Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[C:5](SC#N)=[N:6][C:7]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][C:19]([F:22])([F:21])[F:20])=[N:8][CH:9]=1)([O-:3])=[O:2].[NH2:26][CH2:27][C@@H:28]1[CH2:33][CH2:32][C@H:31]([OH:34])[CH2:30][CH2:29]1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[N+:1]([C:4]1[C:5]([NH:26][CH2:27][C@@H:28]2[CH2:33][CH2:32][C@H:31]([OH:34])[CH2:30][CH2:29]2)=[N:6][C:7]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][C:19]([F:21])([F:20])[F:22])=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: N#CSc1nc(NCc2ccccc2OC(F)(F)F)ncc1[N+](=O)[O-]
Reactant: NC[C@H]1CC[C@@H](O)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=[N+]([O-])c1cnc(NCc2ccccc2OC(F)(F)F)nc1NC[C@H]1CC[C@@H](O)CC1
Reaction time: 8 h

Procedure:
(5-Nitro-4-thiocyanato-pyrimidin-2-yl)-(2-trifluoromethoxy-benzyl)-amine (10 g, 26.9 mmol) was dissolved in DCM (100 ml). cis-4-aminomethyl-cyclohexanol (3.48 g, 26.9 mmol) and diisopropylethylamine (10 mL, 53.8 mmol) were added to the solution and stirred overnight. The reaction mixture was evaporated in-vacuo and purified by column chromatography (1% MeOH/99% CH2Cl2). The resulting solid was washed with cold methanol to give a pale yellow solid as cis-4-{[5-nitro-2-(2-trifluoromethoxy-benzylamino)-pyrimidin-4-ylamino]-methyl}-cyclohexanol (11.3 g, 25.6 mmol, 95.1%).
Reaction SMILES: [CH3:1][C:2]([NH:11][N:12]=C(C)C)([CH3:10])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O=[C:17]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:18][C:19]([O:21]CC)=O.C(=O)([O-])O.[Na+]>C(O)(=O)C.C(OCC)(=O)C>[CH3:10][C:2]([N:11]1[C:19](=[O:21])[CH2:18][C:17]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[N:12]1)([CH3:1])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)=NNC(C)(C)Cc1ccccc1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)(Cc1ccccc1)N1N=C(c2ccccc2)CC1=O
Temperature: 100 °C
Reaction time: 4 h
Yield: 50.6 %

Procedure:
500 mg (2.45 mmol) of 1-(2-methyl-1-phenylpropan-2-yl)-2-(propan-2-ylidene)hydrazine was dissolved in 3.0 mL of glacial acetic acid, mixed with 429 mg (2.23 mmol) of ethyl 3-oxo-3-phenylpropanoate and stirred at 100° C. for 4 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate, neutralized with saturated aqueous sodium hydrogen carbonate (100 ml) and extracted with ethyl acetate. The resulting organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using hexane-ethyl acetate (100:1 to 9:1) as the eluent to give 330 mg of the desired product as a pale orange solid.
Reaction SMILES: [C:1]([O:4][CH:5]([CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:6](O)=[O:7])(=[O:3])[CH3:2].S(Cl)([Cl:19])=O>>[O:10]([CH2:9][CH:5]([O:4][C:1](=[O:3])[CH3:2])[C:6]([Cl:19])=[O:7])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=S(Cl)Cl
Reactant: CC(=O)OC(COc1ccccc1)C(=O)O
Product: CC(=O)OC(COc1ccccc1)C(=O)Cl

Procedure:
To 22.42 g (0.1 mole) of 2-acetoxy 3-phenoxy propanoic acid, was added 24 g of thionyl chloride and the mixture was heated under reflux for 2 hours. The excess of thionyl chloride was driven off on a rotary evaporator and the residue was distilled under nitrogen. B.P.14 =163°-8° C.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5](=[O:7])=[O:6].[C:8]([F:23])([O:12][C:13]([F:22])([F:21])[C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16])=[C:9]([F:11])[F:10].S(=O)(=O)(O)O>CS(C)=O.O>[OH2:6].[N:1]([C:9]([F:11])([F:10])[C:8]([F:23])([O:12][C:13]([F:21])([F:22])[C:14]([F:19])([F:20])[C:15]([F:16])([F:17])[F:18])[C:5]([OH:7])=[O:6])=[N+:2]=[N-:3]
Reactant: FC(F)=C(F)OC(F)(F)C(F)(F)C(F)(F)F
Reactant: O=C=O
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: [N-]=[N+]=NC(F)(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(=O)O
Yield: 100.6 %

