Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[C@H:6]([NH:7][C:8]2[N:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[C:23]([Cl:24])=[C:22]([O:25][CH3:26])[CH:21]=[C:20]([O:27][CH3:28])[C:19]=4[Cl:29])[CH:14]=3)[N:9]=2)[CH2:5][C@H:4]([C:30]([N:32]([CH3:34])[CH3:33])=[O:31])[CH2:3]1.CCN(C(C)C)C(C)C.[C:44](Cl)(=[O:47])[CH:45]=[CH2:46]>C(Cl)Cl>[C:44]([NH:1][C@@H:2]1[C@H:6]([NH:7][C:8]2[N:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[C:23]([Cl:24])=[C:22]([O:25][CH3:26])[CH:21]=[C:20]([O:27][CH3:28])[C:19]=4[Cl:29])[CH:14]=3)[N:9]=2)[CH2:5][C@H:4]([C:30]([N:32]([CH3:34])[CH3:33])=[O:31])[CH2:3]1)(=[O:47])[CH:45]=[CH2:46]
Reactant: COc1cc(OC)c(Cl)c(-c2ccc3nc(N[C@@H]4C[C@H](C(=O)N(C)C)C[C@@H]4N)ncc3c2)c1Cl
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)N[C@H]1C[C@@H](C(=O)N(C)C)C[C@H]1Nc1ncc2cc(-c3c(Cl)c(OC)cc(OC)c3Cl)ccc2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 52.5 %

Procedure:
(1R,3S,4R)-3-amino-4-((6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)amino)-N,N-dimethylcyclopentanecarboxamide (0.050 g, 0.099 mmol) was taken up in CH2Cl2 (25 ml) and cooled to 0° C., followed by addition of DIEA (0.017 ml, 0.099 mmol) then acryloyl chloride (8.86 μl, 0.109 mmol) slowly. The reaction mixture was stirred at 0° C. for 30 minutes. After the reaction was complete, it was loaded directly onto silica and purified via flash chromatography (0-10% CH2Cl2/MeOH; 12 g column) to afford (1S,3S,4R)-3-acrylamido-4-((6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)amino)-N,N-dimethylcyclopentanecarboxamide (0.029 g, 0.052 mmol, 52.4% yield). MS (ES+) C27H29Cl2N5O4 requires: 558, found: 559 [M+H]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH:11]2[C:15](=[O:16])[C:14]3[CH:17]=[CH:18][C:19]([OH:35])=[C:20]([CH2:21][N:22]4[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]4)[C:13]=3[O:12]2)=[CH:2]1.Cl>C(Cl)Cl.O1CCOCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]2[O:12][C:13]3[C:20]([CH2:21][N:22]4[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]4)=[C:19]([OH:35])[CH:18]=[CH:17][C:14]=3[C:15]=2[OH:16])=[CH:2]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2OC(Cc2c[nH]c4ccccc24)C3=O)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Oc1ccc2c(O)c(Cc3c[nH]c4ccccc34)oc2c1CN1CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.4 %

Procedure:
A solution of tert-butyl 4-({2-[(1H-indol-3-yl)methyl]-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.020 g, 0.042 mmol) in methylene chloride (2.0 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (2.0 mL), and then the mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure, and then the residue was added with triethylamine and thereby made basic. Then, the mixture was azeotroped twice with toluene under reduced pressure, and the residue was subjected to silica gel column chromatography (aminopropyl silica was used, eluted with chloroform/methanol (90:10)) to obtain 2-[(1H-indol-3-yl)methyl]-7-(piperazin-1-ylmethyl)benzofuran-3,6-diol (0.011 g, 69%).
Reaction SMILES: Cl.[CH2:2]([NH2:4])[CH3:3].C[Al](C)C.[OH:9][CH:10]([CH3:18])[CH2:11][CH2:12][CH2:13][CH2:14][C:15](O)=[O:16].Cl>C1(C)C=CC=CC=1.CCCCCC>[CH2:2]([NH:4][C:15](=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]([OH:9])[CH3:18])[CH3:3]
Reactant: CCN
Reactant: CC(O)CCCCC(=O)O
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CCNC(=O)CCCCC(C)O
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 81.9 %

