washed 3 times with 100 mL of water to wash out the excess base. The solid is dried over a medium frit sintered glass funnel in vacuo to provide 4 as a light pink powder in 96% yield. [See Contreras, J M et al. Journal of Medicinal Chemistry, 2001, 44(17), 2707-2718; Nelson, D A. US 20050137397A1.]
Reaction SMILES: [OH-].[Na+].CCCCCC.[CH2:9]([C:11]1([CH2:15][OH:16])[CH2:14][O:13][CH2:12]1)[CH3:10].[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]Br>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:16][CH2:15][C:11]1([CH2:9][CH3:10])[CH2:14][O:13][CH2:12]1
Reactant: BrCCCCCCBr
Reactant: CCC1(CO)COC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Product: CCC1(COCCCCCCBr)COC1
Temperature: 25 °C
Yield: 55.4 %

Procedure:
To a solution consisting of sodium hydroxide (50% in water, 50 g), hexane (50 ml) and tetrabutylammonium bromide (0.7 g) was added 3-ethyl-3-oxetanemethanol (5.0 g, 43.0 mmol) and 1,6-dibromohexane (30 g, 122.9 mmol). This mixture was heated at reflux for 5 h. After cooling to room temperature, the resulting mixture was diluted with water (100 ml) and extracted with ethyl acetate (3×100 ml). The extracts were combined and dried over sodium sulphate. The solvent was removed under reduced pressure and the residue was purified by column chromatography, eluting with petrol/ethyl acetate (9:1), to give a colourless oil (6.65 g, 55%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.44 (d, J=5.8 Hz, 2H, OCH2), 4.37 (d, J=5.8 Hz, 2H, OCH2), 3.52 (s, 2H, OCH2), 3.46 (t, J=6.4 Hz, 2H, OCH2), 3.40 (t, J=6.8 Hz 2H, BrCH2), 1.35-1.91 (m, 10H, CH2), 0.88 (t, J=7.5 Hz, 6H, CH3); 13C NMR (75 MHz, CDCl3): δ (ppm) 78.5 (OCH2), 73.4 (OCH2), 71.3 (OCH2), 43.4 (quat.), 33.8 (CH2), 32.7 (CH2), 29.3 (CH2), 27.9 (CH2) 26.8 (CH2), 25.4 (CH2), 8.2 (CH3). MS (m/e): 279 (MH+, 0.1%) □281 (MH+, 0.1%), 248 (3), 250 (3), 83 (89), 55 (100), 41 (86).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.CC([O-])(C)C.[K+].Cl[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([C:22]([NH2:24])=[O:23])[CH:17]=1>CN(C=O)C.CCOC(C)=O.O>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([C:22]([NH2:24])=[O:23])[CH:17]=2)=[CH:4][CH:3]=1
Reactant: NC(=O)c1cc(Cl)ccn1
Reactant: Nc1ccc(O)cn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1cc(Oc2ccc(N)nc2)ccn1
Temperature: 80 °C
Yield: 50 %

Procedure:
To a mixture of 6-aminopyridin-3-ol (220 mg, 2 mmol) and t-BuOK (225 mg, 2.16 mmol) in DMF (2.5 mL) was added 4-chloropicolinamide (315 mg, 2 mmol). The reaction was heated to 80° C. for 5 hours, then cooled to rt and diluted with EtOAc (50 mL) and H2O (50 mL). The organic phase was concentrated in vacuo and the residue was purified by a silica gel column chromatography (DCM/CH3OH (v/v)=30/1) to give the title compound as a brown solid (230 mg, 50%).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][C:12](Br)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[CH:18]#[C:19][CH2:20][CH2:21][CH3:22].FC1C(F)=C(OCCCCCCCC)C=CC=1C1N=CC(C#CCCCCCCC)=CN=1.[K+].[Br-]>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.[Cu]I.C(NC(C)C)(C)C>[F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][C:12]([C:18]#[C:19][CH2:20][CH2:21][CH3:22])=[CH:11][N:10]=2)=[CH:5][CH:4]=1
Reactant: C#CCCC
Reactant: FC(F)(F)c1ccc(-c2ncc(Br)cn2)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCCCCCC#Cc1cnc(-c2ccc(OCCCCCCCC)c(F)c2F)nc1
Solvent: CC(C)NC(C)C
Product: CCCC#Cc1cnc(-c2ccc(C(F)(F)F)cc2)nc1
Yield: 86.1 %