Procedure:
Reaction of 26.0 g (0.40 mole) of sodium azide, 33 g (0.75 mole) of carbon dioxide, and 106 g (0.40 mole) of perfluoro(propyl vinyl ether) in dimethyl sulfoxide was carried out in a 400 ml metal tube at 25°. The reaction mixture was poured into a solution of 250 ml of concentrated sulfuric acid in 900 ml of water. Continuous extraction with ether and evaporation of the extracts afforded 140 g of crude 3-azido-2-heptafluoropropoxytrifluoropropionic acid hydrate. This acid was reacted in a 1 L metal tube under autogenous pressure with 150 g (1.39 moles) of SF4 and 84 g (2.0 moles) of NaF in 80 ml of CFCl2CF2Cl at 80° for 12 hr. Distillation gave 82.9 g (58% overall yield) of 3-azido-2-heptafluoropropoxytrifluoropropionyl fluoride, bp 51°-53° (100 mm, 13.3 kPa). IR (CCl4): 2150 (N3), 1875 (COF), and 1300-1100 cm-1 (CF, C--O). NMR (CCl4): 19 F 26.0 (p, JFF 6 Hz, 1F, COF), -82.0 (t, JFF 7.5 Hz, 3F, CF3), -129.3 (d of p, JFF 20, 6 Hz, 1F, CF), and -130.2 ppm (s, 2F, CF2) with an AB pattern for CF2O at -7417 and -7567 Hz (d of q, JFF 20, 7.5 Hz, 1F) and -8181 and -8332 Hz (q, JFF 7.5 Hz, 1F), and for CF2N3 at -8244 and -8430 Hz (t, JFF 5.5 Hz, 1F) and -8465 and -8651 Hz (t, JFF 6.2 Hz, 1F).
Reaction SMILES: [SH:1][CH2:2][C:3]([O:5][CH3:6])=[O:4].CS(O[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Br:20])(=O)=O.N1CCCN2CCCCCC=12>C1COCC1>[CH3:6][O:5][C:3](=[O:4])[CH2:2][S:1][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Br:20]
Reactant: CS(=O)(=O)OCCc1ccccc1Br
Reactant: COC(=O)CS
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COC(=O)CSCCc1ccccc1Br
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 74.5 %

Procedure:
A mixture of methyl 2-mercaptoacetate (2.2 g), 2-bromophenethyl methanesulfonate (5.7 g), 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (3.7 g) and THF (30 ml) was stirred at ambient temperature for 1.5 hrs and separation method A and E yielded the title compound (4.4 g).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3](=[O:13])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>CC(C)=O.C1(C)C=CC=CC=1>[F:1][C:2]([F:14])([F:15])[C:3](=[O:13])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:8][CH:7]=1
Reactant: O=C(/C=C/c1ccc(O)cc1)C(F)(F)F
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)COc1ccc(/C=C/C(=O)C(F)(F)F)cc1
Temperature: 22 °C
Reaction time: 3 h
Yield: 92.7 %

