Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.C([O:10][C:11](=[O:40])[C@@H:12]([O:37][CH2:38][CH3:39])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([NH:29]C(OC(C)(C)C)=O)=[CH:25][CH:24]=2)=[CH:16][CH:15]=1)C.[Cl:41]CCl>>[ClH:41].[NH2:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][CH2:21][O:20][C:17]2[CH:18]=[CH:19][C:14]([CH2:13][C@H:12]([O:37][CH2:38][CH3:39])[C:11]([OH:40])=[O:10])=[CH:15][CH:16]=2)=[CH:28][CH:27]=1
Reactant: ClCCl
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCc2ccc(NC(=O)OC(C)(C)C)cc2)cc1)OCC
Solvent: O=C(O)C(F)(F)F
Product: CCO[C@@H](Cc1ccc(OCCc2ccc(N)cc2)cc1)C(=O)O
Product: Cl
Temperature: 25 °C
Yield: 96.5 %

Procedure:
Trifluoroacetic acid (12 ml; 0.0706 mole) was added to a solution of 3-{4-[2-(4-tert-butoxycarbonylaminophenyl)ethoxy]phenyl}-(S)-2-ethoxypropanoic acid ethyl ester (30 g; 0.065 mole) in dichloromethane (150 ml). The reaction mixture was stirred over night at room temperature and then washed three times with water. The organic phase was dried with magnesium sulfate and evaporated. 1H-NMR of the product showed a mixture of product and starting material. The crude product (27.3 g) was redissolved in ethyl acetate, ethyl acetate saturated with hydrochloric acid (500 ml) was added and the mixture was stirred over night at room temperature. Evaporation gave 24.7 g (96.5% yield) of 3-{4-[2-(4-aminophenyl)ethoxy]phenyl}-(S)-2-ethoxypropanoic acid hydro chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([NH2:28])[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.F[C:30](F)(F)[C:31](O)=O.[C:36](=[O:39])(O)[O-].[Na+]>C(Cl)Cl>[NH2:17][CH:4]([C:31]1[CH:30]=[CH:2][CH:7]=[CH:6][CH:5]=1)[CH2:3][C:36]([NH:28][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][N:19]=[C:18]2[NH:17][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)=[C:2]([Cl:1])[CH:3]=1)=[O:39]
Reactant: O=C([O-])O
Reactant: Nc1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1
Reactant: O=C(O)C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Product: NC(CC(=O)Nc1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1)c1ccccc1
Yield: 98 %

Procedure:
0.64 g of the compound obtained in Example 45 dissolved in 20 ml of methylene chloride and 20 ml of trifluoroacetic acid was stirred at room temperature for 4 hours. The residue obtained from distillation of the reacted solution under a reduced pressure was stirred in 5 ml of methylene chloride while adding 20 ml of saturated sodium bicarbonate slowly and filtered under a reduced pressure to obtain the title compound as solid (0.53 g, 98%).
Reaction SMILES: C1(CBr)CC1.[CH:6]1([CH2:9][O:10][CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([CH3:21])[CH:15]=2)[CH2:8][CH2:7]1.[CH2:22]([CH:24]1[O:26][CH2:25]1)Cl.N1CCCCC1>O1CCCC1.[Pd]>[CH3:21][C:16]1[CH:15]=[C:14]([O:13][CH2:12][CH2:11][O:10][CH2:9][CH:6]2[CH2:8][CH2:7]2)[CH:19]=[CH:18][C:17]=1[O:20][CH2:22][CH:24]1[O:26][CH2:25]1
Reactant: Cc1cc(OCCOCC2CC2)ccc1O
Reactant: ClCC1CO1
Agent: [Pd]
Agent: BrCC1CC1
Solvent: C1CCNCC1
Solvent: C1CCOC1
Product: Cc1cc(OCCOCC2CC2)ccc1OCC1CO1