Procedure:
--Quantities: 2-[4'-Trifluoromethylphenyl]-5-bromopyrimidine 10 (1.48 g, 4.88 mmol), pent-1-yne (0.96 ml, 9.76 mmol), tetrakis(triphenylphosphine)palladium (350 mg, 0.30 mmol), copper(I) iodide (57 mg, 0.30 mmol), diisopropylamine (20 ml). The experimental procedure was as described for compound 38 to give the pentynylpyrimidine 40 (1.22 g, 86%) (from MeOH), m.p. 140.5° C., νmax /cm-1 (KBr) 2970, 2200(C≡C), 1520, 1430, 1325s, 1165, 1115, 1075 and 1015, ≡ 1.07(3H, t, Me), 1.68 (2H, sext, CH2CH3), 2.47 (2H, t, CH2C≡C), 7.74 (2H, d, 3'- and 5'-H), 8.55(2H, d, 2' and 6'-H) and 8.79 (2H, s, 4- and 6-H); m/z 290 (M+), 275, 261, 248, 172 and 152.
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].Br[C:15]1[N:20]=[CH:19][CH:18]=[CH:17][N:16]=1.O>CN(C=O)C>[N:16]1[CH:17]=[CH:18][CH:19]=[N:20][C:15]=1[CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: Brc1ncccn1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)OCC)c1ncccn1
Temperature: 100 °C
Yield: 49.5 %

Procedure:
To a solution of sodium hydride (4.4 g of a 60% dispersion in oil, 0.11 mol) in DMF (200 ml) was added diethyl malonate (16 ml, 0.11 mol) in DMF (50 ml) dropwise at room temperature. After 30 min 2-bromopyrimidine (8.0 g, 0.05 mol) was added portionwise and the solution heated at 100° C. for 3 h. The solution was cooled to room temperature, water (100 ml) was added and the mixture extracted with EtOAc (3×60 ml). The combined organic layers were dried (MgSO4) and evaporated. The residue was chromatographed on silica, using hexane:EtOAc (3:1) as the eluant, to afford the ester (5.9 g, 49%) as a pale yellow oil which solidified on standing at 0° C. 1H NMR (360 MHz, CDCl3) δ 1.29 (6H, t, J=7.1 Hz), 4.29 (4H, q, J=7.1 Hz), 5.10 (1H, s), 7.26 (1H, t, J=4.9 Hz), 8.74 (2H, d, J=4.9 Hz).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C@H:4]([NH2:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[F:12].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>C(#N)C>[CH3:1][O:2][C:3](=[O:14])[C@H:4]([N:13]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[F:12]
Reactant: BrCc1ccccc1
Reactant: COC(=O)[C@H](N)Cc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)[C@@H](Cc1ccccc1F)N(Cc1ccccc1)Cc1ccccc1
Temperature: 50 °C

Procedure:
To a solution of (R)-2-Amino-3-(2-fluoro-phenyl)-propionic acid methyl ester (4 g, 17 mmol) and benzyl bromide (4.5 mL, 38 mmol) in 200 mL of acetonitrile is added potassium carbonate. After 5 hours the reaction is heated at 50° C. for 16 hours. The reaction mixture is then cooled to room temperature and is poured into 500 mL of saturated ammonium chloride. The product is extracted into dichloromethane and the combined organic phases are dried over sodium sulfate, filtered and concentrated. Purification of the crude residue by silica gel flash column chromatography gives the title compound.
Reaction SMILES: S(=O)(=O)(O)O.CSC.CO.[C:11](O)(C)(C)C.[C:16]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[OH-].[K+]>>[C:17]1([C:16]2([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:23][CH2:11]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)O
Reactant: O=C(c1ccccc1)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CSC
Product: c1ccc(C2(c3ccccc3)CO2)cc1
Reaction time: 2 h

