Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[N:11]1[CH:15]=[CH:14][CH:13]=[N:12]1)[CH:6]=O.[Br-].[O:17]1CCO[CH:18]1[CH2:22][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOCCN(CCOCCOC)CCOCCOC>ClCCl.C([O-])([O-])=O.[K+].[K+]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:22][CH:18]=[O:17])[CH:8]=[CH:9][C:10]=1[N:11]1[CH:15]=[CH:14][CH:13]=[N:12]1
Reactant: c1ccc([P+](CC2OCCO2)(c2ccccc2)c2ccccc2)cc1
Reactant: COc1cc(C=O)ccc1-n1cccn1
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: ClCCl
Product: COc1cc(C=CC=O)ccc1-n1cccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.6 %

Procedure:
A mixture of 3-methoxy-4-(1H-pyrazol-1-yl)benzaldehyde (1.52 g, 7.52 mmol, prepared as described in Reference Example 5), (1,3-dioxolan-2-ylmethyl)triphenylphosphonium bromide (4.85 g, 11.30 mmol), and TDA-1 (2.40 mL, 7.50 mmol) in dichloromethane (35 mL) and sat. aq. K2CO3 (35 mL) was heated to reflux for 18 h. The layers were separated and the aqueous layer was extracted with dichloromethane (2×20 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried (MgSO4), and concentrated. THF (20 mL) and 10% HCl (20 mL) were added and the mixture was stirred for 1 h at rt. The reaction mixture was cooled to 0° C., made basic with 10% NaOH, and extracted with ethyl acetate (3×25 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried (MgSO4), and concentrated. Purification by chromatography (SiO2, 2:1 hexane/ethyl acetate) provided 1.47 g (86%) of the title compound as a yellow solid. MS 229 (M+H)+.
Reaction SMILES: [CH3:1][C@H:2]1[CH:7]2[C:8]([CH3:10])([CH3:9])[CH:5]([CH2:6]2)[CH2:4][C@@H:3]1[NH2:11].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.N[C@@H](CCSSCC[C@H](N)C(O)=O)C(O)=O.[CH3:50][N:51]([CH2:53][C@@H:54]([NH:62][CH2:63][C:64]1[CH:65]=[C:66]([CH:78]=[CH:79][CH:80]=1)[CH2:67][N:68]1[CH:72]([C:73](O)=[O:74])[CH2:71][CH2:70][S:69]1(=[O:77])=[O:76])[CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[CH3:52].C(N(CC)C(C)C)(C)C>CN(C)C=O.C[C@H]1C2C(C)(C)C(C2)C[C@@H]1N.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.N[C@@H](CCSSCC[C@H](N)C(O)=O)C(O)=O>[CH3:1][C@@H:2]1[C@@H:3]([NH:11][C:73]([CH:72]2[CH2:71][CH2:70][S:69](=[O:77])(=[O:76])[N:68]2[CH2:67][C:66]2[CH:78]=[CH:79][CH:80]=[C:64]([CH2:63][NH:62][C@H:54]([CH2:53][N:51]([CH3:50])[CH3:52])[CH2:55][C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)[CH:65]=2)=[O:74])[CH2:4][C@H:5]2[CH2:6][C@@H:7]1[C:8]2([CH3:10])[CH3:9]
Reactant: C[C@H]1C2CC(C[C@@H]1N)C2(C)C
Reactant: CN(C)C[C@H](Cc1ccccc1)NCc1cccc(CN2C(C(=O)O)CCS2(=O)=O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: N[C@@H](CCSSCC[C@H](N)C(=O)O)C(=O)O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1[C@@H](NC(=O)C2CCS(=O)(=O)N2Cc2cccc(CN[C@@H](Cc3ccccc3)CN(C)C)c2)C[C@H]2C[C@@H]1C2(C)C
Temperature: 25 °C
Yield: 244.9 %