Procedure:
The epoxide starting material is obtained from reaction of 4-hydroxy-3-methylphenyl benzoate with benzyl bromide to give 4-benzyloxy-3-methylphenyl benzoate (M.P. 120°-121° from methanol/ether), followed by de-esterification with 2M NaOH solution to give 4-benzyloxy-3-methylphenol (M.P. 69°-70° from ether/hexane) and reaction with 2-bromoethanol (light brown oil) to form an alcohol which is reacted with cyclopropylmethyl bromide in tetrahydrofuran. Debenzylation of the cyclopropylmethoxyethoxy derivative (unpurified) with 10% Pd on activated charcoal forms 4-(2-(cyclopropylmethoxy)ethoxy)-2-methylphenol which is then reacted with epichlorhydrin in the presence of a catalytic amount of piperidine to give 2-methyl-1-(2,3-epoxypropoxy)-4-(2-(cyclopropylmethoxy)ethoxy)benzene (light brown oil after chromatography on silica gel with toluene/ethyl-acetate (8:2)).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[Cl:15][C:16]1[CH:17]=[N:18][CH:19]=[C:20]([OH:22])[CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:15][C:16]1[CH:17]=[N:18][CH:19]=[C:20]([O:22][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[C:11]([F:14])([F:13])[F:12])[CH:21]=1
Reactant: Oc1cncc(Cl)c1
Reactant: O=[N+]([O-])c1ccc(F)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2cncc(Cl)c2)c(C(F)(F)F)c1
Temperature: 60 °C
Yield: 110.2 %

Procedure:
Using the method of Example 21.2, 2-fluoro-5-nitrobenzotrifluoride (5.0 g) and 3-chloro-5-hydroxypyridine (3.1 g) were combined with potassium carbonate (5.4 g) in DMF and heated overnight at 60° C. Workup gave the title compound (8.4 g) as a crude yellow solid which was used directly in the next reaction.
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:17]([CH:18]=[O:19])[O:16][C@H:15]2[C@H:11]([N:12]=[C:13]([N:20]([CH3:28])C(=O)OC(C)(C)C)[S:14]2)[C@@H:10]1[F:29])C1C=CC=CC=1.[CH3:30][Mg+].[Br-].B(Cl)(Cl)Cl>C1COCC1.C(Cl)Cl>[F:29][C@H:10]1[C@H:11]2[N:12]=[C:13]([NH:20][CH3:28])[S:14][C@H:15]2[O:16][C@H:17]([C@H:18]([OH:19])[CH3:30])[C@H:9]1[OH:8]
Reactant: C[Mg+]
Reactant: CN(C(=O)OC(C)(C)C)C1=N[C@@H]2[C@H](F)[C@H](OCc3ccccc3)[C@@H](C=O)O[C@@H]2S1
Agent: ClB(Cl)Cl
Agent: [Br-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CNC1=N[C@@H]2[C@H](F)[C@H](O)[C@@H]([C@@H](C)O)O[C@@H]2S1
Temperature: 25 °C
Reaction time: 2 h
Yield: 18.8 %