Procedure:
Sulphuric acid (23.7 g at 98%, 0.237 moles) was added dropwise, with stirring, to dimethylsulphide (20.0 g at 98%, 0.316 moles) over 60 minutes, maintaining the temperature below 26° C. Methanol (5.0 g, 0.156 mole) was added slowly to the stirred mixture maintaining the temperature below 31° C. The reaction mixture was stirred for 41/2 hours and head overnight unagitated at room temperature. Tertiary butanol (3.6 g, 0.048 mole) and benzophenone (27.4 g, 0.15 mole) were added to the reaction mixture. Potassium hydroxide flake (43.4 g, 0.73 mole) was added in 10 equal aliquots over 3 hours while maintaining the temperature below 40° C. The reaction was monitored by GC and then stirred overnight at room temperature.
Reaction SMILES: [CH2:1]([C:5]12[CH2:17][CH2:16][C:15](=[O:18])[C:14]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][N:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[CH:21][CH:20]=3)=[C:13]1[C:12]1[C:7](=[CH:8][C:9]([O:34]C)=[CH:10][CH:11]=1)[CH2:6]2)[CH2:2][CH2:3][CH3:4].CCS.[Al+3].[Cl-].[Cl-].[Cl-].Cl.C([O-])(O)=O.[Na+]>C(Cl)Cl.CCOC(C)=O.O.O1CCCC1>[CH2:1]([C:5]12[CH2:17][CH2:16][C:15](=[O:18])[C:14]([C:19]3[CH:20]=[CH:21][C:22]([O:25][CH2:26][CH2:27][N:28]4[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]4)=[CH:23][CH:24]=3)=[C:13]1[C:12]1[C:7](=[CH:8][C:9]([OH:34])=[CH:10][CH:11]=1)[CH2:6]2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC12CCC(=O)C(c3ccc(OCCN4CCCCC4)cc3)=C1c1ccc(OC)cc1C2
Agent: Cl
Agent: O=C([O-])O
Agent: [Al+3]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCC12CCC(=O)C(c3ccc(OCCN4CCCCC4)cc3)=C1c1ccc(O)cc1C2
Temperature: 0 °C
Reaction time: 0.05 h

Procedure:
An ice-cold solution of 9a-butyl-7-methoxy-4-{4-[2-(1-piperidinyl)-ethoxy]phenyl}-1,2,9,9a-tetrahydro-3H-fluoren-3-one (85 mg, 96% weight pure, 0.172 mmol) in anhydrous CH2Cl2 (1.2 mL) was placed under a nitrogen atmosphere and treated with EtSH (0.055 mL, 0.743 mmol). The resulting solution was added by syringe to AlCl3 (115.2 mg, 0.864 mmol) contained in an ice-cold flask and kept under nitrogen. The resulting solution was stirred at 0° C. for 3 minutes, then at room temperature for 35 minutes. The mixture was cooled in an ice bath, treated with 0.5N HCl (1.6 mL) and tetrahydrofuran (1.0 mL), and stirred at 0° C. for 10 minutes. The resulting mixture was diluted with EtOAc (20 mL) and water (15 mL) and stirred while basifying with solid NaHCO3. The layers were separated and the aqueous portion extracted with EtOAc. The combined organics were washed with brine, dried over MgSO4, filtered, and evaporated under vacuum to afford 9a-butyl-7-hydroxy-4-{4-[2-(1-piperidinyl)ethoxy]phenyl}-1,2,9,9a-tetrahydro-3H-fluoren-3-one as a yellow semi-solid.
Reaction SMILES: [N:1]([CH:4]1[CH2:19][CH2:18][C:7]2=[C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[S:9][C:10]([S:11][CH3:12])=[C:6]2[C:5]1=[O:20])=[N+]=[N-].[C:21](OC(=O)C)(=[O:23])[CH3:22]>[C].[Pd].C(O)(=O)C>[C:21]([NH:1][CH:4]1[CH2:19][CH2:18][C:7]2=[C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[S:9][C:10]([S:11][CH3:12])=[C:6]2[C:5]1=[O:20])(=[O:23])[CH3:22]
Reactant: CCOC(=O)c1sc(SC)c2c1CCC(N=[N+]=[N-])C2=O
Reactant: CC(=O)OC(C)=O
Agent: [Pd]
Solvent: CC(=O)O
Product: CCOC(=O)c1sc(SC)c2c1CCC(NC(C)=O)C2=O
Yield: 73.8 %

