Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)/C=C\CO.[CH2:7]([N:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[CH3:8].CS(Cl)(=O)=O.C(N)[C:20]1[CH:25]=[CH:24]C=[CH:22][CH:21]=1>C(OCC)(=O)C>[CH2:7]([N:9]1[CH2:12][CH:13]=[CH:11][CH2:10]1)[C:8]1[CH:24]=[CH:25][CH:20]=[CH:21][CH:22]=1
Reactant: CCN(CC)CC
Reactant: NCc1ccccc1
Agent: CS(=O)(=O)Cl
Agent: OC/C=C\CO
Solvent: CCOC(C)=O
Product: C1=CCN(Cc2ccccc2)C1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 41 %

Procedure:
To a solution containing 35.4 g (0.4 mol) of cis-2-butene-1,4-diol, 83.8 g (0.8 mol) of triethylamine, and 416.6 g of ethyl acetate in a round flask reactor, methanesulfonyl chloride was added dropwise with stirring for 30 min. at about 5° C. using an ice-bath. After addition, the mixture was allowed to react with stirring for 2 hours at room temperature. To the mixture, 171.7 g (1.6 mol) of benzylamine was added continuously dropwise with stirring for 30 min. at ambient temperature. After 2 hours of stirring, the crystallized solid was removed by filtration; 42.0 g of 35% HCl (aq) was added to the filtrate, and then excess benzylamine hydrochloride was removed by filtration or extraction. After the solvent was evaporated under reduced pressure, 52.2 g of 1-benzyl-3-pyrroline (yield 82.0%) was obtained.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:17][CH2:16][CH2:15][O:14]2)(=O)=O)=CC=1.BrCC1OC(C(F)(F)F)=CC=1.[F:29][C:30]1[C:35]([C:36]#[N:37])=[CH:34][C:33]2[C:38]3([CH2:48][O:49][C:32]=2[CH:31]=1)[C:46]1[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=1)[NH:40][C:39]3=[O:47].CC1C2C=C3C4(C5C(=CC=CC=5)NC4=O)COC3=CC=2ON=1>>[F:29][C:30]1[C:35]([C:36]#[N:37])=[CH:34][C:33]2[C:38]3([CH2:48][O:49][C:32]=2[CH:31]=1)[C:46]1[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=1)[N:40]([CH2:12][C@H:13]1[CH2:17][CH2:16][CH2:15][O:14]1)[C:39]3=[O:47]
Reactant: N#Cc1cc2c(cc1F)OCC21C(=O)Nc2ccccc21
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCCO2)cc1
Agent: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Agent: FC(F)(F)c1ccc(CBr)o1
Product: N#Cc1cc2c(cc1F)OCC21C(=O)N(C[C@H]2CCCO2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 9 and making non-critical variations using (R)-(tetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, and 6-fluoro-2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, 6-fluoro-2′-oxo-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile was obtained (34%): 1H NMR (300 MHz, CDCl3) δ 7.37-7.27 (m, 1H), 7.12-7.06 (m, 3H), 7.01-6.92 (m, 1H), 6.79-6.74 (m, 1H), 4.94 (ABq, 2H), 4.31-4.21 (m, 1H), 3.91-3.72 (m, 4H), 2.12-1.84 (m, 4H); MS (ES+) m/z 364.9 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:13][CH2:14][N:15]([CH3:23])[CH:16]([CH2:21][CH3:22])[CH:17]([OH:20])[CH2:18][CH3:19])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].F[C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1>>[CH2:21]([CH:16]([N:15]([CH3:23])[CH2:14][CH2:13][C:5]1[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH:17]([O:20][C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1)[CH2:18][CH3:19])[CH3:22]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CCC(O)C(CC)N(C)CCc1cc(OC)c(OC)c(OC)c1
Product: CCC(Oc1ccc([N+](=O)[O-])cc1)C(CC)N(C)CCc1cc(OC)c(OC)c(OC)c1

