Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH2:12][C:13]([OH:15])=O)(=[O:11])=[O:10])=[C:4]([C:16]([F:19])([F:18])[F:17])[CH:3]=1.Cl.[CH2:21]([O:23][C:24](=[O:30])[C@H:25]([C@@H:27]([CH3:29])[OH:28])[NH2:26])[CH3:22].O.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>>[CH2:21]([O:23][C:24](=[O:30])[CH:25]([NH:26][C:13](=[O:15])[CH2:12][S:9](=[O:10])(=[O:11])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[C:16]([F:19])([F:18])[F:17])[CH:27]([OH:28])[CH3:29])[CH3:22]
Reactant: O=C(O)CS(=O)(=O)Nc1ccc(F)cc1C(F)(F)F
Reactant: CCOC(=O)[C@@H](N)[C@@H](C)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)C(NC(=O)CS(=O)(=O)Nc1ccc(F)cc1C(F)(F)F)C(C)O

Procedure:
Under the conditions of Example 2(a), 3.012 g (10 mmol) of 2-[N-(4-fluoro-2-trifluoromethylphenyl)sulfamoyl]acetic acid, 1.736 g (10 mmol) of L-threonine ethyl ester hydrochloride, 1.531 g (10 mmol) of hydroxybenzotriazole, hydrate, as well as 1.012 g (10 mmol) of triethylamine and 2.063 g (10 mmol) of dicyclohexylcarbodiimide are reacted and worked up analogously. The crude product is purified by column chromatography on silica gel. The title compound is eluted with ethanol.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[CH:3]([OH:8])[C:4]([F:7])([F:6])[F:5].N1C=CC=CC=1.[Cl-].[C:18]([O:25][CH2:26][CH:27]([CH2:32][CH3:33])[CH2:28][CH2:29][CH2:30][CH3:31])(=[O:24])/[CH:19]=[CH:20]\[C:21]([O-])=[O:22].C(OCC)(=O)C>C(#N)C>[C:18]([O:25][CH2:26][CH:27]([CH2:32][CH3:33])[CH2:28][CH2:29][CH2:30][CH3:31])(=[O:24])/[CH:19]=[CH:20]\[C:21]([O:8][CH:3]([C:4]([F:7])([F:6])[F:5])[C:2]([F:10])([F:9])[F:1])=[O:22]
Reactant: CCCCC(CC)COC(=O)/C=C\C(=O)[O-]
Reactant: OC(C(F)(F)F)C(F)(F)F
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: c1ccncc1
Product: CCCCC(CC)COC(=O)/C=C\C(=O)OC(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 13.9 %

Procedure:
1,1,1,3,3,3-Hexafluoro-2-propanol (HFIP, 33.7 g, 201 mmol) and pyridine (17.9 mL, 220 mmol) were dissolved in acetonitrile (80 mL) and added dropwise with mono(2-ethylhexyl) maleate chloride (41.8 g, 220 mmol), while the internal temperature was kept at 20° C. or lower by cooling the solution on an ice bath. After completion of the addition, the reaction mixture was stirred at room temperature for 1hour and added with ethyl acetate, and the organic phase was washed with 1 mol/L aqueous hydrochloric acid and a saturated sodium chloride aqueous solution. Then, the organic layer was collected, and the organic solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/chloroform=10/0 to 7/3 (v/v)) to obtain the target compound (10.6 g, yield: 14%) as a colorless transparent oily compound.
Reaction SMILES: C1(C)C=CC=C([Cl:7])C=1.Cl.[C:10]([NH:14][CH2:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:26]=[C:27]([CH3:31])[CH:28]=[CH:29][CH:30]=2)=[C:20]([O:32][C:33]2[CH:34]=[C:35]([CH3:39])[CH:36]=[CH:37][CH:38]=2)[CH:19]=1)=[O:17])([CH3:13])([CH3:12])[CH3:11].Cl>>[ClH:7].[C:35]1([CH3:39])[CH:36]=[CH:37][CH:38]=[C:33]([O:32][C:20]2[CH:19]=[C:18]([CH:23]=[CH:22][C:21]=2[O:24][C:25]2[CH:26]=[C:27]([CH3:31])[CH:28]=[CH:29][CH:30]=2)[CH:16]([OH:17])[CH2:15][NH:14][C:10]([CH3:13])([CH3:12])[CH3:11])[CH:34]=1
Reactant: Cc1cccc(Cl)c1
Reactant: Cc1cccc(Oc2ccc(C(=O)CNC(C)(C)C)cc2Oc2cccc(C)c2)c1
Agent: Cl
Product: Cc1cccc(Oc2ccc(C(O)CNC(C)(C)C)cc2Oc2cccc(C)c2)c1

