Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][CH:6]2O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH2:4][CH:5]=[CH:6]2
Reactant: OC1CCc2c(Br)cc(F)cc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Fc1cc(Br)c2c(c1)C=CC2
Yield: 97.6 %

Procedure:
According to Scheme 2, step 2: A mixture of 4-bromo-6-fluoro-indan-1-ol (4a) (10.0 g, 43.3 mmol) and para-toluene sulfonic acid monohydrate (372 mg, 2.16 mmol) in toluene was heated at reflux for 2.5 h. The solution was washed with aqueous saturated NaHCO3 and brine, dried over MgSO4 and solvents evaporated to give 9.0 g of 7-Bromo-5-fluoro-1H-indene (5a) which was used immediately in the next step without purification.
Reaction SMILES: N[C:2]1[N:7]([CH2:8][C:9]2C=CC(Cl)=CC=2)[C:6](=[O:16])[NH:5][C:4](=O)[C:3]=1NC(=O)C(C)C.CC(C)([O-:27])C.[K+].C(Br)C.Cl>CN(C=O)C>[CH2:8]([N:7]1[C:2](=[O:27])[CH:3]=[CH:4][NH:5][C:6]1=[O:16])[CH3:9]
Reactant: CC(C)C(=O)Nc1c(N)n(Cc2ccc(Cl)cc2)c(=O)[nH]c1=O
Reactant: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCBr
Product: CCn1c(=O)cc[nH]c1=O
Reaction time: 3 h

Procedure:
13.47 g (40 mM) of 6-amino-1-(4-chlorobenzyl)-5-isobutyrylaminouracil were dissolved in 130 ml of DMF, treated at 5° C. with 4.57 g (40.8 mM) potassium t-butoxide and after dissolution, 3.28 ml (44 mM) of ethyl bromide added. After 3 hours, another 1.14 g of t-BuOK and 1.64 ml of ethyl bromide were added. After a further 1.5 hours, 1.64 ml of ethyl bromide was supplemented. After a total of 22 hours, the solution was neutralized with 1N HCl to pH 7 and the solvents evaporated in vacuo. The residue was taken up in dichloromethane-water and the organic phase collected giving 17.66 of crude 3-ethyl uracil, which was dissolved in 17.6 ml of 1N NaOH and heated under reflux for 1 hour. The solution was treated twice with 1 g of charcoal, filtered and neutralized with 5N HCl to pH 7. The solid was diluted with water, collected, and dried. The crude material was recrystallized from methanol to give 7.42 g (49.2%) of 3-(4-chlorobenzyl)-1-ethyl-8-isopropyl-xanthine, mp 221-2° C.
Reaction SMILES: [NH2:1][C@H:2]([C:13]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][C@@H:16]1[CH3:21])=[O:14])[CH2:3][NH:4][C:5]([C:7]1[S:8][C:9]([Cl:12])=[CH:10][CH:11]=1)=[O:6].C(C1C(N2CCOCC2=O)=CC=CC=1S(N[C@H](C(N1CCO[C@H](C)C1)=O)CNC(C1SC(Cl)=CC=1)=O)(=O)=O)C.CCN(C(C)C)C(C)C.[Cl:70][C:71]1[CH:72]=[C:73]([C:79]2[C:80]([CH2:89][CH3:90])=[C:81]([S:85](Cl)(=[O:87])=[O:86])[CH:82]=[CH:83][CH:84]=2)[C:74](=[O:78])[N:75]([CH3:77])[CH:76]=1>C(Cl)Cl.O1CCOCC1.C(Cl)Cl>[Cl:70][C:71]1[CH:72]=[C:73]([C:79]2[C:80]([CH2:89][CH3:90])=[C:81]([S:85]([NH:1][C@H:2]([C:13]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][C@@H:16]3[CH3:21])=[O:14])[CH2:3][NH:4][C:5]([C:7]3[S:8][C:9]([Cl:12])=[CH:10][CH:11]=3)=[O:6])(=[O:86])=[O:87])[CH:82]=[CH:83][CH:84]=2)[C:74](=[O:78])[N:75]([CH3:77])[CH:76]=1
Reactant: CCc1c(-c2cc(Cl)cn(C)c2=O)cccc1S(=O)(=O)Cl
Reactant: C[C@H]1COCCN1C(=O)[C@@H](N)CNC(=O)c1ccc(Cl)s1
Agent: CCc1c(N2CCOCC2=O)cccc1S(=O)(=O)N[C@@H](CNC(=O)c1ccc(Cl)s1)C(=O)N1CCO[C@H](C)C1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCc1c(-c2cc(Cl)cn(C)c2=O)cccc1S(=O)(=O)N[C@@H](CNC(=O)c1ccc(Cl)s1)C(=O)N1CCOC[C@@H]1C
Reaction time: 2 h