Procedure:
A solution of (E)-1,1,1-trifluoro-4-(4-hydroxyphenyl) 3-buten-2-one (0.105 g, 0.49 mmol) in acetone (6 ml) was treated with powdered potassium carbonate (0.3 g) and tert-butyl bromoacetate (0.20 g, 1.02 mmol) and stirred at 22° C. for 3 h. The reaction mixture was then diluted with toluene, washed with brine, dried (magnesium sulfate) and concentrated under reduced pressure. The residue was chromatographed on silica gel (elution toluene-ethyl acetate 2%) and gave 0.150 g (94%) of the title material as yellow needles: mp 112-113° C.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][NH:16][C:15](=[O:19])[CH2:14]3)=[N:10][CH:9]=2)[CH:5]=[CH:4][CH:3]=1.[CH3:20]N(C)C=O.[H-].[Na+].CI>O1CCCC1.O>[Br:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][N:16]([CH3:20])[C:15](=[O:19])[CH2:14]3)=[N:10][CH:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CN(c2ncc(-c3cccc(Br)n3)s2)CCN1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Solvent: O
Product: CN1CCN(c2ncc(-c3cccc(Br)n3)s2)CC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
4-[5-(6-bromopyridin-2-yl)thiazol-2-yl]piperazin-2-one obtained in Step 4 (200 mg, 0.59 mmol) was dissolved in tetrahydrofuran (2 ml) and N,N-dimethylformamide (2 ml) and after sodium hydride (60% oily, 26 mg, 0.65 mmol) was added, methyl iodide (39 μl, 0.62 mmol) was added and the mixture was stirred overnight at room temperature. Water was added to the reaction solution and the residue obtained by vacuum concentration was extracted with ethyl acetate and washed with a saturated brine. The organic layer was dried over sodium sulfate and concentrated in vacuo to give the title compound (188 mg, 90%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N+:17]([O-])=O)[S:5][C:6]=1[C:7]([O-:9])=[O:8].[Sn](Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+].O1CC[CH2:31][CH2:30]1>>[NH2:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[NH:10][C:4]1[S:5][C:6]([C:7]([O:9][CH2:30][CH3:31])=[O:8])=[C:2]([CH3:1])[N:3]=1
Reactant: C1CCOC1
Reactant: Cc1nc(Nc2ccccc2[N+](=O)[O-])sc1C(=O)[O-]
Agent: Cl[Sn]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCOC(=O)c1sc(Nc2ccccc2N)nc1C
Temperature: 80 °C
Yield: 77 %

Procedure:
4-Methyl-2-(2-nitrophenylamino)thiazole-5-carboxylate (0.45 g, 1.46 mmol), tin(II) chloride dehydrate (1.66 g, 7.34 mmol) and tetrahydrofuran (25 mL) was added to a 100-mL round bottom flask. The mixture was refluxed at 75-85° C. for 3 h, cooled down to 0° C. and followed by the addition of saturated aqueous sodium carbonate solution (16 mL). The mixture was filtered through a celite cake and the filtrate was washed with saturated aqueous sodium carbonate solution (18 mL), water (2×15 mL) and brine (15 mL), dried over sodium sulfate, filtered and concentrated in vacuo to a small volume and triturated with diethyl ether. The solid was collected by filtration, washed with hexanes and dried in vacuo to afford ethyl 2-(2-aminophenylamino)-4-methylthiazole-5-carboxylate as a white solid (0.31 g, 77% yield): 1H NMR (300 MHz, CDCl3) δ 7.31-7.24 (m, 1H), 7.17-7.12 (m, 1H), 6.84-6.77 (m, 2H), 4.45-4.06 (m, 5H), 2.48 (s, 3H), 1.25 (t, J=7.05 Hz, 3H); MS (ES+) m/z 278.0 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:13]3[CH2:15][CH2:14]3)[NH:11][CH:12]=2)=[CH:4][CH:3]=1.[C:16](=O)([O-])[O-].[Cs+].[Cs+].IC.O>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([CH:13]3[CH2:15][CH2:14]3)[N:11]([CH3:16])[CH:12]=2)=[CH:6][CH:7]=1
Reactant: Brc1ccc(-c2c[nH]c(C3CC3)n2)cc1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CI
Solvent: C1CCOC1
Product: Cn1cc(-c2ccc(Br)cc2)nc1C1CC1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
To a solution of 4-(4-bromophenyl)-2-cyclopropyl-1H-imidazole (2.43 g, 9.23 mmol) and cesium carbonate (6.02 g, 18.47 mmol) in THF (30 mL) was added iodomethane (1.27 mL, 20.31 mmol). The reaction was stirred at rt for 19 hours. Water was added and the mixture was extracted with ethyl acetate. The organics were dried (MgSO4) and concentrated to afford the title compound which was used without further purification. LCMS: [M+1]+=277.
Reaction SMILES: FC1C(F)=CC(C2C=CC(OCC3C=C4C(C=CN4CCC(O)=O)=CC=3)=CC=2)=C(OC)C=1.C([O:35][C:36](=[O:65])[CH2:37][N:38]1[C:46]2[C:41](=[CH:42][CH:43]=[C:44]([CH2:47][O:48][C:49]3[CH:54]=[CH:53][C:52]([C:55]4[CH:60]=[C:59]([F:61])[C:58]([F:62])=[CH:57][C:56]=4[O:63][CH3:64])=[CH:51][CH:50]=3)[CH:45]=2)[CH:40]=[CH:39]1)C>>[F:62][C:58]1[C:59]([F:61])=[CH:60][C:55]([C:52]2[CH:53]=[CH:54][C:49]([O:48][CH2:47][C:44]3[CH:45]=[C:46]4[C:41]([CH:40]=[CH:39][N:38]4[CH2:37][C:36]([OH:65])=[O:35])=[CH:42][CH:43]=3)=[CH:50][CH:51]=2)=[C:56]([O:63][CH3:64])[CH:57]=1
Reactant: CCOC(=O)Cn1ccc2ccc(COc3ccc(-c4cc(F)c(F)cc4OC)cc3)cc21
Agent: COc1cc(F)c(F)cc1-c1ccc(OCc2ccc3ccn(CCC(=O)O)c3c2)cc1
Product: COc1cc(F)c(F)cc1-c1ccc(OCc2ccc3ccn(CC(=O)O)c3c2)cc1

