Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:39]([OH:41])=O)=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]([N:23]4[CH2:28][CH2:27][CH:26]([N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)[CH2:25][CH2:24]4)=[O:22])=[CH:18][C:17]4[CH:35]=[CH:36][CH:37]=[CH:38][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[NH2:73][CH2:74][C:75]1[NH:79][N:78]=[N:77][N:76]=1>C(Cl)Cl>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:39]([NH:73][CH2:74][C:75]4[NH:79][N:78]=[N:77][N:76]=4)=[O:41])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]([N:23]4[CH2:24][CH2:25][CH:26]([N:29]5[CH2:30][CH2:31][O:32][CH2:33][CH2:34]5)[CH2:27][CH2:28]4)=[O:22])=[CH:18][C:17]4[CH:35]=[CH:36][CH:37]=[CH:38][C:16]=4[C:15]=23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NCc1nnn[nH]1
Reactant: O=C(O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C(=O)N1CCC(N2CCOCC2)CC1)=Cc1ccccc1-3
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1nnn[nH]1)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C(=O)N1CCC(N2CCOCC2)CC1)=Cc1ccccc1-3
Temperature: 25 °C
Reaction time: 23 h
Yield: 45.9 %

Procedure:
To a stirred solution of 13-cyclohexyl-6-[[4-(4-morpholinyl)-1-piperidinyl]carbonyl]-7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid (135 mg, 0.24 mmol) in CH2Cl2 (1 mL) were added N,N-diisopropylethylamine (170 μL, 0.98 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (64 mg, 0.33 mmol), 1-hydroxybenzotriazole (47 mg, 0.35 mmol), and 5-(aminomethyl)tetrazole (33 mg, 0.33 mmol). The suspension was allowed to stir at r.t. for 23 hr, filtered through Celite, and chromatographed on silica gel (gradient elution: 0%→30% MeOH in CH2Cl2) to afford the title compound as a yellow solid (70 mg, 46% yield). LC/MS (ESI) retention time: 1.61 min, m/z 635 (MH+); 1H NMR (400 MHz, CD3OD) δ 1.08-1.23 (m, 1 H) 1.35-1.48 (m, 4 H) 1.66 -1.79 (m, 3 H) 1.86 -1.92 (m, 1 H) 1.96 -2.14 (m, 3 H) 2.44-2.60 (m, 5 H) 2.74 -2.89 (m, 2 H) 3.16 (dd, J=7.55 Hz, 1 H) 3.57 -3.73 (m, 5 H) 4.25 (s, 1 H) 4.94-5.08 (m, 1 H) 6.87 (s, 1 H) 7.43-7.51 (m, 3 H) 7.52-7.59 (m, 2 H) 7.83 (d, J=8.56 Hz, 1 H) 8.11 (s, 1 H).
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH2:4][C:3]1([CH3:18])[CH3:17].[CH2:19]([CH:21]1[O:23][CH2:22]1)Cl>>[CH3:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:19][CH:21]3[CH2:22][O:23]3)=[CH:14][CH:15]=2)[CH2:4][C:3]1([CH3:18])[CH3:17]
Reactant: ClCC1CO1
Reactant: CN1C(C)(C)CC(c2ccc(O)cc2)CC1(C)C
Product: CN1C(C)(C)CC(c2ccc(OCC3CO3)cc2)CC1(C)C

