Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]([CH:20]3[CH2:22][CH2:21]3)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:8][CH:9]=2)[N:4]([CH2:23][CH2:24][CH2:25][O:26][CH3:27])[N:3]=1.[NH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[K+].[K+]>C(O)(C)(C)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[NH:28]([C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]([CH:20]3[CH2:22][CH2:21]3)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:8][CH:9]=2)[N:4]([CH2:23][CH2:24][CH2:25][O:26][CH3:27])[N:3]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: COCCCn1nc(Br)c2ccc(CN(C(=O)OC(C)(C)C)C3CC3)cc21
Reactant: Nc1ccccc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(C)(C)O
Solvent: O
Product: COCCCn1nc(Nc2ccccc2)c2ccc(CN(C(=O)OC(C)(C)C)C3CC3)cc21
Temperature: 100 °C
Reaction time: 24 h
Yield: 78.8 %

Procedure:
A mixture of tert-butyl {[3-bromo-1-(3-methoxypropyl)-1H-indazol-6-yl]methyl}cyclopropylcarbamate (200 mg), aniline (64 mg), 2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl (X-Phos) (8.7 ml), potassium carbonate (88 mg) and tris(dibenzylideneacetone)dipalladium (4.2 mg) in tert-butanol (3 ml) was stirred at 100° C. for 24 hours under argon atmosphere. Water was added to the reaction mixture under ice-cooling and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate and concentrated in vacuo. The resulted residue was purified with a silica gel column chromatography (eluting solvent: n-hexane to n-hexane/ethyl acetate=2/1) to give tert-butyl {[3-anilino-1-(3-methoxypropyl)-1H-indazol-6-yl]methyl}cyclopropylcarbamate (162 mg) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([N:15]2[C:19]3[CH:20]=[CH:21][C:22]([C:24]4[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=4)=[CH:23][C:18]=3[N:17]=[CH:16]2)[CH:12]=[C:11]([NH:30][C:31](=[O:38])[CH2:32][C:33]([O:35]CC)=[O:34])[CH:10]=1.[OH-].[Li+]>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([N:15]2[C:19]3[CH:20]=[CH:21][C:22]([C:24]4[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=4)=[CH:23][C:18]=3[N:17]=[CH:16]2)[CH:12]=[C:11]([NH:30][C:31](=[O:38])[CH2:32][C:33]([OH:35])=[O:34])[CH:10]=1
Reactant: CCOC(=O)CC(=O)Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(-c4cnn(C)c4)ccc32)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cn1cc(-c2ccc3c(c2)ncn3-c2cc(NC(=O)CC(=O)O)cc(-c3ccc(F)cc3F)c2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
To a solution of the compound of Example 223 (20 mg, 0.0388 mmol) in THF (10 ml) was added aqueous solution of lithium hydroxide (4 mg, 0.0776 mmol, 2 eq) and the mixture was stirred at RT for 2 h. The mixture was quenched and extracted as in Example 1(d). The solvent was distilled off to afford the crude residue which was purified by preparative HPLC to give the pure product in 90% yield (25 mg). 1H NMR (400 MHz, DMSO-d6): δ 10.7 (s, 1H), 8.77 (s, 1H), 8.23 (s, 1H), 8.10 (s, 1H), 8.01 (s, 1H), 7.97 (s, 1H), 7.83 (s, 1H), 7.78 (d, 1H), 7.73 (d, 1H), 7.65 (d, 1H), 7.59 (s, 1H), 7.49 (t, 1H), 7.3 (t, 1H), 3.90 (s, 3H), 3.45 (s, 2H); LC-MS (ESI): Calculated mass: 487.15; Observed mass: 488.0 [M+H]+ (rt: 0.638 min).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([CH:14]=[C:15]([NH:17]C(=O)OC(C)(C)C)[N:16]=2)[N:13]=1.[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35]>ClCCl>[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35].[NH2:17][C:15]1[N:16]=[C:11]2[CH:10]=[CH:9][C:8]([O:7][CH2:6][C:5]3[CH:4]=[C:3]([O:2][CH3:1])[C:27]([O:28][CH3:29])=[C:26]([O:30][CH3:31])[CH:25]=3)=[N:13][N:12]2[CH:14]=1
Reactant: COc1cc(COc2ccc3nc(NC(=O)OC(C)(C)C)cn3n2)cc(OC)c1OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(COc2ccc3nc(N)cn3n2)cc(OC)c1OC