Procedure:
Following a procedure similar to that described above in Example 111 but using m-toluyl chloride instead of o-toluyl chloride, there was obtained 14 g. of 3,4-bis(m-toluyloxy)phenyl tert-butylaminomethyl ketone hydrochloride as a white crystalline solid which melted at 215-218° C. When 19 g. of this hydrochloride (5 g. of which was obtained from a second run) was catalytically hydrogenated, using a procedure similar to that described above in Example 30B, there was obtained 3,4-bis(m-toluyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol hydrochloride which was converted to the free base and then to the methanesulfonate, a white crystalline solid which weighed 12.0 g. and melted at 135° C. (uncorr.).
Reaction SMILES: [CH2:1]([O:3][CH:4]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([OH:16])[CH:9]=1)[C:5]([OH:7])=O)[CH3:2].[NH2:17][CH2:18][C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=1>>[C:18]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH:24][C:5](=[O:7])[CH:4]([O:3][CH2:1][CH3:2])[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([OH:16])[CH:9]=2)=[CH:21][CH:20]=1)#[N:17]
Reactant: CCOC(C(=O)O)c1ccc(OC)c(O)c1
Reactant: N#Cc1ccc(CN)cc1
Product: CCOC(C(=O)NCc1ccc(C#N)cc1)c1ccc(OC)c(O)c1

Procedure:
(RS)-Ethoxy-(3-hydroxy-4-methoxy-phenyl)-acetic acid was coupled with 4-aminomethyl benzonitrile according to general procedure C to give (RS)-N-(4-cyano-benzyl)-2-ethoxy-2-(3-hydroxy-4-methoxy-phenyl)-acetamide. Light yellow gum.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][N+:11]([O-])=[C:10]([CH3:15])[CH:9]=1.C(OC(=O)C)(=[O:18])C>>[OH:18][CH2:15][C:10]1[CH:9]=[C:8]([O:7][CH2:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])[CH:13]=[CH:12][N:11]=1
Reactant: COCCCCOc1cc[n+]([O-])c(C)c1
Reactant: CC(=O)OC(C)=O
Product: COCCCCOc1ccnc(CO)c1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
5.06 g (0.024 mol) of 4-(4-methoxybutoxy)-2-methylpyridine 1-oxide was dissolved in 80 ml of acetic anhydride to obtain a solution. This solution was stirred at 100° C. for one hour, cooled and distilled to remove the solvent. 150 ml of 1N hydrochloric acid was added to the residue. The obtained mixture was stirred at 100° C. for one hour, cooled, neutralized with sodium hydrogencarbonate and extracted with 200 ml of chloroform twice. The extract was dried over magnesium sulfate and filtered. The filtrate was distilled to remove the solvent and the residue was dried in a vacuum to obtain 5.66 g of the title compound as a crude oil.
Reaction SMILES: [C:1]([CH2:3][CH:4]([CH2:17]OS(C1C=CC(C)=CC=1)(=O)=O)[CH2:5]OS(C1C=CC(C)=CC=1)(=O)=O)#[N:2].[C:29]([O-:32])(=[S:31])[CH3:30].[K+]>CS(C)=O>[C:1]([CH2:3][CH:4]([CH2:5][S:31][C:29](=[O:32])[CH3:30])[CH2:17][S:31][C:29](=[O:32])[CH3:30])#[N:2]
Reactant: CC([O-])=S
Reactant: Cc1ccc(S(=O)(=O)OCC(CC#N)COS(=O)(=O)c2ccc(C)cc2)cc1
Agent: [K+]
Solvent: CS(C)=O
Product: CC(=O)SCC(CC#N)CSC(C)=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 62 g of 2-cyanomethyl-1,3-bis(tosyloxy)propane in 250 ml DMSO is added dropwise to a stirred solution of 36 g potassium thioacetate in 200 ml of DMSO. After stirring for one hour and adding additional DMSO, the mixture is poured into ice/water. Extraction with diethylether yields a colored organic layer which is washed successively with aqueous NaOH, water and saturated NaCl solution until neutral. Drying and evaporating yields the desired 2-cyanomethyl-1,3-bis(acetylthio)propane as a slightly yellow liquid; b.p. 146°-150° C./0.50.1 mm Hg; yield 20 g. Identification by IR and NMR.
Reaction SMILES: [C:1](Cl)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17].C(O)(=O)CCCCCCCCCCCCCCC(C)C.S(Cl)(Cl)=O.[CH2:45]([NH2:53])[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52].CN(C)C>CCOCC.CN(C)C=O>[CH2:45]([NH:53][C:1](=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52]
Reactant: CC(C)CCCCCCCCCCCCCCC(=O)Cl
Reactant: CCCCCCCCN
Agent: CC(C)CCCCCCCCCCCCCCC(=O)O
Agent: CN(C)C
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCCCCCCCNC(=O)CCCCCCCCCCCCCCC(C)C