Procedure:
The title compound was prepared from 4-(1,2,2,6,6-pentamethyl-piperidin-4-yl)-phenol and epichlorohydrin according to the procedures employed for the preparation of the compound in Step 1 of Example 2.
Reaction SMILES: COC1C=CC=CC=1C([O:18][CH2:19][C@H:20]1[O:24][C@@H:23]([N:25]2[C:48]3[N:47]=[CH:46][N:45]=[C:29]([NH:30][C:31]([O:33][CH2:34][CH2:35][C:36]4[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=4)=[O:32])[C:28]=3[N:27]=[CH:26]2)[C@H:22]([O:49][C:50](=[O:72])[CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][NH:56][C:57](=[O:71])[CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH3:70])[CH2:21]1)(C1C=CC=CC=1)C1C=CC=CC=1.CC1C=CC(S(O)(=O)=O)=CC=1.O>C(Cl)Cl.CO.C(Cl)Cl>[N+:42]([C:39]1[CH:40]=[CH:41][C:36]([CH2:35][CH2:34][O:33][C:31]([NH:30][C:29]2[C:28]3[N:27]=[CH:26][N:25]([C:48]=3[N:47]=[CH:46][N:45]=2)[C@@H:23]2[O:24][C@H:20]([CH2:19][OH:18])[CH2:21][C@H:22]2[O:49][C:50](=[O:72])[CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][NH:56][C:57](=[O:71])[CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH3:70])=[O:32])=[CH:37][CH:38]=1)([O-:44])=[O:43]
Reactant: CCCCCCCCCCCCCC(=O)NCCCCCC(=O)O[C@@H]1C[C@@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2OC)O[C@H]1n1cnc2c(NC(=O)OCCc3ccc([N+](=O)[O-])cc3)ncnc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: CCCCCCCCCCCCCC(=O)NCCCCCC(=O)O[C@@H]1C[C@@H](CO)O[C@H]1n1cnc2c(NC(=O)OCCc3ccc([N+](=O)[O-])cc3)ncnc21
Yield: 88.3 %

Procedure:
Compound 8 (330 mg, 0.317 mmol) was stirred at r.t. in CH2Cl2/MeOH 4:1 (6 ml) containing 2% of TsOH.H2O for 15 min. Then the mixture was diluted with CH2Cl2 (70 ml) and washed with sat. NaHCO3 soln. (2×40 ml), the aq. phase reextracted with CH2Cl2, the combined org. layer dried (MgSO4) and evaporated, and the residue purified by FC (silica gel, 12×2 cm, CHCl3, CHCl3+5% MeOH). The obtained oily substance was treated with small amounts of Et2O/MeCN 2:1 to give 215 mg (88%) of 10. Amorphous solid. UV (CH2Cl2); 272 (sh, 4.36), 267 (4.41). 1H-NMR (CDCl3):8.71, 8.21-8.15 (2m, H—C(8), H—C(2), 2 H o to NO2,NH(ade)); 7.45 (d, 2 H m to NO2); 6.03 (d, H—C(1′)); 5.58 (m, H—C(2′)); 5.55 (br., NH(CH2)5CO); 5.0 (br., OH—C(5′)); 4.65-4.50 (m, t, H—C(4′), OCH2CH2); 4.12, 3,75 (2m, 2 H—C(5′)); 3.25(q, 1 CH2 of NH(CH2)5CO); 3.15 (t, OCH2CH2);2.9, 2.25 (2m, 2 H—C(3′)); 2.35, 2.15 (2t, 2 CH2 of NH(CH2)5CO), 2 H of Me(CH2)12CO); 1.7-1.15 (m, 28 H, 2 CH2 of NH(CH2)5CO, Me(CH2)12CO); 0.87 (t, Me(CH2)12CO)12 Anal. calc. for C39H57N7O9 ½ H2O (782.02): C 59.90, H 7.41, N 12.54; found: C 60.27, H 7.66, N 12.06.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[NH2:11].CN(C)[C:14]1[O:15][C:16](=[O:24])[CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[N:19]=1>C(O)(=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[N:11]1[C:16](=[O:24])[CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[NH:19][C:14]1=[O:15]
Reactant: CN(C)c1nc(C(F)(F)F)cc(=O)o1
Reactant: Nn1ccc2c(Cl)cccc21
Solvent: CC(=O)O
Product: O=c1cc(C(F)(F)F)[nH]c(=O)n1-n1ccc2c(Cl)cccc21
Reaction time: 4.5 h