Procedure:
t-Butyl N-[6-(3,4,5-trimethoxybenzyloxy)imidazo[1,2-b]pyridazin-2-yl]carbamate (Example 13, 0.43 g, 1 mmol) was dissolved in dichloromethane (2 ml) and treated with trifluoroacetic acid (1 ml). After 2 h at ambient temperature the mixture was evaporated in vacuo to give a brown oil which was triturated with diethyl ether to give the title compound (0.25 g) as a cream solid, m.p. 150°-157°, NMR δH (DMSO) 8.0 (1H, JAB 8.8 Hz, 8H), 7.48 (1H, s, 3H), 7.16 (1H, JAB 8.8 Hz, 7H), 6.44 (2H, s, CH2), 4.5 (brs, NH3), 3.89 (6H, s, OMe) and 3.75 (3H, s, OMe).
Reaction SMILES: CO.[CH3:3][N:4]([CH:6]=O)C.C([O-])([O-])=O.[K+].[K+].Cl[CH2:15][C:16]([N:18]1[CH2:23][CH2:22][CH2:21][C:20]2[N:24]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[N:25]=[CH:26][C:19]1=2)=[O:17]>C1COCC1.CCOC(C)=O>[F:33][C:30]1[CH:31]=[CH:32][C:27]([N:24]2[C:20]3[CH2:21][CH2:22][CH2:23][N:18]([C:16](=[O:17])[CH2:15][N:25]4[C:3]5=[N:4][CH:6]=[CH:23][CH:22]=[C:21]5[CH:20]=[N:24]4)[C:19]=3[CH:26]=[N:25]2)=[CH:28][CH:29]=1
Reactant: O=C(CCl)N1CCCc2c1cnn2-c1ccc(F)cc1
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(Cn1ncc2cccnc21)N1CCCc2c1cnn2-c1ccc(F)cc1
Temperature: 75 °C
Yield: 43 %

Procedure:
The carbinol obtained above (69 mg, 0.4 mmol) was diluted in 1.2 mL of THF and 500 μL of DMF and treated with K2CO3 (111 mg, 0.8 mmol) and 2-chloro-1-(1-(4-fluorophenyl)-6,7-dihydro-1H-pyrazolo[4,3-b]pyridin-4(5H)-yl)ethanone (118 mg, 0.4 mmol). The slurry was heated to 75° C. The reaction slurry was diluted with EtOAc and washed with brine, dried on MgSO4, filtered, and concentrated. The residue was purified by reverse phase HPLC (C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to provide 69 mg of the desired product (43%) as a white solid. 1H NMR (400 MHz, CDCl3, mixture of rotamers) δ 8.37 (s, 0.8H), 7.63 (s, 0.2H), 7.42-7.46 (m, 2H), 7.13-7.19 (m, 2H), 5.14 (s, 0.4H), 5.03 (s, 1.6H), 3.90 (m, 0.4H), 3.87 (m, 1.6H), 2.86 (m, 2H), 2.28 (s, 2.4H), 2.25 (s, 0.6H), 2.05-2.13 (m, 2H), 1.62 (s, 6H); MS: (ES) m/z calculated for C21H24ClFN5O2 [M+H]+ 432.2, found 432.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[N:13][C:12]=12.Cl.Cl[CH2:29][CH2:30][N:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1.C(N(CC)CC)C>CN(C)C=O.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([N:21]3[CH2:22][CH2:23][N:24]([CH2:29][CH2:30][N:31]4[CH2:35][CH2:34][CH2:33][CH2:32]4)[CH2:25][CH2:26]3)=[N:13][C:12]=12
Reactant: Fc1ccccc1-c1nnn2c1nc(N1CCNCC1)c1ccccc12
Reactant: ClCCN1CCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccccc1-c1nnn2c1nc(N1CCN(CCN3CCCC3)CC1)c1ccccc12
Temperature: 80 °C
Reaction time: 18 h
Yield: 47.5 %