Procedure:
In a manner similar to Preparation 2, react 4-[[2-(3,4,5-trimethoxyphenyl)ethyl](methyl)amino]hexan-3-ol with 1-fluoro-4-nitrobenzene to obtain the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH:16]([C:18]2[N:27]([C:28]3[CH:33]=[CH:32][C:31]([O:34]C)=[CH:30][CH:29]=3)[C:26](=[O:36])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=2)[CH3:17])[CH3:15])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].B(Br)(Br)Br>C(Cl)Cl>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH:16]([C:18]2[N:27]([C:28]3[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=3)[C:26](=[O:36])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=2)[CH3:17])[CH3:15])(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1ccc(-n2c(C(C)N(C)S(=O)(=O)c3ccc(C(C)(C)C)cc3)nc3ccccc3c2=O)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(c1nc2ccccc2c(=O)n1-c1ccc(O)cc1)N(C)S(=O)(=O)c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 139.7 %

Procedure:
To a suspension of the 4-tert-butyl-N-{1-[3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide (0.5 g, 1.07 mmol) stirring in 15 mL DCM was added boron tribromide (5 mL, 5 mmol 1M in DCM). The reaction was allowed to stir at room temperature for 15 min after which TLC analysis indicated that starting material was completely consumed. The reaction was quenched with 20 mL brine and the resulting mixture was transferred to a separatory funnel. The layers were separated and the aqueous layer extracted with CHCl3 (2×25 mL). The combined organics were washed with brine, dried over MgSO4, and concentrated under vacuum to afford a crude residue that was purified by chromatography (silica gel, 0-75% EtOAc:Hex), yielding the desired product as a white solid (0.735 g, 95%). 1H-NMR (CDCl3): δ 8.26 (d, 1H), 7.67 (t, 1H), 7.51 (d, 2H), 7.45 (t, 1H), 7.36 (m, 2H), 7.26 (d, 2H), 6.98 (m, 1H), 6.90 (m, 2H), 5.00 (q, 1H), 3.19 (s, 3H), 1.28 (d, 3H), 1.17 (s, 9H); MS (ESI) 492 (MH+).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([O:11][C:12](=[O:26])[NH:13][CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]([CH:23]2[CH2:25][CH2:24]2)=[O:22])[CH2:16][CH2:15]1)([CH3:10])([CH3:9])[CH3:8]>O1CCCC1>[C:7]([O:11][C:12](=[O:26])[NH:13][CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH:21]([CH:23]2[CH2:24][CH2:25]2)[OH:22])[CH2:16][CH2:15]1)([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)NC1CCN(CC(=O)C2CC2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCN(CC(O)C2CC2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
Lithium aluminium hydride (1.0M solution in tetrahydrofuran, 1.41 mL, 1.41 mmol, 1.0 eq) is added at 0° C. to a stirred solution of [1-(2-cyclopropyl-2-oxo-ethyl)-piperidin-4-yl]-carbamic acid tert-butyl ester (420 mg, 1.41 mmol, 1.0 eq) in tetrahydrofuran (25 mL). After 2 hours stirring at 0° C., the reaction mixture is cautiously quenched with ice-water (5 mL). Tetrahydrofuran in evaporated and the crude is extracted with dichloromethane (3×30 mL) and water (30 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to afford [1-(2-cyclopropyl-2-hydroxy-ethyl)-piperidin-4-yl]-carbamic acid tert-butyl ester as a white solid (373 mg, 84% yield).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]([OH:13])[CH2:9][CH2:10][CH2:11][CH3:12])[CH:5]=[CH:4][CH:3]=1.[C:14](OC=C)(=[O:16])[CH3:15]>C1CCCCC1>[C:14]([O:13][C@@H:8]([C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=1)[CH2:9][CH2:10][CH2:11][CH3:12])(=[O:16])[CH3:15]
Reactant: C=COC(C)=O
Reactant: CCCCC(O)c1cccc(Br)n1
Solvent: C1CCCCC1
Product: CCCC[C@@H](OC(C)=O)c1cccc(Br)n1
Reaction time: 7.5 h
Yield: 62.8 %

