Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=[CH:10][C:3]=12.CC1(C)C(C)(C)OB([C:27]2[CH:28]=[N:29][NH:30][CH:31]=2)O1.CN(C=O)C.C(=O)([O-])[O-].[K+].[K+]>O.C(OCC)(=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>[NH:29]1[CH:28]=[C:27]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=[CH:10][C:3]=23)[CH:31]=[N:30]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(Br)ccnc21
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ccnc21
Temperature: 120 °C
Yield: 67.8 %

Procedure:
4-Bromo-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine (0.20 g, 0.00061 mol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.15 g, 0.00079 mol) were combined in DMF (5.0 mL, 0.064 mol) and then potassium carbonate (0.25 g, 0.0018 mol) in 1 mL water was added. The reaction was degassed with nitrogen, then tetrakis(triphenylphosphine)palladium(0) (0.08 g, 0.00007 mol) was added and in a sealed tube the reaction was heated to 120° C. oil bath. The reaction was heated for 30 minutes, allowed to cool and then taken up in ethyl acetate. The reaction mixture was washed with brine, dried over magnesium sulfate and concentrated to give an oil. The product was purified by FCC on silica gel eluting with a hexane:ethyl acetate gradient to give 4-(1H-pyrazol-4-yl)-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine (0.13 gm, 70%) as a crystalline white powder, LC/MS (M+H)+: 315, 1H NMR (DMSO-d6) δ 13.35 (bs, 1H), 8.59(bs, 1H), 8.32(d, 1H, J=8.5), 8.26(bs, 1H), 7.76(d, 1H, J=6.0), 7.45(d, 1H, J=8.5), 7.01(d, 1H, J=6.0), 5.73(s, 2H), 3.61(t, 2H), 0.92(t, 2H), 0.0(s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)=[O:4].II.[I:19](O)(=O)=O.S(=O)(=O)(O)O>>[CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[C:10]([I:19])[C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: [O-][I+2]([O-])O
Reactant: COC(=O)c1cccc2cc(OC)ccc12
Agent: II
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc2c(I)c(OC)ccc12

Procedure:
The process for the key intermediate in the copending application is exemplified as follows: 6-methoxy-1-naphthalenecarboxylic acid methyl ester is reacted with iodine and iodic acid in the presence of 98% sulfuric acid to give 5-iodo-6-methoxy-1-naphthalenecarboxylic acid methyl ester, which in turn is reacted with trifluoromethyl iodide and copper powder in a stainless steel autoclave to give 6-methoxy-5-(trifluoromethyl)-1-naphthalenecarboxylic acid methyl ester. Hydrolysis of the latter compound with dilute aqueous sodium hydroxide gives 6-methoxy-5-(trifluoromethyl)-1-naphthalenecarboxylic acid, one of the key intermediate noted hereinbefore. The latter compound also can be named 5-(trifluoromethyl)-6-methoxy-1-naphthalenecarboxylic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=S)=[N:8][CH:9]=[CH:10][CH:11]=1.[NH3:26]>>[CH3:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[NH:26])=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: N
Reactant: Cc1ccccc1COc1cccnc1NC(=S)Nc1ccccc1
Product: Cc1ccccc1COc1cccnc1NC(=N)Nc1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of N-[3-(2-methylbenzyloxy)pyrid-2-yl]-N'-phenylthiourea (1.76 g, 0.005 mol), yellow mercuric oxide (1.31 g, 0.006 mol) and methanolic ammonia (40 ml) was stirred for 3 days at room temperature. The solvent was removed in vacuo and the black residue was boiled with chloroform and filtered hot. Evaporation of the solvent and recrystallisation from acetonitrile gave the desired product. Yield 1.2 g (72%), m.p. 157°-158 ° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C:14]([OH:16])=[O:15])[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]=O>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:1]([O:8][C:9]([N:11]1[C@H:12]([CH3:13])[C:14](=[O:16])[O:15][CH2:17]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: C[C@@H]1C(=O)OCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 85.6 %