Procedure:
3-(2-Fluorophenyl)-5-(piperazin-1-yl)-[1,2,3]triazolo[1,5-α]quinazoline (0.10 g, 0.26 mmol), 1-(2-chloroethyl)pyrrolidine hydrochloride (0.088 g, 0.52 mmol) and triethylamine (0.18 ml, 1.3 mmol) were dissolved in N,N-dimethylformamide (4 ml) and stirred at 80° C. under nitrogen for 18 h. The mixture was cooled, then diluted with water (20 ml) and extracted with CH2Cl2 (2×50 ml). The combined organics were washed with brine (20 ml), dried over MgSO4 and evaporated to give a brown oil. Purification by preparative thin layer chromatography eluting with CH2Cl2:MeOH:NH3(c) (92:8:0.8) gave 3-(2-fluorophenyl)-5-{4-[2-(pyrrolidin-1-yl)ethyl]piperazin-1-yl}-[1,2,3]triazolo[1,5-α]quinazoline as a white solid (0.055 g, 47%). Oxalate salt (EtOH): δH (400 MHz; DMSO) 1.87-1.98 (4H, m), 2.49-2.52 (6H, m, partly obscured by DMSO peak), 2.66-2.78 (6H, m), 3.30-3.35 (2H, m, partly obscured by H20 peak), 3.60-3.72 (2H, m), 7.33-7.39 (2H, m), 7.43-7.49 (1H, m), 7.77 (1H, ddd, J=8, 8 and 1), 8.05-8.13 (2H, m), 8.19 (1H, d, J=8), 8.59 (1H, dd, J=8 and 1); m/z (ES+) 446 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:17]=[CH:16][C:7](/[CH:8]=[C:9]2/[C:10](=[O:15])[NH:11][C:12](=[O:14])[S:13]/2)=[CH:6][CH:5]=1)[CH3:2].[N+:18]([C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1)([O-:20])=[O:19].C(=O)([O-])[O-].[K+].[K+].C(OC1C=CC(/C=C2/C(=O)N(CCC)C(=O)S/2)=CC=1)C>>[CH2:1]([O:3][C:4]1[CH:17]=[CH:16][C:7](/[CH:8]=[C:9]2/[C:10](=[O:15])[N:11]([CH2:25][C:24]3[CH:27]=[CH:28][C:21]([N+:18]([O-:20])=[O:19])=[CH:22][CH:23]=3)[C:12](=[O:14])[S:13]/2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(/C=C2\SC(=O)NC2=O)cc1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: CCCN1C(=O)S/C(=C\c2ccc(OCC)cc2)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOc1ccc(/C=C2\SC(=O)N(Cc3ccc([N+](=O)[O-])cc3)C2=O)cc1

Procedure:
The title compound 28n was prepared from compound 2 (150 mg, 0.60 mmol), p-nitrobenzyl bromide (143 mg, 0.66 mmol) and potassium carbonate (166 mg, 1.20 mmol) in a manner similar to that described for 28d in 99.5% (229 mg) yield as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([O:12][CH3:13])([CH3:11])[C:4](=[O:10])[CH2:5][C:6]([O:8][CH3:9])=[O:7].C(Cl)[Cl:15]>>[Cl:15][CH:5]([C:4](=[O:10])[C:3]([O:2][CH3:1])([O:12][CH3:13])[CH3:11])[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)CC(=O)C(C)(OC)OC
Reactant: ClCCl
Product: COC(=O)C(Cl)C(=O)C(C)(OC)OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
SO2Cl2 (2.2 ml, 27 mmol) was added slowly to a solution of 5.0 g (26 mmol) of methyl 4,4-dimethoxy-3-oxopentanoate in 30 ml CH2Cl2 cooled in an ice water bath. The solution was warmed to room temperature and stirred for 1 h. Solvent was removed and the residue was taken up in EtOAc, which was washed with water and brine. Drying (MgSO4) and removal of solvent gave 6.1 g of an oil. NMR: (CDCl3): 1.5 (s, 3H), 3.25 (2s, 6H), 4.8 (s, 3H), 5.3 (s, 1H).
Reaction SMILES: N[C@H:2]([C:13](O)=O)[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)N[CH:5]=1.CN1[C:21](=O)[CH2:20][CH2:19][CH2:18]1>O>[CH:3]1[C:4]2=[C:12]3[C:7]([C:18]4[C:13]5[C:2](=[CH:3][CH:4]=[CH:5][C:5]2=5)[CH:21]=[CH:20][CH:19]=4)=[CH:8][CH:9]=[CH:10][C:11]3=[CH:13][CH:2]=1
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: CN1CCCC1=O
Solvent: O
Product: c1cc2cccc3c4cccc5cccc(c(c1)c23)c54

