Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH:11]([C:13]2[CH:14]=[N:15][C:16]([O:19][CH2:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:18]=2)[CH3:12])=[O:9])[CH:5]=[CH:4][N:3]=1.[C:26](Cl)(=[O:29])[CH2:27][CH3:28]>>[C:26]([NH:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH:11]([C:13]2[CH:14]=[N:15][C:16]([O:19][CH2:20][CH2:21][C:22]([F:24])([F:25])[F:23])=[CH:17][CH:18]=2)[CH3:12])=[O:9])[CH:5]=[CH:4][N:3]=1)(=[O:29])[CH2:27][CH3:28]
Reactant: CCC(=O)Cl
Reactant: CC(NC(=O)c1ccnc(N)n1)c1ccc(OCCC(F)(F)F)nc1
Product: CCC(=O)Nc1nccc(C(=O)NC(C)c2ccc(OCCC(F)(F)F)nc2)n1

Procedure:
The title compound is prepared from 2-amino-N-(1-(6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)pyrimidine-4-carboxamide (Step-1, single enantiomer) and propionyl chloride according to the procedure similar to that described in Step-2 of Example 8.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[N:8][C:9]([O:12][CH2:13][C:14]2[C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[CH:10][CH:11]=1)=[O:5])C.[F:27][C:28]([F:32])([F:31])[CH2:29][NH2:30]>>[F:27][C:28]([F:32])([F:31])[CH2:29][NH:30][C:4]([C:6]1[N:7]=[N:8][C:9]([O:12][CH2:13][C:14]2[C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[CH:10][CH:11]=1)=[O:5]
Reactant: NCC(F)(F)F
Reactant: CCOC(=O)c1ccc(OCc2c(-c3cccc(F)c3)noc2C)nn1
Product: Cc1onc(-c2cccc(F)c2)c1COc1ccc(C(=O)NCC(F)(F)F)nn1
Yield: 77 %

Procedure:
As described for example 52, 6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-pyridazine-3-carboxylic acid ethyl ester (143 mg, 0.4 mmol) was converted, using 2,2,2-trifluoroethylamine instead of ethanolamine, to the title compound (127 mg, 77%) which was obtained as an off-white solid. MS: m/e=411.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1([Cl:13])[CH:7]2[CH2:8][CH:4]([CH:5]=[CH:6]2)[C:3]1([C:11]#[N:12])[C:9]#[N:10].ClC1C=CC=C(C(OO)=[O:22])C=1.S(=O)(O)[O-].[Na+]>ClC1C=CC=CC=1>[Cl:1][C:2]1([Cl:13])[CH:7]2[CH2:8][CH:4]([CH:5]3[O:22][CH:6]32)[C:3]1([C:9]#[N:10])[C:11]#[N:12]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: N#CC1(C#N)C2C=CC(C2)C1(Cl)Cl
Agent: O=S([O-])O
Agent: [Na+]
Solvent: Clc1ccccc1
Product: N#CC1(C#N)C2CC(C3OC32)C1(Cl)Cl
Yield: 74.2 %

Procedure:
21 g (0.1 mol) of the (IV) prepared in Example 1 are dissolved in 100 ml of chlorobenzene, and 20 g (0.12 mol) of m-chloroperbenzoic acid in 200 ml of chlorobenzene are added dropwise. The mixture is heated under reflux for 4 hours, and is worked up in the customary manner with sodium bisulphite solution to destroy the excess of per-acid, and sodium bicarbonate solution to separate off the m-chlorobenzoic acid. From the organic phase, 17 g (75%) of 3,3-dichloro-5,6-epoxybicyclo[2,2,1]heptane-2,2-dicarbonitrile were isolated, m.p. 229° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[C:10]([I:12])[C:9]([O:13][CH3:14])=[CH:8][C:5]=1[CH:6]=O)[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].CS(Cl)(=O)=O.[I-].[Na+].[P:28]([O:35]CC)([O:32][CH2:33][CH3:34])[O:29][CH2:30][CH3:31]>N1C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:11]=[C:10]([I:12])[C:9]([O:13][CH3:14])=[CH:8][C:5]=1[CH2:6][P:28](=[O:35])([O:32][CH2:33][CH3:34])[O:29][CH2:30][CH3:31])[CH3:2]
Reactant: CCOc1cc(I)c(OC)cc1C=O
Reactant: CCOP(OCC)OCC
Agent: CS(=O)(=O)Cl
Agent: [Al+3]
Agent: [H-]
Solvent: c1ccncc1
Product: CCOc1cc(I)c(OC)cc1CP(=O)(OCC)OCC