Procedure:
A stirred suspension of dry ethylamine hydrochloride (3.26 g, 0.04 mol) in toluene, under nitrogen, was cooled in an ice bath and treated during 40 minutes with 20 ml of a 2.0M solution of trimethylaluminum in hexane. The mixture was kept at 0° for 10 minutes and at ambient temperature for 2.5 hours. A portion of the resulting solution (46.8 ml) was added, under nitrogen, during 15 minutes to a solution of the product from Step I (2.0 g, 0.016 mol) in toluene (100 ml). This mixture was warmed at 80° C. for 3 hours, cooled and added continuously to dilute HCl. The product was extracted with ethyl acetate. The extracts were dried (MgSO4) and concentrated to give 2.27 g of N-ethyl-6-hydroxyheptanamide.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[Cl:54][C:55]1[N:63]=[CH:62][CH:61]=[CH:60][C:56]=1[C:57](Cl)=[O:58]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][CH2:46][CH:47]1[CH2:48][CH2:49][N:50]([C:57]([C:56]2[C:55]([Cl:54])=[N:63][CH:62]=[CH:61][CH:60]=2)=[O:58])[CH2:51][CH2:52]1
Reactant: Clc1cnc2nc1Nc1ccc(OCCC3CCNCC3)c(c1)CCc1cncc(c1)N2
Reactant: O=C(Cl)c1cccnc1Cl
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1cccnc1Cl)N1CCC(CCOc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 30 %

Procedure:
The desired compound was prepared according to the procedure of Example D94 using 6-chloro-12-(2-piperidin-4-ylethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate) and 2-chloronicotinoyl chloride as the starting materials in 30% yield. LCMS for C30H30Cl2N7O2 (M+H)+: m/z=590.0, 592.0.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:28]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:33][CH:32]=2)(=[O:30])=[O:29])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C>[OH-].[Na+]>[CH2:38]([O:37][C:34]1[CH:33]=[CH:32][C:31]([S:28]([C:6]2([C:4]([OH:5])=[O:3])[CH2:7][CH2:8][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]4[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]4)=[CH:15][CH:14]=3)[CH2:10][CH2:11]2)(=[O:30])=[O:29])=[CH:36][CH:35]=1)[CH2:39][CH2:40][CH3:41]
Reactant: CCCCOc1ccc(S(=O)(=O)C2(C(=O)OCC)CCN(Cc3ccc(OCCN4CCCCC4)cc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Product: CCCCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(Cc3ccc(OCCN4CCCCC4)cc3)CC2)cc1

Procedure:
4-(4-Butoxy-benzenesulfonyl)-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-piperidine-4-carboxylic acid was prepared starting from 4-(4-Butoxy-benzenesulfonyl)-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-piperidine-4-carboxylic acid ethyl ester (5.8 g, 10 mmol) dissolved in TBF:methanol 3:1 and 10 N NaOH (40 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 4.8 g (86%); Spongy brown solid; mp 98° C.; MS: 559.6 (M+H)+
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([O:17]CC)=[O:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:20]>>[ClH:20].[ClH:20].[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]([CH2:14][C:15]([OH:17])=[O:16])[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CN1CCN(Cc2ccccc2)CC1
Agent: Cl
Product: O=C(O)CN1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 77.4 %