Procedure:
5.15 mg Trp were dissolved in a minimal amount of water by addition of a molar amount of NaCO3 and sonication. The Trp solution was added to the PDI-NMP-NHS solution and was stirred over night. The compound was transferred to a separating funnel and the aqueous phase was washed with DCM. Then the aqueous phase was acidified to pH 2 using 0.1 M HCl and extracted to DCM. The organic phase was washed 3 times with KCl brine. The extract was concentrated and precipitated from hexane and from diethyl-ether, the precipitant was filtered and re-dissolved in DCM. NMR and mass were measured.
Reaction SMILES: [N:1]1([C:8]2[N:13]=[CH:12][C:11]([NH:14][C:15]([C:17]3[O:21][C:20]([N:22]4[CH2:27][CH2:26][CH:25]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[CH2:24][CH2:23]4)=[N:19][C:18]=3[C:34]([F:37])([F:36])[F:35])=[O:16])=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.ClC1[O:49][C:50]2[CH:56]=[CH:55][CH:54]=[CH:53][C:51]=2[N:52]=1>CN(C=O)C>[O:49]1[C:50]2[CH:56]=[CH:55][CH:54]=[CH:53][C:51]=2[N:52]=[C:5]1[N:4]1[CH2:3][CH2:2][N:1]([C:8]2[N:13]=[CH:12][C:11]([NH:14][C:15]([C:17]3[O:21][C:20]([N:22]4[CH2:23][CH2:24][CH:25]([C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=5)[CH2:26][CH2:27]4)=[N:19][C:18]=3[C:34]([F:36])([F:35])[F:37])=[O:16])=[CH:10][CH:9]=2)[CH2:7][CH2:6]1
Reactant: O=C(Nc1ccc(N2CCCNCC2)nc1)c1oc(N2CCC(c3ccccc3)CC2)nc1C(F)(F)F
Reactant: Clc1nc2ccccc2o1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(N2CCN(c3nc4ccccc4o3)CC2)nc1)c1oc(N2CCC(c3ccccc3)CC2)nc1C(F)(F)F
Yield: 42 %

Procedure:
Compound C-18 was prepared by the general procedure for compound 84. Compound C-18 (150 mg, 0.30 mmol), Hunigs base (78 mg, 0.10 mL, 0.60 mmol), and 2-chlorobenzoxazole (92 mg, 0.60 mmol) in dry DMF (3 mL) was heated at 100° C. for 24 h. The reaction mixture was cooled and concentrated. Water (15 mL) was added, and the aqueous solution was extracted with CH2Cl2. The combined extracts were dried (MgSO4), filtered, and concentrated. Purification by silica gel chromatography (eluant:10-30% EtOAc—CH2Cl2) gave the product 236 (77 mg, 42% yield) as a beige foam.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17][O:18][C:19](=[O:28])[CH:20]([NH2:27])[CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C.ClCCl>[CH3:17][O:18][C:19](=[O:28])[CH:20]([NH:27][C:10](=[O:12])[CH:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:13]([CH3:16])([CH3:15])[CH3:14])[CH:21]1[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)C(C)(C)C
Reactant: COC(=O)C(N)C1CCCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)C(NC(=O)C(NC(=O)OC(C)(C)C)C(C)(C)C)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-tert.butoxycarbonylamino-3,3-dimethyl butyric acid (500 mg, 2.16 mmol), Amino-cyclohexyl-acetic acid methyl ester (444 mg, 2.59 mmol) and HATU (2 g, 5.40 mmol) in DMF (20 mL) was added diisopropylethylamine (1.88 mL, 10.8 mmol). The solution was stirred for 1 hrs at r.t. and diluted with dichloromethane (40 mL). This solution washed with aqueous. NaHCO3 (sat.) and water (×2), dried and concentrated. The product was >95% pure. M+H+385.4.
Reaction SMILES: [C:1]([CH:4]1[C:8](=[O:9])[CH2:7][CH2:6][C:5]1=[O:10])(=[O:3])[CH3:2].[OH:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH:15]=O.N1CCOCC1.Cl>O.C(O)C>[OH:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH:15]=[CH:2][C:1]([CH:4]1[C:8](=[O:9])[CH2:7][CH2:6][C:5]1=[O:10])=[O:3]
Reactant: COc1ccc(C=O)cc1O
Reactant: CC(=O)C1C(=O)CCC1=O
Agent: Cl
Solvent: O
Solvent: C1COCCN1
Solvent: CCO
Product: COc1ccc(C=CC(=O)C2C(=O)CCC2=O)cc1O

