Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(S([N:10]2[C:14]3=[CH:15][N:16]=[CH:17][C:18]([C:19]4[N:20]=[C:21]([N:41]5[CH2:46][CH2:45][O:44][CH2:43][CH2:42]5)[C:22]5[S:27][C:26]([CH2:28][N:29]6[CH2:34][CH2:33][N:32]([C:35]([CH3:40])([CH3:39])[C:36]([NH2:38])=[O:37])[CH2:31][CH2:30]6)=[CH:25][C:23]=5[N:24]=4)=[C:13]3[CH:12]=[C:11]2[CH3:47])(=O)=O)C=CC=CC=1>O1CCOCC1.[OH-].[Na+]>[CH3:40][C:35]([N:32]1[CH2:31][CH2:30][N:29]([CH2:28][C:26]2[S:27][C:22]3[C:21]([N:41]4[CH2:46][CH2:45][O:44][CH2:43][CH2:42]4)=[N:20][C:19]([C:18]4[CH:17]=[N:16][CH:15]=[C:14]5[NH:10][C:11]([CH3:47])=[CH:12][C:13]=45)=[N:24][C:23]=3[CH:25]=2)[CH2:34][CH2:33]1)([CH3:39])[C:36]([NH2:38])=[O:37]
Reactant: Cc1cc2c(-c3nc(N4CCOCC4)c4sc(CN5CCN(C(C)(C)C(N)=O)CC5)cc4n3)cncc2n1S(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1cc2c(-c3nc(N4CCOCC4)c4sc(CN5CCN(C(C)(C)C(N)=O)CC5)cc4n3)cncc2[nH]1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 35.2 %