Procedure:
Ethyl 4-benzylpiperazineacetate (2.38 g, 9.0 mmol) was added to 3M hydrochloric acid solution(12 ml), refluxed for 2 hours, stirred for 1 day at a room temperature, and then concentrated under reduced pressure. The resulting residue was dissolved in methanol and reconcentrated. The resulting solid was suspended in ethyl ether, filtered and dried under a reduced pressure to give 2.14 g of the titled compound. (Yield 77.4%)
Reaction SMILES: [H-].[Na+].[C:3]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[C:13](=[O:17])[CH2:14][CH2:15][CH:16]=1)(O)=[O:4].C(Cl)(=O)C([Cl:21])=O>O1CCCC1.CCOCC>[Cl:21][C:3]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[C:13](=[O:17])[CH2:14][CH2:15][CH:16]=1)=[O:4]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)CCCCCCC1=CCCC1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(Cl)CCCCCCC1=CCCC1=O
Temperature: 0 °C

Procedure:
To a suspension of 1.94 g (0.08 mol) of sodium hydride in 100 ml of tetrahydrofuran is added with stirring under argon dropwise a solution of 17 g. (0.08 mol) of 2-(6-carboxyhexyl)cyclopent-2-en-1-one in 160 ml of tetrahydrofuran. After the addition is complete, the mixture is stirred for 1 hour 15 minutes. The mixture is cooled to 0° C. and 13 ml of oxalyl chloride is added. The mixture is stirred at 0° C. for 30 minutes and at room temperature for 30 minutes. The solution is diluted with 500 ml of ether and filtered through Celite. The solvent is removed from the filtrate and the residue is extracted with hot hexane twice. The hexane is removed to given 16.0 g of the title compound.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1.[Al+3].[Cl-].[Cl-].[Cl-]>ClCC(Cl)(Cl)Cl>[F:12][C:13]1[CH:14]=[C:15]([F:19])[CH:16]=[CH:17][C:18]=1[C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[C:1]([OH:6])=[O:11])=[O:5]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Fc1cccc(F)c1
Agent: ClCC(Cl)(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(O)c1ccccc1C(=O)c1ccc(F)cc1F
Temperature: 90 °C
Yield: 75.3 %

Procedure:
To a mixture of phthalic anhydride (64.8 g, 438 mmol), tetrachloroethane (600 mL) and 1,3-difluorobenzene (100 g, 877 mmol) was added anhydrous AlCl3 (141 g, 964 mmol) over 20 minutes while maintaining the reaction temperature below 40° C. The temperature was increased to 90° C. for 2 hours, the reaction mixture was cooled and poured into ice/6N HCl. The mixture was extracted with ether (2×1.2 L) and the combined ether extracts were dried over Na2SO4. The solvent was removed in vacuo and the residue was recrystallized from hot ethyl acetate to afford 86.5 g (75%) of 2-(2,4-difluorobenzoyl)benzoic acid, m.p. 129°-131° C.
Reaction SMILES: [CH:1]1([CH:4]2[O:8][C:7]([C:10]3[CH:11]=[C:12]([S:15][C:16]4[CH:21]=[CH:20][C:19]([C:22](=O)[CH3:23])=[CH:18][CH:17]=4)[S:13][CH:14]=3)([CH3:9])[CH2:6][O:5]2)[CH2:3][CH2:2]1.Cl.[NH2:26][OH:27]>>[CH:1]1([CH:4]2[O:8][C:7]([C:10]3[CH:11]=[C:12]([S:15][C:16]4[CH:21]=[CH:20][C:19]([C:22](=[N:26][OH:27])[CH3:23])=[CH:18][CH:17]=4)[S:13][CH:14]=3)([CH3:9])[CH2:6][O:5]2)[CH2:3][CH2:2]1
Reactant: CC(=O)c1ccc(Sc2cc(C3(C)COC(C4CC4)O3)cs2)cc1
Reactant: NO
Agent: Cl
Product: CC(=NO)c1ccc(Sc2cc(C3(C)COC(C4CC4)O3)cs2)cc1
Yield: 50 %