Procedure:
[6-(4′,5′-Difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-indol-1-yl]-acetic acid was synthesized by a procedure similar to 3-[6-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-indol-1-yl]-propionic acid from starting material [6-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-indol-1-yl]-acetic acid ethyl ester to yield the product as a white solid (23 mg, 82%). LC-MS (ES) calculated for C24H19F2NO4, 423.1; found m/z 424 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.[C:7]([N+:11]#[C-:12])([CH3:10])([CH3:9])[CH3:8].[Cl:13][C:14]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:15]=1[CH:16]=O>Cl(O)(=O)(=O)=O>[C:7]([NH:11][C:12]1[N:3]2[NH:4][CH:5]=[N:6][C:2]2=[N:1][C:16]=1[C:15]1[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:14]=1[Cl:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: Nc1nc[nH]n1
Reactant: [C-]#[N+]C(C)(C)C
Reactant: O=Cc1ccc(Cl)cc1Cl
Agent: [O-][Cl+3]([O-])([O-])O
Product: CC(C)(C)Nc1c(-c2ccc(Cl)cc2Cl)nc2nc[nH]n12

Procedure:
Compound 29 was prepared in accordance with the general synthesis instructions from 1.0 ml (0.1 mmol) 3-amino-1,2,4-triazole solution (0.1 M, MC), 0.575 ml (0.115 mmol) tert-butylisonitrile solution (0.2 M, MC), 0.500 ml (0.15 mmol) 2,4-dichlorobenzaldehyde solution (0.3 M, MC) and 10 μl perchloric acid (w=20%) in a substance library.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH:16]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)[CH2:17][CH2:18][OH:19])[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>ClCCl>[CH3:37][S:38]([O:19][CH2:18][CH2:17][CH:16]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[O:9][CH2:8][CH2:7][N:4]1[CH2:3][CH2:2][O:1][CH2:6][CH2:5]1)[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=1)(=[O:40])=[O:39]
Reactant: COc1ccc(C(CCO)c2ccccc2OCCN2CCOCC2)cc1OC
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(CCOS(C)(=O)=O)c2ccccc2OCCN2CCOCC2)cc1OC
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 87.6 %