Procedure:
A 25 mL round-bottomed flask, under nitrogen, fitted with a condenser/inert gas bubbler (via a Claisen head), was charged with a solution of 2-{4-[2-(1-benzenesulfonyl-2-methyl-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl]piperazine-1-yl}isobutyramide (0.17 g, 0.25 mmol) in dioxane (4 mL), IMS (4 mL) and NaOH 12.5M (0.4 mL). The resulting mixture was stirred at room temperature for 2.5 h. The solution was concentrated in vacuo, the residue diluted with MeOH and loaded onto a Isolute® SCX-2 cartridge treated with MeOH. The cartridge was washed with MeOH (100 mL) and the product was recovered eluting with 2N NH3 in MeOH, the eluent concentrated, suspended in dioxane/water and freeze-dried overnight. The resultant solid was dissolved in DMSO and purified by preparative HPLC (C18 column) gradient: (acetonitrile/20 mM triethylamine) 10% to 98% in (water/20 mM triethylamine) over 20 min (flow rate 18 ml/min). The product was freeze-dried overnight yielding 142 as a white powder (0.047 g, 35%). LCMS (Method E): RT=5.27 min, [M+H]+ 535.2. 1H NMR (DMSO, 400 MHz): δ 11.43 (s, 1 H); 8.22 (d, J=5.4 Hz, 1 H); 7.43 (s, 1 H); 7.33 (dd, J=6.3, 0.9 Hz, 1 H); 7.07 (d, J=3.5 Hz, 1 H); 6.95 (d, J=3.45 Hz, 1 H); 6.87 (s, 1 H); 3.98 (t, J=4.6 Hz, 4 H); 3.87 (s, 2 H); 3.81 (t, J=4.6 Hz, 4 H); 3.57 (s, 3 H); 2.61-2.53 (m, 2 H); 2.49-2.45 (m, 2 H); 2.44 (s, 4 H); 1.08 (s, 6 H)
Reaction SMILES: [C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([C:21]5[CH:32]=[CH:31][C:24]([C:25]([O:27]CC=C)=[O:26])=[CH:23][CH:22]=5)=[CH:18]4)=[CH:13][C:12]=3[O:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.N1CCOCC1>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.C1COCC1>[C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([C:21]5[CH:32]=[CH:31][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=5)=[CH:18]4)=[CH:13][C:12]=3[O:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: C=CCOC(=O)c1ccc(-c2ccc3cc(OCCCCCC(=O)OCC)c(C45CC6CC(CC(C6)C4)C5)cc3c2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: C1COCCN1
Product: CCOC(=O)CCCCCOc1cc2ccc(-c3ccc(C(=O)O)cc3)cc2cc1C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.5 g (2.58 mmol) of allyl 4-[7-(1-adamantyl)-6-ethoxycarbonylpentyloxy-2-naphthyl]benzoate, 50 ml of THF and 90 mg (0.08 mmol) of tetrakis(triphenylphosphine)palladium(0) were introduced into a three-necked flask under a stream of nitrogen. 1.13 ml (13 mmol) of morpholine were added dropwise and the reaction mixture was stirred at room temperature for two hours. The reaction mixture was evaporated to dryness, the residue was taken up in water, acidified to pH 1 with hydrochloric acid and extracted with ethyl ether and the organic phase was separated by settling, dried over magnesium sulfate and evaporated. The solid was triturated in heptane, filtered and dried. 1 g (72%) of the expected acid was collected, which acid had a melting point of 270°-1° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([N:8]2[C:12](=[O:13])[CH2:11][S:10][C:9]2=[O:14])[CH2:4][CH2:3]1.[Cl:15][C:16]1[CH:33]=[CH:32][C:19]([CH2:20][N:21]2[C:29]3[C:24](=[CH:25][C:26]([CH:30]=O)=[CH:27][CH:28]=3)[CH:23]=[N:22]2)=[C:18]([C:34]([F:37])([F:36])[F:35])[CH:17]=1>>[Cl:15][C:16]1[CH:33]=[CH:32][C:19]([CH2:20][N:21]2[C:29]3[C:24](=[CH:25][C:26](/[CH:30]=[C:11]4/[C:12](=[O:13])[N:8]([N:5]5[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]5)[C:9](=[O:14])[S:10]/4)=[CH:27][CH:28]=3)[CH:23]=[N:22]2)=[C:18]([C:34]([F:35])([F:37])[F:36])[CH:17]=1
Reactant: CN1CCN(N2C(=O)CSC2=O)CC1
Reactant: O=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1
Product: CN1CCN(N2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)CC1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-(4-methylpiperazin-1-yl)-1,3-thiazolidine-2,4-dione was prepared from 3-(4-methyl-piperazin-1-yl)-thiazolidine-2,4-dione and [4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-carbaldehyde (from Example 1) following General Procedure E.
Reaction SMILES: ClC1C=NC=C(Cl)C=1[NH:8][C:9]([C:11]1[C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([NH2:24])[CH:21]=3)[N:16]([CH3:25])[C:15]=2[C:14]([O:26][CH3:27])=[CH:13][CH:12]=1)=[O:10].N1C=CC=CC=1.[CH2:35]([S:37](Cl)(=[O:39])=[O:38])[CH3:36]>C1COCC1>[CH3:27][O:26][C:14]1[C:15]2[N:16]([CH3:25])[C:17]3[C:22](=[CH:21][C:20]([NH:24][S:37]([CH2:35][CH3:36])(=[O:39])=[O:38])=[CH:19][CH:18]=3)[C:23]=2[C:11]([C:9]([NH2:8])=[O:10])=[CH:12][CH:13]=1
Reactant: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c3cc(N)ccc3n(C)c12
Reactant: CCS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCS(=O)(=O)Nc1ccc2c(c1)c1c(C(N)=O)ccc(OC)c1n2C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 30.7 %