Procedure:
5-Chloro-thiophene-2-carboxylic acid [(S)-2-amino-3-((S)-3-methyl-morpholin-4-yl)-3-oxo-propyl]-amide, Intermediate 3 (78 mg, 0.235 mmol) was dissolved in 3 ml DCM/1,4-Dioxane (1:1) and DIPEA (164 μl, 0.94 mmol). Intermediate 65 (82 mg, 0.235 mmol) in 1.5 ml DCM was slowly added and the reaction was stirred for 2 h. Then the solution was evaporated to dryness and purified by prep. HPLC. After lyophilization the title compound is obtained as colorless, amorphous solid.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:5](=[O:14])[CH2:6][CH2:7][CH2:8][C:9]=2[C:10]=1[C:11]([OH:13])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(N(CC)CC)C.[CH2:43]([N:45]([CH2:49][CH3:50])[CH2:46][CH2:47][NH2:48])[CH3:44]>CN(C=O)C>[CH2:43]([N:45]([CH2:49][CH3:50])[CH2:46][CH2:47][NH:48][C:11]([C:10]1[C:9]2[CH2:8][CH2:7][CH2:6][C:5](=[O:14])[C:4]=2[NH:3][C:2]=1[CH3:1])=[O:13])[CH3:44]
Reactant: Cc1[nH]c2c(c1C(=O)O)CCCC2=O
Reactant: CCN(CC)CCN
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c2c1CCCC2=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 78.9 %

Procedure:
A mixture of 2-methyl-7-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid (S4) 0.2 g (1.0 mmol), HOBt 0.16 g (1.2 mmol), EDCI 0.24 g (1.2 mmol) and triethylamine 0.2 g (2.0 mmol) in 10 ml DMF was stirred at room temperature for 20 min, then N1,N1-diethylethane-1,2-diamine 0.24 g (2.1 mmol) was added. After stirred at room temperature for 24 hours, the mixture was poured into the ice water and extracted with CH2Cl2. The organic layer separated was washed with water and saturated sodium chloride solution, then dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column, eluted with CH2Cl2/MeOH (30:1), to give 0.23 g (79%) of the titled compound as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][O:12][CH:11]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:25]=1F.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOCC>[C:1]([O:5][C:6](=[O:22])[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][O:12][CH:11]([C:15]2[CH:16]=[CH:17][C:18]([O:21][C:25]3[C:24]([Cl:23])=[CH:29][CH:28]=[CH:27][C:26]=3[Cl:30])=[CH:19][CH:20]=2)[CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Fc1c(Cl)cccc1Cl
Reactant: CC(C)(C)OC(=O)CCN1CCOC(c2ccc(O)cc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CCN1CCOC(c2ccc(Oc3c(Cl)cccc3Cl)cc2)C1
Temperature: 25 °C