Procedure:
Using an analogous procedure to that described in Example 68, 4'-[4-(2-cyclopropyl-4-methyl-1,3-dioxolan-4-yl)thien-2-ylthio]acetophenone was reacted with hydroxylamine hydrochloride to give 4'-[4-(2-cyclopropyl-4-methyl-1,3-dioxolan-4-yl)thien-2-ylthio]acetophenone oxime in 50% yield as an oil.
Reaction SMILES: Br[CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[CH:4]=1.[N-:22]=[N+:23]=[N-:24].[Na+].CN(C=O)C>C(OCC)(=O)C>[N:22]([CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[CH:4]=1)=[N+:23]=[N-:24]
Reactant: [N-]=[N+]=[N-]
Reactant: O=c1c(CBr)cn(-c2ccccc2Cl)c2cc(Cl)ccc12
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: [N-]=[N+]=NCc1cn(-c2ccccc2Cl)c2cc(Cl)ccc2c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.2 %

Procedure:
To a 25 mL round-bottom flask containing the crude 3-bromomethyl-7-chloro-1-(2-chloro-phenyl)-1H-quinolin-4-one (410 mg, 1.07 mmol) was added sodium azide (83.5 mg, 1.28 mmol) and DMF (9 mL). The reaction mixture was stirred overnight at room temperature. The mixture was diluted with ethyl acetate (100 mL) and washed with brine (100 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated. The crude was purified by flash chromatography (silica gel, 24 g, 0-50% ethyl acetate in hexanes) to yield 3-azidomethyl-7-chloro-1-(2-chloro-phenyl)-1H-quinolin-4-one (215 mg, 58%) as a light yellow solid. 1H NMR (DMSO-d6) δ ppm 8.17-8.36 (m, 2H) 7.83 (ddd, J=9.8, 7.9, 1.7 Hz, 2H) 7.68 (ddd, J=9.8, 7.8, 1.6 Hz, 2H) 7.48 (dd, J=8.7, 1.8 Hz, 1H) 6.70 (d, J=1.8 Hz, 1H) 4.09-4.44 (m, 2H). MS calcd. for C16H10Cl2N4O [(M+H)+] 346.0, obsd. 345.0.
Reaction SMILES: [CH:1]1[C:11]2[C:10](=O)[NH:9][C:8]3[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=3[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:17][N:18]([CH3:22])[CH2:19][CH2:20][NH2:21]>>[CH:1]1[C:11]2[C:10]([NH:21][CH2:20][CH2:19][N:18]([CH3:22])[CH3:17])=[N:9][C:8]3[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=3[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C1Nc2ccccc2Nc2ccccc21
Reactant: CN(C)CCN
Product: CN(C)CCNC1=Nc2ccccc2Nc2ccccc21
Yield: 27.1 %

Procedure:
5,10-Dihydro-dibenzo[b,e][1,4]diazepine-11-one (160FE15A) (21 mg, 0.1 mmol) and N,N-dimethylethylenediamine (88 mg, 1.0 mmol) were reacted according to GP4 to give 7.6 mg of the title compound (160FE20B). MS (ESI) 281 (MH+). Purity for MH+ (UV/MS) 100/100.
Reaction SMILES: ClC1N=CC2C(=O)N3N=C(C)C=C3NC=2C=1.Cl[C:18]1[N:27]=[CH:26][C:25]2[C:24](=[O:28])[N:23]3[N:29]=[C:30]([CH3:32])[CH:31]=[C:22]3[N:21]([CH3:33])[C:20]=2[CH:19]=1>>[CH3:32][C:30]1[CH:31]=[C:22]2[N:21]([CH3:33])[C:20]3[CH:19]=[CH:18][N:27]=[CH:26][C:25]=3[C:24](=[O:28])[N:23]2[N:29]=1
Reactant: Cc1cc2n(C)c3cc(Cl)ncc3c(=O)n2n1
Agent: Cc1cc2[nH]c3cc(Cl)ncc3c(=O)n2n1
Product: Cc1cc2n(C)c3ccncc3c(=O)n2n1
Yield: 76 %