Procedure:
2-Acetyl-1,3-cyclopentanedione (3.83 g.) was treated with 5.0 g. of 3-hydroxy-4-methoxybenzaldehyde in 120 ml. of ethanol in the presence of 5 ml. of morpholine under reflux for 5 hours. After cooling, the reaction mixture was poured into 200 ml. of water containing 8 ml. of conc. hydrochloric acid. Deposited crystals were separated by filtration, washed with water and ethanol successively, and dried. 2-(3-Hydroxy-4-methoxycinnamoyl)-1,3-cyclopentanedione (5.46 g.) was obtained, in the form of yellow crystals which showed mp. 137°-139° C. after recrystallisation from a mixed solvent of ethanol and dioxane.
Reaction SMILES: [CH2:1]([C:3]1([C:8]2[S:9][CH:10]=[C:11]([CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][OH:22])=[C:17]([CH2:23][OH:24])[CH:16]=3)[CH:12]=2)OCC[O:4]1)[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O.O>[OH:24][CH2:23][C:17]1[CH:16]=[C:15]([CH2:14][CH2:13][C:11]2[CH:12]=[C:8]([C:3](=[O:4])[CH2:1][CH3:2])[S:9][CH:10]=2)[CH:20]=[CH:19][C:18]=1[CH2:21][OH:22]
Reactant: CCC1(c2cc(CCc3ccc(CO)c(CO)c3)cs2)OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Product: CCC(=O)c1cc(CCc2ccc(CO)c(CO)c2)cs1

Procedure:
In a manner similar to that of Example 6(g), by reaction of 5.3 g (15 mmol) of (4-{2-[2-(2-ethyl-[1,3]dioxolan-2-yl)-4-thienyl]ethyl}-2-hydroxymethyl-phenyl)methanol with a solution of para-toluenesulphonic acid in an acetone/water mixture, the desired product is obtained in the form of a white powder (m=4 g; Y=86%).
Reaction SMILES: [CH3:1][CH:2]1[CH:27]2[O:28][C:26]2([CH3:29])[CH:25]([OH:30])[CH2:24][C:22](=[O:23])[N:21]([CH3:31])[C:14]2=[C:15]([Cl:20])[C:16]([O:18][CH3:19])=[CH:17][C:12](=[CH:13]2)[CH2:11][C:10]([CH3:32])=[CH:9][CH:8]=[CH:7][CH:6]([O:33][CH3:34])[C:5]2([OH:39])[NH:35][C:36]([O:38][CH:3]1[CH2:4]2)=[O:37].[CH:40]1([C:46]([OH:48])=[O:47])[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1.C1CCC(N=C=NC2CCCCC2)CC1.C(OCC)C>ClCCl.C(OCC)(=O)C>[CH3:1][CH:2]1[CH:27]2[O:28][C:26]2([CH3:29])[CH:25]([OH:30])[CH2:24][C:22](=[O:23])[N:21]([CH3:31])[C:14]2=[C:15]([Cl:20])[C:16]([O:18][CH3:19])=[CH:17][C:12](=[CH:13]2)[CH2:11][C:10]([CH3:32])=[CH:9][CH:8]=[CH:7][CH:6]([O:33][CH3:34])[C:5]2([OH:39])[NH:35][C:36]([O:38][CH:3]1[CH2:4]2)=[O:37].[CH2:42]1[CH2:43][CH2:44][CH2:45][CH:40]([C:46]([O-:48])=[O:47])[CH2:41]1
Reactant: O=C(O)C1CCCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: COc1cc2cc(c1Cl)N(C)C(=O)CC(O)C1(C)OC1C(C)C1CC(O)(NC(=O)O1)C(OC)/C=C/C=C(\C)C2
Agent: COc1cc2cc(c1Cl)N(C)C(=O)CC(O)C1(C)OC1C(C)C1CC(O)(NC(=O)O1)C(OC)C=CC=C(C)C2
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCOCC
Product: O=C([O-])C1CCCCC1
Temperature: 25 °C

