Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1.C1(C)C=CC=CC=1.[N+:26]([C:29]1[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=1[CH2:31]Br)([O-:28])=[O:27]>O1CCCC1>[CH3:1][O:2][C:3](=[O:18])[CH:4]([CH:5]1[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])[CH2:9][CH2:10]1)[CH2:31][C:30]1[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=1[N+:26]([O-:28])=[O:27]
Reactant: COC(=O)CC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=[N+]([O-])c1ccccc1CBr
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)C(Cc1ccccc1[N+](=O)[O-])C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 41 %

Procedure:
tert-Butyl 4-(2-methoxy-2-oxoethyl)piperidine-1-carboxylate (240 mg, 0.93 mmol) was dissolved in tetrahydrofuran (7 mL). Mixture was cooled to −78° C. A 0.5 M solution of potassium bistrimethylsilyl)amide in toluene (2.2 mL, 1.1 mmol) was added to the mixture drop-wise. Reaction stirred at −78° C. for 20 minutes. A solution of 2-nitrobenzylbromide (240 mg, 1.1 mmol) in tetrahydrofuran (2 mL) was added to the reaction mixture drop-wise. Reaction stirred at −78° C. for 40 minutes. Dry ice bath was removed and the reaction mixture was allowed to warm to room temperature over 30 minutes. Reaction was quenched with aqueous ammonium chloride. Mixture was extracted with ethyl acetate (2×20 mL). Combined extracts were dried (magnesium sulfate), filtered and concentrated in vacuo. Silica gel chromatography afforded the title compound as yellow oil in 41% yield. MS m/e (M−C4H8+H)+=337.3.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[C:5]([C:13]([F:16])([F:15])[F:14])[C:4]=1[CH2:17]Br.C(O)C.[Na].CC1C=CC(S([NH2:33])(=O)=O)=CC=1>C(O)(=O)C.CO>[F:14][C:13]([F:16])([F:15])[C:5]1[C:6]([C:9]([F:12])([F:11])[F:10])=[CH:7][CH:8]=[C:3]2[C:4]=1[CH2:17][NH:33][CH2:2]2
Reactant: FC(F)(F)c1ccc(CBr)c(CBr)c1C(F)(F)F
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Agent: [Na]
Solvent: CC(=O)O
Solvent: CCO
Solvent: CO
Product: FC(F)(F)c1ccc2c(c1C(F)(F)F)CNC2

Procedure:
1,2-Bis(bromomethyl)-3,4-bis(trifluoromethyl)benzene (120 g., 0.3 mol.) in 450 ml. of ethanol is refluxed and treated with a solution of the sodium salt of p-methyl-benzene sulfonamide prepared by dissolving sodium (15.2 g., 0.66 mol.) in a mixture of p-methylbenzenesulfonamide (51.2 g., 0.3 mol.) in 650 ml. of methanol. The mixture is refluxed for two hours, cooled, neutralized with acetic acid and filtered to give 4,5-bis(trifluoromethyl)-2,3-di-hydro-1H-isoindole.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH2:3][CH2:4][O:5][C:6]1[CH:19]=[CH:18][C:9]([CH:10](O)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][CH:7]=1.[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[C:22]1[C:30]([O:32][CH2:33][CH3:34])=[O:31]>>[CH3:1][N:2]([CH3:20])[CH2:3][CH2:4][O:5][C:6]1[CH:19]=[CH:18][C:9]([CH:10]([C:23]2[C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[NH:21][C:22]=2[C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][CH:7]=1
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Reactant: CN(C)CCOc1ccc(C(O)c2ccccc2)cc1
Product: CCOC(=O)c1[nH]c2ccccc2c1C(c1ccccc1)c1ccc(OCCN(C)C)cc1
Yield: 86.2 %