Procedure:
In toluene (190 mL) were suspended benzyloxycarbonyl-D-alanine (19.3 g), paraformaldehyde (6.56 g) and p-toluenesulfonic acid monohydrate (0.17 g), and the mixture was heated at reflux while removing water produced. At the end of the reaction, the mixture was cooled to room temperature, and washed with saturated aqueous sodium hydrogen carbonate solution and saturated saline. The toluene solution was dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure. The precipitated crystals were filtered to give the title compound (17.4 g) as white crystals in a yield of 85%.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6](=[O:23])[N:7]([CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:8]([CH3:14])=[N:9]2.[Cl:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[Cl:34])[C:28](Cl)=[O:29].C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[Cl:34])[C:28]([NH:2][CH2:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6](=[O:23])[N:7]([CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:8]([CH3:14])=[N:9]2)=[O:29]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: Cc1nc2cccc(CN)c2c(=O)n1C1CCC(=O)NC1=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1nc2cccc(CNC(=O)c3ccc(Cl)c(Cl)c3)c2c(=O)n1C1CCC(=O)NC1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67.9 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.46 g, 1.4 mmol) in acetonitrile (10 mL), was added 3,4-dichloro-benzoyl chloride (0.34 g, 1.6 mmol) and N,N-diisopropyl ethylamine (0.54 mL, 3.3 mmol). The mixture was stirred at room temp for 15 minutes. The solvent was evaporated, and the residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give 3,4-dichloro-N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-benzamide as a white solid (450 mg, 70% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, gradient to 95/5 in 5 min, kept for 5 min, 6.60 min (99.6%); mp, 271-273° C.; 1HNMR (DMSO-d6) 2.17-2.22 (m, 1H, CHH), 2.58-2.90 (m, 6H, CHCH2, CH3), 4.97-5.09 (m, 2H, CH2NH), 5.26 (dd, J=6, 11 Hz, 1H, CH), 7.34-8.17 (m, 6H, Ar), 9.14 (t, J=5 Hz, 1H, CH2NH), 11.04 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.80, 23.29, 30.60, 42.30, 56.52, 117.66, 124.17, 125.56, 127.58, 129.28, 130.76, 131.31, 133.97, 134.11, 134.56, 140.39, 148.50, 154.86, 161.06, 164.10, 169.53, 172.62. LCMS MH=473, 475; Anal Calcd For C22H18N4O4Cl2+0.1 CH2Cl2: C, 55.09; H, 3.81; N, 11.63; Cl, 16.19. Found: C, 54.88; H, 3.60; N, 11.46; Cl, 16.38.
Reaction SMILES: [CH2:1]([C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:5][CH:4]=1)[CH3:2].[Br:19]Br.S(OS(O)=O)(O)=O.[Na]>CN(C=O)C>[Br:19][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]([CH2:7][C:6]2[CH:17]=[CH:18][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=2)[CH:9]=1
Reactant: BrBr
Reactant: CCc1ccc(Cn2ccc3ccccc32)cc1
Agent: O=S(O)OS(=O)O
Agent: [Na]
Solvent: CN(C)C=O
Product: CCc1ccc(Cn2cc(Br)c3ccccc32)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 62.9 %

Procedure:
A solution of 1-(4-ethylbenzyl)-1H-indole (2.0 g, 8.50 mmol) in DMF (20 mL) was added dropwise to a solution of bromine (0.46 mL, 8.93 mmol) in DMF (20 mL) at room temperature. The reaction mixture was stirred for two hours, and then poured into an ice-cooled sodium pyrosulfurous acid aqueous solution. The resulting mixture was extracted with ethyl acetate, and the organic layer was washed with a saturated sodium hydrogencarbonate aqueous solution and a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure. The residue was recrystallized from ethyl acetate and n-hexane to obtain the title compound (1.68 g, 63%).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][N:6]2[CH:15]=1.Cl.Cl.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1.C(N(C(C)C)CC)(C)C>C1COCC1>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([N:25]2[CH2:30][CH2:29][N:28]([CH2:2][C:3]3[N:4]=[C:5]4[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][N:6]4[CH:15]=3)[CH2:27][CH2:26]2)=[CH:23][CH:24]=1
Reactant: FC(F)(F)c1ccc2nc(CCl)cn2c1
Reactant: Clc1ccc(N2CCNCC2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)(F)c1ccc2nc(CN3CCN(c4ccc(Cl)cc4)CC3)cn2c1
Yield: 41 %