Procedure:
(+)-Isopinocampheylamine (Aldrich; 29 mg, 0.19 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (available from Aldrich; 58.4 mg, 0.18 mmol), N-hydroxybenzotriazole (available from 3B Scientific Corporation, Libertyville, Ill. 60048, USA; 24.3 mg, 0.18 mmol) were added to a cooled (0° C.) solution of 2-{3-[((S)-1-dimethylaminomethyl-2-phenyl-ethylamino)-methyl]-benzyl}-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid (100 mg 80% pure, 0.18 mmol) in dry N,N-dimethylformamide (3 mL) under argon. N,N-Diisopropylethylamine (70 μL, 0.4 mmol) was then added. The solution was then stirred at room temperature. After 30 minutes more (+)-isopinocampheylamine (6 mg, 0.04 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (available from Aldrich; 6 mg, 0.002 mmol) and N-hydroxybenzotriazole (available from 3B Scientific Corporation, Libertyville, Ill. 60048, USA; 3 mg, 0.002 mmol) were added. After 90 minutes all of the starting material had been consumed. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with 1N NaOH (3×15 mL), and brine (20 mL). The organic phase was dried over sodium sulfate, filtered and concentrated to give the crude product (132 mg). This material was combined with the crude product from an identical experiment using 2-{3-[((S)-1-dimethylaminomethyl-2-phenyl-ethylamino)-methyl]-benzyl}-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid (250 mg). The combined lots were chromatographed, eluting with 0-10% methanol/dichloromethane to give 2-{3-[((S)-1-dimethylaminomethyl-2-phenyl-ethylamino)-methyl]-benzyl}-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid((1S,2S,3S,5R)-2,6,6-trimethyl-bicylo[3.1.1]hept-3-yl)amide (256 mg, 60%) as a tan foam.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:7]([NH:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[ClH:26]>C(O)C.[Pd]>[NH2:1][C@H:2]([C:7]([NH:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:8])[CH2:3][CH:4]([CH3:5])[CH3:6].[ClH:26]
Reactant: CCOC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)CNC(=O)[C@@H](N)CC(C)C

Procedure:
14 g of Z-Leu-Gly-OEt [manufactured according to J. R. Vaughan & R. L. Osato, J.Am.Chem.Soc. 73, 5553 (1951)] are dissolved in 150 ml of absolute ethanol, mixed with 11.5 ml of a 6.9 N hydrogen chloride solution in ethanol and hydrogenated in the presence of 2.8 g of palladium on charcoal (10 % Pd). After 1 hour the catalyst is filtered off and the filtrate evaporated in vacuo at 40°C bath temperature. The residue is an oil and is directly processed further. Rf1 = 0.50 (on silica gel).
Reaction SMILES: C([O:8][C:9]1[CH:19]=[CH:18][C:12]([C:13]([N:15]([CH3:17])[CH3:16])=[O:14])=[CH:11][C:10]=1[C:20]([NH:22][C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:24]=1)=[O:21])C1C=CC=CC=1.C(O)C>[Pd].C(OCC)(=O)C>[F:30][C:29]([F:31])([F:32])[C:27]1[CH:28]=[C:23]([NH:22][C:20](=[O:21])[C:10]2[CH:11]=[C:12]([CH:18]=[CH:19][C:9]=2[OH:8])[C:13]([N:15]([CH3:17])[CH3:16])=[O:14])[CH:24]=[C:25]([C:33]([F:35])([F:34])[F:36])[CH:26]=1
Reactant: CN(C)C(=O)c1ccc(OCc2ccccc2)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CN(C)C(=O)c1ccc(O)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Yield: 90.1 %

Procedure:
A solution of 4-benzyloxy-N3-[3,5-bis(trifluoromethyl)phenyl]-N1,N1-dimethyl-isophthalamide (141 mg, 0.28 mmol) and 5% Pd—C (14 mg) in a mixed solvent of ethanol (5 ml) and ethyl acetate (5 ml) was stirred at room temperature for 1 hour under hydrogen atmosphere. The reaction mixture was filtered and the filtrate was evaporated under reduced pressure to give the title compound (106 mg, 91.2%) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-])=O>C1COCC1.CCOC(C)=O>[NH2:1][C:4]1[CH:5]=[C:6]([S:10]([NH:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Nc2ccccc2)c1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1cccc(S(=O)(=O)Nc2ccccc2)c1
Temperature: 135 °C
Reaction time: 0.23 h
Yield: 78 %