Procedure:
To a solution of tert-butyl ((3aR,5S,6R,7S,7aR)-6-(benzyloxy)-7-fluoro-5-formyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate (0.35 g, 0.83 mmol) in anhydrous THF (15 mL), at 0° C. and under N2, was added MeMgBr (1.4 M in THF/toluene, 3.0 mL, 4.2 mmol). After addition the mixture was stirred at room temperature for 2 h. The reaction was quenched with saturated NaHCO3 aqueous solution (30 mL), and then extracted with EtOAc (30 mL) and DCM (3×30 mL). The combined extract was dried over anhydrous Na2SO4. After filtration the solvent was evaporated under reduced pressure, and the residue was dried under high vacuum. To the residue and PMB (0.50 g, 3.4 mmol) in dry DCM (8 mL) at −78° C. under N2, was added BCl3 (1.0 M in DCM, 3.0 mL, 3.0 mmol). The mixture was stirred for ˜3 h while the temperature of the cooling bath slowly warmed to room temperature. The reaction mixture was cooled at −78° C., quenched with mixed MeOH/DCM, and then concentrated to dryness. The residue was purified on silica gel by flash column chromatography (1.0 M NH3 in MeOH/DCM, 1:10), affording (3aR,5R,6R,7S,7aR)-7-fluoro-5-((R)-1-hydroxyethyl)-2-(methylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol as a white solid (0.039 g, 19%). 1H NMR (400 MHz, CD3OD) δ 6.40 (d, J=6.7 Hz, 1H), 4.78 (td, J=3.6, 49.3 Hz, 1H), 4.40 (ddd, J=3.6, 6.6, 18.0 Hz, 1H), 4.00-3.89 (m, 2H), 3.79 (dd, J=3.2, 8.0 Hz, 1H), 2.86 (s, 3H), 1.19 (d, J=6.6 Hz, 1H); 13C NMR (100 MHz, CD3OD) δ 165.99, 91.11 (d, J=5.31 Hz), 90.74 (d, J=184.1 Hz), 76.85 (q, J=3.7 Hz), 71.64 (d, J=16.4 Hz), 68.64, 68.22 (d, J=16.9 Hz), 30.55, 17.74; MS, (ES, m/z) [M+H]+ 251.1.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]([OH:10])=O)[CH:4]=[N:3]1.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:22][C:23]1[CH:24]=[C:25]([CH:42]=[CH:43][C:44]=1[F:45])[O:26][C:27]1[CH:28]=[CH:29][C:30]2[N:31]([CH:33]=[C:34]([NH:36][C:37]([CH:39]3[CH2:41][CH2:40]3)=[O:38])[N:35]=2)[N:32]=1>CN(C)C=O.CN1CCCC1=O>[CH:39]1([C:37]([NH:36][C:34]2[N:35]=[C:30]3[CH:29]=[CH:28][C:27]([O:26][C:25]4[CH:42]=[CH:43][C:44]([F:45])=[C:23]([NH:22][C:8]([C:5]5[CH:4]=[N:3][N:2]([CH3:1])[C:6]=5[CH3:7])=[O:10])[CH:24]=4)=[N:32][N:31]3[CH:33]=2)=[O:38])[CH2:40][CH2:41]1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Reactant: Cc1c(C(=O)O)cnn1C
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: Cc1c(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)ccc2F)cnn1C
Yield: 47.2 %

Procedure:
Using 1,5-dimethyl-1H-pyrazole-4-carboxylic acid (140 mg, 1.0 mmol), N,N-dimethylformamide (2 drops), tetrahydrofuran (10 mL), oxalyl chloride (0.172 mL, 2.0 mmol), N-methylpyrrolidone (5 mL) and N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (164 mg, 0.50 mmol), and in the same manner as in Example 173, the title compound (106 mg, yield 47%) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2O.P(Cl)(Cl)([Cl:15])=O.C(N(CC)CC)C>C(Cl)Cl>[Cl:15][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=2)[N:8]=[CH:7][N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ncnc2ccc(F)cc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Fc1ccc2ncnc(Cl)c2c1