Procedure:
A mixture of 169A, glacial acetic acid (30 mL) and 2-dimethylamino-4-trifluoromethyl-[1,3]oxazin-6-one (2.76 g, 13.3 mmol) is stirred for 4.5 h under reflux, whereupon the acetic acid was removed in vacuo. The residue is diluted with ethyl acetate, washed with water and subsequently dried over sodium sulfate. The crude product (3 g) is obtained after removal of the drying agent by filtration and evaporation of the solvent. The product (0.88 g) is obtained as a brown oil after flash chromatography (ethyl acetate/petrol ether 2/8).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:16]=2[CH2:17][C:18]([OH:20])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.O>CN(C)C=O>[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([C:18]([CH2:17][C:16]2[N:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]3=[N:9][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[O:20])[CH2:30][CH2:29]1
Reactant: CN1CCNCC1
Reactant: O=C(O)Cc1c(-c2ccc(Cl)cc2)nc2ccccn12
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCN(C(=O)Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
4.5 g (15.64 millimols) of 2-(4-chlorophenyl)-imidazo[1,2-a]pyridine-3-acetic acid are added to a suspension of N,N-dimethyl-chloro-methyleneiminium chloride prepared by adding 2.2 g (17.75 millimols) of oxalyl chloride to 30 ml of dimethylformamide (DMF) at -10° C. The suspension is stirred for 15 minutes at 0° C. and a solution of 5.4 g (54 millimols) of 4-methylpiperazine in 10 ml of dry DMF is then added gradually thereto at 0° C. The solution is stirred for 8 hours and then poured into 750 ml of water. The amide is extracted with CH2Cl2, the organic phase is dried over Na2SO4 and concentrated, the residue is passed through a silica column (eluant: CH2Cl2 /CH3OH 9/1) and the compound obtained is recrystallised from an isopropyl ether/acetonitrile mixture. Melting point=175° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:30][CH3:31])=[CH:4][C:5]([O:28][CH3:29])=[C:6]([NH:8][C:9]([CH2:11][N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[N:14]([CH2:23][C:24]([OH:26])=O)[C:13]2=[O:27])=[O:10])[CH:7]=1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:63][N:64]1[CH2:69][CH2:68][NH:67][CH2:66][CH2:65]1>CN1C(=O)CCC1.CC#N>[Cl:1][C:2]1[C:3]([O:30][CH3:31])=[CH:4][C:5]([O:28][CH3:29])=[C:6]([NH:8][C:9](=[O:10])[CH2:11][N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[N:14]([CH2:23][C:24]([N:67]3[CH2:68][CH2:69][N:64]([CH3:63])[CH2:65][CH2:66]3)=[O:26])[C:13]2=[O:27])[CH:7]=1
Reactant: CN1CCNCC1
Reactant: COc1cc(OC)c(NC(=O)Cn2c(=O)n(CC(=O)O)c(=O)c3ccccc32)cc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: COc1cc(OC)c(NC(=O)Cn2c(=O)n(CC(=O)N3CCN(C)CC3)c(=O)c3ccccc32)cc1Cl
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of {1-[(5-Chloro-2,4-dimethoxy-phenylcarbamoyl)-methyl]-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}-acetic acid (0.515 g, 1.14 mmol) in NMP (8 ml), triethylamine (0.166 ml, 1.26 mmol) is added followed by HATU (0.452 g, 1.26 mmol). The mixture is stirred at RT for 5 minutes and then treated with 1-methylpiperazine (140.3 μL, 1.26 mmol). After 5 minutes at RT the reaction mixture is partitioned between EtOAc (25 ml) and water (25 ml). The phases are separated and the aqueous phase is washed further with EtOAc (2×20 ml). The organic extracts are combined, washed with saturated NaHCO3 (40 ml), brine (40 ml), dried (MgSO4), filtered and concentrated to give a brown oil. The residue is taken up in MeCN (5 ml) and passed through a 10 g Varian pre packed silica cartridge, eluting with MeCN then EtOAc to remove the impurities. The product is eluted off the column with MeOH. The MeOH fractions are combined and concentrated in vacuo and dried to afford the title compound, [M+H]+ 530.
Reaction SMILES: [CH2:1]([NH:4][C@@H:5]1[CH2:14][CH2:13][C:8]2([O:12][CH2:11][CH2:10][O:9]2)[CH2:7][C@H:6]1[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:2][CH3:3].[C:20]([O:24][CH2:25][CH3:26])(=[O:23])[CH:21]=[CH2:22].O>C(O)C>[CH2:25]([O:24][C:20](=[O:23])[CH2:21][CH2:22][N:4]([CH2:1][CH2:2][CH3:3])[C@@H:5]1[CH2:14][CH2:13][C:8]2([O:12][CH2:11][CH2:10][O:9]2)[CH2:7][C@H:6]1[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:26]
Reactant: C=CC(=O)OCC
Reactant: CCCN[C@@H]1CCC2(C[C@H]1C(=O)OCC)OCCO2
Solvent: CCO
Solvent: O
Product: CCCN(CCC(=O)OCC)[C@@H]1CCC2(C[C@H]1C(=O)OCC)OCCO2
Temperature: 25 °C
Reaction time: 60 h
Yield: 57.3 %