Procedure:
To a gently shaking solution of 1-(6-bromo-2-pyridinyl)-1-pentanol (1.00 g, 4.10 mmol) in dry cyclohexane (100 mL) was added Lipase PS-C “Amano” (Pseudomonas cepacia) (9.97 g) followed by vinyl acetate (1.5 mL, 16.27 mmol). Shaking was continued for 7.5 h with continual monitoring by chiral HPLC. The mixture was then filtered and the filtrate reduced under vacuum to give an oil which was purified by SPE (silica, 20 g cartridge) eluting with cyclohexane:EtOAc (gradient 50:1 to 2:1) to afford (1R)-1-(6-bromo-2-pyridinyl)pentyl acetate as an oil (737 mg, 63%). LC/MS: m/z 286.1/288.1 [M+H]+, Rt 3.38 min. Analytical chiral HPLC (25 cm Chiralpak AD) eluting with 2% EtOH in heptane, f=1.0 mL/min, wavelength 215 nm, (S-) Rt 5.1 min and (R-) Rt 5.4 min (43% ee) and the title compound as an oil (349 mg).
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:21][CH2:22][OH:23])[C:4]2[C:9]([C:10]=1[C:11](=[O:20])[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>N1C=CC=CC=1>[CH3:1][C:2]1[N:3]([CH2:21][CH2:22][O:23][S:30]([C:27]2[CH:28]=[CH:29][C:24]([CH3:34])=[CH:25][CH:26]=2)(=[O:32])=[O:31])[C:4]2[C:9]([C:10]=1[C:11](=[O:20])[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc(C(=O)c2c(C)n(CCO)c3ccccc23)cc1
Solvent: c1ccncc1
Product: COc1ccc(C(=O)c2c(C)n(CCOS(=O)(=O)c3ccc(C)cc3)c3ccccc23)cc1

Procedure:
Following a procedure similar to that described above in Preparation 4A, 40 g. (0.015 mole) of 2-methyl-3-(4-methoxybenzoyl)indole in 320 ml. of THF was reacted with 61 ml. of a 2.6 M solution of butyl lithium in hexane and 45.8 ml. of ethylene oxide to give 33.6 g. (72%) of 2-methyl-3-(4-methoxybenzoyl)-1-(2-hydroxyethyl)-1H-indole. Reaction of 17 g. (0.06 mole) of the latter with 72 g. (0.06 mole) of p-toluenesulfonyl chloride in 250 ml. of pyridine afforded 2-methyl-3-(4-methoxybenzoyl)-1-(2-p-toluenesulfonyloxyethyl)-1H-indole as an oil.
Reaction SMILES: [C:1]1([S:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Br.[OH-].[Na+]>O>[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:12][CH2:11][CH2:10][CH2:9][CH2:8][S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrCCCCCCBr
Reactant: OCCCCSc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: BrCCCCCCOCCCCSc1ccccc1
Yield: 55.7 %

Procedure:
4-(Phenylthio)-1-butanol (5.25 g), 1,6-dibromohexane (21.08 g), TAB (1 g) and 40% sodium hydroxide solution (45 ml) were stirred together at room temperature for 18 h. The mixture was diluted with water (150 ml), extracted with diethyl ether (2×150 ml), the organic layer washed with brine (100 ml), dried and evaporated in vacuo to give an oil. Purification by FCC eluting with System A (0:20→1:19) gave the title compound (5.54 g) as a colourless oil. T.l.c. (System A 1:9) Rf 0.12.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10](=O)[NH:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[F:26])[CH3:9])(C)(C)C>Cl.O1CCOCC1>[F:18][C:15]1[CH:16]=[CH:17][C:12]2[N:11]=[C:10]([C@@H:8]([NH2:7])[CH3:9])[N:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[C:13]=2[CH:14]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(F)cc1Nc1ccccc1F
Agent: Cl
Solvent: C1COCCO1
Product: C[C@H](N)c1nc2ccc(F)cc2n1-c1ccccc1F
Temperature: 70 °C
Yield: 44.7 %