Procedure:
Preparation D2, Step 2: 6-fluoroquinazolin-4-ol (1.00 g, 6.09 mmol, 1 eq.), phosphorus oxychloride (3.41 mL, 36.6 mmol, 6 eq.) and triethylamine (5.09 mL, 36.6 mmol, 6 eq.) were mixed at room temperature and then refluxed for 2 hours. Worked up by stripping 3 times from methylene chloride. The residue was dissolved in methylene chloride (25 mL) and rinsed 3 times with saturated sodium bicarbonate (25 mL) and 1× with brine (25 mL). The organic layer was dried (sodium sulfate) and stripped to give a crude oil. Purified over silica gel in 9:1 to 3:1 hexanes/ethyl acetate. Obtained 4-chloro-6-fluoroquinazoline (0.96 g) as a tan solid. Yield=86%. LCMS detects (M+H)+=183.16.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[C:5]([C:7]1[C:11]([O:12][CH:13]([F:15])[F:14])=[CH:10][N:9]([C:16]2[C:21]([Cl:22])=[CH:20][C:19]([C:23]([F:26])([F:25])[F:24])=[CH:18][C:17]=2[Cl:27])[N:8]=1)#[N:6]>S(=O)(=O)(O)O>[C:5]([C:7]1[C:11]([O:12][CH:13]([F:15])[F:14])=[C:10]([N+:1]([O-:4])=[O:2])[N:9]([C:16]2[C:21]([Cl:22])=[CH:20][C:19]([C:23]([F:24])([F:25])[F:26])=[CH:18][C:17]=2[Cl:27])[N:8]=1)#[N:6]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1OC(F)F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c([N+](=O)[O-])c1OC(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Fuming nitric acid (5 ml) was added to an ice-cooled solution of 3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-difluoromethoxypyrazole (1.5g) in concentrated sulfuric acid (20 ml). The mixture was stirred at room temperature for 3 hours then poured into ice/water and extracted into dichloromethane (3×50 ml). The combined dichloromethane extracts were washed with water (30 ml), filtered through phase-separation paper and evaporated in vacuo. The resultant gum was purified by dry-column chromatography (eluant ether:hexane 1:3) t give 3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-difluoromethoxy-5-nitropyrazole (0.3g) as a yellow solid, m.p. 72.5°-74° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([OH:7])[CH2:2]1.[C:8](OC)(=[O:23])[C:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[OH:10].C[O-].[Na+].Cl>CO.C1C=CC=CC=1>[C:8]([O:7][CH:3]1[CH2:4][CH2:5][CH2:6][NH:1][CH2:2]1)(=[O:23])[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[OH:10]
Reactant: COC(=O)C(O)(c1ccccc1)c1ccccc1
Reactant: OC1CCCNC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CO
Product: O=C(OC1CCCNC1)C(O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 40.1 %

Procedure:
30 ml of benzene, 0.4 g (4 mmol) of 3-piperidinol and 1.0 g (4 mmol) of methyl benzilate were put into a 50 ml 3-mouth flask equipped with a stirrer, a reflux condenser, and a molecular sieve 4A (15 g) tube and a soda lime tube for trapping methanol from out of the solvent that drips down through the reflux condensation, and the mixture was refluxed by heating while stirring. After all of the methyl benzilate had dissolved, 20 mg of sodium methoxide (made by Aldrich) was added to the solution and reaction was carried out for 3 hours. After the reaction had been completed, the reaction liquid was cooled to room temperature, and then 50 ml of 1N hydrochloric acid was added, and the organic solvent layer was removed. The aqueous solution layer obtained was washed twice with 50 ml of ether, and was then made basic using a 28% ammonium hydroxide aqueous solution. The aqueous solution was subjected to ether extraction, the ether layer obtained was washed twice with 50 ml of water, and then drying was carried out using anhydrous potassium carbonate. After removing the drying agent, the solvent was evaporated off under reduced pressure, thus obtaining an oily residue, and then this residue was recrystallized from ether-hexane, thus obtaining 0.5 g of (±)3-piperidyl benzilate ((±)3-PB) as crystals (yield 40%).
Reaction SMILES: [NH:1]([C:3]1[N:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:7](=[O:13])[NH:6][C:5](=[O:14])[CH:4]=1)[NH2:2].[Cl:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[N:22]=[CH:21][CH:20]=[C:19]2[CH:26]=O.[CH:28]([C:30]1[N:34]([CH3:35])[CH:33]=[C:32]([C:36]#[N:37])[CH:31]=1)=O>>[Cl:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[N:22]=[CH:21][CH:20]=[C:19]2[CH2:26][N:2]1[C:28]([C:30]2[N:34]([CH3:35])[CH:33]=[C:32]([C:36]#[N:37])[CH:31]=2)=[C:4]2[C:3]([N:8]([CH2:9][CH:10]([CH3:11])[CH3:12])[C:7](=[O:13])[NH:6][C:5]2=[O:14])=[N:1]1
Reactant: O=Cc1ccnc2ccc(Cl)cc12
Reactant: CC(C)Cn1c(NN)cc(=O)[nH]c1=O
Reactant: Cn1cc(C#N)cc1C=O
Product: CC(C)Cn1c(=O)[nH]c(=O)c2c(-c3cc(C#N)cn3C)n(Cc3ccnc4ccc(Cl)cc34)nc21