Procedure:
N-(3,5-dichloropyrid-4-yl)-1-methoxy-9-methyl-6-amino-9H-4-carbazolecarboxamide (75 mg, 0.00018 mol) was suspended in THF (5 ml) and added with pyridine (28 mg, 0.00036 mol) and stirred at room temperature for 10 minutes. The solution obtained, was added with a solution of ethane sulphonyl chloride (34 mg, 0.00027 mol) in dry THF (5 ml). The reaction mixture was stirred for 1 hr. THF was evaporated and the solid was washed with water to get crude solid which was column chromatographed using 10% methanol in chloroform to give N-3,5-dichloropyrid-4-yl)-1-methoxy-9-methyl-6-ethane sulphonamido-9H-4-carbazolecarboxamide (20 mg), mp>250° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1F)[N:8]([CH:14]1[CH2:16][CH2:15]1)[CH:7]=[C:6]([C:17]([OH:19])=[O:18])[C:5]2=[O:20]>C(O)(=O)C>[CH3:14][N:8]1[CH2:9][CH2:4][CH:5]([O:20][C:11]2[C:10]([F:13])=[C:9]3[C:4]([C:5](=[O:20])[C:6]([C:17]([OH:19])=[O:18])=[CH:7][N:8]3[CH:14]3[CH2:16][CH2:15]3)=[CH:3][C:2]=2[F:1])[CH2:6][CH2:7]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Solvent: CC(=O)O
Product: CN1CCC(Oc2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CC1
Yield: 42 %

Procedure:
6,7,8-Trifluoro-1-cyclopropyl-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (570 mg) was reacted in a similar manner to Example 9. Acetic acid (480 mg) was added and DMF was distilled off under reduced pressure. The residue was purified by columnchromatography on silica gel, whereby 160 mg of the title compound was obtained.
Reaction SMILES: CCN(C(C)C)C(C)C.[N:10]1[CH:15]=[C:14]([C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][CH:17]=2)[CH:13]=[N:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:47][CH2:48][C:49]([N:51]1[CH2:56][CH2:55][N:54]([C:57](=[O:68])[C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=2[C:64]([F:67])([F:66])[F:65])[CH2:53][CH2:52]1)=[O:50]>CN(C=O)C.O>[O:50]=[C:49]([N:51]1[CH2:52][CH2:53][N:54]([C:57](=[O:68])[C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=2[C:64]([F:67])([F:66])[F:65])[CH2:55][CH2:56]1)[CH2:48][NH:47][C:20](=[O:22])[C:19]1[CH:18]=[CH:17][C:16]([C:14]2[CH:13]=[N:12][CH:11]=[N:10][CH:15]=2)=[CH:24][CH:23]=1
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Reactant: O=C(O)c1ccc(-c2cncnc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1ccc(-c2cncnc2)cc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 31.1 %

Procedure:
DIPEA (185 mg, 0.24 mL, 1.1 mmol) was added to a stirred solution of 4-pyrimidin-5-yl-benzoic acid (85 mg, 0.42 mmol) in DMF (2 mL). HOBT (75 mg, 0.46 mmol) and EDCI (98 mg, 0.46 mmol) were then added at room temperature. After 2 minutes, 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone hydrochloride salt (165 mg, 0.46 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and filtered the residue. The obtained residue was purified by column chromatography (using silica gel of 60-120 mesh and 70% EtOAc in Hexane as eluent) to afford 65 mg (31% yield) of N-{2-Oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-4-pyrimidin-5-yl-benzamide. LCMS Purity: 97%. 1H NMR (CDCl3): δ 9.2 (s, 1H), 9.0 (s, 2H), 8.0 (dd, 2H), 7.56 (d, 1H), 7.65 (m, 4H), 7.35 (m, 2H), 4.35 (m, 1H), 4.25 (m, 1H), 4.0 (m, 2H), 3.7 (m, 2H), 3.6 (m, 2H), 3.42 (m, 1H), 3.25 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:31])[C:7]=1[NH:8][C:9]([C:11]1[C:19]2[C:18]3[CH:20]=[C:21]([N+:24]([O-])=O)[CH:22]=[CH:23][C:17]=3[O:16][C:15]=2[C:14]([O:27][CH:28]([F:30])[F:29])=[CH:13][CH:12]=1)=[O:10]>[Pd].CO>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:31])[C:7]=1[NH:8][C:9]([C:11]1[C:19]2[C:18]3[CH:20]=[C:21]([NH2:24])[CH:22]=[CH:23][C:17]=3[O:16][C:15]=2[C:14]([O:27][CH:28]([F:29])[F:30])=[CH:13][CH:12]=1)=[O:10]
Reactant: O=C(Nc1c(Cl)cncc1Cl)c1ccc(OC(F)F)c2oc3ccc([N+](=O)[O-])cc3c12
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2oc3c(OC(F)F)ccc(C(=O)Nc4c(Cl)cncc4Cl)c3c2c1
Reaction time: 12 h