Procedure:
A mixture of ethyl 5-azido-4,5,6,7-tetrahydro-3-methylthio-4-oxobenzo[c]thiophene-1-carboxylate (3.62 g), palladium-carbon (5%, 50% wet, 4.0 g), acetic acid (70 ml) and acetic anhydride (35 ml) was subjected to a catalytic reduction reaction at room temperature under 1 atm. The insoluble substances were filtered off; the filtrate was concentrated under reduced pressure; the residue was dissolved in ethyl acetate-tetrahydrofuran (3:1, v/v). This solution was washed with water, a saturated aqueous solution of sodium hydrogen carbonate and water in that order, and dried (MgSO4), after which the solvent was distilled off to yield ethyl 5-acetylamino-4,5,6,7-tetrahydro-3-methylthio-4-oxobenzo[c]thiophene-1-carboxylate (2.81 g, 73.8%), which was then recrystallized from chloroform-ethanol. Colorless needles. Melting point 215-216° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(=O)([O-])[O-].[Cs+].[Cs+].[C:18]([N:21]1[C@@H:25]([CH3:26])[CH2:24][CH2:23][C@@H:22]1[C:27]1[C:32](F)=[CH:31][C:30]([NH:34][C:35]([C:37]2[CH:42]=[N:41][CH:40]=[CH:39][N:38]=2)=O)=[C:29]([N+:43]([O-])=O)[CH:28]=1)(=[O:20])[CH3:19].O.O.[Sn](Cl)Cl.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.CN1CCCC1=O>[C:18]([N:21]1[C@@H:25]([CH3:26])[CH2:24][CH2:23][C@@H:22]1[C:27]1[C:32]([O:11][C:8]2[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=2)=[CH:31][C:30]2[N:34]=[C:35]([C:37]3[CH:42]=[N:41][CH:40]=[CH:39][N:38]=3)[NH:43][C:29]=2[CH:28]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)N1[C@@H](c2cc([N+](=O)[O-])c(NC(=O)c3cnccn3)cc2F)CC[C@@H]1C
Reactant: CS(=O)(=O)c1ccc(O)cc1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)N1[C@@H](c2cc3[nH]c(-c4cnccn4)nc3cc2Oc2ccc(S(C)(=O)=O)cc2)CC[C@@H]1C
Temperature: 90 °C
Reaction time: 1 h

Procedure:
9.2 mg of 4-methanesulfonyl-phenol and 26.2 mg of cesium carbonate were added to an N-methylpyrrolidinone (1 ml) solution of 10.4 mg of N-(4-((2R,5S)-1-acetyl-5-methylpyrrolidin-2-yl)-5-fluoro-2-nitrophenyl)pyrazine-2-carboxamide, and the reaction liquid was stirred at 90° C. for 1 hour. 60 mg of tin(II) chloride dihydrate was added to it, and the reaction liquid was stirred at 90° C. for 1 h our and at 100° C. for 2 hours. Ethyl acetate and aqueous saturated sodium bicarbonate were added to the reaction liquid, the resulting deposit was removed through filtration, extracted with ethyl acetate, and the organic layer was washed with water and saturated saline, and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, and purified through partitioning thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol=10/1) to obtain the entitled compound as a pale yellow oily substance.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([CH2:12][CH2:13][NH2:14])[C:9]2[C:4](=[CH:5][C:6]([C:15]([F:18])([F:17])[F:16])=[CH:7][CH:8]=2)[N:3]=1.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:19][C:20]([F:31])([F:30])[C:21]1[CH:26]=[CH:25][C:24]([C:2]2[N:11]=[C:10]([CH2:12][CH2:13][NH2:14])[C:9]3[C:4](=[CH:5][C:6]([C:15]([F:18])([F:17])[F:16])=[CH:7][CH:8]=3)[N:3]=2)=[CH:23][CH:22]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: NCCc1nc(Cl)nc2cc(C(F)(F)F)ccc12
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: O
Solvent: COCCOC
Product: NCCc1nc(-c2ccc(C(F)(F)F)cc2)nc2cc(C(F)(F)F)ccc12