Procedure:
Hydroquinone can be added to a solution of sodium hydride (NaH) dissolved in tetrahydrofuran (THF) and combined with methyl bromide yielding para-methoxyphenol. The para-methoxyphenol can be extracted and added to a solution of tosyl chloride (TsCl) dissolved in pyridine and tetrahydrofuran (THF) at room temperature, yielding para-methoxytosyloxybenzene. The para-methoxytosyloxybenzene can be extracted and added to a solution of diatomic iodine (I2) and potassium iodide trioxide (KIO3) dissolved in sulfuric acid (H2SO4) and acetic acid (CH3COOH) yielding 4-methoxy-3-iodo-1-tosyloxybenzene. The 4-methoxy-3-iodo-1-tosyloxybenzene can be extracted and added to a solution of aqueous sodium hydroxide (NaOH) and tert-butanol, removing the tosylate protecting group and yielding 4-methoxy-3-iodophenol. The 4-methoxy-3-iodophenol can be extracted and exposed to resin-bound triphenyphosphine (PPh3) in a solution of azopyridine and ethanol (CH3CH2OH) in a salt bath at 0° C., yielding 4-ethoxy-2-iodomethoxybenzene. The 4-ethoxy-2-iodomethoxybenzene can be extracted and added to a solution of titanium tetrachloride (TiCl4) and 1,1-dichlorodimethylether (CHCl2OCH3) dissolved in dichloromethane (CH2Cl2) in a salt bath at −10° C., yielding 2-ethoxy-4-iodo-5-methoxybenzaldehyde. The 2-ethoxy-4-iodo-5-methoxybenzaldehyde can be added to lithium aluminum hydride (LiAlH4) and methanesulfonyl chloride (CH3SO2Cl) dissolved in pyridine, and then sodium iodide (NaI) and triethyl phosphite (P(OCH2CH3)3) can be added to the reaction mixture, yielding diethyl 2-ethoxy-4-iodo-5-methoxybenzylphosphonate.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[CH2:16][C:17]([OH:19])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C=O)C.C(Cl)(=O)C(Cl)=O.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[CH3:15][O:14][C:12]1[CH:11]=[CH:10][C:9]2[CH2:16][C:17](=[O:19])[C:7]3[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=3[CH2:1][C:8]=2[CH:13]=1
Reactant: COc1ccc(CC(=O)O)c(Cc2ccccc2)c1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)Cc1ccccc1C(=O)C2
Temperature: 25 °C
Reaction time: 16 h
Yield: 92 %

Procedure:
A solution of 2-benzyl-4methoxyphenylacetic acid (215 g of crude material that contained 204.6 g (0.80 mole) of pure material) in CH2Cl2 (1 L) was stirred under argon at ambient temperature, and DMF (1 mL) was added, followed by oxalyl chloride (400 mL, 4.59 mole). The oxalyl chloride was added over 1 hr, dropwise initially to control the vigorous gas evolution. The solution was stirred for 16 h at ambient temperature and then was concentrated to give the crude acid chloride (207.7 g, 0.756 mol, 95%) as a yellow liquid. This liquid was dissolved in CH2Cl2 to a total volume of 500 mL, and the solution and AlCl3 (100.8 g, 0.756 mol) were added concurrently over 1 hr to CH2Cl2 (3.7 L) with stirring under argon at ambient temperature. The temperature was 28° C. at the completion of the addition. The reaction mixture was stirred for 16 h at ambient temperature, during which time a solid precipitated. H2O (1 L) was added, initially dropwise, over a period of 30 min. The mixture was then separated and the organic phase was washed sequentially with H2O (1 L) and 5% aqueous NaHCO3 (1 L). The CH2Cl2 solution was then concentrated to give a yellow solid (175.3 g). Recrystallization from EtOAc/hexane gave the title compound (128 g, 71%): mp 107-109° C.
Reaction SMILES: C([O:4][CH2:5][CH:6]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]/[CH:36]=[CH:37]\[CH2:38]/[CH:39]=[CH:40]\[CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]\[CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])C=C.FC(F)(F)C(O)=O>C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:28]([O:27][CH:6]([CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]\[CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:5][OH:4])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]/[CH:36]=[CH:37]\[CH2:38]/[CH:39]=[CH:40]\[CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]
Reactant: C=CCOCC(COCCCCCCCC/C=C\C/C=C\CCCCC)OCCCCCCCC/C=C\C/C=C\CCCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: CCCCC/C=C\C/C=C\CCCCCCCCOCC(CO)OCCCCCCCC/C=C\C/C=C\CCCCC
Temperature: 25 °C
Yield: 72.4 %