Procedure:
Ethyl 8-(propylamino)-trans-1,4-dioxaspiro -[4.5]-decane-7-carboxylate (129.6 g, 0.48 mole) was dissolved in ethanol (1500 ml), then ethyl acrylate (479 g, 4.8 mole) was added. The mixture was refluxed overnight, then additional ethyl acrylate (479 g, 4.8 mole) was added. The mixture was refluxed for 24 hours, at which time a third addition of ethyl acrylate (479 g, 0.48 mole) was made, followed by 60 hours of reflux. The mixture was then cooled to room temperature, poured into water, and the hydrogen ion concentration was adjusted to pH 10. The product was extracted with methylene chloride, dried with sodium sulfate and evaporated to give 177.4 g of crude product. This was purified by HPLC to give 102.1 g of the title product (59.8%).
Reaction SMILES: O.S(=O)(=O)(O)O.[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:13](OC(=O)N)C.[C:19]1([C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[NH:27][C:26]=2[CH2:34][CH2:35][NH2:36])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.S([O-])([O-])(=O)=O.[Na+].[Na+].[OH-].[Na+]>O1CCCC1>[CH3:13][NH:36][CH2:35][CH2:34][C:26]1[NH:27][C:28]2[C:33]([C:25]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[CH:32][CH:31]=[CH:30][CH:29]=2
Reactant: NCCc1[nH]c2ccccc2c1-c1ccccc1
Reactant: CCOC(N)=O
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Solvent: C1CCOC1
Solvent: O
Product: CNCCc1[nH]c2ccccc2c1-c1ccccc1
Reaction time: 0.25 h

Procedure:
A cold solution of 8.6 ml sulphuric acid monohydrate in 85.6 ml tetrahydrofuran is added dropwise to a suspension of 12.1 g lithium aluminium hydride in 243 ml tetrahydrofuran at 0°. The mixture is stirred at 0° for 15 minutes and treated at 0° to 10° dropwise with 24.6 g 3-phenyl-1H-indol-2-ethanamine carbamic acid ethyl ester in 274 ml tetrahydrofuran. The mixture is heated under reflux for 45 minutes, then cooled to 0° and treated dropwise with 43 ml of a saturated sodium sulfate solution. 21 ml of 30% sodium hydroxide solution are further added and the mixture stirred for 1 hour. The mixture is filtered and the residue washed with ether. The filtrate is evaporated under reduced pressure and the residue cristallised from ether/pentane to give the heading compound, m.p. 148°-151°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][N:11]([CH3:14])[CH2:12][CH:13]=2)=[CH:4][CH:3]=1.Cl.[CH2:16]=[O:17].N>S(=O)(=O)(O)O.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]([CH2:16][OH:17])[CH2:12][N:11]([CH3:14])[CH2:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CN1CC=C(c2ccc(F)cc2)CC1
Reactant: C=O
Agent: Cl
Agent: N
Agent: O=S(=O)(O)O
Solvent: O
Product: CN1CC=C(c2ccc(F)cc2)C(CO)C1

Procedure:
4-(4-Fluorophenyl)-1-methyl-1,2,3,6-tetrahydropyridine (50 g) was dissolved in a mixture of 21.6 ml of concentrated sulphuric acid and 50 ml of water. To the solution were added 25 ml of concentrated hydrochloric acid and 22.4 ml of 37% formaldehyde solution. The mixture was refluxed for 5 hours, cooled, and 125 ml of concentrated ammonia were added. The mixture was extracted with 50 ml of toluene. Drying of the toluene solution and distillation gave 38 g of 4-(4-fluorophenyl)-3-hydroxymethyl-1-methyl-1,2,3,6-tetrahydropyridine with b.p. 110°-120° C at 0.1 mm Hg.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7](=[O:14])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH:2]=1.N1CCCC[CH2:16]1.C(O)(=O)C.C=O>CO>[CH2:16]=[C:8]([CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:7]([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)=[O:14]
Reactant: C1CCNCC1
Reactant: CCCCCCC(=O)c1cccnc1
Agent: C=O
Solvent: CO
Solvent: CC(=O)O
Product: C=C(CCCCC)C(=O)c1cccnc1
Yield: 95 %