Procedure:
A solution of (2-chloro-7-trifluoromethyl-quinazolin-4-yl)ethylamine (276 mg, 1.00 mmol), p-trifluoromethylphenylboronic acid (285 mg, 1.50 mmol), tetrakis(triphenylphosphine)palladium (116 mg, 0.10 mmol) and sodium carbonate (0.21 g, 2.0 mmol) in dimethoxyethane/water (3 mL, 2:1) was heated at 80° C. for 16 h. The reaction mixture was then concentrated under reduced pressure, diluted with water (50 mL) and extracted with CH2Cl2 (3×25 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. Purification by flash chromatography using cyclohexane:ethyl acetate (4:1) as solvent afforded [2-(4-trifluoromethylphenyl)-7-trifluoromethyl-quinazolin-4-yl]ethylamine. Yield=0.20 g, 52%; LC-MS: 3.2 min, 385 (M+); 1H NMR (DMSO-d6): δ 1.34 (t, 3 H, J=7.2 Hz), 3.68-3-78 (m, 2 H), 7.82 (dd, 1 H, J=8.6, 1.7 Hz), 7.88 (d, 2 H, J=8.1 Hz), 8.07 (s, 1 H), 8.50 (d, 1 H, J=8.6 Hz), 8.67 (d, 2 H, J=8.1 Hz), 8.70-8.76 (m, 1 H).
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[F:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[NH:13][NH2:14]>C(O)C>[F:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[NH:13][NH:14][CH2:3][CH2:2][C:1]#[N:4]
Reactant: C=CC#N
Reactant: NNc1cc(F)ccc1F
Solvent: CCO
Product: N#CCCNNc1cc(F)ccc1F
Yield: 73 %

Procedure:
A solution of acrylonitrile (10 mL), ethanol (20 mL) and 2,5-difluorophenylhydrazine (790 mg) was heated to reflux for 2 days. The reaction was concentrated under vacuum and the product purified by flash chromatography on silica gel with methylene chloride to give 790 mg (73%) 3-(2-(2,5-difluorophenyl)hydrazinyl)propanenitrile. LCMS (ESI) m+H=198.2; 1H NMR (400 MHz, CDCl3) δ 6.99 (ddd, 1H), 6.89 (ddd, 1H), 6.38 (tt, 1H), 5.45 (s, 1H), 3.91 (s, 1H), 3.19 (td, 2H), 2.61 (t, 2H).
Reaction SMILES: [CH3:1][CH:2]([C:8](OCC)=O)[C:3]([O:5]CC)=O.[Br:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1CBr.[OH-].[K+].Cl.O=S(Cl)Cl.[Al+3].[Cl-].[Cl-].[Cl-]>C(O)C.O.ClCCl>[Br:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[C:16]2[C:15]=1[CH2:8][CH:2]([CH3:1])[C:3]2=[O:5]
Reactant: CCOC(=O)C(C)C(=O)OCC
Reactant: Fc1ccc(CBr)c(Br)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: CC1Cc2c(Br)cc(F)cc2C1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of sodium ethoxide in ethanol obtained from 5.95 g (0.26 mmol) of sodium and 200 ml of anhydrous ethanol, a solution of 45.1 g (0.26 mmol) of diethyl methylmalonate in 200 ml of ethanol was added dropwise, while vigorously stirring, over 15 min. Then, 64.3 g (0.24 mmol) of 2-bromo-1-(bromomethyl)-4-fluorobenzene in 50 ml of ethanol was added dropwise with such a rate, so the reaction mixture would be slowly refluxing. The resulting mixture was additionally refluxed for 4 h, then cooled to room temperature, and a solution of 51.8 g of potassium hydroxide in 150 ml of water was added. This mixture was refluxed for 3 h, and then ethanol was distilled off at atmospheric pressure. The solution obtained was cooled to ambient temperature and acidified by saturated hydrochloric acid to pH 1. The precipitate formed was filtered off, washed with 2×150 ml of cold water, and dried in air. The dibacic acid obtained was then dehcarboxylated by heating it at 160° C. for 2 h. To the viscous oil obtained, 60 ml of SOCl2 was added, and the resulting mixture was stirred for 24 h at room temperature. The excess of SOCl2 was distilled off, and the residue was dissolved in 200 ml of anhydrous dichloromethane. The solution obtained was added dropwise to a suspension of 37.7 g (0.28 mmol) of AlCl3 in 800 ml of dichloromethane for 1 h at 0° C. The reaction mixture was refluxed for 3 h, then cooled to room temperature, poured on 300 cm3 of ice, and finally acidified by saturated HCl to pH 3. The organic layer was separated, and the aqueous layer was washed with 3×200 ml of methyl-tert-butyl ether. The combined organic fractions were dried over K2CO3 and then evaporated to dryness. The title product was isolated using flash chromatography (d 50 mm, l 800 mm, eluent: hexanes-CH2Cl2, 2:1, vol.). Yield 47.3 g (81%).
Reaction SMILES: Cl[C:2]([CH:4]=[CH:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:3].[NH2:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][C:21]=1[O:22][CH2:23][CH:24]1[CH2:26][CH2:25]1)[N:18]=[CH:17][N:16]=[C:15]2[NH:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[C:30]([Cl:35])[CH:29]=1.C(N(C(C)C)CC)(C)C>O1CCCC1>[Cl:35][C:30]1[CH:29]=[C:28]([NH:27][C:15]2[C:14]3[C:19](=[CH:20][C:21]([O:22][CH2:23][CH:24]4[CH2:25][CH2:26]4)=[C:12]([NH:11][C:2](=[O:3])[CH:4]=[CH:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:13]=3)[N:18]=[CH:17][N:16]=2)[CH:33]=[CH:32][C:31]=1[F:34]
Reactant: Nc1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1OCC1CC1
Reactant: CCOC(=O)C=CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C=CC(=O)Nc1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1OCC1CC1