Procedure:
To a mixed solution of maytansinol (103.2 mg. 0.183 m mole) and cyclohexanecarboxylic acid (140 mg, 1.094 m moles) in 5 ml of dry dichloromethane was added DCC (267 mg, 1.296 m moles), and after stirring at room temperature for a short while until insolubles began to separate out, DMAP (50.8 mg, 0.416 m mole) was added. The mixture was stirred at room temperature overnight. Then, the insolubles were filtered off, the filtrate washed with 0.5 N-HCl(ca. 10 ml) and saturated aqueous sodium hydrogen carbonate (ca. 10 ml) in that order, and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was chromatographed on a column of silica gel (75 g.). Elution was carried out with ethyl acetate, the eluate being collected in 16 g. fractions, and fractions No.14 through No.30 were pooled and concentrated to remove the solvent, whereupon 59 mg of crude product was obtained. This crude product was dissolved in ethyl acetate, followed by addition of diethyl ether. By the above procedure there was obtained 24.3 mg of maytansinol 3-cyclohexanecarboxylate as crystals melting at 202°-206° C.(decomp.).
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][C:9]1[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]2[O:17][CH2:16]2)=[CH:11][CH:10]=1)([CH3:3])[CH3:2].[NH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH2:31][CH2:32][C:33](=[O:36])[NH:34][N:35]=2)=[CH:26][CH:25]=1>>[CH:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][C:9]1[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]([OH:17])[CH2:16][NH:20][CH2:21][CH2:22][O:23][C:24]2[CH:25]=[CH:26][C:27]([C:30]3[CH2:31][CH2:32][C:33](=[O:36])[NH:34][N:35]=3)=[CH:28][CH:29]=2)=[CH:11][CH:10]=1)([CH3:3])[CH3:2]
Reactant: CC(C)OCCOCc1ccc(OCC2CO2)cc1
Reactant: NCCOc1ccc(C2=NNC(=O)CC2)cc1
Product: CC(C)OCCOCc1ccc(OCC(O)CNCCOc2ccc(C3=NNC(=O)CC3)cc2)cc1

Procedure:
Prepared analogously to Example 1 from 1-[4-((2-isopropoxyethoxy)methyl)phenoxy]-2,3-epoxypropane and 6-[4-(2-aminoethoxy)-phenyl]-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: [C:1](=[O:4])([O-:3])O.[Na+].[CH2:6]([O:8][C:9]([C:11]1([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)[CH2:15][CH2:14][NH:13][CH2:12]1)=[O:10])[CH3:7]>ClCCl>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[O:3][C:1]([N:13]1[CH2:14][CH2:15][C:11]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=3)=[CH:20][CH:19]=2)([C:9]([O:8][CH2:6][CH3:7])=[O:10])[CH2:12]1)=[O:4]
Reactant: O=C([O-])O
Reactant: CCOC(=O)C1(COc2ccc(-c3ccc(F)cc3)cc2)CCNC1
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)C1(COc2ccc(-c3ccc(F)cc3)cc2)CCN(C(=O)Oc2ccccc2OC)C1
Temperature: 0 °C
Reaction time: 16 h
Yield: 146.7 %