Procedure:
A mixture of N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-nitro-dibenzo[b,d]furan-1-carboxamide (step 8) (100 mg), methanol (10 ml) and 10% Pd/C (10 mg) was hydrogenated at 60 psi for 12 h. Filteration of the reaction mixture over celite bed and removal of solvent methanol under reduced pressure afforded N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-amino-dibenzo[b,d]furan-1-carboxamide as white solid. mp: >270° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([O:7][CH2:8][CH2:9][O:10][CH:11]2[CH2:16][CH2:15][N:14](C(OCC3C=CC=CC=3)=O)[CH2:13][CH2:12]2)[CH2:3][CH2:2]1>CO.[OH-].[Pd+2].[OH-]>[O:1]1[CH2:2][CH2:3][CH:4]([O:7][CH2:8][CH2:9][O:10][CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH2:5][CH2:6]1
Reactant: O=C(OCc1ccccc1)N1CCC(OCCOC2CCOCC2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: C1CC(OCCOC2CCOCC2)CCN1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.8 %

Procedure:
Benzyl 4-[2-(tetrahydro-2H-pyran-4-yloxy)ethoxy]piperidine-1-carboxylate (505 mg, 1.39 mmol) produced in Reference Example 1 (1e) was dissolved in methanol (15 mL), to which palladium hydroxide (50 mg) was added, followed by stirring at room temperature for 18 hours under a hydrogen atmosphere. The resulting reaction liquid was filtered through Celite, and the solvent was distilled off under reduced pressure to give the desired title compound (318 mg, yield 100%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][N:3]=1.[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[C:18]1[C:23]([C:24]2[NH:25][CH:26]=[CH:27][N:28]=2)=[CH:22][N:21]=[C:20]([NH:29][CH2:30][CH2:31][NH:32]C2C=CC([N+]([O-])=O)=CN=2)[N:19]=1>>[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[C:18]1[C:23]([C:24]2[NH:28][CH:27]=[CH:26][N:25]=2)=[CH:22][N:21]=[C:20]([NH:29][CH2:30][CH2:31][NH:32][C:2]2[N:3]=[CH:4][C:5]([C:8]#[N:9])=[CH:6][CH:7]=2)[N:19]=1
Reactant: O=[N+]([O-])c1ccc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)nc1
Reactant: N#Cc1ccc(Cl)nc1
Product: N#Cc1ccc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)nc1

Procedure:
6-[(2-{[4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]amino}ethyl)amino]pyridine-3-carbonitrile was prepared from 2-chloro-5-(cyano)pyridine using the general method for [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]{2-[(5-nitro(2-pyridyl))amino]ethyl}amine.
Reaction SMILES: [CH3:1][C:2]1[C@@H:19]([OH:20])[CH2:18][C@:14]2([OH:21])[C:15]([CH3:17])([CH3:16])[C:3]=1[C@@H:4]([O:38]C(C)=O)[C:5]([C@@:7]1([CH3:37])[C@H:12]([C@@H:13]2[O:22][C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:24])[C@:11]2([O:33][C:34]([CH3:36])=[O:35])[CH2:31][O:32][C@@H:10]2[CH2:9][CH2:8]1)=[O:6].O.NN.C(OCC)(=O)C>C(O)C>[CH3:1][C:2]1[C@@H:19]([OH:20])[CH2:18][C@:14]2([OH:21])[C:15]([CH3:16])([CH3:17])[C:3]=1[C@@H:4]([OH:38])[C:5]([C@@:7]1([CH3:37])[C@H:12]([C@@H:13]2[O:22][C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:24])[C@:11]2([O:33][C:34]([CH3:36])=[O:35])[CH2:31][O:32][C@@H:10]2[CH2:9][CH2:8]1)=[O:6]
Reactant: CC(=O)O[C@H]1C(=O)[C@]2(C)CC[C@H]3OC[C@@]3(OC(C)=O)[C@H]2[C@H](OC(=O)c2ccccc2)[C@]2(O)C[C@H](O)C(C)=C1C2(C)C
Agent: NN
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)O[C@@]12CO[C@@H]1CC[C@@]1(C)C(=O)[C@H](O)C3=C(C)[C@@H](O)C[C@@](O)([C@@H](OC(=O)c4ccccc4)[C@H]21)C3(C)C
Temperature: 25 °C
Reaction time: 7 h
Yield: 52.6 %