Procedure:
Isostearoyl chloride, prepared from 20 g isostearic acid, 10.1 g thionyl chloride and 0.2 ml dimethyl formamide, according to the procedure of Example 1, is added to 11 g (0.09 mole) n-octylamine and 10 g (0.10 mole) trimethylamine in 100 ml ether. The reaction mixture is treated in accordance with the procedure of Example 2, yielding 22 g of an amber oil, which exhibits infrared spectra values typical of a secondary amide.
Reaction SMILES: [CH3:1][CH:2]([CH2:4]/[CH:5]=[CH:6]/[C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@H:18]([OH:28])[CH2:19][CH2:20]2)=[CH:15][CH:14]=3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].C1C=CC=CC=1>CCOCC>[CH3:22][C:21]1[CH2:20][CH2:19][C@H:18]([OH:28])[CH2:17][C:16]=1/[CH:15]=[CH:14]\[C:13]1[C@@H:12]2[CH2:11][CH2:10][C@H:9]([C@@H:7]([CH2:6][CH2:5][CH2:4][CH:2]([CH3:3])[CH3:1])[CH3:8])[C@@:26]2([CH3:27])[CH2:25][CH2:24][CH:23]=1
Reactant: CC(C)C/C=C/[C@@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: CCOCC
Solvent: c1ccccc1
Product: CC1=C(/C=C\C2=CCC[C@]3(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@@H]23)C[C@@H](O)CC1
Yield: 40.4 %