Procedure:
This compound was made following the procedure described above, starting with 6-hydrazino-1-isobutylpyrimidine-2,4(1H,3H)-dione, and condensing first with 6-chloroquinoline-4-carbaldehyde, followed by 5-formyl-1-methyl-1H-pyrrole-3-carbonitrile. ES M+H+=463.
Reaction SMILES: [CH3:1][SH:2].[Na].[CH3:4][C:5]1([CH3:19])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[N:7]([CH2:16]Cl)[C:6]1=[O:18]>C(O)C>[CH3:4][C:5]1([CH3:19])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[N:7]([CH2:16][S:2][CH3:1])[C:6]1=[O:18]
Reactant: CS
Reactant: CC1(C)C(=O)N(CCl)C(=O)c2ccccc21
Agent: [Na]
Solvent: CCO
Product: CSCN1C(=O)c2ccccc2C(C)(C)C1=O
Temperature: 0 °C

Procedure:
1.92 gm of methylmercaptan were added to an ice-cooled solution of 0.92 gm of sodium in 50 ml of ethanol. A suspension of 8.6 gm of 4,4-dimethyl-2-chloromethyl-2H,4H-isoquinoline-1,3-dione in 100 ml of ethanol was added, and the mixture was refluxed for 45 minutes. Thereafter, the reaction mixture was evaporated, the residue was triturated with water, filtered, the filter cake was recrystallized from isopropanol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][CH2:11][OH:12])=[C:4]([N+:13]([O-])=O)[CH:3]=1.[H][H]>[Ni].C(O)C>[NH2:13][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[NH:8][CH2:9][CH2:10][CH2:11][OH:12]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(Cl)ccc1NCCCO
Agent: [Ni]
Solvent: CCO
Product: Nc1cc(Cl)ccc1NCCCO

Procedure:
A mixture of 34.6 parts of 3-[(4-chloro-2-nitrophenyl)-amino]-1-propanol and 320 parts of ethanol is hydrogenated at normal pressure and at room temperature with 8 parts of Raney-nickel catalyst. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated, yielding 30 parts of 3-[(2-amino-4-chlorophenyl)amino]-1-propanol as an oily residue.
Reaction SMILES: [CH3:1][Mg]I.[Cl:4][C:5]1[CH:14]=[C:13]([C:15]([C:17]2[N:18]=[CH:19][N:20]([C:22]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:21]=2)=[O:16])[C:8]2[O:9][CH2:10][O:11][CH2:12][C:7]=2[CH:6]=1.[Cl-].[NH4+].O>C(OCC)C.O1CCCC1>[Cl:4][C:5]1[CH:14]=[C:13]([C:15]([CH3:1])([C:17]2[N:18]=[CH:19][N:20]([C:22]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:21]=2)[OH:16])[C:8]2[O:9][CH2:10][O:11][CH2:12][C:7]=2[CH:6]=1
Reactant: C[Mg]I
Reactant: O=C(c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1cc(Cl)cc2c1OCOC2
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(O)(c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1cc(Cl)cc2c1OCOC2
Temperature: 40 °C
Yield: 79.8 %