Procedure:
6.85 g of 7-deoxybaccatin III was dissolved in 250 ml of 95% ethanol, and 25 ml of hydrazine monohydrate was added thereto, followed by stirring at room temperature for 7 hours. Ethyl acetate was added to the reaction solution, the resulting mixture was washed successively with water and a saturated aqueous sodium chloride solution, and the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel thin layer chromatography (a developing solvent; hexane:ethyl acetate=3:2 (v/v)) to yield 3.34 g of the titled compound as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:13]([NH:14][CH3:15])[CH2:12][N:11]([C:16]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([C:26]4([CH3:29])[CH2:28][CH2:27]4)=[O:25])[CH2:20][CH2:19]3)=[O:17])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)C(C)C)(C)C.[CH3:39][O:40][C:41]1[CH:49]=[CH:48][C:44]([C:45](Cl)=[O:46])=[CH:43][C:42]=1[C:50]([F:53])([F:52])[F:51]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:10][N:11]([C:16]([CH:18]3[CH2:19][CH2:20][N:21]([C:24]([C:26]4([CH3:29])[CH2:27][CH2:28]4)=[O:25])[CH2:22][CH2:23]3)=[O:17])[CH2:12][CH:13]2[N:14]([CH3:15])[C:45](=[O:46])[C:44]2[CH:48]=[CH:49][C:41]([O:40][CH3:39])=[C:42]([C:50]([F:53])([F:52])[F:51])[CH:43]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1ccc(C(=O)Cl)cc1C(F)(F)F
Reactant: CNC1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)CC1c1ccc(Cl)c(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(C(=O)N(C)C2CN(C(=O)C3CCN(C(=O)C4(C)CC4)CC3)CC2c2ccc(Cl)c(Cl)c2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 78.7 %

Procedure:
To a solution of {4-[(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone (200 mg, 0.456 mmol) in THF (2 mL) was added N,N-diisopropyl ethyl amine (117 μl, 0.684 mmol), 4-methoxy-3-(trifluoromethyl)benzoyl chloride (131 mg, 0.547 mmol) and stirred for 4 h at ambient temperature. The reaction mixture was diluted with ethzl acetatec (10 mL) and was washed with an aqueous solution of sodium carbonate (1 M, 10 mL), water (10 mL) and brine (10 mL). The aqueous layers were extracted with ethyl acetate (20 mL) and the combined organic layers were dried over sodium sulfate. Purification by chromatography (SiO2, heptane:ethyl acetate:methanol=50:50:0 to 0:90:10) afforded the title compound (230 mg, 79%) as a colorless oil. MS m/e: 640.3 [M]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CC#N>[C:1]([O:5][C:6]([N:8]1[CH:13]=[CH:12][CH2:11][NH:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCN(C(=O)OC(C)(C)C)C1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1C=CCNC1