Procedure:
(5Z,7E,22E)-9,10-Secocholesta-5,7,10(19),22-tetraen-3α-ol (5) A solution of compound (4) (100 mg, 0.26 mmol) in ether (120 ml)-benzene (30 ml) mixture was degassed with argon for 40 min. The solution was irradiated at 0° C. for 13 min in a quartz immersion well equipped with UV lamp and filter. The solvent was removed under reduced pressure and the residue separated by HPLC, using 1% 2-propanol in hexane as eluent to obtain the pure previtamin D derivative (40.4 mg, 40%) which was collected at 24 ml; NMR δ 0.72 (3H, s, 18-H3), 0.87 (6H, d, J=6.7 Hz, 26-H3 and 27-H3), 1.04 (3H, d, J=6.8 Hz, 21-H3), 1.65 (3H, s, 19-H3), 3.91 (1H, m, 3-H), 5.28 (2H, br m, 22-H and 23-H, 5.50 (1H, m, 11-H), 5.69 and 5.96 (2H, AB q, J=12.5 Hz, 7-H and 6-H); UV λmax 260.5 nm; λmin 234 nm. The previtamin (40 mg, 0.1 mmol) in ethanol (100 ml) was heated under reflux for 3 h. After removal of solvent, the product mixture was separated by HPLC (elution with 1% 2-propanol in hexane). The yield of the vitamin (5) (collected at 34 ml) was 30.8 mg (77%) mp (hexane) 99°-101° C.; NMR δ 0.56 (3H, s, 18-H3), 0.88 (6H, d, J=6.7 Hz, 26-H3 and 27-H3), 1.02 (3H, d, J=6.6 Hz, 21-H3), 3.96 (1H, m, 3-H), 4.82 and 5.05 (2H, each narr. m, 19-H2), 5.27 (2H, br m, 22-H and 23-H), 6.03 and 6.24 (2H, ABq, J=11.4 Hz, 7-H and 6-H; UV λmax 265 nm, λmin 228 nm; IR: 3420,1458,1441,1378,1366,1050,970,943,891,862 cm-1 ; mass spectrum, m/e (M+, 22), 349 (M+ -H2O-Me, 4), 271 (M+ -side chain, 8), 253 (M+ -side chain-H2O, 13), 136 (100), 118 (80).
Reaction SMILES: [C:1]([O:5][CH2:6][CH:7]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][Si](C(C)(C)C)(C)C)=[CH:15][C:14]=2[O:27][Si](C(C)(C)C)(C)C)[CH2:9][CH2:8]1)(=[O:4])[CH2:2][CH3:3].[F-]>CO>[C:1]([O:5][CH2:6][CH:7]1[CH2:8][CH2:9][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]=2[OH:27])[CH2:11][CH2:12]1)(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)OCC1CCC(c2ccc(O[Si](C)(C)C(C)(C)C)cc2O[Si](C)(C)C(C)(C)C)CC1
Agent: [F-]
Solvent: CO
Product: CCC(=O)OCC1CCC(c2ccc(O)cc2O)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of [4-(2,4-Bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl]methyl propionate (110 mg), methanol (10 ml) and Amberlyst fluoride resin (0.4 g) were stirred at room temperature for 72 hr. The reaction mixture was filtered, and the filtrate was evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, ethyl acetate/petrol, 1:2 v/v) to give the title compound as a cream solid and a mixture of diastereoisomers (44 mg, 73%). δH(CDCl3) 1.17 (3H, t), 1.38-2.14 (9H, m), 2.34-2.40 (2H, q), 2.64-2.80 (1H, m), 3.96 (0.6H, d), 4.20 (0.4H, d), 5.10-5.24 (2H, m), 6.28-6.33 (1H, m), 6.36-6.40 (1H, m), 6.98 (1H, dd); m/z (ES+) 279 (M+H)+.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][C:8]1[CH:9]=[N:10][NH:11][CH:12]=1.Cl[C:14]1[S:15][CH:16]=[CH:17][C:18]=1[N+:19]([O-:21])=[O:20]>CN(C=O)C.[Cl-].[Na+].O>[CH3:7][C:8]1[CH:9]=[N:10][N:11]([C:14]2[S:15][CH:16]=[CH:17][C:18]=2[N+:19]([O-:21])=[O:20])[CH:12]=1
Reactant: O=[N+]([O-])c1ccsc1Cl
Reactant: Cc1cn[nH]c1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cnn(-c2sccc2[N+](=O)[O-])c1
Reaction time: 1 h

Procedure:
Potassium tert-butoxide (2.78 g, 24.8 mmol) and 4-methyl-1H-pyrazole (3.0 ml g, 37.3 mmol) in DMF (50 ml) was stirred for 30 min. 2-chloro-3-nitrothiophene (3.08 g, 18.7 mmol) was added and the solution was placed into a preheated oil bath at 100° C. After stirring for 1 h, the solution was diluted with brine and extracted with diethyl ether. The combined organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was flash chromatographed with 9:1, 4:1, 7:3, 3:2, and 1:1 hexane:ethyl acetate as the eluant to yield 4-methyl-1-(3-nitrothiophen-2-yl)-1H-pyrazole. Method [1] Retention time 1.80 min by HPLC (MH+ 210).
Reaction SMILES: C1(S([CH2:10][C:11]2[N:12]=[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[NH:14][N:15]=2)(=O)=O)C=CC=CC=1.[CH2:22]([C:24]1[CH:29]=[C:28](/[CH:30]=[CH:31]/[C:32]#[N:33])[CH:27]=[CH:26][N:25]=1)[CH3:23]>>[CH2:22]([C:24]1[CH:29]=[C:28]([C:30]2[CH:31]=[C:32]([NH2:33])[N:15]3[N:14]=[C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=4)[N:12]=[C:11]3[CH:10]=2)[CH:27]=[CH:26][N:25]=1)[CH3:23]
Reactant: CCc1cc(/C=C/C#N)ccn1
Reactant: O=S(=O)(Cc1n[nH]c(-c2ccccn2)n1)c1ccccc1
Product: CCc1cc(-c2cc(N)n3nc(-c4ccccn4)nc3c2)ccn1