Procedure:
To 1 g (5.2 mmol) of compound 3, dissolved in 10 ml of MeOH, was added 0.1 ml of piperidine, 0.1 ml of acetic acid and 3 ml of an aqueous formaldehyde solution (37% formaldehyde in water). The mixture was heated to reflux for 48 hour. The mixture was cooled and concentrated in vacuo. Ethyl acetate was added and the organic layer was washed with a 5% NaHCO3 solution, dried (Na2SO4), filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography (diethyl ether/PE 1/1) to give compound 4 as an oil (1.05 g, 95%). 1H-NMR (200 MHz, CDCl3): δ 8.94 (d, J=2 Hz, 1H), 8.76 (d, J=5 Hz, 2 Hz, 1H), 8.05 (dt, J=8 Hz, 2 Hz, 1H), 7.46-7.35 (m, 1H), 5.94 (s, 1H), 5.64 (s, 1H), 2.48 (bt, J=7 Hz, 2H), 1.60-1.25 (m, 6H), 0.99-0.82 (m, 3H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][C:6]([NH2:9])([CH3:8])[CH2:5][CH:4]([CH3:10])[O:3]1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:18][C:19]([N:21]1[CH2:25][C@@H:24]([F:26])[CH2:23][C@H:22]1[C:27]#[N:28])=[O:20].[Na+].[I-]>O1CCCC1>[F:26][C@@H:24]1[CH2:25][N:21]([C:19](=[O:20])[CH2:18][NH:9][C:6]2([CH3:8])[CH2:5][CH:4]([CH3:10])[O:3][CH:2]([CH3:1])[CH2:7]2)[C@H:22]([C:27]#[N:28])[CH2:23]1
Reactant: CC1CC(C)(N)CC(C)O1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC1CC(C)(NCC(=O)N2C[C@@H](F)C[C@H]2C#N)CC(C)O1
Temperature: 25 °C
Reaction time: 65 h

Procedure:
To a mixture of (2,4,6-Trimethyltetrahydro-2H-pyran-4-yl)amine obtained in Example 9-4 (900 mg) and K2CO3 (1.2 g) in tetrahydrofuran (10 mL) cooled on an ice bath, were added (2S,4S)-1-(chloroacetyl)-4-fluoro-2-pyrrolidinecarbonitrile obtained in Example 7-11 (700 mg) and a catalytic amount of NaI. The reaction mixture was warmed to room temperature and stirred for 65 hrs.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH:11]([OH:14])[C:12]#[N:13].B.Cl>C1COCC1>[NH2:13][CH2:12][CH:11]([C:4]1[CH:5]=[C:6]([O:9][CH3:10])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[OH:14]
Reactant: COc1ccc(OC)c(C(O)C#N)c1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccc(OC)c(C(O)CN)c1
Yield: 51.7 %

Procedure:
A solution of 2.84 g (14.7 mmol) of (2, 5 dimethoxyphenyl)-hydroxy acetonitrile in 10 ml of dry THF was stirred and cooled using ice bath as a 1 M solution of borane in THF (90 mL) was added dropwise. After the addition was complete, the mixture was heated at reflux for 20 h. It was cooled and treated with 40 mL of 6N hydrochloric acid and washed with ethyl acetate. The aqueous layer was neutralized with 1N sodium hydroxide and extracted with ethyl acetate and concentrated to afford the desired compound as a white solid 1.5 g (52%). 1H NMR (300MHz, CDCl3) δ 6.97 (d, 1H, J=2.5 Hz), 6.73-6.69(m, 2H), 4.83-4.81(t, 1H, J=4.1 Hz), 3.72(s, 3H), 3.71(s, 3H), 2.89-2.65(m, 2H), 2.16(brs, 2H)
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>C(OCC)(=O)C>[N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH:8][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)CBr
Solvent: CCOC(C)=O
Product: CCOC(=O)CNc1ccc([N+](=O)[O-])cc1
Yield: 64.6 %