Procedure:
To 3-nitro-N-phenylbenzenesulfonamide (255.5 mg, 0.919 mmol) in 4 mL of THF is added SnCl2 dihydrate (1.015 g, 4.486 mmol). The resulting mixture is heated in a microwave reactor at a power of 75 Watts and 135° C. for 1 min then at 15 Watts and 135° C. for 14 min. The reaction is cooled to room temperature, diluted with EtOAc (20 mL), washed with saturated aqueous NaHCO3 (10 mL) and allowed to stir for about 12 hours. The reaction mixture is then extracted with EtOAc (75 mL). The organic layer is washed with H2O (75 mL), saturated aqueous NaCl (2×75 mL), dried (MgSO4) and concentrated in vacuo to yield a yellow residue. This residue is purified over silica (0-4% MeOH in CH2Cl2) to afford 178 mg (78% yield) of the desired compound. 1H NMR (DMSO-d6, 300 MHz): δ 5.57 (s, 2H), 6.69 (d, J=8.1 Hz, 1H), 6.84 (d, J=7.5 Hz, 1H), 6.95 (s, 1H), 6.99 (t, J=7.5 Hz, 1H), 7.07 (d, J=8.1 Hz, 2H), 7.12 (t, J=8.1 Hz, 1H), 7.21 (t, J=8.1 Hz, 2H), 10.12 (s, 1H). MS (ESI, pos. ion) m/z: 249 (M+1).
Reaction SMILES: [C:1]([C:3]1[C:11]2[CH2:10][CH2:9][N:8]([C:12](=[O:18])[CH2:13][O:14]C(=O)C)[CH2:7][C:6]=2[S:5][C:4]=1[NH:19][C:20](=[O:29])/[CH:21]=[CH:22]/[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)#[N:2].[OH-].[Na+]>CO>[C:1]([C:3]1[C:11]2[CH2:10][CH2:9][N:8]([C:12](=[O:18])[CH2:13][OH:14])[CH2:7][C:6]=2[S:5][C:4]=1[NH:19][C:20](=[O:29])/[CH:21]=[CH:22]/[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)#[N:2]
Reactant: CC(=O)OCC(=O)N1CCc2c(sc(NC(=O)/C=C/c3ccccc3)c2C#N)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: N#Cc1c(NC(=O)/C=C/c2ccccc2)sc2c1CCN(C(=O)CO)C2

Procedure:
1 mmol of acetic acid 2-[3-cyano-2-((E)-3-phenyl-allanoylamino)-4,7-dihydro-5H-thieno[2,3-c]pyridin-6-yl]-2-oxo-ethyl ester are stirred in 5 ml methanol and 1 ml 45% aqueous NaOH until the reaction is completed. Purification according to the previous preparation affords the desired compound.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:8][C:4]=2[N:5]=[CH:6][N:7]=1.[C:25]1([CH:32]=[CH:31][CH:30]=[C:28]([OH:29])[CH:27]=1)[OH:26].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]2[C:3]3[C:2]([O:26][C:25]4[CH:27]=[C:28]([OH:29])[CH:30]=[CH:31][CH:32]=4)=[N:7][CH:6]=[N:5][C:4]=3[O:8][C:9]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:12][CH:13]=1
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(Cl)c23)cc1
Reactant: Oc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(Oc4cccc(O)c4)c23)cc1

Procedure:
Heat 500 mg (1.49 mmol) of 4-chloro-5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidine, 654 mg (5.94 mmol) of resorcinol and 726 mg (2.23 mmol) of caesium carbonate in 10 ml of DMF to 120° C. for 2 h. After cooling, filter and purify the filtrate directly by means of preparative HPLC. Stir the resulting product with dichloromethane, filter with suction, wash with dichloromethane and dry under reduced pressure. 171.4 mg (27% of theory) of the target product are obtained as a beige solid.
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C:11]2=[O:21])[CH2:3]1.[O:22]=[O:23]>>[O:22]([C@:4]12[CH2:3][C@@H:2]([OH:1])[CH2:19][CH2:18][C@:17]1([CH3:20])[C@@H:16]1[C@H:7]([C@H:8]3[C@@:12]([CH2:14][CH2:15]1)([CH3:13])[C:11](=[O:21])[CH2:10][CH2:9]3)[CH:6]=[CH:5]2)[OH:23]
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: O=O
Product: C[C@]12CC[C@H]3[C@@H](C=C[C@@]4(OO)C[C@@H](O)CC[C@]34C)[C@@H]1CCC2=O