Procedure:
A solution of 3.00 g of ethyl 3-chlorocarbonyl-acrylate in 50 ml of tetrahydrofuran is added dropwise to 5.00 g of 6-amino-4-[(3-chloro-4-fluorophenyl)amino]-7-cyclopropylmethoxy-quinazoline and 3.5 ml of diisopropylethylamine in 150 ml of tetrahydrofuran while cooling with an ice bath. The reaction mixture is stirred for a further hour while cooling with an ice bath and then stirred overnight at ambient temperature. Next, the solvent is largely distilled off in the rotary evaporator and the residue is partitioned between water and ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried over magnesium sulphate and concentrated by evaporation. The brown, oily crude product is stirred with diethylether, the precipitate formed is suction filtered and washed with a little diethylether. Yield: 3.20 g (47% of theory), Rf value: 0.80 (silica gel, ethyl acetate) Mass spectrum (ESI*): m/z=485, 487 [M+]*
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8]([C:11]3[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][N:12]=3)=[CH:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[H][H]>CO.C(OCC)(=O)C.[OH-].[OH-].[Pd+2]>[O:4]1[C:5]2([CH2:6][CH2:7][CH:8]([C:11]3[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][N:12]=3)[CH2:9][CH2:10]2)[O:1][CH2:2][CH2:3]1
Reactant: [H][H]
Reactant: COC(=O)c1ccc(C2=CCC3(CC2)OCCO3)nc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C2CCC3(CC2)OCCO3)nc1
Reaction time: 3 h

Procedure:
Palladium hydroxide on carbon (1 g, 20 wt % Pd) was added to a solution of Example 93A (2.66 g, 9.66 mmol) in methanol (40 mL) and ethyl acetate (10 mL). The mixture was placed under vacuum and filled with hydrogen (balloon) and allowed to stir for 3 hours before it was filtered through a pad of Celite using methanol to rinse. The solvent was evaporated and the product was dissolved in dichloromethane and dried over Na2SO4. After filtration and concentration, the title compound was isolated as a slightly yellow solid and used in the following step without further purification.