Procedure:
Substantially the same procedure as in Reference Example 5 was repeated using 4-(2-dimethylaminoethoxy)benzhydrol (14.78 g, 54.5 mmol) and ethyl indole-2-carboxylate (11.3 g, 59.9 mmol) to give 20.8 g (yield: 86%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH2:7][C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:5][C:4](=[O:20])[CH:3]=1.C1(C)C=CC([S:27](=S)(O)=O)=CC=1.[CH3:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.CCN(CC)CC.C([O-])(O)=O.[Na+]>C(OCC)C.C(O)C>[C:34]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[CH2:32][S:27][C:3]1[C:4](=[O:20])[O:5][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:7][C:2]=1[OH:1]
Reactant: Cc1ccccc1-c1ccccc1
Reactant: Cc1ccc(S(=O)(O)=S)cc1
Reactant: O=C1C=C(O)CC(c2ccccc2)(c2ccccc2)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: O=C1OC(c2ccccc2)(c2ccccc2)CC(O)=C1SCc1ccccc1-c1ccccc1
Temperature: 40 °C

Procedure:
The title compound was prepared as described in General Method 7 using the following: 5,6-dihydro-4-hydroxy-6,6-diphenyl-2H-pyran-2-one (0.250 g, 0.94 mmol), (2-methylbiphenyl)-p-toluenethiosulfonate (0.389 g, 1.1 mmol), Et3N (0.26 mL, 1.9 mmol), absolute ethanol (5.0 mL), NaHCO3 (0.5 g). The mixture was heated to 40° C. for 16 h, then diluted with diethyl ether (100 mL) and washed with H2O. The solvent was then removed in vacuo and the residue submitted to column chromatography (SiO2, 100% CH2Cl2 to 2% methanol in CH2Cl2) to provide a thick oil (0.286 g). 1H NMR (400 MHz, DMSO-d6) δ 11.770 (bs, 1 H), 7.434-7.148 (m, 18 H), 6.969 (d, 1 H, J=7 Hz), 3.595 (s, 2 H), 3.407 (s, 2 H).
Reaction SMILES: [C:1]1(C)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1[N:13]([CH2:30][C:31]([F:34])([F:33])[F:32])C(=O)C1C=C(C(F)(F)F)N=C(C(F)(F)F)C=1.[F:36]C1C=CC=CC=1B(O)O>CCCCCCC.CCOC(C)=O>[F:36][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1[NH:13][CH2:30][C:31]([F:34])([F:33])[F:32]
Reactant: Cc1ccccc1-c1ccncc1N(CC(F)(F)F)C(=O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1
Reactant: OB(O)c1ccccc1F
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: Fc1ccccc1-c1ccncc1NCC(F)(F)F

Procedure:
The title compound was prepared from (4-iodo-pyridin-3-yl)-(2,2,2-trifluoro-ethyl)-amine (example 150, intermediate b) and 2-fluorophenylboronic acid (CAS RN 1193-03-9) and using a gradient of n-heptane:EtOAc (100:0 to 50:50) for the chromatographic purification. Light brown solid (85%). MS (ESI): m/z=271.09 [M+H]+.
Reaction SMILES: [CH3:1][NH2:2].ClC[O:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][O:17][C:18]([O:20]CCl)=[O:19])[N:11]=1)=[O:7]>>[CH3:1][NH:2][C:18](=[O:19])[OH:20].[CH3:1][NH:2][C:6](=[O:5])[OH:7].[OH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][OH:17])[N:11]=1
Reactant: O=C(OCCl)OCc1cccc(COC(=O)OCCl)n1
Reactant: CN
Product: CNC(=O)O
Product: OCc1cccc(CO)n1
Temperature: 10 °C
Yield: 83.8 %