Procedure:
{(S)-1-[4-Fluoro-2-(2-fluorophenylamino)phenylcarbamoyl]ethyl}carbamic acid tert-butyl ester (0.7 g, 1.80 mmol) was dissolved in 4M HCl in dioxane (10 mL) and the reaction mixture was heated to 70° C. for 5 h. The resultant mixture was concentrated in vacuo and the residue dissolved in DCM (40 mL) and washed with saturated aqueous NaHCO3 (20 mL) and brine (20 mL). The organic fraction was dried (MgSO4), filtered and concentrated in vacuo to afford a red gum. This was purified by column chromatography (silica gel, gradient 0-10% MeOH in DCM) to afford the title compound (0.22 g, 46%). LCMS (Method C): RT 1.74 min [M+H]+ 274.3
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].[H-].[Na+].[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Cl)=[CH:19][CH:18]=1>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:21][C:20]1[CH:23]=[CH:24][C:17]([O:16][CH3:15])=[CH:18][CH:19]=1)[C:6](=[O:11])[C:5]2=[O:12]
Reactant: COc1ccc(CCl)cc1
Reactant: O=C1Nc2ccc(F)cc2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CN2C(=O)C(=O)c3cc(F)ccc32)cc1
Reaction time: 0.25 h
Yield: 82.4 %

Procedure:
A solution of 5-fluoroisatin (5 g, 30.2 mmol) in DMF (60 mL) was cooled in an ice/water bath and treated with sodium hydride (1.44 g, 60.6 mmol) portionwise. The reaction was stirred for 15 minutes after the addition of the last portion and then treated with p-methoxybenzyl chloride (5.32 g, 45.3 mmol) and allowed to stir for 1 hour. The reaction was then quenched by slow addition of excess methanol. After bubbling had stopped, the reaction was poured into water (100 mL) and extracted twice with ethyl acetate. The organics were combined, dried over MgSO4 and the solvent was removed. The residue was purified by silica gel chromatography using a gradient of 0-100% ethyl acetate in hexane to afford 7.1 g (82%) of 5-Fluoro-1-(4-methoxy-benzyl)-1H-indole-2,3-dione; 1H NMR (CDCl3, 400 MHz) δ 3.79 (s, 3H), 4.86 (s, 2H), 6.75 (dd, 1H, J1=3.6, J2=8.6), 6.84-6.90 (m, 2H), 7.19 (ddd, 1H, J1=J2=8.6, J3=3.6), 7.22-7.27 (m, 1H), 7.26-7.31 (m, 2H); HPLC-MS calcd. for C16H12FNO3 (M+H+) 286.1. found 286.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH2:18][C:17](=[O:19])[N:16]([CH3:20])[C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:21][C:22]1[CH:26]=[C:25]([CH3:27])[NH:24][C:23]=1[CH:28]=O>N1CCCCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18](=[CH:28][C:23]4[NH:24][C:25]([CH3:27])=[CH:26][C:22]=4[CH3:21])[C:17](=[O:19])[N:16]([CH3:20])[C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CN1C(=O)Cc2c(Nc3ccc(F)c(Cl)c3)ncnc21
Reactant: Cc1cc(C)c(C=O)[nH]1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cc(C)c(C=C2C(=O)N(C)c3ncnc(Nc4ccc(F)c(Cl)c4)c32)[nH]1
Yield: 37 %

Procedure:
4-(3-Chloro-4-fluoro-phenylamino)-7-methyl-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (100 mg, 0.34 mmol) was condensed with 3,5-dimethyl-1H-pyrrole-2-carbaldehyde (50 mg, 0.41 mmol) and piperidine (2 drops) in ethanol (3 mL) at 80° C. for 2 hours to give 50 mg (37%) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 13.07 (br s, 1H, NH), 9.18 (s, 1H), 8.34 (s, 1H), 7.69 (m, 1H), 7.35 (s, 1H), 7.30-7.40 (m, 2H), 6.05 (s, 1H), 3.32 (s, 3H, CH3), 2.34 (s, 3H, CH3), 2.16 (s, 3H, CH3). MS 398 [M++1].
Reaction SMILES: [O:1]=[C:2]([N:26]1[CH2:31][CH2:30][N:29]([C:32](=[O:43])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[C:39]([F:42])([F:41])[F:40])[CH2:28][CH2:27]1)[CH2:3][NH:4][C:5]([C:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18]CC2C=CC=CC=2)[O:9][N:8]=1)=[O:6]>CO.[Pd]>[O:1]=[C:2]([N:26]1[CH2:27][CH2:28][N:29]([C:32](=[O:43])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[C:39]([F:40])([F:42])[F:41])[CH2:30][CH2:31]1)[CH2:3][NH:4][C:5]([C:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[OH:18])[O:9][N:8]=1)=[O:6]
Reactant: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1cc(-c2ccccc2OCc2ccccc2)on1
Agent: [Pd]
Solvent: CO
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1cc(-c2ccccc2O)on1
Yield: 62.8 %