Procedure:
3β-Hydroxyandrost-5-en-17-one (DHEA) 1 reacts with singlet oxygen to yield 5α-hydroperoxy-3β-hydroxyandrost-6-en-17-one 2. This hydroperoxide undergoes a rearrangement when in chloroform solution to yield 7α-hydroperoxy-3β-hydroxyandrost-5-en-17-one, 3. Treatment of the hydroperoxide with zinc and acetic acid yields 3β,7α-dihydroxy-androst-5-en-17-one, 4. ##STR37##
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]O)=[CH:5][CH:4]=1.[ClH:11]>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][Cl:11])=[CH:5][CH:4]=1
Reactant: COc1ccc(CO)cc1
Reactant: Cl
Product: COc1ccc(CCl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Methoxybenzylalcohol (50 g, 0.36 mol) (Aldrich) was added dropwise to 100 mL of conc. HCl and stirred vigorously for 2 h at rt. The reaction mixture was extracted four times with Et2O, the Et2O extracts were combined, washed with brine, dried (Na2SO4), and concentrated. The yellow oil was distilled at 70°-73° C. (0.2 mmHg) to give 52 g (93%) as a colorless oil: 1H NMR (CDCl3) d 3.85 (s, 3H, OCH3), 4.62 (s, 2H, CH2Cl), 6.91-6.93 (d, 2H, J=8 Hz, ArH), 7.38-7.40 (d, 2H, J=8 Hz, ArH) ; MS(FD) 156(M+).
Reaction SMILES: [CH3:1][C:2]1([CH2:8][C:9]([F:12])([F:11])[F:10])[CH2:6][O:5][C:4](=[O:7])[NH:3]1.C(O[Cl:18])(C)(C)C>CO>[Cl:18][N:3]1[C:2]([CH3:1])([CH2:8][C:9]([F:12])([F:10])[F:11])[CH2:6][O:5][C:4]1=[O:7]
Reactant: CC(C)(C)OCl
Reactant: CC1(CC(F)(F)F)COC(=O)N1
Solvent: CO
Product: CC1(CC(F)(F)F)COC(=O)N1Cl
Reaction time: 2 h
Yield: 73.8 %

Procedure:
A solution of 4-methyl-4-(2,2,2-trifluoroethyl)oxazolidin-2-one (400 mg, 2.18 mmol) in MeOH (6 ml) was cooled to 0° C. and tert-butylhypochlorite (294 mg, 2.73 mmol) was added. The solution was stirred for 2 h, concentrated in vacuo, and the residue purified by flash chromatography (0% to 10% MeOH in DCM) to afford the title compound as a white solid (350 mg, 74%). 1H NMR (CDCl3, 400 MHz) δ 1.54 (s, 3H), 2.48-2.57 (m, 1H), 2.64-2.76 (m, 1H), 4.28 (d, J=8.4 Hz, 1H), 4.45 (d, J=8.8 Hz, 1H). 19F NMR (CDCl3, 376 MHz) δ −60.93 (t, J=10.5 Hz). 13C NMR (CDCl3, 100 MHz) δ 20.8, 39.8 (q, J=28 Hz), 62.1, 72.8, 125 (q, J=265 Hz), 155.4. LRMS (ESI/APCI): 259 [M+H+CH3CN]+, 218 [M+H]+.
Reaction SMILES: Br[C:2]1[C:3]([C:15]#[N:16])=[N:4][N:5]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:6]=1[CH2:7][CH2:8][CH2:9][CH3:10].[CH3:17][C:18]([CH3:32])([CH3:31])[C:19]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O)=[O:20].C(O)CC.C(=O)([O-])[O-].[Na+].[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[CH2:7]([C:6]1[N:5]([C:11]([CH3:14])([CH3:13])[CH3:12])[N:4]=[C:3]([C:15]#[N:16])[C:2]=1[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[NH:21][C:19](=[O:20])[C:18]([CH3:31])([CH3:17])[CH3:32])[CH2:8][CH2:9][CH3:10]
Reactant: CC(C)(C)C(=O)Nc1ccccc1B(O)O
Reactant: CCCCc1c(Br)c(C#N)nn1C(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCCO
Solvent: O
Product: CCCCc1c(-c2ccccc2NC(=O)C(C)(C)C)c(C#N)nn1C(C)(C)C
Yield: 40.4 %