Procedure:
A mixture of 3-[2-(4-hydroxy-phenyl)-morpholin-4-yl]-propionic acid tert-butyl ester (200 mg; 0.65 mmol), 2,6-dichlorofluorobenzene (107.35 mg; 0.65 mmol) and K2CO3 (134.9 mg; 0.98 mmol), in DMF (10 mL) was heated at 100° C., for 2 days. After cooling to RT the mixture was diluted with Et2O and washed with water (3 times). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography (Et2O) to afford 3-{2-[4-(2,6-dichloro-phenoxy)-phenyl]-morpholin-4-yl}-propionic acid tert-butyl ester: (150.00 mg).
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[C:13]3[C:8]=2[CH:9]=[CH:10][CH:11]=[N:12]3)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[Sn]Cl>CCO>[N:1]1([C:7]2[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]3[C:8]=2[CH:9]=[CH:10][CH:11]=[N:12]3)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(N2CCOCC2)c2cccnc12
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Nc1ccc(N2CCOCC2)c2cccnc12
Yield: 87.2 %

Procedure:
In a similar fashion using route 19 general procedure 29, 5-morpholin-4-yl-8-nitro-quinoline 580 (200 mg, 0.77 mmol), SnCl2 (696 mg, 3.09 mmol) and EtOH (5 ml) gave the title compound (154 mg, 87%) which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]1)[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24](Cl)=[O:25])=[CH:19][CH:18]=1>>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]([N:7]([CH2:1][C:2]2[O:6][CH:5]=[CH:4][CH:3]=2)[CH:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[O:25])=[CH:19][CH:18]=1
Reactant: COc1ccc(CC(=O)Cl)cc1
Reactant: CN1CCC(NCc2ccco2)CC1
Product: COc1ccc(CC(=O)N(Cc2ccco2)C2CCN(C)CC2)cc1

Procedure:
Starting materials: 50ELH66B (0.21 g, 1.08 mmol, 1.0 eq.), 4-methoxyphenylacetylchloride (0.2 g, 1.0 eq.).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][C:16]=2[C:17]2[CH2:22][CH:21]([CH3:23])[CH2:20][CH:19]([O:24][Si](C(C)(C)C)(C)C)[CH:18]=2)=[O:9])[CH:5]=[CH:4][C:3]=1[F:32].[F:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[C:35]=1B(O)O.C(N(CC)CC)C>CCO.C1(C)C=CC=CC=1>[F:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[C:35]=1[C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][C:16]=2[C:17]2[CH2:22][CH:21]([CH3:23])[CH2:20][CH:19]([OH:24])[CH:18]=2)=[O:9])[CH:5]=[CH:4][C:3]=1[F:32]
Reactant: OB(O)c1c(F)cccc1F
Reactant: CC1CC(c2ccncc2NC(=O)c2ccc(F)c(Br)n2)=CC(O[Si](C)(C)C(C)(C)C)C1
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC1CC(c2ccncc2NC(=O)c2ccc(F)c(-c3c(F)cccc3F)n2)=CC(O)C1

Procedure:
A solution of 6-bromo-N-(4-(3-(tert-butyldimethylsilyloxy)-5-methylcyclohex-1-enyl)pyridin-3-yl)-5-fluoropicolinamide (1.0 equiv), 2,6-difluorophenyl boronic acid (3.0 equiv.), tetrakistriphenylphosphine (0.2 equiv.) and triethylamine (3.0 equiv.) in 1:1 EtOH/toluene (0.1 M) was heated at 120° C. with microwave irradiation for 1200 seconds. Upon cooling, removal of the volatiles in vacuo, the Suzuki product was directly purified by reverse phase HPLC. The product fraction was lyophilized and the resulting TBDMS ether was deprotected as described in Method 9 yielding, after RP HPLC purification and lyophilization, 6-(2,6-difluorophenyl)-5-fluoro-N-(4-(3-hydroxy-5-methylcyclohex-1-enyl)pyridin-3-yl)picolinamide as the TFA salt. LCMS (m/z): 438.2 (MH+); LC Rt=2.00 min.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][CH:13]=[CH:12]3)[C:5]([NH2:18])=[N:4][CH:3]=1.[C:19](N1C=CN=C1)(N1C=CN=C1)=[O:20]>C1COCC1>[Br:1][C:2]1[N:7]=[C:6]2[N:8]([C:9]3[CH:10]=[C:11]4[C:15](=[CH:16][CH:17]=3)[NH:14][CH:13]=[CH:12]4)[C:19](=[O:20])[NH:18][C:5]2=[N:4][CH:3]=1
Reactant: Nc1ncc(Br)nc1Nc1ccc2[nH]ccc2c1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=c1[nH]c2ncc(Br)nc2n1-c1ccc2[nH]ccc2c1
Temperature: 65 °C
Yield: 40.9 %