Procedure:
10% Pd/c (20 mg) was added to a stirred solution of 5-(2-benzyloxy-phenyl)-isoxazole-3-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide (90 mg, 0.15 mmol) (prepared by the method as described above) in MeOH (50 mL) and stirred under hydrogen atmosphere. The reaction mixture was then stirred for 6 hrs. The mixture was filtered over a bed of celite. The celite was washed with MeOH and the filtrate was concentrated under reduced pressure to afford 47.3 mg (62% yield) of 5-(2-hydroxy-phenyl)-isoxazole-3-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide. LCMS Purity: 91.92%. 1H NMR (DMSO): δ 9.95 (s, 1H), 8.7 (s, 1H), 7.5 (m, 4H), 7.2 (m, 3H), 6.9 (m, 1H), 4.2 (m, 2H), 3.6 (m, 4H), 3.4 (m, 2H), 3.1 (m, 2H).
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: 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
Reactant: CC(CO)(CO)C(=O)O
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: Cl[C:2]1[CH:17]=[CH:16][C:5]([C:6]([N:8]([CH3:15])[CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[O:7])=[C:4]([S:18][CH2:19][CH2:20][CH3:21])[N:3]=1.[NH:22]1[CH2:27][CH2:26][CH2:25][C@@H:24]([CH2:28][C:29]([O:31][CH3:32])=[O:30])[CH2:23]1.Cl.C(=O)([O-])[O-].[K+].[K+]>C(#N)CCC.C(Cl)Cl>[CH3:15][N:8]([CH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)[C:6]([C:5]1[CH:16]=[CH:17][C:2]([N:22]2[CH2:27][CH2:26][CH2:25][C@@H:24]([CH2:28][C:29]([O:31][CH3:32])=[O:30])[CH2:23]2)=[N:3][C:4]=1[S:18][CH2:19][CH2:20][CH3:21])=[O:7]
Reactant: CCCSc1nc(Cl)ccc1C(=O)N(C)C1CCOCC1
Reactant: COC(=O)C[C@@H]1CCCNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCCC#N
Product: CCCSc1nc(N2CCC[C@@H](CC(=O)OC)C2)ccc1C(=O)N(C)C1CCOCC1
Yield: 57 %

Procedure:
6-chloro-N-methyl-2-(propylthio)-N-(tetrahydro-2H-pyran-4-yl)nicotinamide (0.398 g, 1.21 mmol) was added to (S)-methyl 2-(piperidin-3-yl)acetate.HCl (0.353 g, 1.82 mmol) and potassium carbonate (0.753 g, 5.45 mmol) in butyronitrile (3 mL) was heated at 150° C. for 4 hours. The reaction mixture was diluted with DCM (60 mL), and washed sequentially with water (20 mL) and brine (20 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 100% EtOAc in DCM. Pure fractions were evaporated to dryness to afford methyl [(3S)-1-{5-[methyl(tetrahydro-2H-pyran-4-yl)carbamoyl]-6-(propylthio)pyridin-2-yl}piperidin-3-yl]acetate (0.310 g, 57%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[N:6][NH:5][C:4](=O)[C:3]=1[C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1.O=P(Cl)(Cl)[Cl:17]>>[Cl:17][C:4]1[N:5]=[N:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1
Reactant: O=c1[nH]ncc(Cl)c1-c1ccncc1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1cnnc(Cl)c1-c1ccncc1
Temperature: 120 °C
Yield: 67 %