Procedure:
Following the same general procedure as for Example 49, Step 2, and making non-critical variations, 2-(chloromethyl)-6-trifluoromethylimidazo[1,2-a]pyridine (Example 49, Step 1; 0.435 g), 1-(4-chlorophenyl)piperazine dihydrochloride (Aldrich; 0.550 g), diisopropylethylamine (Aldrich; 0.815 g), and THF (6 mL) give 0.30 g of 2-[[4-(4-chlorophenyl)-1-piperazinyl]methyl]-6-(trifluoromethyl)imidazo[1,2-a]pyridine after crystallization from ethyl acetate/hexane; mp 128-135° C.; MS m/z 394; IR (mineral oil) 1331, 1141, 1127, 1055, 1500, 830 cm-1. 1H NMR (CDCl3) δ 2.74, 3.20, 3.80, 6.83, 7.19, 7.31, 7.66, 7.68, 8.47.
Reaction SMILES: Cl[C:2]1[N:24]=[C:5]2[C:6]([NH:10][CH2:11][C:12]3[C:13]([N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])=[N:14][CH:15]=[CH:16][CH:17]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:25][S:26]([C:29]1[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=1)(=[O:28])=[O:27].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:25][S:26]([C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:2]2[N:24]=[C:5]3[C:6]([NH:10][CH2:11][C:12]4[C:13]([N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])=[N:14][CH:15]=[CH:16][CH:17]=4)=[CH:7][CH:8]=[CH:9][N:4]3[N:3]=2)=[CH:31][CH:30]=1)(=[O:27])=[O:28]
Reactant: CN(c1ncccc1CNc1cccn2nc(Cl)nc12)S(C)(=O)=O
Reactant: CS(=O)(=O)c1ccc(N)cc1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN(c1ncccc1CNc1cccn2nc(Nc3ccc(S(C)(=O)=O)cc3)nc12)S(C)(=O)=O

Procedure:
N-(3-{[2-(4-Methanesulfonyl-phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino]-methyl}-pyridin-2-yl)-N-methyl-methanesulfonamide was prepared from N-{3-[(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-methyl]-pyridin-2-yl}-N-methyl-methanesulfonamide (75.0 mg, 0.204 mmol) and 4-methanesulfonyl-phenylamine (39.0 mg, 0.228 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a tan foam (0.009 g, 9%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.43 (dd, J=4.6, 1.4 Hz, 1H), 7.92-7.83 (m, 4H), 7.76 (d, J=8.8 Hz, 2H), 7.29 (dd, J=7.7, 4.7 Hz, 1H), 7.12 (s, 1H), 6.74 (t, J=7.5 Hz, 1H), 6.38 (d, J=7.7 Hz, 1H), 5.37 (t, J=6.4 Hz, 1H), 4.78 (d, J=6.3 Hz, 2H), 3.33 (s, 3H), 3.10 (s, 3H), 3.05 (s, 3H). MS=502 (MH)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH2:12])[CH:7]=1)[CH3:2].[N:14]([O-])=O.[Na+].O.O.[Cl:20][Sn]Cl>Cl>[ClH:20].[CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][NH2:14])[CH:7]=1)[CH3:2]
Reactant: O=N[O-]
Reactant: CCOC(=O)Cc1cccc(N)c1
Reactant: Cl[Sn]Cl
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCOC(=O)Cc1cccc(NN)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87.7 %