Procedure:
A suspension of 0.148 mole of methyl magnesium iodide in 150 ml of diethyl ether at a temperature of 30° C., is added at ambient temperature to 17.3 g (0.033 mole) of (6-chloro-4H-1,3-benzodioxin-8-yl)(1-triphenylmethyl-1H-imidazol-4-yl)ketone dissolved in 200 ml of tetrahydrofuran. The temperature of the reaction mixture increases to 40° C. When the addition is complete, stirring is maintained for 1 hour at ambient temperature. There is then added 8 g of ammonium chloride and stirring is continued for a further hour. Subsequently, 100 ml of water are added and the reaction mixture is extracted twice with dichloromethane. The organic phases are dried over anhydrous sodium sulfate and the solvent is removed under reduced pressure. The residue is recrystallized from 100 ml of ethyl acetate. 13.77 g of alpha-(6-chloro-4H-1,3-benzodioxin-8-yl)-alpha-methyl-1-triphenylmethyl-1H-imidazole-4-methanol are obtained. Yield: 80% of theory; M.P.: 248°-250° C. (decomposition).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:25][C:24]([OH:27])([CH3:26])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:28]1[CH:33]=[C:32](B(O)O)[CH:31]=[N:30][CH:29]=1.C([O-])([O-])=O.[Na+].[Na+].CCO>COCCOC.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.CCOC(C)=O>[OH:27][C:24]1([CH3:26])[CH2:25][N:22]([C:3]2[C:2]([C:32]3[CH:33]=[N:28][CH:29]=[N:30][CH:31]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: CC1(O)CN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2Br)C1
Reactant: OB(O)c1cncnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CC1(O)CN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2-c2cncnc2)C1
Temperature: 95 °C

Procedure:
5-Bromo-6-(3-hydroxy-3-methylazetidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 128.1, 89 mg, 0.2 mmol) and pyrimidin-5-ylboronic acid (50 mg, 0.4 mmol) were dissolved in DME (0.8 mL). A solution of 2 M Na2CO3 (0.300 mL, 0.6 mmol) and EtOH (120 μL) were added, the mixture was flushed with argon, Pd(PPh3)2Cl2 (17 mg, 0.02 mmol) was added and the RM was heated at 95° C. for 3 h in a pressure safe vial. After cooling at RT, the RM was treated with EtOAc and washed with brine. The organic phase was dried over Na2SO4 and evaporated to dryness under reduced pressure. The crude product was purified by flash chromatography (RediSep® Silica gel column, first EtOAc/MeOH from 0 to 10% MeOH; then second flash DCM/MeOH, from 2% to 5% MeOH) and treated with Si-Thiol (80 mg) in MeOH to afford the title compound as a white crystalline solid. HPLC (Condition 4) tR=4.74 min, UPLC-MS (Condition 7) m/z=446.3 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.29 (s, 4H) 3.50-3.64 (m, 3H) 5.49 (s, 1H) 7.34 (d, J=8.60 Hz, 2H) 7.83 (d, J=8.99 Hz, 2H) 8.09 (d, J=1.56 Hz, 1H) 8.78 (d, J=1.95 Hz, 1H) 8.90 (s, 2H) 9.20 (s, 1H) 10.20 (s, 1H).
Reaction SMILES: Br[C:2]1[C:6]([CH3:8])([CH3:7])[O:5]/[C:4](=[C:9]2/[C:10](=[O:19])[NH:11][C:12]3[C:17]/2=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)/[CH:3]=1.[CH:20]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)=[O:21].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C1COCC1.O>[F:18][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:19])/[C:9]/2=[C:4]1\[CH:3]=[C:2]([C:25]2[CH:26]=[CH:27][C:22]([CH:20]=[O:21])=[CH:23][CH:24]=2)[C:6]([CH3:8])([CH3:7])[O:5]\1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: CC1(C)O/C(=C2/C(=O)Nc3ccc(F)cc32)C=C1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(C)O/C(=C2/C(=O)Nc3ccc(F)cc32)C=C1c1ccc(C=O)cc1
Temperature: 65 °C
Yield: 51.5 %