Procedure:
By substituting for the 6-chloro-2-methylpyrazolo[1,5-a]pyrido[4,3-d]pyrimidin-9(4H)-one in the procedure of Example 4, 6-chloro-2,4-dimethylpyrazolo[1,5-a]pyrido[4,3-d]pyrimidin-9(4H)-one, 2,4-dimethylpyrazolo[1,5-a]pyrido[4,3-d]pyrimidin-9(4H)-one is formed, yield: 76%; m.p. >300° (DMF).
Reaction SMILES: [C:1]1([C:7]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:11][C:10](=[O:12])[NH:9][C:8]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[O:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[C:27](Cl)=[O:28].O>O1CCCC1.C(OCC)(=O)C>[O:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[C:27]([N:9]1[C:8](=[O:13])[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:11][C:10]1=[O:12])=[O:28]
Reactant: O=C(Cl)c1ccco1
Reactant: O=C1NC(=O)C(c2ccccc2)(c2ccccc2)N1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1NC(c2ccccc2)(c2ccccc2)C(=O)N1C(=O)c1ccco1
Reaction time: 0.5 h
Yield: 43.8 %

Procedure:
5,5-Diphenylimidazolidine-2,4-dione (0.5 g) was dissolved in tetrahydrofuran (5 mL), and sodium hydride (60%, in oil) (87 mg) was added at 0° C. under ice-cooling. After stirred for 30 minutes, 2-furoyl chloride (235 mg) was added 0° C., and the mixture was stirred at room temperature for 2.5 hours. After water was added carefully, ethyl acetate (200 mL) was added, and the layers were separated. The resulting organic layer was washed with a saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was distilled off. Further purification by silica gel chromatography (hexane:ethyl acetate=2:1) afforded white powders. The resulting foam was recrystallized from IPE to obtain 273 mg of white crystals.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([O:15][CH:16]3[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]3)[CH:14]=1)[N:11]=[CH:10][CH:9]=[CH:8]2)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([O:15][CH:16]3[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]3)[CH:14]=1)[N:11]=[CH:10][CH:9]=[CH:8]2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)c2ncccc2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCc1cc(OC2CCNCC2)c2ncccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
1,1-Dimethylethyl 4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinecarboxylate (for example, as prepared for Intermediate 3) (21.5 g, 56 mmol) was dissolved in DCM (50 ml) and trifluoroacetic acid (50 ml) was added very slowly. The mixture was stirred at room temperature for 1 h. The solvent was evaporated to dryness and the residue treated with saturated aqueous sodium carbonate solution. The mixture was extracted with EtOAc (×2), washed with water, and dried (MgSO4). The drying agent was removed by filtration and the filtrate was evaporated to dryness (22 g). This was still a trifluoracetic acid salt and was re-dissolved in EtOAc, washed with aqueous sodium carbonate, water, and dried (MgSO4). The drying agent was removed by filtration and the filtrate was evaporated to dryness to afford the title compound (15.9 g). LCMS RT=2.45 min, ES+ve m/z 285 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][O:8][C:9]([O:11]N=C(C2C=CC=CC=2)C#N)=O)=[CH:5][CH:4]=1.[NH2:24][C@H:25]([C:33]([OH:35])=[O:34])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(CC)CC)C.O1CCOCC1>CO.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9]([NH:24][C@H:25]([C:33]([OH:35])=[O:34])[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:11])=[CH:22][CH:23]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: COc1ccc(COC(=O)ON=C(C#N)c2ccccc2)cc1
Solvent: O
Solvent: C1COCCO1
Solvent: CO
Product: COc1ccc(COC(=O)N[C@@H](Cc2ccccc2)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.7 %