Procedure:
3.15 ml of methanolic methylamine solution (containing 33.6% by weight, i.e. 0.024 moles, of methylamine) are added to a solution of 1.3 g (0.004 moles) of 2,6-bis(chloromethyloxy-carbonyloxymethyl)pyridine (prepared as described in Example 1) at about 0° C. under cooling at such a rate that the temperature is maintained at 10° C. or lower. A crystalline precipitate is separated. After completing the addition, 5 ml of water are added to the mixture which is then cooled to 2° to 5° C. The precipitate is separated by filtration and dried to give 0.97 g of the title compound, m.p.: 132°-135° C. The yield is 97% as calculated for 2,6-bis(hydroxymethyl)pyridine. The 2,6-bis(hydroxymethyl)pyridine bis(N-methylcarbamate) content of the thus-obtained product is 98% based on the spectrophotometric determination.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[C:16]([O:19][CH2:20][C:21]2[CH:25]=[CH:24][O:23][CH:22]=2)[CH:15]=[CH:14][CH:13]=3)=[O:9])[CH2:3][CH2:2]1.O[C@H:27](C)[CH2:28][N:29]1[CH2:34][CH2:33][C@@H:32]([O:35]C(=O)C(C)(C)C)[C@H:31]([CH3:42])[CH2:30]1.[C:44](OC(=O)NC1CCN(C[C@@H](N2CCC(O)CC2)C)CC1)(C)(C)C>>[OH:35][C@@H:32]1[CH2:33][CH2:34][N:29]([C@@H:28]([CH3:27])[CH2:44][N:1]2[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]3[NH:11][C:12]4[C:17]([CH:18]=3)=[C:16]([O:19][CH2:20][C:21]3[CH:25]=[CH:24][O:23][CH:22]=3)[CH:15]=[CH:14][CH:13]=4)=[O:9])[CH2:3][CH2:2]2)[CH2:30][C@H:31]1[CH3:42]
Reactant: C[C@@H]1CN(C[C@@H](C)O)CC[C@H]1OC(=O)C(C)(C)C
Reactant: O=C(NC1CCNCC1)c1cc2c(OCc3ccoc3)cccc2[nH]1
Reactant: C[C@@H](CN1CCC(NC(=O)OC(C)(C)C)CC1)N1CCC(O)CC1
Product: C[C@@H]1CN([C@@H](C)CN2CCC(NC(=O)c3cc4c(OCc5ccoc5)cccc4[nH]3)CC2)CC[C@H]1O

Procedure:
This compound is synthesized from 4-(furan-3-ylmethoxy)-1H-indole-2-carboxylic acid piperidin-4-ylamide, 165 (see example 133) and 2,2-dimethyl-propionic acid (3R,4R)-1-((R)-2-hydroxy-propyl)-3-methyl-piperidin-4-yl ester, 164 (preparation see example 130) analogously to the method described in example 127, followed by pivaloyl cleavage as described for amine 55.
Reaction SMILES: [OH:1][C@H:2]1[CH2:16][CH:15]=[C:14]2[C@:4]([CH3:17])([CH2:5][C:6]3[C:7](=[CH:13]2)[O:8][C:9](=[O:12])[C:10]=3[CH3:11])[C@H:3]1[CH3:18].[C:19]1([C:24](Cl)=[O:25])[S:23][CH:22]=[CH:21][CH:20]=1>>[C:19]1([C:24]([O:1][C@H:2]2[CH2:16][CH:15]=[C:14]3[C@:4]([CH3:17])([CH2:5][C:6]4[C:7](=[CH:13]3)[O:8][C:9](=[O:12])[C:10]=4[CH3:11])[C@H:3]2[CH3:18])=[O:25])[S:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC1=C2C[C@@]3(C)C(=CC[C@H](O)[C@@H]3C)C=C2OC1=O
Reactant: O=C(Cl)c1cccs1
Product: CC1=C2C[C@@]3(C)C(=CC[C@H](OC(=O)c4cccs4)[C@@H]3C)C=C2OC1=O

Procedure:
The title compound was prepared in the same manner as in Example B2, except that the compound prepared in Example B1 was reacted with 2-thenoyl chloride.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)([O-:3])=[O:2].[O:16]1[CH2:20][CH2:19][C:18](=O)[CH2:17]1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CC#N>[N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][N:13]([CH:18]2[CH2:19][CH2:20][O:16][CH2:17]2)[CH2:12][CH2:11]1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cnccc1N1CCNCC1
Reactant: O=C1CCOC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: O=[N+]([O-])c1cnccc1N1CCN(C2CCOC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A round-bottomed flask was charged with 1-(3-nitro-4-pyridyl)piperazine (prepared according to methods similar to the one depicted in Step 1 of Preparation N-1), dihydrofuran-3(2H)-one (98 mg, 1.13 mmol) and acetic acid (129 uL, 2.27 mmol) in MeCN (4 mL). Na(OAc)3BH (482.4 mg, 2.27 mmol) was added and the reaction mixture was stirred at RT for 1 h. The reaction mixture was partitioned between EtOAC and an aqueous saturated solution of Na2CO3. The organic extracts were dried over MgSO4, and concentrated under reduced pressure to give 1-(3-nitropyridin-4-yl)-4-(tetrahydrofuran-3-yl)piperazine as a yellow solid. MS (ES+) 279.1.
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[Cl:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:31][C:32]1[CH:37]=[C:36]([N:11]2[C:12]3[C:17](=[CH:16][C:15]([C:19]([N:21]4[CH2:26][CH2:25][CH:24]([N:27]([CH3:28])[CH3:29])[CH2:23][CH2:22]4)=[O:20])=[CH:14][CH:13]=3)[CH:18]=[C:10]2[C:8]([N:5]2[CH2:6][CH2:7][C:2]([F:1])([F:30])[CH2:3][CH2:4]2)=[O:9])[CH:35]=[CH:34][CH:33]=1
Reactant: CN(C)C1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Reactant: OB(O)c1cccc(Cl)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(C)C1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3-c2cccc(Cl)c2)CC1
Yield: 28 %