Procedure:
4-Bromo-5-butyl-1-tert-butyl-1H-pyrazole-3-carbonitrile (3.0 g, 10.6 mmol) was treated with triphenylphosphine (0.085 g, 0.32 mmol), 2-[(2,2-dimethylpropanoyl)amino]phenylboronic acid (prepared as described in Part G of Example 23, 2.41 g, 15.8 mmol), 1-propanol (22 mL), palladium (II) acetate (0.024 g, 0.11 mmol), 2 M aqueous sodium carbonate (6.5 mL, 13.0 mmol), and water (4.4 mL) according to the general procedure described in Examples 37-39. The crude product was purified by chromatography on a HORIZON HPFC system (silica gel, gradient elution with 0-25% ethyl acetate in hexanes) to yield 1.63 g of N-[2-(5-butyl-1-tert-butyl-3-cyano-1H-pyrazol-4-yl)phenyl]-2,2-dimethylpropanamide as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:12]#[C:13][Si](C)(C)C)[C:5]([NH:8]C(=O)C)=[N:6][CH:7]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[CH:12]=[CH:13][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(=O)Nc1ncc(Br)cc1C#C[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Brc1cnc2[nH]ccc2c1
Yield: 76.2 %

Procedure:
To a solution of N-(5-bromo-3-trimethylsilanylethynyl-pyridin-2-yl)-acetamide (4.75 g, 15.26 mmol) in THF (90 ml) was added dropwise a 1 M solution of tetra-n-butyl ammonium fluoride in THF (30.5 ml, 30.5 mmol). After stirring at reflux for 15 hours, the reaction mixture was concentrated in vacuo and water was added. The aqueous layer was extracted three times with dichloromethane with, and the combined extracts were directly adsorbed on silica gel. Purification by flash chromotography on silica gel with a gradient of ethyl acetate/hexanes afforded 2.29 g of a beige solid. Recrystallization from ethyl acetate/hexanes provided the title compound as light beige flakes (1.33 g). Further purification of the filtrate on silica gel with a gradient of ethyl acetate/hexanes afforded more of the title compound as a crystalline powder (675 mg) for a combined yield of 2.01 g; 67%. 1H NMR (DMSO-d6): δ 11.89 (s, 1H), 8.24 (d, J=2.0 Hz, 1H), 8.17 (d, J=2.5 Hz, 1H), 7.53 (t, J=3.0 Hz, 1H), 6.42 (dd, J=1.0, 3.0 Hz, 1H); HPLC/MS m/z: 197 [MH]+.
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]1[CH2:24][C@@:11]2([O:15][C:14](=[O:16])[N:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=3)[CH2:12]2)[CH2:10][NH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:25]1([CH2:31][C:32]([NH:34][C@@H:35]([C:39]([CH3:42])([CH3:41])[CH3:40])[C:36](O)=[O:37])=[O:33])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[C:1]([O:5][C:6]([C@@H:8]1[CH2:24][C@@:11]2([O:15][C:14](=[O:16])[N:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=3)[CH2:12]2)[CH2:10][N:9]1[C:36](=[O:37])[C@@H:35]([NH:34][C:32](=[O:33])[CH2:31][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)[C:39]([CH3:41])([CH3:42])[CH3:40])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@@H]1C[C@@]2(CN1)CN(c1cccc(Cl)c1)C(=O)O2
Reactant: CC(C)(C)[C@H](NC(=O)CC1CCCCC1)C(=O)O
Product: CC(C)(C)OC(=O)[C@@H]1C[C@]2(CN(c3cccc(Cl)c3)C(=O)O2)CN1C(=O)[C@@H](NC(=O)CC1CCCCC1)C(C)(C)C
Yield: 50 %