Procedure:
To a solution of (6Z,9Z)-18-(3-(allyloxy)-2-((9Z,12Z)-octadeca-9,12-dienyloxy)propoxy)octadeca-6,9-diene (9.1 g, 14.3 mmol) in ethanol (100 ml) was added trifluoroacetic acid (15.0 mL) and tetrakis(triphenylphosphine)palladium(0) (1.65 g, 1.43 mmol). The solution was refluxed for 16 hours, cooled to room temperature and concentrated in vacuo to dryness. The residue was purified by column chromatography on silica gel 60 (eluted with a gradient of 100% hexanes to 1:1 hexanes/DCM to 100% DCM) to afford 2,3-bis((9Z,12Z)-octadeca-9,12-dienyloxy)propan-1-ol as a colorless oil (6.1 g, 54%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([C:13](=[O:26])[CH2:14][O:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([O:24][CH3:25])=[O:23])=[CH:18][CH:17]=3)=[CH:10][C:9]=2[CH:27]=1)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO>[C:1]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([CH:13]([OH:26])[CH2:14][O:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([O:24][CH3:25])=[O:23])=[CH:18][CH:17]=3)=[CH:10][C:9]=2[CH:27]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(OCC(=O)c2cc3cc(C(C)(C)C)ccc3o2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(OCC(O)c2cc3cc(C(C)(C)C)ccc3o2)cc1
Temperature: 0 °C
Yield: 96.3 %

Procedure:
5-tert-Butyl-2-(4-methoxycarbonylphenoxyacetyl)benzofuran (124 g) was suspended in 980 ml of methanol and, with cooling with ice and stirring, 30 g of sodium borohydride was added thereto little by little. After stirring for 2 hours, 8.8 g of sodium borohydride was added and the mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into 10 liters of ice water (acidified with hydrochloric acid) and the resulting crystals were collected by filtration. The crystals were dissolved in chloroform, the solution was washed with water twice and the chloroform layer was dried over anhydrous magnesium sulfate followed by concentrating in vacuo to give 120.1 g of crystals. M.p. 110°-112° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH:8]2[CH2:10][CH2:9]2)[CH:5]=[C:4]([CH3:11])[N:3]=1.[CH3:12][C:13]1([CH3:28])[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:21]([S:22]([N:25]=[C:26]=[O:27])(=[O:24])=[O:23])[C:15]=2[O:14]1>C(Cl)Cl>[CH:8]1([C:6]2[CH:5]=[C:4]([CH3:11])[N:3]=[C:2]([NH:1][C:26]([NH:25][S:22]([C:21]3[C:15]4[O:14][C:13]([CH3:28])([CH3:12])[CH2:17][C:16]=4[CH:18]=[CH:19][CH:20]=3)(=[O:23])=[O:24])=[O:27])[N:7]=2)[CH2:10][CH2:9]1
Reactant: Cc1cc(C2CC2)nc(N)n1
Reactant: CC1(C)Cc2cccc(S(=O)(=O)N=C=O)c2O1
Solvent: ClCCl
Product: Cc1cc(C2CC2)nc(NC(=O)NS(=O)(=O)c2cccc3c2OC(C)(C)C3)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 0.47 g of 2-amino-4-cyclopropyl-6-methylpyrimidine in 15 ml of methylene chloride is added one g of the sulfonyl isocyanate prepared in Example 4. After stirring at room temperature overnight, the suspension is concentrated in vacuo, and the residue is triturated with 1-chlorobutane and filtered to give the subject compound.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O>[C:13]1([N:12]2[C:1](=[O:11])[C:2]3=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]3[C:4]2=[O:6])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Nc1ccccc1
Solvent: O
Product: O=C1c2ccccc2C(=O)N1c1ccccc1
Yield: 97.8 %