Procedure:
4-Nitroaniline (25.0 g, 181 mmol) and ethyl bromoacetate (10.0 ml, 90.5 mmol) were stirred at 80°-90° C. for 20 hours under a nitrogen atmosphere. Ethyl acetate (30 ml) was added to the reaction mixture and the mixture was refluxed under heating for 10 minutes. The obtained solid was collected by filtration and recrystallized from ethanol to give 13.1 g of ethyl (4-nitroanilino)acetate as a yellow solid (64%). This solid (1.00 g, 4.46 mmol) and benzyloxycarbonyl chloride (8 ml) were stirred at 80°-90° C. for 1.5 hours under a nitrogen atmosphere. Toluene (20 ml) was added to the reaction mixture and low boiling matters were distilled away under reduced pressure, which was followed by purification by silica gel column chromatography (n-hexane/ethyl acetate=5/2) to quantitatively give 962 mg of ethyl [4-nitro-N-(benzyloxycarbonyl)anilino]acetate as a yellow oil. Ethanol (100 ml) and water (30 ml) were added to the oil (716 mg, 2.00 mmol) and activated zinc (6.55 g, 100 mmol) and calcium chloride (2.22 g, 20.0 mmol) were added, which was followed by refluxing under heating for 2 hours. The reaction mixture was filtrated and low boiling matters were distilled away from the filtrate under reduced pressure. Water (100 ml) was added to the residue and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, low boiling matters were distilled away from the filtrate under reduced pressure to give 576 mg of ethyl [4-amino-N-(benzyloxycarbonyl)anilino]acetate as a yellow oil (88%).
Reaction SMILES: C(OC[N:9]1[CH:13]=[C:12]([CH2:14][CH2:15][CH2:16][C:17]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][CH2:29][C:30]3[CH:35]=[C:34]([F:36])[CH:33]=[C:32]([Cl:37])[CH:31]=3)=[O:27])[CH2:22][CH2:21]2)=[O:18])[N:11]=[N:10]1)(=O)C(C)(C)C.[OH-].[Na+].Cl>CO>[NH:9]1[CH:13]=[C:12]([CH2:14][CH2:15][CH2:16][C:17]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][CH2:29][C:30]3[CH:35]=[C:34]([F:36])[CH:33]=[C:32]([Cl:37])[CH:31]=3)=[O:27])[CH2:22][CH2:21]2)=[O:18])[N:11]=[N:10]1
Reactant: CC(C)(C)C(=O)OCn1cc(CCCC(=O)NC2CCN(C(=O)OCc3cc(F)cc(Cl)c3)CC2)nn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(CCCc1c[nH]nn1)NC1CCN(C(=O)OCc2cc(F)cc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 3-chloro-5-fluorobenzyl 4-(4-(1-((pivaloyloxy)methyl)-1H-1,2,3-triazol-4-yl)butanamido)piperidine-1-carboxylate (200 mg, 0.372 mmol) in MeOH (1 mL) was added 1M NaOH (0.818 mL, 0.818 mmol). The reaction mixture was allowed to stir at RT for 1 hour. An equivalent of 1M HCl (0.8 ml) was added to neutralise the reaction mixture and the MeOH was removed under reduced pressure. The mixture was diluted with water and extracted with EtOAc. The organic portion was dried over MgSO4, filtered and concentrated under reduced pressure. Purification was carried out by chromatography on silica using 0-100% EtOAc in hexanes and then 0-10% MeOH in EtOAc to afford the title product;
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10][CH2:9][CH2:8][C:7]1=[O:17].BrCCCCN1C2C=CC=CC=2CCCC1=O.[C:35]([C:39]1[N:44]=[C:43]([N:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[CH:42]=[C:41]([C:51]([F:54])([F:53])[F:52])[N:40]=1)([CH3:38])([CH3:37])[CH3:36].[Na+].[Br-].C(N(C(C)C)CC)(C)C>CN1CCCC1=O>[C:35]([C:39]1[N:44]=[C:43]([N:45]2[CH2:46][CH2:47][N:48]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=4[CH2:10][CH2:9][CH2:8][C:7]3=[O:17])[CH2:49][CH2:50]2)[CH:42]=[C:41]([C:51]([F:52])([F:53])[F:54])[N:40]=1)([CH3:38])([CH3:36])[CH3:37]
Reactant: O=C1CCCc2ccccc2N1CCCCCl
Reactant: CC(C)(C)c1nc(N2CCNCC2)cc(C(F)(F)F)n1
Agent: O=C1CCCc2ccccc2N1CCCCBr
Agent: [Br-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(C)(C)c1nc(N2CCN(CCCCN3C(=O)CCCc4ccccc43)CC2)cc(C(F)(F)F)n1
Temperature: 120 °C