Procedure:
Sodium hydrogen carbonate (244 mg, 2.9 mmol) was added to a stirred solution of 3-(4′-fluoro-biphenyl-4-yloxymethyl)-pyrrolidine-3-carboxylic acid ethyl ester (see Preparation 65) (200 mg, 0.58 mmol) in dichloromethane (10 mL) and the resulting mixture cooled to 0° C. 2-Methoxy phenyl chloroformate (0.09 mL, 0.64 mmol) was added and the reaction mixture stirred at room temperature for 16 hours. The mixture was partitioned between water (25 mL) and dichloromethane (25 mL). The organic layer was separated, washed brine (25 mL), dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with 15% ethyl acetate in hexane to afford the title compound as a white solid (210 mg, 74%).
Reaction SMILES: [N:1]1[S:2][N:3]=[C:4]2[CH:9]=[C:8]([O:10][C:11]3[N:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13]([OH:15])=O)[CH:7]=[CH:6][C:5]=12.[C:20]([O:24][C:25](=[O:38])[CH:26]([O:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][NH2:36])=[C:31]([F:37])[CH:30]=1)[CH3:27])([CH3:23])([CH3:22])[CH3:21].O1C2C=CC(OC3N=CC=CC=3C(O)=O)=CC=2OC1.COC(=O)COC1C=CC(CN)=C(F)C=1>>[C:20]([O:24][C:25](=[O:38])[CH:26]([O:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][NH:36][C:13]([C:12]2[C:11]([O:10][C:8]3[CH:7]=[CH:6][C:5]4=[N:1][S:2][N:3]=[C:4]4[CH:9]=3)=[N:19][CH:18]=[CH:17][CH:16]=2)=[O:15])=[C:31]([F:37])[CH:30]=1)[CH3:27])([CH3:21])([CH3:22])[CH3:23]
Reactant: O=C(O)c1cccnc1Oc1ccc2nsnc2c1
Reactant: CC(Oc1ccc(CN)c(F)c1)C(=O)OC(C)(C)C
Agent: COC(=O)COc1ccc(CN)c(F)c1
Agent: O=C(O)c1cccnc1Oc1ccc2c(c1)OCO2
Product: CC(Oc1ccc(CNC(=O)c2cccnc2Oc2ccc3nsnc3c2)c(F)c1)C(=O)OC(C)(C)C

Procedure:
The compound of Formula (5.0.27) was prepared in a manner analogous to that described in Preparation 20, substituting 2-(benzo[2,1,3]thiadiazol-5-yloxy)-nicotinic acid and (+)-2-(4-aminomethyl-3-fluoro-phenoxy)-propionic acid tert-butyl ester for the corresponding 2-(benzo-[1,3]-dioxol-5-yloxy)-nicotinic acid and (4-aminomethyl-3-fluoro-phenoxy)-acetic acid methyl ester materials, respectively.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C@H:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[NH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.Br[CH2:22][C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([F:31])[CH:24]=1.CCN(C(C)C)C(C)C>CC#N>[CH3:1][C:2]1[C:3]([C@H:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[N:9]2[CH2:22][C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([F:31])[CH:24]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(CBr)cc1F
Reactant: Cc1cccnc1[C@@H]1CCC[C@H](c2ncccc2C)N1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1cccnc1[C@H]1CCC[C@@H](c2ncccc2C)N1Cc1ccc(C#N)c(F)c1
Temperature: 60 °C
Reaction time: 16 h
Yield: 99.9 %

Procedure:
A mixture of (2′R,6′S)-3,3″-dimethyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,2′;6′,2″]terpyridine (0.267 g, 1.00 mmol), 4-bromomethyl-2-fluoro-benzonitrile (0.321 g, 0.1.50 mmol), DIPEA (0.259 g, 2.00 mmol) and KI (0.017 g, 0.10 mmol) in dry CH3CN (10 mL) was stirred at 60° C. for 16 h. After that period of time the CH3CN was removed by evaporation under vacuum, and saturated aqueous NaHCO3 (20 mL) was added. The aqueous mixture was extracted with CH2Cl2 (3×30 mL, and the extract was dried over Na2SO4. After filtration the solvent was removed by evaporation under vacuum, and the residue was purified on a silica gel column (1000:30:1, CH2Cl2/CH3OH/NH4OH), affording 4-((2′R,6′S)-3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-ylmethyl)-2-fluoro-benzonitrile as a white foam (0.400 g, 100%). 1H NMR (CDCl3) δ 1.65-1.80 (m, 3H), 2.09-2.14 (m, 1H), 2.20-2.38 (m, 2H), 2.44 (s, 6H), 3.58 (s, 2H), 4.16 (s, 1H), 4.20 (s, 1H), 6.37-6.43 (m, 2H), 6.93-7.03 (m, 3H), 7.23 (d, 2H, J=7.5 Hz), 8.35 (dd, 2H, J=0.9, 4.5 Hz).