Procedure:
A mixture of phthalic anhydride (19 g) and aniline (14 g) is heated at 140° to 145° C. for 50 minutes, and to the reaction mixture is added water (50 ml). The resulting powder is collected by filtration, washed with 10% aqueous potassium carbonate solution (50 ml) and water (100 ml), and dried to give colorless powder (28 g, 97%). Recrystallization from acetic acid gives colorless needles.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([N:7]([C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.C([Li])CCC.[B:26](OC)([O:29]C)[O:27]C.Cl>CCCCCC.O1CCCC1>[C:4]1([N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14]2[CH:19]=[CH:18][C:17]([B:26]([OH:29])[OH:27])=[CH:16][CH:15]=2)[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: COB(OC)OC
Reactant: Brc1ccc(N(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OB(O)c1ccc(N(c2ccccc2)c2ccccc2)cc1
Temperature: -80 °C
Yield: 59.9 %

Procedure:
10 g (30 mmol) of 4-bromotriphenylamine was put into a 500 mL three-neck flask. The air in the flask was replaced with nitrogen. To the mixture were added 20 mL of tetrahydrofuran (THF), and then the mixture was stirred at −80° C. Into this solution, 20 mL (32 mmol) of n-butyllithium (a 1.6 mol/L hexane solution) was dropped by a syringe. After the dropping, this solution was stirred at the same temperature for 1 hour. After the stirring, 40 mL (60 mmol) of trimethyl borate was added to the solution, and the solution was stirred for 1 hour while the temperature of the solution was being increased to room temperature. To the solution was added 200 mL (1.0 mol/L) of hydrochloric acid, and then the solution was stirred for about 15 hours. The organic layer was washed with a saturated sodium hydrogen carbonate solution and then a saturated saline solution. Then, the organic layer was dried with magnesium sulfate. This mixture was subjected to gravity filtration. The obtained filtrate was condensed to give a white solid. The obtained solid was recrystallized with chloroform/hexane to give 5.2 g of a white powdered solid, which was the object of the synthesis, at a yield of 58%. A synthesis scheme of Step 2 is shown in (c-2) given below.
Reaction SMILES: [CH2:1]=[CH:2][C:3](=[O:6])[CH2:4][CH3:5].[CH2:7]=[CH:8][CH:9]=[CH2:10].C1(C=CC(O)=CC=1)O>>[CH2:2]([C:3]([CH:4]1[CH2:10][CH2:9][CH:8]=[CH:7][CH2:5]1)=[O:6])[CH3:1]
Reactant: C=CC(=O)CC
Reactant: C=CC=C
Agent: Oc1ccc(O)cc1
Product: CCC(=O)C1CC=CCC1
Reaction time: 5 h
Yield: 76 %

Procedure:
50 g of pent-1-en-3-one and 50 g of butadiene are reacted, in the presence of 1 g of hydroquinone, in a 250 ml shaken bomb, at 100° C. After 5 hours, the bomb is cooled and the product is distilled. 55 g=76% of cyclohex-3-enyl ethyl ketone, of boiling point 78°-81° C./10 mm Hg, are obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11].C([O-])([O-])=O.[Na+].[Na+].[C:31]1(B(O)O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>COCCOC>[C:2]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11]
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)CSc1ccccc1Br
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)CSc1ccccc1-c1ccccc1
Temperature: 90 °C
Yield: 14.5 %