Procedure:
A mixture of 1-(4-chlorobutyl)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one and 1-(4-bromobutyl)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (0.40 g), 2-tert-butyl-4-piperazin-1-yl-6-(trifluoromethyl)pyrimidine (1.59 mmol, 0.46 g, prepared as in DE 19735410), NaBr (7.94 mmol, 0.82 g), diisopropylethylamine (15.57 mmol, 2.01 g) and N-methylpyrrolidinone (0.6 ml) was heated at 120° C. for 5 hours. The suspension was then filtered, and the filtrate was evaporated to dryness. The residue was taken up in ethyl acetate and extracted with saturated brine. The organic phase was dried, the desiccant was filtered off, and the solution was evaporated to dryness. The residue was purified by chromatography on silica gel (eluent: dichloromethane/MeOH (0-100%), resulting in 0.58 g of the title compound.
Reaction SMILES: NC1C=CNN=1.O/[CH:8]=[C:9]1\[C:10](=[O:18])[NH:11][C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2.[C:19]([C:23]1[O:27][C:26]([CH3:28])=[C:25]([C:29]2[CH:30]=[C:31]([NH2:35])[N:32]([CH3:34])[N:33]=2)[CH:24]=1)([CH3:22])([CH3:21])[CH3:20]>O1CCCC1>[C:19]([C:23]1[O:27][C:26]([CH3:28])=[C:25]([C:29]2[CH:30]=[C:31]([NH:35][CH:8]=[C:9]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:11][C:10]3=[O:18])[N:32]([CH3:34])[N:33]=2)[CH:24]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: Cc1oc(C(C)(C)C)cc1-c1cc(N)n(C)n1
Reactant: O=C1Nc2ccccc2/C1=C/O
Agent: Nc1cc[nH]n1
Solvent: C1CCOC1
Product: Cc1oc(C(C)(C)C)cc1-c1cc(NC=C2C(=O)Nc3ccccc32)n(C)n1

Procedure:
The named compound is prepared by substituting 5-(5-tert-butyl-2-methyl-furan-3-yl)-2-methyl-2H-pyrazol-3-ylamine for 3-aminopyrazole in the reaction of Example 1. Specifically, E & Z-3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one (0.100 gms.) is reacted with 0.2377 gms. 5-(5-tert-butyl-2-methyl-furan-3-yl)-2-methyl-2H-pyrazol-3-ylamine by refluxing in tetrahydrofuran (2.5 mL).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:10])=[N:4][C:5](Br)=[CH:6][N:7]=1.[CH2:18]([S:20]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)(=[O:22])=[O:21])[CH3:19]>>[NH2:1][C:2]1[C:3]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:10])=[N:4][C:5]([N:26]2[CH2:25][CH2:24][N:23]([S:20]([CH2:18][CH3:19])(=[O:21])=[O:22])[CH2:28][CH2:27]2)=[CH:6][N:7]=1
Reactant: CCS(=O)(=O)N1CCNCC1
Reactant: Nc1ncc(Br)nc1C(=O)Nc1ccccc1
Product: CCS(=O)(=O)N1CCN(c2cnc(N)c(C(=O)Nc3ccccc3)n2)CC1
Yield: 58 %

Procedure:
3-amino-6-bromo-N-phenyl-pyrazine-2-carboxamide (50 mg, 0.1706 mmol) was heated in neat 1-ethylsulfonylpiperazine (excess) at 190° C. for 115 mins in the microwave. The mixture was partitioned between water and EtOAc and the aqueous layer separated. The organic phase was dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 uM, 100A column, gradient 10%-95% B (solvent A: 0.05% TFA in water, solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected and freeze-dried to give the title compound (41.2 mg, 58% Yield).