Procedure:
Following the procedure from Example 1 step G using (5R,8S)-tert-butyl-3-(3-chlorophenyl)-2-oxo-1-oxa-3,7-diazaspiro[4.4]nonane-8-carboxylate (B4) (20 mg, 54 μmol, 1 eq.) and (S)-2-(2-cyclohexylacetamido)-3,3-dimethylbutanoic acid (16 mg, 63 μmol, 1.2 eq.) gave 16 mg (27 μmol) of (5R,8S)-tert-butyl-3-(3-chlorophenyl)-7-((S)-2-(2-cyclohexylacetamido)-3,3-dimethylbutanoyl)-2-oxo-1-oxa-3,7-diazaspiro[4.4]nonane-8-carboxylate (C4). LC MS+/−: 590.31/589.47 at 3.95 min (10-90%, 3-5 min, Formic Acid).
Reaction SMILES: [CH2:1]=[C:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([O:13]C)=O)[C:5]=2[CH2:4][CH2:3]1.[OH-:15].[Na+].OO.[NH4+].[Cl-].CC(C[AlH]CC(C)C)C>C1COCC1.O.C(Cl)Cl>[CH:2]1([CH2:1][OH:15])[C:10]2[C:5](=[C:6]([CH2:11][OH:13])[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1
Reactant: C=C1CCc2c1cccc2C(=O)OC
Reactant: [OH-]
Agent: CC(C)C[AlH]CC(C)C
Agent: OO
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: OCc1cccc2c1CCC2CO
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of methyl 1-methylidene-2,3-dihydro-1H-indene-4-carboxylate (1.4 g, 7.4 mmol) in THF (15 mL) was added borane THF complex (1.0 M, 9.7 mL, 9.7 mmol) at 0° C. The mixture was allowed to stir for 3 hours. To the reaction was added 2N sodium hydroxide (7.5 mL, 15 mmol) and 30% hydrogen peroxide (1.7 mL, 15 mmol). The mixture was then allowed to warm to RT. LC analysis showed complete reaction within 30 minutes. The reaction was neutralized with NH4Cl, diluted with water, extracted with EtOAc, dried over sodium sulfate, and purified by silica gel chromatography. The intermediate hydroxyester (1.1 g) was collected after removal of solvents. To a DCM (10 mL) solution of the hydroxyester (750 mg, 3.6 mmol) was added DIBAL-H (18 mL, 18 mmol) at −78° C. The reaction was allowed to stir for 16 h, warming to RT slowly. The reaction was diluted with DCM (30 mL), and worked up with Roschelle's salt. The organic layer was separated using a separatory funnel, dried over sodium sulfate, and the crude product was purified by silica gel chromatography to afford 2,3-dihydro-1H-indene-1,4-diyldimethanol. 1H-NMR (500 MHz, CDCl3) δ ppm 7.25-7.30 (m, 3H), 4.72 (s, 3H), 3.85 (m, 2H), 3.42 (m, 1H), 3.03 (m, 1H), 2.95 (m, 1H), 2.34 (m, 1H), 2.04 (m, 1H).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:13])[CH:11]=2)[C:6](=[C:14](Cl)[C:15]2[CH:20]=[CH:19][C:18]([CH2:21][N:22]3[CH:26]=[CH:25][N:24]=[CH:23]3)=[CH:17][CH:16]=2)[C:5]1=[O:28])(=O)C.[CH3:29][N:30]([CH2:32][C:33]([N:35]([CH3:43])[C:36]1[CH:41]=[CH:40][C:39]([NH2:42])=[CH:38][CH:37]=1)=[O:34])[CH3:31].C(N(CC)CC)C.N>CN(C)C=O.O.CO>[CH3:31][N:30]([CH2:32][C:33]([N:35]([C:36]1[CH:37]=[CH:38][C:39]([NH:42]/[C:14](=[C:6]2\[C:5](=[O:28])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([Cl:13])[CH:11]=3)/[C:15]2[CH:16]=[CH:17][C:18]([CH2:21][N:22]3[CH:26]=[CH:25][N:24]=[CH:23]3)=[CH:19][CH:20]=2)=[CH:40][CH:41]=1)[CH3:43])=[O:34])[CH3:29]
Reactant: CN(C)CC(=O)N(C)c1ccc(N)cc1
Reactant: CC(=O)N1C(=O)C(=C(Cl)c2ccc(Cn3ccnc3)cc2)c2ccc(Cl)cc21
Agent: N
Solvent: O
Solvent: CO
Solvent: CN(C)C=O
Product: CN(C)CC(=O)N(C)c1ccc(N/C(=C2\C(=O)Nc3cc(Cl)ccc32)c2ccc(Cn3ccnc3)cc2)cc1
Temperature: 60 °C
Reaction time: 15 h