Procedure:
The title compound, MS m/e (%):316(M+,100), was prepared in accordance with the general method of example 1 from 2-(5-benzenesulfonylmethyl-2H-[1,2,4]triazol-3-yl)-pyridine and (E)-3-(2-ethyl-pyridin-4-yl)-acrylonitrile.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][N:12]([CH3:16])[CH2:11]1.[I-].[Na+].[OH:19][C:20]1[CH:29]=[CH:28][C:27]2[N:26]=[C:25]([NH2:30])[C:24]3[N:31]=[C:32]([CH2:37][O:38][CH3:39])[N:33]([CH2:34][CH2:35][CH3:36])[C:23]=3[C:22]=2[CH:21]=1>CC(C)=O>[CH3:39][O:38][CH2:37][C:32]1[N:33]([CH2:34][CH2:35][CH3:36])[C:23]2[C:22]3[CH:21]=[C:20]([O:19][CH2:9][CH:10]4[CH2:15][CH2:14][CH2:13][N:12]([CH3:16])[CH2:11]4)[CH:29]=[CH:28][C:27]=3[N:26]=[C:25]([NH2:30])[C:24]=2[N:31]=1
Reactant: CCCn1c(COC)nc2c(N)nc3ccc(O)cc3c21
Reactant: CN1CCCC(CCl)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(C)=O
Product: CCCn1c(COC)nc2c(N)nc3ccc(OCC4CCCN(C)C4)cc3c21

Procedure:
Potassium carbonate (1.48 g, 10.75 mmol), 3-chloromethyl-1-methyl-piperidine hydrochloride (483 mg, 2.62 mmol), sodium iodide (100 mg, 0.66 mmol), and 8-hydroxy-2-methoxymethyl-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine (500 mg, 1.75 mmol) were combined in acetone and heated at reflux overnight. No desired product was detected and the reaction mixture was filtered. The filtrate was concentrated under reduced pressure, dissolved in DMF, and heated at 90° C. overnight. The reaction mixture was then cooled to ambient temperature, filtered, and concentrated under reduced pressure to provide a dark oil. The oil was dissolved in dichloromethane, filtered, purified by chromatography on a HORIZON HPFC system (eluted with a gradient of CMA:chloroform from 0:100 to 35:65), and crystallized from acetonitrile to afford 160 mg of 2-methoxymethyl-8-(1-methyl-piperidin-3-yl-methoxy)-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine as a tan powder, mp 194-196° C.
Reaction SMILES: [C:1]([C:4](=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=1)[C:5]([O:7]CCC#N)=[O:6])(=O)[CH3:2].[NH2:22]/[C:23](/[CH3:49])=[CH:24]\[C:25]([O:27][CH2:28][CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][C:34]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:33][CH2:32]1)=[O:26].C(O)(=O)C>CC(O)C>[C:43]1([C:34]2([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH2:33][CH2:32][N:31]([CH2:30][CH2:29][CH2:28][O:27][C:25]([C:24]3[CH:12]([C:13]4[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=4)[C:4]([C:5]([OH:7])=[O:6])=[C:1]([CH3:2])[NH:22][C:23]=3[CH3:49])=[O:26])[CH2:36][CH2:35]2)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: C/C(N)=C/C(=O)OCCCN1CCC(c2ccccc2)(c2ccccc2)CC1
Reactant: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)OCCC#N
Solvent: CC(=O)O
Solvent: CC(C)O
Product: CC1=C(C(=O)O)C(c2cccc([N+](=O)[O-])c2)C(C(=O)OCCCN2CCC(c3ccccc3)(c3ccccc3)CC2)=C(C)N1

Procedure:
8.1 g of 2-cyanoethyl 2-acetyl-3-(3-nitrophenyl)acrylate and 10.6 g of 3-(4,4-diphenylpiperid-1-yl)-propyl 3-aminocrotonate are heated at the boiling point under reflux in 120 ml of 2-propanol and 0.5 ml of glacial acetic acid for 4 hours. After most of the solvent has been distilled off and 2 portions of 50 ml of toluene each have been added, the residue is concentrated to dryness. The residue, which has foamed as a solid, is taken up in isopropanol, and diethyl ether is added to the clear solution until the resulting cloudiness first persists. After the mixture has been left to stand in a refrigerator, the starting compound crystallizes out in the form of fine platelets. m.p.: 158°-160° C.; yield: 14.3 g.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]1[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].[Cl:14][C:15]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:16]=1[C:17](Cl)=[O:18].CN(C)CCCN>C1(C)C(C)=CC=CC=1.O>[Cl:14][C:15]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:16]=1[C:17]([C:6]1[N:2]([CH3:1])[C:3]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][C:5]=1[CH3:7])=[O:18]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: CCOC(=O)Cc1cc(C)cn1C
Agent: CN(C)CCCN
Solvent: Cc1ccccc1C
Solvent: O
Product: CCOC(=O)Cc1cc(C)c(C(=O)c2ccc(Cl)cc2Cl)n1C
Reaction time: 1 h
Yield: 81.2 %