Procedure:
To a solution of (S)-1-(3-(2-morpholinoethoxyphenyl)-3-(3,4-dimethoxyphenyl)propan-1-ol (0.4 g, 1.0 mmol) in dichloromethane (5.0 mL) under N2 was added triethylamine (0.4 g, 4.0 mmol). The solution was then cooled to 0° C., methanesulfonyl chloride (0.28 g, 2.5 mmol) was added, and the reaction was stirred at 0° C. for 1.5 h. Ice cold water (5.0 mL) was added to the reaction mixture and it was extracted with dichloromethane. The combined organic extract was washed with a cold solution of ammonium chloride, brine, then dried over anhydrous MgSO4. Evaporation of the solvent afforded (S)-1-(3-(2-morpholinoethoxyphenyl)-3-(3,4-dimethoxyphenyl)propyl methanesulfonate (0.42 g, 88% yield).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]1[C:5]([CH3:16])=[N:6][C:7]2[N:8]([CH:11]=[N:12][C:13]=2[C:14]#[N:15])[C:9]=1[OH:10].[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)=[C:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:20][CH:19]=1>>[ClH:1].[F:37][C:34]1[CH:35]=[CH:36][C:31]([C:24]([C:21]2[CH:20]=[CH:19][C:18]([F:17])=[CH:23][CH:22]=2)=[C:25]2[CH2:30][CH2:29][N:28]([CH2:2][CH2:3][C:4]3[C:5]([CH3:16])=[N:6][C:7]4[N:8]([CH:11]=[N:12][C:13]=4[C:14]#[N:15])[C:9]=3[OH:10])[CH2:27][CH2:26]2)=[CH:32][CH:33]=1
Reactant: Cc1nc2c(C#N)ncn2c(O)c1CCCl
Reactant: Fc1ccc(C(=C2CCNCC2)c2ccc(F)cc2)cc1
Product: Cc1nc2c(C#N)ncn2c(O)c1CCN1CCC(=C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Product: Cl

Procedure:
This compound was prepared from 3-chloroethyl-8-cyano-4-hydroxy-2-methylimidazo[1,5-a]pyrimidine and 4-[bis(4-fluorophenyl)methylene]piperidine according to the process described in Example 4, Stage B.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[F:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>C(Cl)Cl>[C:1]([NH:5][S:20]([C:17]1[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=1)(=[O:22])=[O:21])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)NS(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 80.1 %

Procedure:
Into a DCM solution (50 mL) of tert-butylamine (5.9 mL, 56.5 mmol) and triethylamine (7.16 mL, 51.3 mmol) at 0° C. was slowly added a DCM solution (20 mL) of 4-fluoro-benzenesulfonyl chloride (10 g, 51.3 mmol), and the reaction stirred at RT for 19 h. The reaction was concentrated and the resulting solid recrystalized from ether/hexanes to get the product (9.5 g, 80%)as white crystals. MS: APCI (AP+): 230.1 (M)+.
Reaction SMILES: [C:1]1(=[O:7])[NH:5][C:4](=[O:6])[CH:3]=[CH:2]1.[C:8]([O:12][C:13]([NH:15][CH:16]=[CH:17][CH:18]=[CH2:19])=[O:14])([CH3:11])([CH3:10])[CH3:9]>O1CCCC1>[C:8]([O:12][C:13]([NH:15][CH:16]1[CH:17]=[CH:18][CH2:19][CH:3]2[CH:2]1[C:1](=[O:7])[NH:5][C:4]2=[O:6])=[O:14])([CH3:10])([CH3:11])[CH3:9]
Reactant: C=CC=CNC(=O)OC(C)(C)C
Reactant: O=C1C=CC(=O)N1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1C=CCC2C(=O)NC(=O)C12
Reaction time: 8 h