Procedure:
2-(4-Methoxybenzyl)oxycarbonyloxyimino-2-phenylacetonitrile (1.55 g.) was added to a solution of L-phenylalanine (826 mg.) and triethylamine (0.75 ml.) in a mixture of methanol (10 ml.), dioxane (1.5 ml.) and water (7.5 ml.) at room temperature the resulting mixture was stirred for 2 hours at room temperature. The reaction mixture was concentrated and benzene and a sodium bicarbonate aqueous solution were added to the residue. After shaking the resultant mixture, the aqueous layer was separated from the mixture, washed with ether, acidified with hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. N-Hexane was added to the residue, and the precipitated crystals were collected by filtration and dried to give N-(4-methoxybenzyl)oxycarbonyl-L-phenylalanine (1.064 g.), mp 87° to 88° C.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[CH2:3][CH2:4][CH2:5][OH:6].C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C1COCC1>[CH3:16][S:17]([O:6][CH2:5][CH2:4][CH2:3][C:2]([F:8])([F:7])[F:1])(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCC(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCC(F)(F)F

Procedure:
The 4,4,4-trifluoro-1-butanol (Lancaster, 0.16 g, 1.2 mmol), triethylamine (0.56 mL, 4.1 mmol), and methanesulfonyl chloride (0.15 mL, 1.9 mmol) in 10 mL THF were processed as described in Example 1C to give the title compound that was used directly in the next reaction.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([O:24][CH3:25])[CH:4]=1)#[N:2].[CH3:26][O:27][CH2:28][CH2:29][CH2:30][NH:31][CH3:32]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([N:31]([CH2:30][CH2:29][CH2:28][O:27][CH3:26])[CH3:32])=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([O:24][CH3:25])[CH:4]=1)#[N:2]
Reactant: CNCCCOC
Reactant: COc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Product: COCCCN(C)C(=O)c1ccc(-n2ncc(-c3ccc(C#N)cc3OC)c2O)nc1

Procedure:
The title compound was prepared in a manner similar to Example 227 using 6-(4-(4-cyano-2-methoxyphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 3-methoxy-N-methylpropan-1-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.76-2.04 (m, 2H) 3.09 (d, J=7.3 Hz, 3H) 3.21 (s, 2H) 3.36 (s, 2H) 3.43-3.56 (m, 2H) 3.65 (t, J=6.9 Hz, 1H) 3.98 (s, 3H) 7.31-7.36 (m, 2H) 8.05 (br. s., 1H) 8.28-8.64 (m, 3H). MS m/z [M+H]+ 422.4.
Reaction SMILES: [NH2:1][C@@H:2]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH2:15][CH3:16])[CH:7]=1)[CH2:3][CH2:4][OH:5].C[O:18][C:19](=O)[C:20]1[C:25]([NH:26][C:27]([CH:29]2[CH2:31][CH2:30]2)=[O:28])=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:32]Br.C(N(CC)CC)C.CCCCCC>CN(C=O)C.CCOCC>[CH2:15]([O:14][C:8]1[CH:7]=[C:6]([C@H:2]([N:1]2[C:19](=[O:18])[C:20]3[C:21](=[CH:22][CH:23]=[CH:24][C:25]=3[NH:26][C:27]([CH:29]3[CH2:31][CH2:30]3)=[O:28])[CH2:32]2)[CH2:3][CH2:4][OH:5])[CH:11]=[CH:10][C:9]=1[O:12][CH3:13])[CH3:16]
Reactant: CCOc1cc([C@H](N)CCO)ccc1OC
Reactant: COC(=O)c1c(CBr)cccc1NC(=O)C1CC1
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOCC
Product: CCOc1cc([C@@H](CCO)N2Cc3cccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Yield: 63.8 %