Procedure:
A solution of 50 g (0.276 mole) of ethyl 1,4-dimethyl-1H-pyrrole-2-acetate and 64 g (0.303 mole) of 2,4-dichlorobenzoyl chloride in 310 mL of xylene was heated under reflux for 4 h under argon. After cooling, a 20% solution of 3-dimethylaminopropylamine in H2O was added and stirred one hour. The organic layer was washed twice with 1N HCl, water, brine, and dried (MgSO4). Evaporation of the solvent in vacuo gave a solid which was recrystallized from methanol to give 79.39 g of product: mp 90-92° C.; mass spectrum (Cl—CH4) m/z=354 (M+1); NMR 300 MHz (CDCl3) d 7.5 (s, 1H); 7.3 (dd, 2H); 6.0 (s, 1H); 4.2 (q, 2H); 3.9 (s, 3H); 3.65 (s, 2H); 1.6 (s, 3H); 1.25 (t, 3H). Anal Calcd for C17H17Cl2NO3: C, 57.64; H, 4.84; N, 3.95. Found: C, 57.52; H, 4.60; N, 3.80.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[Cl:30])[CH2:5][NH:6][C:7](=[O:26])[NH:8][C:9]1[S:10][CH:11]=[C:12]([CH2:14][O:15][CH2:16][CH2:17][NH:18]C(=O)OC(C)(C)C)[N:13]=1.Cl.C(OCC)C>O1CCOCC1>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[Cl:30])[CH2:5][NH:6][C:7]([NH:8][C:9]1[S:10][CH:11]=[C:12]([CH2:14][O:15][CH2:16][CH2:17][NH2:18])[N:13]=1)=[O:26]
Reactant: CC(C)(C)OC(=O)NCCOCc1csc(NC(=O)NCc2ccc(Cl)c(Cl)c2)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: NCCOCc1csc(NC(=O)NCc2ccc(Cl)c(Cl)c2)n1
Reaction time: 8 h

Procedure:
A solution of tert-butyl 2-((2-(3-(3,4-dichlorobenzyl)ureido)thiazol-4-yl)methoxy)-ethylcarbamate (Example 77) (350 mg) in 1,4-dioxane (3 mL) was treated with 4N HCl in 1,4-dioxane (4 mL). The mixture was stirred overnight, 5 mL of diethyl ether was added, and the precipitated material was isolated by filtration. 1H-NMR (300 MHz, DMSO-d6): 10.85 (bs, 1H), 7.90 (bs, 2H), 7.60 (d, 1H), 7.50 (s, 1H), 7.27 (d, 1H), 6.97 (s, 1H), 4.43 (s, 2H), 4.30 (d, 2H), 3.60 (m, 2H), 2.98 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:17]([O:18][CH3:19])=[CH:16][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][C:12]([NH:14][CH3:15])=[O:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]3)=[CH:30][C:29]=2[O:41][CH3:42])[C:24]([F:43])=[CH:23][N:22]=1>>[F:43][C:24]1[C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]3)=[CH:30][C:29]=2[O:41][CH3:42])=[N:26][C:21]([NH:1][C:2]2[C:17]([O:18][CH3:19])=[CH:16][C:5]3[CH2:6][CH2:7][N:8]([CH2:11][C:12]([NH:14][CH3:15])=[O:13])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:22][CH:23]=1
Reactant: CNC(=O)CN1CCc2cc(N)c(OC)cc2CC1
Reactant: COc1cc(N2CCN(C)CC2)ccc1Nc1nc(Cl)ncc1F
Product: CNC(=O)CN1CCc2cc(Nc3ncc(F)c(Nc4ccc(N5CCN(C)CC5)cc4OC)n3)c(OC)cc2CC1