Procedure:
48.8 g (0.5 mol) of maleimide dissolved in 200 ml of absolute tetrahydrofuran are initially introduced, and 120 g (0.5 mol) of approximately 70% 1-(tert.-butyloxycarbonylamino)-1,3-butadiene in the form of a solution in 500 ml of absolute tetrahydrofuran are added dropwise, the temperature being maintained at 20° to 30° C. Stirring is continued overnight at room temperature. The mixture is then concentrated and recrystallized from ethyl acetate. This gives 57 g of product with a melting point of 177° to 182° C. A further 13 g with a melting point of 158° to 160°C. are obtained from the mother liquor.
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([CH:6]=[N:7][C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([CH:18]4[CH2:23][CH2:22][N:21]([CH2:24][C:25]([NH2:27])=[O:26])[CH2:20][CH2:19]4)=[CH:14][CH:13]=3)=[N:9]2)=[CH:4][CH:3]=1.[CH3:28][S:29]([N:32]1[CH2:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][C:38]=2B2OC(C)(C)C(C)(C)O2)[CH2:33]1)(=[O:31])=[O:30].C(=O)([O-])[O-].[Na+].[Na+].O.O1CCCC1>C(Cl)Cl.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>[CH3:28][S:29]([N:32]1[CH2:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][C:38]=2[C:2]2[N:10]3[C:5]([CH:6]=[N:7][C:8]([NH:11][C:12]4[CH:17]=[CH:16][C:15]([CH:18]5[CH2:23][CH2:22][N:21]([CH2:24][C:25]([NH2:27])=[O:26])[CH2:20][CH2:19]5)=[CH:14][CH:13]=4)=[N:9]3)=[CH:4][CH:3]=2)[CH2:33]1)(=[O:31])=[O:30]
Reactant: NC(=O)CN1CCC(c2ccc(Nc3ncc4ccc(Br)n4n3)cc2)CC1
Reactant: CC1(C)OB(c2cccc3c2CN(S(C)(=O)=O)C3)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: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CS(=O)(=O)N1Cc2cccc(-c3ccc4cnc(Nc5ccc(C6CCN(CC(N)=O)CC6)cc5)nn34)c2C1
Temperature: 25 °C
Yield: 1.9 %

Procedure:
2-{4-[4-(7-Bromo-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino)-phenyl]-piperidin-1-yl}-acetamide (150 mg, 0.00035 mol), 2-Methanesulfonyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-isoindole (169.4 mg, 0.0005241 mol), 0.9 M of Sodium carbonate in water (0.23 mL, 0.00021 mol), Tetrakis(triphenylphosphine)palladium (O) (0.040 g, 0.000035 mol) and Tetrahydrofuran (2 mL, 0.03 mol) were heated at 80° C. overnight. The reaction was cooled to RT, dissolved partially in DCM and filtered. The filtrate was placed onto a 40 gm column eluting with DCM to 5% MeOH/DCM. Dissolved in DMSO, filtered and placed onto the Gilson. Most pure fractions were free based and worked up to give 2-(4-{4-[7-(2-Methanesulfonyl-2,3-dihydro-1H-isoindol-4-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-1-yl)-acetamide as a yellow solid (3.7 mg, 1.9%). MP 244-247° C. LCMS (E/I+) 546 (M+H). NMR 1H (DMSO-d6)-9.45 (s, 1H), 9.01 (s, 1H), 7.97 (d, 1H, J=7.77 Hz), 7.62 (d, 2H, J=8.60 Hz), 7.56 (t, 1H, J=7.68 Hz), 7.44 (d, 1H, J=7.54 Hz), 7.20 (s, 1H), 7.12 (s, 1H), 7.10 (d, 1H, J=8.51 Hz), 7.06 (d, 1H, J=4.63 Hz), 6.98 (d, 1H, J=4.80 Hz), 4.74 (s, 4H), 2.91-2.92 (m, 4H), 2.86-2.89 (m, 3H), 2.38-2.42 (m, 1H), 2.10-2.20 (m, 2H), 1.65-1.74 (m, 4H).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH3:11][C:12]1[N:17]=[C:16]([CH2:18][CH2:19][CH2:20][OH:21])[CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[CH3:11][C:12]1[N:17]=[C:16]([CH2:18][CH2:19][CH:20]=[O:21])[CH:15]=[CH:14][CH:13]=1
Reactant: Cc1cccc(CCCO)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1cccc(CCC=O)n1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 77 %