Procedure:
The title compound was synthesized in analogy to example 66, from (4,4-difluoro-piperidin-1-yl)-[5-(4-dimethylamino-piperidine-1-carbonyl)-1H-indol-2-yl]-methanone, 3-chlorophenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as an off-white foam (28%).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:18][C:19]([CH3:22])=[N:20][N:21]=2)=[CH:13][C:12]=1[C:23]1[CH:28]=[CH:27][C:26]([C:29]([OH:31])=O)=[CH:25][CH:24]=1.[CH3:32][N:33]([CH3:38])[CH2:34][CH2:35][CH2:36][NH2:37].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[CH3:32][N:33]([CH2:34][CH2:35][CH2:36][NH:37][C:29]([C:26]1[CH:25]=[CH:24][C:23]([C:12]2[CH:13]=[C:14]([C:17]3[O:18][C:19]([CH3:22])=[N:20][N:21]=3)[CH:15]=[CH:16][C:11]=2[CH3:10])=[CH:28][CH:27]=1)=[O:31])[CH3:38]
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Reactant: CN(C)CCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)NCCCN(C)C)cc3)c2)o1
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.9 %

Procedure:
DIPEA (76 μl, 0.6 mmol) was added to a solution of 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid (59 mg, 0.2 mmol), 3-dimethylaminopropylamine (20 mg, 0.2 mmol), HBTU (91 mg, 0.24 mmol) and HOBT (27 mg, 0.2 mmol) in DMF (0.5 ml). The reaction was stirred at room temperature for 16 h. The DMF was evaporated under vacuum and the residue partitioned between DCM (5 ml) and water (5 ml). The organic phase was absorbed onto a silica flash column and eluted with DCM/ethanol/ammonia (80:8:1). The product fractions were concentrated under vacuum to give N-[(dimethylamino)propyl]-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide (37 mg, 49%).
Reaction SMILES: OCC[N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][CH:11]=2)[CH:6]=[CH:5]1.C(OC(=O)C)(=O)C.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.C1COCC1>[CH2:14]([O:13][C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][CH:10]=1)[NH:4][CH:5]=[CH:6]2)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: OCCn1ccc2cc(OCc3ccccc3)ccc21
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: c1ccc(COc2ccc3[nH]ccc3c2)cc1
Yield: 138.3 %

Procedure:
Crude N-(2-hydroxyethyl)-5-benzyloxyindole (11.09 g, 42.1 mmol), acetic anhydride (4.36 mL, 46.3 mmol), triethylamine (6.50 mL,46.3 mmol), and DMAP (100 mg) were stirred together in THF for 1 hour before standard aqueous workup provided N-2-acetoxyethyl)-5-benzyloxyindole as a clear oil (13.0 g, 99%). 1H NMR (500 MHz, CDCl3) δ 7.51 (d, J=8.1 Hz, 2H), 7.42 (t, J=8.1 Hz, 2H), 7.35 (s, 1H), 7.27 (d, J=8.9 Hz, 1H), 7.21 (d, J=2.4 Hz, 1H), 7.09 (d, J=3.1 Hz, 1H), 7.01 (dd, J=2.4, 8.1 Hz, 1H), 6.47 (dd, J=0.8, 3.1 Hz, 1H),5.14(s,2H), 4.37 (t, J=5.0 Hz 2H), 4.31(t, J=5.0 Hz, 2H), 2.02 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([CH:7]=[CH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[NH:4][N:3]=1.[OH-].[Na+].[CH3:18][N:19]=[C:20]=[S:21].Cl>O1CCCC1>[NH2:1][C:2]1[N:3]([C:20]([NH:19][CH3:18])=[S:21])[N:4]=[C:5]([CH:7]=[CH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[N:6]=1
Reactant: Nc1n[nH]c(C=Cc2ccc(Cl)cc2)n1
Reactant: CN=C=S
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CNC(=S)n1nc(C=Cc2ccc(Cl)cc2)nc1N
Yield: 69 %