Procedure:
The title compound was prepared from 2-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-N-methyl-acetamide and (2-Chloro-5-fluoro-pyrimidin-4-yl)-[2-methoxy-4-(4-methyl-piperazin-1-yl)-phenyl]-amine in an analogous manner to Example 61e. Product isolated as an off-white solid (0.041 g, 42%). MP: 95-136° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.27 (d, 1H, J=8.6 Hz), 8.15 (s, 1H), 7.92-7.89 (m, 1H), 7.39 (s, 1H), 7.38-7.32 (m, 1H), 7.20-7.17 (m, 1H), 6.63 (s, 1H), 6.58-6.55 (m, 1H), 6.54-6.49 (m, 1H), 3.90 (s, 3H), 3.86 (s, 3H), 3.22-3.16 (m, 4H), 3.11 (s, 2H), 2.90 (d, 3H, J=5.1 Hz), 2.88-2.82 (m, 4H), 2.72-2.66 (m, 4H), 2.63-2.57 (m, 4H), 2.37 (s, 3H). MS: 579.30 (MH)+.
Reaction SMILES: [F:1][CH:2]([F:26])[O:3][C:4]1[C:5]([OH:25])=[C:6](/[CH:10]=[CH:11]/[C:12]2[N:13]=[C:14]3[N:18]([C:19]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:17]=[CH:16][S:15]3)[CH:7]=[CH:8][CH:9]=1.Br[CH2:28][CH:29]1[CH2:32][CH2:31][CH2:30]1.C(=O)([O-])[O-].[K+].[K+].FC(F)OC1C(OCC(C)(C)C)=C(/C=C/C2N=C3N(C=2C(O)=O)C=CS3)C=CC=1>CN(C)C=O>[CH:29]1([CH2:28][O:25][C:5]2[C:4]([O:3][CH:2]([F:1])[F:26])=[CH:9][CH:8]=[CH:7][C:6]=2/[CH:10]=[CH:11]/[C:12]2[N:13]=[C:14]3[N:18]([C:19]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:17]=[CH:16][S:15]3)[CH2:32][CH2:31][CH2:30]1
Reactant: CCOC(=O)c1c(/C=C/c2cccc(OC(F)F)c2O)nc2sccn12
Reactant: BrCC1CCC1
Agent: CC(C)(C)COc1c(/C=C/c2nc3sccn3c2C(=O)O)cccc1OC(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(/C=C/c2cccc(OC(F)F)c2OCC2CCC2)nc2sccn12
Yield: 88.2 %

Procedure:
Alkylation of Intermediate 6 (500 mg, 1.315 mmol) with (bromomethyl)cyclobutane (178 mg, 1.578 mmol) in presence of potassium carbonate (199 mg, 1.446 mmol) in anhydrous N,N-dimethylformamide (5 mL) as described in Intermediate 7A gave 520 mg of the product as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.40 (t, J=6.9 Hz, 3H), 1.84-1.93 (m, 4H), 2.02-2.10 (m, 2H), 2.70-2.76 (m, 1H), 3.93 (d, J=6.9 Hz, 2H), 4.41 (q, J=6.9 Hz, 2H), 7.19 (t, J=74.7 Hz, 1H), 7.20-7.28 (m, 2H), 7.42-7.51 (m, 1H), 7.54-7.60 (m, 1H), 7.70-7.78 (m, 1H), 7.85 (d, J=15.9 Hz, 1H), 8.13 (d, J=4.2 Hz, 1H); APCI-MS (m/z) 449.18 (M+H)+.
Reaction SMILES: C(OCC(C[O:14][C:15]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)CCOC(=O)C)(=O)C>C(O)(=O)C>[C:15]([OH:14])([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(=O)OCCC(COC(C)=O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC(=O)O
Product: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Yield: 74.7 %

Procedure:
2-Trityloxymethyl-1,4-butanediol diacetate (60.90 g, 0.136 mol) was dissolved in acetic acid (320 ml) at 100° C. for 15 min, evaporated in vacuum to small volume and cooled to 0° C. The precipitate was filtered off and washed with cold ethyl acetate to give 26.44 g (theory 35.51 g) of tritylalcohol. The combined filtrate was evaporated to small volume. The compound was purified on a silica gel column (500 g SiO2); eluent 0-2700 ml ethyl acetate+n-hexane (1+1), 2700-3740 ml ethyl acetate+n-hexane (2+1), then neat ethyl acetate. The fractions 2540-4800 ml were evaporated to give 14.20 g (51%) of pure 4-acetoxy-2-hydroxy-methylbutyl acetate. TLC on silica (ethyl acetate+n-hexane 1+1): Rf 0.30.