Procedure:
To a mixture of (3-aminophenyl)acetic acid ethyl ester (15 g, 84 mmol) in conc. HCl (20 mL) was added sodium nitrite (6 g, 87 mmol) aqueous solution dropwise under ice-salt bath. The resulting mixture was stirred at 0° C. for 30 min and then added a solution of SnCl2.2H2O (38 g, 168 mmol) in conc. HCl dropwise also at such a rate that the reaction mixture never rose above 5° C. After the addition was completed, the mixture was stirred for another 2 h at room temperature. The precipitate was collected by suction and washed with ethyl ether to afford (3-Hydrazinophenyl)acetic acid ethyl ester hydrochloride (17 g, 88%) as a brown solid. MS (ESI) m/z: 195 (M+H+). A solution of (3-hydrazinophenyl)acetic acid ethyl ester hydrochloride (17 g, 74 mmol) and 3-cyclopentyl-3-oxopropionitrile (12.2 g, 88.8 mol) in alcohol (150 mL) containing conc. HCl (10 mL) was heated to reflux overnight. After removed of the solvent, the precipitate was collected by suction and washed with ethyl ether to afford the crude product, which was purified by column chromatography to afford [3-(5-amino-3-cyclopentylpyrazol-1-yl)phenyl]acetic acid ethyl ester hydrochloride (8.8 g, 34% yield) as a yellow solid. 1H NMR (300 MHz, DMSO-d6): δ 7.40-7.66 (m, 4H), 5.68 (s, 1H), 4.05 (q, J=7.2 Hz, 2H), 3.75 (s, 2H), 3.00-3.08 (m, 1H), 1.98-2.00 (m, 2H), 1.58-1.70 (m, 6H), 1.17 (t, J=7.2 Hz, 3H); MS (ESI) m/z: 314 (M+H+).
Reaction SMILES: [CH2:1]([Zn]CC)C.FC(F)(F)C(O)=O.ICI.[F:16][C:17]1[C:27]2[CH2:26][CH2:25][CH2:24][C:23](=[O:28])[N:22]([CH:29]=[CH2:30])[C:21]=2[C:20]([F:31])=[CH:19][C:18]=1[F:32].[NH4+].[Cl-]>C(Cl)Cl>[CH:29]1([N:22]2[C:23](=[O:28])[CH2:24][CH2:25][CH2:26][C:27]3[C:17]([F:16])=[C:18]([F:32])[CH:19]=[C:20]([F:31])[C:21]2=3)[CH2:1][CH2:30]1
Reactant: CC[Zn]CC
Reactant: C=CN1C(=O)CCCc2c(F)c(F)cc(F)c21
Agent: [Cl-]
Agent: [NH4+]
Solvent: ICI
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CCCc2c(F)c(F)cc(F)c2N1C1CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
An oven-dried 250 mL round-bottom flask was fitted with a stirbar and septa and flushed with nitrogen. Diethyl zinc (12.0 mL, 1.0 M/hexanes, 12.0 mmol) was added and cooled to 0° C. Trifluoroacetic acid (0.90 mL, 11.7 mmol) was added in a careful, dropwise manner over 5 minutes, and the reaction was then stirred for 15 minutes. Methylene chloride (10 mL) and diiodomethane (1.20 mL, 14.9 mmol) were then added, and the reaction was stirred for an additional 20 minutes. A solution of the product of Step 1 (1.01 g, 4.19 mmol) in methylene chloride (20 mL) was then added, and the reaction was stirred overnight with gradual warming to room temperature. After 25 hours, the reaction was poured into saturated aqueous NH4Cl solution (50 mL) and extracted with methylene chloride (3×50 mL). The organic extracts were combined, dried over MgSO4, filtered and concentrated in vacuo to give an oil that was purified via flash chromatography on silica gel (0% to 20% ethyl acetate/hexanes linear gradient) to give the desired product.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]([C:11]3[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH:16]=3)[N:6]2[N:5]=[CH:4][N:3]=1>C(O)(=O)C.[Pt](=O)=O>[NH2:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc3c(N)ncnn23)CC1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc3c(N)ncnn23)CC1
Reaction time: 16 h
Yield: 103.3 %