Procedure:
A solution of 5-2 (19.0 g, 63 mmol), Mg(ClO4)2 (2.8 g, 12.7 mmol), and CH3CN was heated at 50° C. for 2 hr. The cooled solution was diluted with CDCl3 and then washed with 1N HCl, sat. NaHCO3, and brine, dried (MgSO4), and concentrated. Flash chromatography (silica, 75% EtOAc/hexanes→EtOAc) gave 5-3 as a brown solid.
Reaction SMILES: C([O:3][C:4](=[O:50])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)[CH:25]=[C:24]([C:34]3[CH:42]=[CH:41][C:37]4[O:38][CH2:39][O:40][C:36]=4[CH:35]=3)[CH:23]=2)[C:10]=1[CH2:43][CH2:44][C:45]([O:47]CC)=[O:46])C.[OH-].[Na+]>>[O:38]1[C:37]2[CH:41]=[CH:42][C:34]([C:24]3[CH:23]=[C:22]([CH:27]=[C:26]([C:28]4[CH:29]=[CH:30][N:31]=[CH:32][CH:33]=4)[CH:25]=3)[O:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:11]3[C:10]([CH2:43][CH2:44][C:45]([OH:47])=[O:46])=[C:9]([CH:14]=[CH:13][CH:12]=3)[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:50])=[O:3])=[CH:35][C:36]=2[O:40][CH2:39]1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(-c3ccncc3)cc(-c3ccc4c(c3)OCO4)c2)c1CCC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCCOc1cccc(CCCCCCOc2cc(-c3ccncc3)cc(-c3ccc4c(c3)OCO4)c2)c1CCC(=O)O
Yield: 29.3 %

Procedure:
A similar procedure as described in Example 12, step 9 was used, starting from 4-{3-[6-(3-benzo[1,3]dioxol-5-yl-5-pyridin-4-yl-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy}-butyric acid ethyl ester (45 mg, 0.12 mmol) and 1.0 N aqueous sodium hydroxide (4 mL) to afford 4-{3-[6-(3-benzo[1,3]dioxol-5-yl-5-pyridin-4-yl-phenoxy)-hexyl]-2-(2-carboxy-ethyl)-phenoxy}-butyric acid (22 mg, 54%) as an amorphous white solid: ES(+)-HRMS m/e calculated for C37H39NO8 (M+H)+ 626.2749, found 626.2748.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C@@H:9]1[C:21]([O-:23])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:24]1([CH2:29][CH2:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][NH:32]2)[CH:28]=[CH:27][N:26]=[CH:25]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C>[N:24]1([CH2:29][CH2:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][N:32]2[C:21]([C@H:9]2[CH2:10][N:11]([C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])[CH2:12][CH2:13][N:8]2[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:23])[CH:28]=[CH:27][N:26]=[CH:25]1
Reactant: c1cn(CCC2CCCCN2)cn1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](C(=O)[O-])C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](C(=O)N2CCCCC2CCn2ccnc2)C1
Temperature: 25 °C
Reaction time: 122 h
Yield: 30.3 %

Procedure:
1,4-Di-N-tert-butoxycarbonylpiperazine-2(R)-carboxylate (prepared as described in Preparative Example 2) (0.6946 g, 2.1 mmoles), 2(R/S)-[2-(1H-imidazol-1-yl)ethyl]piperidine (0.49 g, 2.73 mmoles) (prepared as described in Preparative Example 57, Step D) (INO972), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.524 g, 2.73 mmoles), 1-hydroxybenzotriazole (0.3693 g, 2.73 mmoles) and 4-methylmorpholine (0.2765 g, 0.3005 mL, 2.73 mmoles) were dissolved in anhydrous DMF (3 mL) and the mixture was stirred under argon at 25° C. for 122 h. The mixture was evaporated to dryness and chromatographed on silica gel using 2-3%(10% conc. ammonium hydroxide in methanol)-dichloromethane as the eluant to give the title compound (0.3127 g, 30%): CIMS: m/z 492.4 (MH+); δH (CDCl3) 1.47 (18H, s, CH3), 7.01 (1H, s, Im-H5), 7.05 (1H, s, Im-H4) and 7.63 ppm (1H, s, Im-H2); δC (CDCl3) CH3: 28.2, 28.2, 28.2, 28.4, 28.4, 28.4; CH2: 19.1, 25.9, 26.2, 31.9, 40.8/41.3, 41.7, 43.0, 44.0; CH: 46.0, ˜52.1, 128.4, 137.2; C: ˜80.4, 80.6, ˜154.3, ˜154.3 and ˜169.8.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:32]=[CH:31][C:6]2[CH2:7][CH2:8][CH2:9][CH:10]([N:12]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:13][C@H:14]([OH:23])[CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:11][C:5]=2[CH:4]=1.[C:33]([O:37][C:38](=[O:41])[CH:39]=[CH2:40])([CH3:36])([CH3:35])[CH3:34]>CO>[C:33]([O:37][C:38](=[O:41])[CH2:39][CH2:40][NH:1][CH2:2][C:3]1[CH:32]=[CH:31][C:6]2[CH2:7][CH2:8][CH2:9][CH:10]([N:12]([CH2:13][C@H:14]([OH:23])[CH2:15][O:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:11][C:5]=2[CH:4]=1)([CH3:36])([CH3:35])[CH3:34]
Reactant: NCc1ccc2c(c1)CC(N(Cc1ccccc1)C[C@H](O)COc1ccccc1)CCC2
Reactant: C=CC(=O)OC(C)(C)C
Solvent: CO
Product: CC(C)(C)OC(=O)CCNCc1ccc2c(c1)CC(N(Cc1ccccc1)C[C@H](O)COc1ccccc1)CCC2
Reaction time: 18 h