Procedure:
The synthesis method of Example 7-(3) was applied. The compound (4.00 g) obtained in (2) above, 0.67N sodium hydroxide (30 ml), methyl isothiocyanate (1.52 g) and tetrahydrofuran (30 ml) were used as reagents and the mixture was reacted at room temperature for 4 hours. After the reaction, the mixture was neutralized with 2N hydrochloric acid. The resulting substance was collected by filtration and washed with water and hexane-ethyl acetate to give 3.67 g of white crystals (yield 69%).
Reaction SMILES: N[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5](SC2C=CC(S(O)(=O)=O)=C(N)C=2)=[CH:4][C:3]=1C(O)=O.N1C(Cl)=NC(Cl)=NC=1Cl.[Cl-].[Na+]>>[CH:9]1[C:8]2[C:7](=[O:17])[C:6]3[C:15](=[CH:2][CH:3]=[CH:4][CH:5]=3)[C:14](=[O:16])[C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: Nc1cc(Sc2cc(C(=O)O)c(N)c3c2C(=O)c2ccccc2C3=O)ccc1S(=O)(=O)O
Agent: Clc1nc(Cl)nc(Cl)n1
Agent: [Cl-]
Agent: [Na+]
Product: O=C1c2ccccc2C(=O)c2ccccc21

Procedure:
1-Amino-2-carboxy-4-(3'-amino-4'-sulfophenylthio)anthraquinone (9.4 parts) and cyanuric chloride (3.7 parts) were subjected to condensation reaction in an aqueous medium in a usual manner, followed by condensation reaction with 1-aminobenzene-3-β-sulfatoethylsulfone (5.6 parts) at 20° to 40° C. under a weak acid condition. Thereafter, salting out of the reaction mixture with sodium chloride gave an anthraquinone compound of the following formula (free acid form). ##STR270##
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:12][C:13](=[O:19])[C@H:14]([CH:16]([CH3:18])[CH3:17])[NH2:15])([CH3:11])([CH3:10])[CH3:9].[CH3:20][O:21][CH2:22][CH2:23][O:24][CH2:25][C:26](O)=[O:27].C(OP(C#N)(=O)OCC)C>CN(C=O)C.C(Cl)Cl>[C:8]([O:12][C:13](=[O:19])[C@H:14]([CH:16]([CH3:17])[CH3:18])[NH:15][C:26](=[O:27])[CH2:25][O:24][CH2:23][CH2:22][O:21][CH3:20])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)[C@H](N)C(=O)OC(C)(C)C
Reactant: COCCOCC(=O)O
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COCCOCC(=O)N[C@H](C(=O)OC(C)(C)C)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.2 %

Procedure:
At 0°, 6.4 ml (45.7 mmol) of triethylamine are added to a solution of 5 g (23.9 mmol) of (L)-valine tert-butyl ester, 2.91 g (21.7 mmol) of 2-(methoxyethoxy)-acetic acid and 3.55 g (21.7 mmol) of cyanophosphonic acid diethyl ester in 30 ml of DMF and the mixture is then stirred overnight at RT. The reaction mixture is diluted with methylene chloride, washed in succession with 10% citric acid, saturated sodium hydrogen carbonate solution and saturated sodium chloride solution and, after concentration by evaporation of the organic phase, yields 5.1 g of N-methoxyethoxyacetyl-(L)-valine tert-butyl ester, which is stirred for 1 h at RT in 22 ml of a (1:1) mixture of methylene chloride and TFA. Concentration by evaporation of the reaction solution yields the title compound in the form of a colourless oil. 1H-NMR (200 MHz, CDCl3): 10.0 (s, broad, 1H), 7.62 d, broad, 1H), 4.55 (m, 1H), 4.10 (s, 2H), 3.70 (m, 2H), 3.58 (m, 2H), 3.40 (s, 3H), 2.28 (m, 1H), 0.98 (d, J=7 Hz, 3H), 0.95 (d, J=7 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][C:13](=O)[CH:12]([O:17][CH3:18])[CH2:11]2)=[CH:4][CH:3]=1.C([NH2:28])C1C=CC=CC=1.S1C=CC=C1>C1COCC1.[Pd]>[F:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([NH2:28])[CH:12]([O:17][CH3:18])[CH2:11]2)=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: COC1CN(CCCOc2ccc(F)cc2)CCC1=O
Agent: [Pd]
Solvent: c1ccsc1
Solvent: C1CCOC1
Product: COC1CN(CCCOc2ccc(F)cc2)CCC1N