Procedure:
To a dry flask purged with N2 was added platinum(IV) oxide (127 mg, 0.56 mmol) followed by tert-butyl 4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,6-dihydropyridine-1(2H)-carboxylate (587 mg, 1.86 mmol) as a solution in acetic acid (19 mL). The mixture was stirred under an H2 atmosphere for 16 h. The mixture was filtered through a pad of Celite® rinsing with acetic acid and ethanol. The solvent was evaporated under reduced pressure and the residue was dissolved in ethyl acetate (100 mL). The organic was washed with saturated aqueous NaHCO3 (2×75 mL) and the aqueous mixture was back extracted with ethyl acetate (3×50 mL). The combined organics were washed with brine, dried (Na2SO4) and concentrated to dryness to afford 610 mg (100%) of the desired product as a gray solid.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:15])([F:14])[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]#[N:13])=[CH:7][CH:6]=1.Br[CH2:17][CH2:18][CH2:19][CH2:20]Br.Cl>CS(C)=O.CS(C)=O.CCOCC.O>[F:3][C:4]([F:14])([F:15])[C:5]1[CH:6]=[CH:7][C:8]([C:11]2([C:12]#[N:13])[CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:9][CH:10]=1
Reactant: BrCCCCBr
Reactant: N#CCc1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CS(C)=O
Product: N#CC1(c2ccc(C(F)(F)F)cc2)CCCC1
Reaction time: 2 h
Yield: 65 %

Procedure:
To a suspension of NaH (8.18 g, 135.13 mmol, 60%) in dimethyl sulfoxide (100 mL) were added dropwise a mixture of (4-trifluoromethyl-phenyl)-acetonitrile (236) (25 g, 135.13 mmol) and 1,4-dibromobutane (16 mL, 135.13 mmol) dissolved in dimethyl sulfoxide:ether (1:1) (300 mL) at 0° C. and the reaction mixture was stirred at this temperature for 2 h. After completion of the reaction, water (100 mL) and 10% HCl solution (50 mL) were added to the mixture and extracted with ethyl acetate (2×400 ml). The organic layer was dried over Na2SO4, concentrated and purified by 100-200 silica column chromatography using hexane as the eluent to give 1-(4-trifluoromethyl-phenyl)-cyclopentanecarbonitrile (237) (21 g, 65%) as a colorless liquid.
Reaction SMILES: [BH4-].[Na+].FC(F)(F)C(O)=O.[O:10]=[C:11]([N:25]1[CH2:30][CH2:29][N:28]2[C:31]([C:34]([F:37])([F:36])[F:35])=[N:32][N:33]=[C:27]2[CH2:26]1)[CH:12]=[C:13]([NH2:24])[CH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=1[F:23].N>O.C1COCC1>[O:10]=[C:11]([N:25]1[CH2:30][CH2:29][N:28]2[C:31]([C:34]([F:37])([F:36])[F:35])=[N:32][N:33]=[C:27]2[CH2:26]1)[CH2:12][CH:13]([NH2:24])[CH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=1[F:23]
Reactant: NC(=CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Agent: N
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: NC(CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Temperature: -6.5 °C
Reaction time: 1 h

Procedure:
In a 250 mL round bottom flask THF (75 mL) was taken. It was cooled to −8 to −5° C. and NaBH4 (1.87 g) was added. After that trifluoroacetic acid (11.3 g) was added dropwise at −15 to −5° C. over a period of 30-45 min. Separately, 4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)but-2-en-2-amine (5.0 g) was added in small portions into the reaction mixture, keeping the temperature between −10 to −5° C. It was stirred for 1 h at −10 to −0° C. Reaction mixture was poured into cold water. It was basified by adding aq. ammonia solution. Product was extracted in ethyl acetate. The organic layer was collected. It was washed with water and dried over anhydrous sodium sulfate. Solvent was evaporated at reduced pressure to obtain the product. (Wt.-4.9 g; % Y-97.6%; % Purity by HPLC-81.6%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[C:17]([C:18]3[O:22][CH:21]=[N:20][CH:19]=3)=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:23][N:24]([CH3:41])[CH2:25][CH2:26][CH2:27][N:28]([CH3:40])[C:29]1[C:30]([NH2:39])=[CH:31][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:34]=1.C1COCC1>C(N(CC)CC)C>[CH3:41][N:24]([CH3:23])[CH2:25][CH2:26][CH2:27][N:28]([CH3:40])[C:29]1[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:36])[F:37])=[CH:31][C:30]=1[NH:39][C:4](=[O:5])[C:3]1[CH:7]=[C:8]([O:11][C:12]2[C:17]([C:18]3[O:22][CH:21]=[N:20][CH:19]=3)=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:9]=[CH:10][C:2]=1[F:1]
Reactant: CN(C)CCCN(C)c1ccc(C(F)(F)F)cc1N
Reactant: O=C(Cl)c1cc(Oc2ncccc2-c2cnco2)ccc1F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)CCCN(C)c1ccc(C(F)(F)F)cc1NC(=O)c1cc(Oc2ncccc2-c2cnco2)ccc1F
Temperature: 25 °C
Reaction time: 108 h