Procedure:
A solution of DMSO (1.78 g, 22.9 mmol) in dichloromethane (4mL) was added dropwise over 3 min into solution of oxalyl chloride (11.3 mmol) in dichloromethane (6 mL) cooled to -78° C. under nitrogen. The reaction mixture was stirred for 5 min when 3-(6-methyl-2-pyridyl)propanol (1.57 g, 10.4 mmol) in dichloromethane (20 mL) was added over 5 min. The stirring continued for 20 min at -78° C. and triethylamine (8 ml) was added resulting in dark slurry. The cooling bath was removed and after 3 hr, the reaction mixture was quenched with brine followed by dichloromethane extraction (3×). After solvent removal, the dark residue was purified by column chromatography (silica gel, ethyl acetate) yielding a yellow oil (77%). MS (DCI) (M+H)+ at m/z 150.
Reaction SMILES: Cl[CH:2](P(=O)(OCC)OCC)[C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=1.[CH2:18]([C:20]1[C:21]([CH:34]=O)=[CH:22][C:23]2[C:24]([CH3:33])([CH3:32])[CH2:25][CH2:26][C:27]([CH3:31])([CH3:30])[C:28]=2[CH:29]=1)[CH3:19]>>[CH2:18]([C:20]1[C:21]([C:34]#[C:2][C:3]2[CH:4]=[CH:5][C:6]([CH3:9])=[CH:7][CH:8]=2)=[CH:22][C:23]2[C:24]([CH3:33])([CH3:32])[CH2:25][CH2:26][C:27]([CH3:31])([CH3:30])[C:28]=2[CH:29]=1)[CH3:19]
Reactant: CCOP(=O)(OCC)C(Cl)c1ccc(C)cc1
Reactant: CCc1cc2c(cc1C=O)C(C)(C)CCC2(C)C
Product: CCc1cc2c(cc1C#Cc1ccc(C)cc1)C(C)(C)CCC2(C)C
Yield: 25.1 %

Procedure:
Using a process similar to that described in Example 13, 27.7 g (0.1 mole) of diethyl 1-chloro-1-(4-tolyl)-methylphosphonate, 24.4 g (0.1 mole) of 3-ethyl-2-formyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene and 22.5 g (0.2 mole) of potassium tert.-butylate were reacted for 1 hour to give 8.3 g (25%) of the title compound of melting point 72°-73° C., the reaction mixture being poured onto water and acidified, and the precipitate which had separated out being recrystallized from methanol and once again from isopropanol.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[C:6](Cl)=[N:7][C:8]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[N:9][C:10]=1[N:11]([CH3:13])[CH3:12].[Cl-].[CH3:27][NH2+:28][CH3:29].C(N(CC)C(C)C)(C)C.O>CN1C(=O)N(C)CCC1>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[C:6]([N:28]([CH3:29])[CH3:27])=[N:7][C:8]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[N:9][C:10]=1[N:11]([CH3:13])[CH3:12]
Reactant: C[NH2+]C
Reactant: COC(=O)Cc1c(Cl)nc(Cc2ccc([N+](=O)[O-])cc2)nc1N(C)C
Agent: [Cl-]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCN(C)C1=O
Product: COC(=O)Cc1c(N(C)C)nc(Cc2ccc([N+](=O)[O-])cc2)nc1N(C)C
Temperature: 150 °C
Yield: 68.6 %

Procedure:
A mixture of methyl[4-chloro-6-(dimethylamino)-2-(4-nitrobenzyl)pyrimidin-5-yl]acetate (7.75 g, 21.25 mmol), dimethylammonium chloride (5.20 g, 63.74 mmol), and N,N-diisopropylethylamine (10.98 g, 84.98 mmol) in DMPU (50 mL) was heated at 150° C. in a sealed tube for 15 hours. After cooling to room temperature, the dark mixture was poured into water and extracted with ethyl acetate. The combined extracts were washed sequentially with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated to yield the crude product as a dark oil. Chromatographic purification of this crude product over silica gel eluting with 25% ethyl acetate in n-hexane containing 0.1% triethylamine gave methyl[4,6-bis(dimethylamino)-2-(4-nitro-benzyl)pyrimidin-5-yl]acetate (5.44 g, 69%) as a red colored oil.