Procedure:
A mixture of 1-[3-(4-fluorophenoxy)-propyl]-3-methoxy-4-piperidinone (140 mg, intermediate 1), benzylamine (61 mg), Pd 10% on charcoal (100 mg) and a 0.02% solution of thiophene in THF was reacted under hydrogen gas for 3 hours at 50° C. The catalyst was filtered off and fresh palladium 10% on charcoal (100 mg) was added. Debenzylation of the formed intermediate took place under hydrogen atmosphere for 18 hours at 50° C. The reaction mixture was filtered and evaporated under a gentle stream of nitrogen to yield 1-[3-(4-fluorophenoxy)-propyl]-3-methoxy-4-piperidinamine (compound I-1) having a cis/trans ratio of about 93/7.
Reaction SMILES: [CH3:1][C@H:2]1[C@@:41]2([OH:43])[O:42][C@H:5]([CH2:6][C@H:7]([O:64][CH3:65])[C:8]([CH3:63])=[CH:9][CH:10]=[CH:11][CH:12]=[CH:13][C@@H:14]([CH3:62])[CH2:15][C@@H:16]([CH3:61])[C:17]([C@H:19]([O:59][CH3:60])[C@H:20]([OH:58])[C:21]([CH3:57])=[CH:22][C@@H:23]([CH3:56])[C:24]([CH2:26][C@@H:27]([C@@H:44]([CH2:46][C@H:47]3[CH2:52][C@@H:51]([O:53][CH3:54])[C@H:50]([OH:55])[CH2:49][CH2:48]3)[CH3:45])[O:28][C:29]([C@H:31]3[N:36]([C:37]([C:39]2=[O:40])=[O:38])[CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:30])=[O:25])=[O:18])[CH2:4][CH2:3]1.[OH:66][CH2:67][C:68]([CH2:73][OH:74])([CH3:72])[C:69](O)=[O:70]>>[CH3:1][C@H:2]1[C@@:41]2([OH:43])[O:42][C@H:5]([CH2:6][C@H:7]([O:64][CH3:65])[C:8]([CH3:63])=[CH:9][CH:10]=[CH:11][CH:12]=[CH:13][C@@H:14]([CH3:62])[CH2:15][C@@H:16]([CH3:61])[C:17]([C@H:19]([O:59][CH3:60])[C@H:20]([OH:58])[C:21]([CH3:57])=[CH:22][C@@H:23]([CH3:56])[C:24]([CH2:26][C@@H:27]([C@@H:44]([CH2:46][C@H:47]3[CH2:52][C@@H:51]([O:53][CH3:54])[C@H:50]([O:55][C:67]([C:68]([CH2:73][OH:74])([CH2:69][OH:70])[CH3:72])=[O:66])[CH2:49][CH2:48]3)[CH3:45])[O:28][C:29]([C@H:31]3[N:36]([C:37]([C:39]2=[O:40])=[O:38])[CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:30])=[O:25])=[O:18])[CH2:4][CH2:3]1
Reactant: CC(CO)(CO)C(=O)O
Reactant: CO[C@H]1C[C@@H]2CC[C@@H](C)[C@@](O)(O2)C(=O)C(=O)N2CCCC[C@H]2C(=O)O[C@H]([C@H](C)C[C@@H]2CC[C@@H](O)[C@H](OC)C2)CC(=O)[C@H](C)C=C(C)[C@@H](O)[C@@H](OC)C(=O)[C@H](C)C[C@H](C)C=CC=CC=C1C
Agent: CO[C@H]1C[C@@H]2CC[C@@H](C)[C@@](O)(O2)C(=O)C(=O)N2CCCC[C@H]2C(=O)O[C@H]([C@H](C)C[C@@H]2CC[C@@H](O)[C@H](OC)C2)CC(=O)[C@H](C)/C=C(\C)[C@@H](O)[C@@H](OC)C(=O)[C@H](C)C[C@H](C)/C=C/C=C/C=C/1C
Agent: CO[C@H]1C[C@@H]2CC[C@@H](C)[C@@](O)(O2)C(=O)C(=O)N2CCCC[C@H]2C(=O)O[C@H]([C@H](C)C[C@@H]2CC[C@@H](OC(=O)C(C)(CO)CO)[C@H](OC)C2)CC(=O)[C@H](C)/C=C(\C)[C@@H](O)[C@@H](OC)C(=O)[C@H](C)C[C@H](C)/C=C/C=C/C=C/1C
Product: CO[C@H]1C[C@@H]2CC[C@@H](C)[C@@](O)(O2)C(=O)C(=O)N2CCCC[C@H]2C(=O)O[C@H]([C@H](C)C[C@@H]2CC[C@@H](OC(=O)C(C)(CO)CO)[C@H](OC)C2)CC(=O)[C@H](C)C=C(C)[C@@H](O)[C@@H](OC)C(=O)[C@H](C)C[C@H](C)C=CC=CC=C1C