Procedure:
To a solution of (2S)-1-[N-(3-aminomethyl-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)benzylamino]-3-phenoxy-2-propanol (100 mg) in methanol (2 ml) was added tert-butylacrylate (0.033 ml) at room temperature, and the mixture was stirred at the same temperature for 18 hours. The resulting mixture was evaporated in vacuo. The residue was chromatographed (hexane-ethyl acetate) over silica gel to afford 3-(8-[N-benzyl-(2S)-(2-hydroxy-3-phenoxypropyl)amino]-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylmethylamino]-propionic acid tert-butyl ester (100 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:32])[NH:20][C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[C:24]([CH3:31])[CH:25]=[CH:26][CH:27]=4)[N:22]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:33]([O:35]CC)=[O:34].[OH-].[Na+]>C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19](=[O:32])[NH:20][C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[C:24]([CH3:31])[CH:25]=[CH:26][CH:27]=4)[N:22]=3)=[CH:17][CH:18]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:33]([OH:35])=[O:34]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4ccc5cccc(C)c5n4)cc3)c(Cl)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cccc2ccc(NC(=O)c3ccc(Oc4cc5c(cc4Cl)C(C(=O)O)CCO5)cc3)nc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.1 %

Procedure:
To a solution of ethyl 6-chloro-7-(4-(8-methylquinolin-2-ylcarbamoyl)phenoxy)chroman-4-carboxylate (0.024 g, 0.0464 mmol) in 3:1 THF/MeOH (1 ml) was added 1M sodium hydroxide (0.0511 ml, 0.0511 mmol), and the reaction was stirred for 16 hours at ambient temperature. The reaction was concentrated to dryness and acidified with diluted hydrochloric acid. The reaction was extracted with EtOAc twice, and the combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated to yield the desired compound (0.02 g, 0.0409 mmol, 88.1% yield). MS (apci) m/z=489.1 (M+H).
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([CH:21]=[CH:22][C:23]=3[O:24][CH3:25])[NH:14]C(=O)C(F)(F)F)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.O.[OH-].[K+]>CO>[C:1]12([C:11]3[CH:12]=[C:13]([CH:21]=[CH:22][C:23]=3[O:24][CH3:25])[NH2:14])[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: COc1ccc(NC(=O)C(F)(F)F)cc1C12CC3CC(CC(C3)C1)C2
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(N)cc1C12CC3CC(CC(C3)C1)C2
Temperature: 50 °C
Reaction time: 18 h

Procedure:
11.03 g (31.2 mmol) of 3-(1-adamantyl)4-methoxy-N-(trifluoroacetyl)aniline dissolved in 40 ml of methanol and 160 ml of water are treated with 7.12 g (51.5 mmol) of potassium hydroxide. The reaction medium is heated to 50° C. for 20 hours and then 80° C. for 18 hours. After evaporation to dryness, the residue is taken up with ethyl ether, the insoluble matter is filtered off and the filtrate is dried over magnesium sulphate and evaporated. The solid is washed in hexane to yield, after drying, 7.44 g (93%) of 3-(1-adamantyl)-4-methoxyaniline, melting point 140°-141° C.