Procedure:
To a mixture of 3-[4-bromo-5,5-dimethyl-5H-furan-(2E)-ylidene]-5-fluoro-1,3-dihydro-indol-2-one (6.5 g, 20 mmol), 4-formyl phenyl boronic acid (3.6 g, 24 mmol) in THF (250 mL), was added a solution of potassium carbonate (27.6 g, 200 mmol) in water (25 mL). The resulting mixture was deoxygenated with nitrogen, and palladium(0)tetrakis(triphenylphosphine) (1.15 g, 1.0 mmol, 5 mol %) then added. The reaction mixture was heated at 65° C. for 20 hours and then it was allowed to cool to room temperature. Ethyl acetate (800 mL) was added. The organic phase was washed with water (200 mL×2), dried over sodium sulfate and evaporated to give crude product. The purification first by column (SiO2) chromatography (5% CH3OH/CH2Cl2) and then by titration with ethyl acetate led to 4-{5-[5-fluoro-2-oxo-1,2-dihydro-indol-(3E)-ylidene]-2,2-dimethyl-2,5-dihydro-furan-3-yl}-benzaldehyde as a deep red solid (3.6 g, yield 51.5%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=3)=[C:16]([F:31])[CH:15]=2)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[OH-].[Na+]>C(#N)C.O>[F:31][C:16]1[CH:15]=[C:14]([CH:10]2[O:11][CH2:12][CH2:13][NH:8][CH2:9]2)[CH:19]=[CH:18][C:17]=1[NH:20][C:21]1[N:22]=[CH:23][C:24]([C:27]([F:29])([F:30])[F:28])=[CH:25][N:26]=1
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(Nc3ncc(C(F)(F)F)cn3)c(F)c2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Fc1cc(C2CNCCO2)ccc1Nc1ncc(C(F)(F)F)cn1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a stirred solution of (RS)-2-[3-fluoro-4-(5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholine-4-carboxylic acid tert-butyl ester (110 mg) in acetonitrile (2 ml) and water (4 ml) was added trifluoroacetic acid (190 μl). The reaction mixture was then capped and the mixture was shaken at 80° C. for 4 h. The reaction mixture was then cooled to room temperature and poured into 1 M aq. NaOH and extracted twice with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash column chromatography (Isolute® Flash-NH2 from Separtis; gradient: heptane/EtOAc) to (RS)-(2-fluoro-4-morpholin-2-yl-phenyl)-(5-trifluoromethyl-pyrimidin-2-yl)-amine (23 mg, 27%) as a white solid. MS (ISP): 343.1 ([M+H]+).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:8]2[O:13][CH:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:11][C:10](=[O:19])[C:9]=2[CH:20]=1)([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4].C1(C)C=CC=CC=1>C(O)C>[C:1]([C:5]1[CH:6]=[C:7]([C:21]([CH3:22])([CH3:24])[CH3:23])[C:8]2[O:13][C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11][C:10](=[O:19])[C:9]=2[CH:20]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C1CC(=O)c2cc(C(C)(C)C)cc(C(C)(C)C)c2O1
Agent: CC(=O)[O-]
Agent: [Pb+4]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(=O)c2cc(C(C)(C)C)cc(C(C)(C)C)c2o1
Reaction time: 3.25 h

Procedure:
A mixture of 3.32 parts of 6,8-di-t-butyl-2,3-dihydro-4-oxo-4H-1-benzopyran-2-carboxylic acid, ethyl ester and 9.9 parts of lead tetraccetate was refluxed in 30 parts of glacial acetic acid for 6.5 hours. A further 9.9 parts of lead tetracetate were added and the reflux was continued for another 3.25 hours. After cooling, the reaction mixture was extracted with ether. The ether extract was washed with sodium bicarbonate solution and water and was dried. Evaporation of the ether gave an oil which was chromotographed on silica gel using a 9:1 mixture of toluene and ethanol for elution. This yielded 0.23 parts of 6,8-di-t-butyl-4-oxo-4H-1-benzopyran-2-carboxylic acid, ethyl ester, m.p. 130°-131.5° C (after crystallisation from light petroleum (b.p. 40°-60° C). This product was shown by spectral means to be the same as that of Example 13.