Procedure:
The synthesis requires two steps. The first step is a microbial lipase-catalyzed acylation of rapamycin with an activated ester of 2,2-bis(hydroxymethyl)propionic acid derivative in an organic solvent. This reaction is highly regioselective, resulting in the exclusive formation of mono-42-acylated product (i.e., protected CCI-779), in nearly quantitative yield. Subsequent deprotection furnishes CCI-779 in excellent overall yield. Compared with chemical preparation, this chemo-enzymatic route offers a much shorter procedure with higher yield. Further, this method does not require any steps to protect the rapamycin's 31-OH group.
Reaction SMILES: C1(O[C:8](=[O:48])[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]4([C:38](=[O:47])[NH:39][C:40]5[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=5)[CH2:37][CH2:36]4)=[O:34])=[CH:28][CH:27]=3)[CH:22]=[CH:21][N:20]=2)C(OC2C=CC=CC=2)=O)C=CC=CC=1.Cl.Cl.[N:51]1([CH2:55][CH:56]2[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]2)[CH2:54][CH2:53][CH2:52]1.C(N(CC)CC)C.O>CN(C)C=O>[N:51]1([CH2:55][CH:56]2[CH2:61][CH2:60][N:59]([C:8]([NH:9][C:19]3[CH:24]=[C:23]([O:25][C:26]4[CH:27]=[CH:28][C:29]([NH:32][C:33]([C:35]5([C:38]([NH:39][C:40]6[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=6)=[O:47])[CH2:37][CH2:36]5)=[O:34])=[CH:30][CH:31]=4)[CH:22]=[CH:21][N:20]=3)=[O:48])[CH2:58][CH2:57]2)[CH2:54][CH2:53][CH2:52]1
Reactant: C1CN(CC2CCNCC2)C1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2)ccn1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2)ccn1)N1CCC(CN2CCC2)CC1
Reaction time: 62 h
Yield: 78.9 %

Procedure:
[4-(4-{[1-(4-Fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamic acid phenyl ester (50 mg) was dissolved in N,N-dimethylformamide (1.0 ml), and 4-(azetidin-1-ylmethyl)piperidine dihydrochloride (70.2 mg), triethylamine (0.0862 ml) and water (0.100 ml) were added thereto in this order, followed by stirring for 62 hr. The reaction mixture was partitioned between ethyl acetate (50 ml) and a saturated aqueous solution of ammonium chloride (20 ml). The organic layer was washed with a saturated aqueous solution of ammonium chloride (20 ml), water (20 ml) and brine (20 ml) in this order, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=95:5). Fractions containing the target compound were concentrated under reduced pressure, and the resultant residue was suspended in diethyl ether (2 ml) and hexane (4 ml). The solid was collected by filtration and dried under aeration to provide the titled compound as white powder (35.8 mg, 78.9%).