Procedure:
0.7 g of 1-acetyl-3-(1-chloro-1-(4-(imidazol-1-yl-methyl)-phenyl)-methylene)-6-chloro-2-indolinone (educt X.1), 0.4 g of N-(dimethylamino-methylcarbonyl)-N-methyl-p-phenylenediamine (educt XV.125) and 1.2 ml of triethylamine are dissolved in 10 ml of dimethylformamide and stirred for 15 hours at 60° C. After cooling, 10 ml of methanol and 2 ml concentrated ammonia are added and the mixture is stirred for a further three hours at ambient temperature. Water is added and the mixture is extracted with ethyl acetate. The organic phase is washed three times with water, dried over sodium sulphate and concentrated in the rotary evaporator. The residue is purified through a silica gel column with methylene chloride/methanol/ammonia 10:1:0.1 as eluant.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[F:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][N:13]=1.[Br:19][C:20]1[CH:30]=[CH:29][C:23]([C:24](OCC)=[O:25])=[CH:22][CH:21]=1.Cl.[OH-].[Na+]>C1COCC1>[Br:19][C:20]1[CH:30]=[CH:29][C:23]([C:24](=[O:25])[CH2:18][C:16]2[CH:15]=[CH:14][N:13]=[C:12]([F:11])[CH:17]=2)=[CH:22][CH:21]=1
Reactant: Cc1ccnc(F)c1
Reactant: CCOC(=O)c1ccc(Br)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(Cc1ccnc(F)c1)c1ccc(Br)cc1
Reaction time: 0.75 h

Procedure:
To a solution of sodium bis(trimethylsilyl)amide (235 mL, 2M) in THF (750 mL) under nitrogen, cooled to 2° C., was added 2-fluoro-4-methylpyridine (25 g, 0.225 mol) and the solution stirred for 45 minutes in an ice bath. Ethyl 4-bromobenzoate (55 g, 0.239 mol) was added and the reaction was stirred overnight at RT. The reaction mixture was poured into excess aqueous 2N HCl, and the aqueous layer was made basic with 5 N NaOH and extracted with EtOAc. The organic extracts were combined, washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was dissolved in CH2Cl2 and filtered through a cotton plug. Hexanes were added and the CH2Cl2 was removed under reduced pressure until precipitation of the title compound occurred as a pale yellow solid. 1H NMR (400 MHz, CDCl3): δ8.20 (m, 1H), 7.85 (m, 2H), 7.65 (m, 2H), 7.05 (m, 1H), 6.82 (m, 1H), 4.30(s, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:10][CH:9]=2)=[N:6][CH:7]=1.CS(O[CH2:27][CH2:28][C@H:29]([F:34])[CH2:30][CH2:31][CH2:32][CH3:33])(=O)=O.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[F:34][C@H:29]([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:28][CH2:27][O:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:13]=2)=[N:6][CH:7]=1
Reactant: CCCC[C@@H](F)CCOS(C)(=O)=O
Reactant: Oc1cnc(-c2ccc(OCc3ccccc3)cc2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCC[C@@H](F)CCOc1cnc(-c2ccc(OCc3ccccc3)cc2)nc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 88.8 %

Procedure:
A mixture of 1.12 g of 5-hydroxy-2-(4-benzyloxyphenyl)pyrimidine, 1.30 g of 3-(R)-fluoroheptyl methanesulfonate, 1.2 g of potassium carbonate, and 50 ml of DMF was stirred at 80° C. for 4 hours. After cooling, the reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water and distilled to remove the solvent to obtain a residue weighing 2.12 g. Recrystallization of the residue from ethanol furnished 1.41 g (percent yield: 87.7%) of 5-[3-(R)-fluoroheptyloxy]-2-(4-benzyloxyphenyl)pyrimidine.