Procedure:
To 2-fluoro-5-(3-(oxazol-5-yl)pyridin-2-yloxy)benzoyl chloride (60 mg, 0.17 mmol) and N1-(3-(dimethylamino)propyl)-N1-methyl-4-(trifluoromethyl)benzene-1,2-diamine (44.1 mg, 0.160 mmol) was added THF (1.0 mL). The mixture was stirred at rt for 4.5 days. The reaction was quenced with excess triethylamine, filtered and concentrated. The residue was purified by Gilson reverse-phase HPLC (0.1% TFA in water/acetonitrile). After basic workup, N-(2-((3-(dimethylamino)propyl)(methyl)amino)-5-(trifluoromethyl)phenyl)-2-fluoro-5-(3-(oxazol-5-yl)pyridin-2-yloxy)benzamide was obtained as a white solid. MS m/z=558 [M+1]+. Calc'd for C28H27F4N5O3: 557.55.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH:13]([CH3:15])[CH3:14])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:16])[N:3]=1.[C:17]1(B(O)O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([O-])([O-])=O.[Na+].[Na+].CCO>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.C1C=CC=CC=1>[CH:13]([O:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[C:4]([CH3:16])[N:3]=[C:2]2[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:15])[CH3:14]
Reactant: Cc1nc(Cl)c2cccc(OC(C)C)c2n1
Reactant: OB(O)c1ccccc1
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: c1ccccc1
Solvent: CCO
Product: Cc1nc(-c2ccccc2)c2cccc(OC(C)C)c2n1

Procedure:
To a stirred mixture of 4-chloro-8-isopropoxy-2-methyl-quinazoline (35) (0.58 mmol), phenylboronic acid (0.62 mmol), 2 N Na2CO3 (7.2 mL), EtOH (1.2 mL) and benzene (6 mL) was added, under a blanket of argon, Pd(PPh3)4 (20 mg). The mixture was stirred under reflux for 16 h, cooled, and concentrated. Subsequent column chromatography (ethyl acetate/hexane) provided 8-isopropoxy-2-methyl-4-phenyl-quinazoline (36) as a solid.
Reaction SMILES: [C:1]1([CH:7]2[O:11][CH:10]([CH2:12][O:13][CH3:14])[CH2:9][O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:15]N1C(=O)CCC1=O.CCCCCCC.C(OCC)(=O)C>ClC(Cl)C>[C:7]([O:11][CH:10]([CH2:12][O:13][CH3:14])[CH2:9][Br:15])(=[O:8])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COCC1COC(c2ccccc2)O1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Solvent: CCCCCCC
Product: COCC(CBr)OC(=O)c1ccccc1
Reaction time: 1 h
Yield: 93 %

Procedure:
To a solution of 13.6 g (0.07 mol) of 2-phenyl 4-methoxymethyl 1,3-dioxolane (S) (Austr. J. Chem. 761, 29. 1976) in 40 ml of dichloroethane, are gradually added 12.5 g (0.07 mol) of N-bromosuccinimide while keeping temperature at 25° C. After 1 h of stirring, the reaction medium is poured on water. The organic phase is washed with a solution of sodium thiosulphate, and then with water, dried over magnesium sulphate and concentrated. The product is obtained with a 93% yield, after chromatography (Silica, Heptane: 60 Ethyl acetate: 40).