Procedure:
A solution of benzoic acid N′-[2-(2-bromo-phenylsulfanyl)-acetyl]-N′-isopropyl-hydrazide (50 mg, 0.123 mmol) in DME (4 ml)/2M Na2CO3 (0.215 ml, 0.43 mmoles) was treated with phenylboronic acid (30 mg, 0.25 mmol) and Pd[PPh3]4 (14 mg, 0.012 mmol) for 12 hours at 90° C. Additional amounts of Pd[PPh3]4 (28 mg, 0.025 mmol) and 2M Na2CO3 (0.215 ml, 0.43 mmoles) were added and the mixture was stirred at 90° C. for another night. The reaction mixture was partitioned between water and DCM. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was adsorbed on silica and purified on a silica gel column with a 20-50% ethyl acetate/hexane gradient. Further purification by RP HPLC afforded the product (7.2 mg, 15%). MS m/e 405.26 (M+H+)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[CH3:11].C(O)C.O.O.[Sn](Cl)Cl.C(=O)([O-])[O-].[K+].[K+]>C(OC(=O)C)C>[Br:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[CH3:11])[NH2:8]
Reactant: Cc1ccc([N+](=O)[O-])cc1Br
Agent: Cl[Sn]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(N)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of 2-bromo-4-nitrotoluene (50 g, 0.231 mol in ethylacetate (330 mL) and Ethanol (150 mL) was added Tin(II)chloride dihydrate (208 g, 0.924 mol) portionwise. The reaction mixture was stirred at room temperature overnight. The solution was then treated with potassium carbonate until pH=7 and filtered over celite. The filtrate was washed with water, aqueous NaHCO3, water and brine, dried (Mg2SO4), filtered and evaporated to give 42.71 g (100%) of 3-bromo-4-methylaniline. 1H NMR (300 MHz; CDCl3): 2.27 (s, 3 H), 3.57 (br s, 2 H), 6.54 (dd, J=2.7 Hz and 8.1 Hz, 1 H), 6.90 (d, J=2.1 Hz, 1 H), 6.98 (d, J=8.1 H).
Reaction SMILES: [CH:1]1([C:4]2[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[C:5]=2[CH2:6][N:7]2[C:12]3[N:13]=[C:14]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([N:24]5[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]5)=[CH:20][CH:19]=4)[N:15]=[CH:16][C:11]=3[CH:10]=[C:9]([C:31]#[C:32]C)[C:8]2=[O:34])[CH2:3][CH2:2]1.C([Si](C)(C)C)#C.C(=O)([O-])[O-].[K+].[K+]>C(N(CC)CC)C.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.[Cu]I>[CH:1]1([C:4]2[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[C:5]=2[CH2:6][N:7]2[C:12]3[N:13]=[C:14]([NH:17][C:18]4[CH:19]=[CH:20][C:21]([N:24]5[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]5)=[CH:22][CH:23]=4)[N:15]=[CH:16][C:11]=3[CH:10]=[C:9]([C:31]#[CH:32])[C:8]2=[O:34])[CH2:2][CH2:3]1
Reactant: CC#Cc1cc2cnc(Nc3ccc(N4CCN(C)CC4)cc3)nc2n(Cc2c(F)cccc2C2CC2)c1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: C#C[Si](C)(C)C
Solvent: CCN(CC)CC
Product: C#Cc1cc2cnc(Nc3ccc(N4CCN(C)CC4)cc3)nc2n(Cc2c(F)cccc2C2CC2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 19 %

Procedure:
The mixture of 6-bromo-8-(2-cyclopropyl-6-fluorobenzyl)-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one (11, 120 mg, 0.21 mmol), ethynyltrimethylsilane (74 μl, 0.53 mmol), PdCl2(PPh3)2 (15 mg, 0.02 mmol) and CuI (3 mg, 0.02 mmol) in triethylamine (1.5 mL) was irradiated for 90 min at 80° C. in a microwave reactor. The reaction mixture was cooled, filtered through Celite (washed with triethylamine and dichloromethane) and evaporated to dryness. The crude material was purified by column chromatography over silica eluting with chloroform. The isolated material (87 mg) was suspended in 5 mL methanol, potassium carbonate (38 mg, 0.28 mmol) was added and the yellow suspension was stirred for 30 min at room temperature and evaporated. The solid residue was partitioned between water (10 mL) and dichloromethane (2×15 mL). The combined organic layers were washed with brine (15 mL), dried over sodium sulfate, filtered, evaporated and purified by filtration through silica with chloroform:methanol (95:5) followed by preparative HPLC. The title compound (19 mg, 0.04 mmol, 17%) was obtained as a yellow powder. ESMS m/z 509 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 8.50 (s, 1H) 7.79 (s, 1H) 7.34 (d, J=8.5 Hz, 2H) 7.19 (br. s, 1H) 7.07-7.14 (m, 1H) 6.82-6.92 (m, 3H) 6.78 (dd, J=10.5, 8.8 Hz, 1H) 5.80 (s, 2H) 3.28 (s, 1H) 3.16-3.25 (m, 4H) 2.60-2.69 (m, 4H) 2.39 (s, 3H) 2.16-2.27 (m, 1H) 0.80-0.87 (m, 2H) 0.61-0.68 (m, 2H).
Reaction SMILES: [CH2:1]([N:8]1[C:15](=[O:16])[CH2:14][C:12](=[O:13])[N:11]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:30]1([CH2:36][C:37](Cl)=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>ClCCl>[CH2:1]([N:8]1[C:15](=[O:16])[CH:14]([C:37](=[O:38])[CH2:36][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:12](=[O:13])[N:11]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:9]1=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CC(=O)N(Cc2ccccc2)C(=O)N1Cc1ccccc1
Reactant: O=C(Cl)Cc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Cc1ccccc1)C1C(=O)N(Cc2ccccc2)C(=O)N(Cc2ccccc2)C1=O
Temperature: 0 °C
Yield: 88.8 %