Procedure:
A suspension of compound 5-chloro-4-(pyridin-4-yl)pyridazin-3(2H)-one (2.5 g, 12 mmol) in POCl3 (20 mL) was heated at 120° C. for 3 h. After this time, the reaction mixture was cooled to RT. The reaction mixture was concentrated under reduced pressure. The obtained residue was treated with ice-cold saturated aqueous NaHCO3. The formed precipitate was collected by filtration and washed with water to give the title compound, 3,5-dichloro-4-(pyridin-4-yl)pyridazine as an off-white solid (1.8 g, 67%). LC/MS (method A): RT=0.70 min, (M+H)+=226.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[N:14][CH:15]=2)=[CH:5][CH:4]=1)#[N:2].[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Cl)=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][N:9]([C:10]2[CH:15]=[N:14][CH:13]=[N:12][CH:11]=2)[C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)=[CH:19][CH:18]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: N#Cc1ccc(Nc2cncnc2)cc1
Product: N#Cc1ccc(N(Cc2ccc(Cl)cc2)c2cncnc2)cc1

Procedure:
Starting compounds: 5-[(4-cyanophenyl)amino]pyrimidine and 4-chlorobenzyl chloride
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:25][C@H:26]2[CH2:46][CH2:45][C:28]3([O:32][C@H:31]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C@@H:30]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[O:29]3)[CH2:27]2)[C:13](=O)[CH2:14][CH2:15][C:16]([C:18]2[CH:23]=[N:22][CH:21]=[CH:20][N:19]=2)=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C([O-])(=O)C.[NH4+:51].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([C:13]2[NH:51][C:16]([C:18]3[CH:23]=[N:22][CH:21]=[CH:20][N:19]=3)=[CH:15][CH:14]=2)[CH2:25][C@H:26]2[CH2:46][CH2:45][C:28]3([O:29][C@H:30]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[C@@H:31]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[O:32]3)[CH2:27]2)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: CS(=O)(=O)c1ccc(C(C[C@H]2CCC3(C2)O[C@H](c2ccccc2)[C@@H](c2ccccc2)O3)C(=O)CCC(=O)c2cnccn2)cc1Cl
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CS(=O)(=O)c1ccc(C(C[C@H]2CCC3(C2)O[C@H](c2ccccc2)[C@@H](c2ccccc2)O3)c2ccc(-c3cnccn3)[nH]2)cc1Cl
Temperature: 110 °C
Reaction time: 1 h
Yield: 34.2 %

Procedure:
To a solution of 5-[3-chloro-4-(methylsulfonyl)phenyl]-6-[(2R,3R,7R)-2,3-diphenyl-1,4-dioxaspiro[4.4]non-7-yl]-1-(pyrazin-2-yl)hexane-1,4-dione (284 mg) in acetic acid (2.2 mL) was added ammonium acetate (530 mg), and the mixture was stirred at 110° C. for 1 hr. After cooling to room temperature, the mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution. The reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (94.3 mg, yield 34%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (4:1, volume ratio).
Reaction SMILES: [CH2:1]1[C@@H:14]2[C@@:5]([C:15]([OH:17])=[O:16])([C:6]3[C:11]([CH2:12][CH2:13]2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:4][CH2:3][CH2:2]1.C(O)(=[O:20])C>O.[O-2].[O-2].[O-2].[Cr+6]>[O:20]=[C:12]1[CH2:13][C@H:14]2[C@:5]([C:15]([OH:17])=[O:16])([CH2:4][CH2:3][CH2:2][CH2:1]2)[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: O=C(O)[C@]12CCCC[C@H]1CCc1ccccc12
Reactant: CC(=O)O
Agent: [Cr+6]
Agent: [O-2]
Solvent: O
Product: O=C1C[C@@H]2CCCC[C@]2(C(=O)O)c2ccccc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of the compound from Example 6 (42 g, 0.182 mol) in 900 mL glacial acetic acid was treated dropwise with a solution of chromium trioxide (91 g, 0.912 mol) in 850 mL of glacial acetic acid and 50 mL of water. The reaction was stirred at room temperature for 5 hours and concentrated. The residue was partitioned between benzene and water. The aqueous layer was saturated with NaCl and extracted with additional benzene. The combined organic layers were dried (MgSO4), filtered and concentrated to give a brown solid (37 g). The solid was suspended in 150 mL ethyl acetate and collected by suction filtration, and washed with additional ethyl acetate. The resulting material was dried under vacuum to give the title compound (21.0 g, 47%) as a white solid.