Procedure:
A solution of (3R)-3-amino-3-(3-ethoxy-4-methoxy-phenyl)-propan-1-ol (1.1 g, 4.9 mmol), 2-bromomethyl-6-(cyclopropanecarbonyl-amino)-benzoic acid methyl ester (1.5 g, 4.8 mmol) and triethylamine (0.75 mL, 5.4 mmol) in DMF (10 mL) was heated at 100° C. for 18 h. The solvent was removed in vacuo. The residue was extracted with ethyl acetate (50 mL) and water (50 mL). The organic layer was washed with HCl (1N, 50 mL), brine (50 mL), and dried over MgSO4. The solvent was removed in vacuo to give an oil. The oil was stirred in ether (5 mL) and hexane (5 mL) to give a suspension. The suspension was filtered to give (1R)-cyclopropanecarboxylic acid {2-[1-(3-ethoxy-4-methoxy-phenyl)-3-hydroxy-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide as a white solid (1.3 g, 64% yield): mp, 103-105° C.; 1H NMR (CDCl3) δ 0.86-0.93 (m, 2H, CH2), 1.08-1.12 (m, 2H, CH2), 1.44 (t, J=7 Hz, 3H, CH3), 1.64-1.73 (m, 1H, CH), 2.11-2.32 (m, 2H, CH2), 3.37 (dd, J=4, 9 Hz, 1H, OH), 3.50-3.59 (m, 1H, CHH), 3.74-3.79 (m, 2H, NCHH, CHH), 3.80 (s, 3H, CH3), 4.06 (q, J=7 Hz, 2H, CH2), 4.16 (d, J=18 Hz, 1H, NCHH), 6.65 (dd, J=4, 11 Hz, 1H, NCH), 6.83-6.99 (m, 4H, Ar), 7.44 (t, J=8 Hz, 1H, Ar), 8.45 (d, J=8 Hz, 1H, Ar), 10.52 (s, 1H, NH); 13C NMR (CDCl3) δ 8.35, 14.77, 16.22, 33.85, 46.23, 50.52, 55.98, 58.59, 64.55, 111.36, 112.99, 116.77, 116.99, 117.83, 119.77,130.73,133.37, 138.05,141.49, 148.62, 149.25,170.33, 172.76; Anal Calcd for C24H28N2O5: C, 67.91; H, 6.65; N, 6.60. Found: C, 67.92; H, 6.67; N, 6.37.
Reaction SMILES: [CH2:1]([N:3]([CH2:23][CH3:24])[CH2:4][CH2:5][CH2:6][NH:7][CH:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH2:12][S:11][C:10]2[CH:19]=[CH:20][CH:21]=[CH:22][C:9]1=2)[CH3:2].O1CCCC1.Cl[O-].[Na+]>O>[CH2:23]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][N:7]=[C:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH2:12][S:11][C:10]2[CH:19]=[CH:20][CH:21]=[CH:22][C:9]1=2)[CH3:24]
Reactant: CCN(CC)CCCNC1c2ccccc2CSc2ccccc21
Agent: [Na+]
Agent: [O-]Cl
Solvent: C1CCOC1
Solvent: O
Product: CCN(CC)CCCN=C1c2ccccc2CSc2ccccc21

Procedure:
2.3 G. of N,N-diethyl-N'-{6,11-dihydro-dibenzo[b,e]thiepin-11-yl}-1,3-propanediamine are dissolved in 50 ml. of absolute tetrahydrofuran and treated dropwise, while stirring, with 6 ml. of 14% aqueous sodium hypochlorite solution. The mixture is stirred at 40°-50° C. for 4 hours, cooled and mixed with 100 ml. of water. The organic phase is extracted with ether. The ether extract is dried over sodium sulfate and evaporated under reduced pressure. The residue is purified by chromatography over aluminum oxide using toluene for the elution. There is obtained N,N-diethyl-N'-{dibenzo[b,e]thiepin-11(6H)-ylidene}-1,3-propanediamine which is taken up in acetone and treated with a solution of 0.4 g. of oxalic acid in 10 ml. of absolute acetone. There is thus obtained N,N-diethyl-N'-{dibenzo[b,e]thiepin-11(6H)-ylidene}-1,3-propanediamine oxalate of melting point 130°-133° C.