Procedure:
To a solution of 1,3-dibenzyl barbituric acid 192 mg (0.623 mmol) in dry dichloromethane 2.0 mL under nitrogen atmosphere, added was pyridine 1.0 mL (12 mmol) and stirred at 0° C. Added was phenylacetyl chloride 96 mg (0.623 mmol, 1.00 equivalent) in dichloromethane 1.0 mL to the solution slowly during a period of 20 minutes, then stirred at room temperature for 3 hours. Added was dichloromethane 40 mL and washed the organic layer with 2 M hydrochloric acid and saturated brine, and dried over sodium sulfate. Purified was the crude product 273 mg, after removal of the solvent under the reduced pressure, by column chromatography (silica gel, eluted with dichloromethane). It obtained 1,3-dibenzyl-5-(phenylacetyl)barbituric acid 236 mg as colorless viscous oil at first (88.7% yield) and it gradually turned white plates.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[NH:10]2)=[CH:6][CH:5]=1.IC.[CH2:20](O)C>CN(C)C=O>[Cl:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:10]2[CH3:20])=[CH:6][CH:5]=1
Reactant: CCOC(=O)c1cc2ccc(Cl)cc2[nH]1
Reactant: CCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)c1cc2ccc(Cl)cc2n1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A suspension of 1.8 g (45 mmol) of 60% sodium hydride (washed beforehand with petroleum ether) and of 8.0 g (35.8 mmol) of ethyl 6-chloro-1H-indole-2-carboxylate in 80 ml of N,N-dimethylformamide is stirred for 2 h at room temperature, 2.8 ml (45 mmol) of iodomethane are subsequently added and the mixture is stirred at room temperature for 4 h. 5 ml of absolute ethanol are added and the solvent is evaporated under reduced pressure. The residue is taken up in water and the mixture is extracted with dichloromethane, the organic phase is dried and filtered, the solvent is evaporated under reduced pressure and the residue is purified by chromatography on a column of silica gel. 8.5 g (35.7 mmol) of a white crystalline compound are isolated.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([Cl:9])[N:3]=1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>ClCCl>[CH3:1][C:2]1[N:3]=[C:4]([Cl:9])[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[N:7]=1
Reactant: C1COCCN1
Reactant: Cc1nc(Cl)cc(Cl)n1
Solvent: ClCCl
Product: Cc1nc(Cl)cc(N2CCOCC2)n1
Temperature: -78 °C
Reaction time: 8 h
Yield: 88.7 %

Procedure:
The crude 2-methyl-4,6-dichloropyrimidine (41.8 g.; 256 mmol) was dissolved in dichloromethane (200 mL) and chilled to −78° C. in an inert atmosphere. Morpholine (48 g.; 550 mol) dissolved in dichloromethane (100 mL) was added slowly. The reaction was allowed to warm to room temperature while stirring overnight. The organic layer was washed with saturated ammonium chloride (2×100 mL), dried with sodium sulfate, and evaporated to give 2-methyl-4-chloro-6-morpholino-pyrimidine (48.5 g.; 227 mmol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:12]C(=O)[NH:10][CH:9]2[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[NH2:10][CH:9]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:22])[F:23])[CH:16]=1)[CH:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[OH:12]
Reactant: O=C1NC(Cc2cccc(C(F)(F)F)c2)C(c2ccc(F)cc2)O1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NC(Cc1cccc(C(F)(F)F)c1)C(O)c1ccc(F)cc1
Yield: 80.3 %

Procedure:
To a solution of (4RS,5SR)-5-(4-fluorophenyl)-4-((3-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidin-2-one (4.0 g, 11.8 mmol) in ethanol (80 ml) was added 8N aqueous sodium hydroxide solution (7.4 ml, 59 mmol) and the mixture was heated under reflux for 4 hrs. The reaction solution was concentrated, diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(3-(trifluoromethyl)phenyl)-1-propanol (2.97 g, 80%).