Procedure:
To a solution of 6-bromo-N2-(1H-indol-5-yl)pyrazine-2,3-diamine (0.450 g, 1.48 mmol) in THF (5 mL) was added carbonyldiimidazole (1.20 g, 7.40 mmol). The resulting mixture was heated at 65° C. for 48 hr, after which it was concentrated in vacuo and partitioned between EtOAc and H2O. The organic layer was separated, dried over MgSO4, filtered, and concentrated in vacuo to yield a residue that was purified via silica gel chromatography eluting with EtOAc to yield the title compound (0.20 g, 41%). HPLC retention time: 2.07 minutes; MS ESI (m/z): 330.2/332.2 (M+1)+, calc. 329.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][CH:14]2[N:18]=[C:17](C(Cl)(Cl)Cl)[O:16][N:15]2[NH2:23])=[CH:7][CH:6]=1)[CH3:3].[CH3:24][NH2:25]>C(O)C>[CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][CH:14]2[N:18]=[C:17]([NH:25][CH3:24])[O:16][N:15]2[NH2:23])=[CH:7][CH:6]=1)[CH3:3]
Reactant: CN(C)Cc1ccc(CSCCC2N=C(C(Cl)(Cl)Cl)ON2N)o1
Reactant: CN
Solvent: CCO
Product: CNC1=NC(CCSCc2ccc(CN(C)C)o2)N(N)O1
Temperature: 50 °C

Procedure:
The oxadiazole from Example 16 (3 g, 7.5 mmol) is dissolved in 25 ml of ethanol saturated with methylamine and the solution heated in a sealed tube at 50° C. for 16 hours. The mixture is concentrated to provide 3-[2-[(5-Dimethylaminomethyl-2-furanyl)methylthio]ethyl]-amino-5-methylamino-1,2,4-oxadiazole as an oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([O:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:8])=[CH:3][C:2]=1[C:16]([O:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:17].C1C=C(Cl)C=C(C(OO)=[O:33])C=1>>[N+:1]1([O-:33])[C:2]([C:16]([O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:17])=[CH:3][C:4]([C:7]([O:9][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]2)=[O:8])=[CH:5][CH:6]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(OC1CCCCC1)c1ccnc(C(=O)OC2CCCCC2)c1
Product: O=C(OC1CCCCC1)c1cc[n+]([O-])c(C(=O)OC2CCCCC2)c1

Procedure:
From 1 g of dicyclohexyl pyridine-2,4-dicarboxylate and 0.75 g of MCPBA.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C:10]2[CH:11]=[N:12][N:13]([CH3:32])[C:14]=2[C@H:15]2[O:21][CH2:20][C@H:19]([O:22][CH3:23])[C@H:18]([NH:24]C(=O)OC(C)(C)C)[CH2:17][CH2:16]2)=[O:8])[N:6]=1.[F:33][C:34]1[C:39]([F:40])=[CH:38][CH:37]=[C:36]([F:41])[C:35]=1B(O)O>>[NH2:24][C@H:18]1[C@@H:19]([O:22][CH3:23])[CH2:20][O:21][C@H:15]([C:14]2[N:13]([CH3:32])[N:12]=[CH:11][C:10]=2[NH:9][C:7]([C:5]2[N:6]=[C:2]([C:35]3[C:36]([F:41])=[CH:37][CH:38]=[C:39]([F:40])[C:34]=3[F:33])[S:3][CH:4]=2)=[O:8])[CH2:16][CH2:17]1
Reactant: CO[C@H]1CO[C@H](c2c(NC(=O)c3csc(Br)n3)cnn2C)CC[C@H]1NC(=O)OC(C)(C)C
Reactant: OB(O)c1c(F)ccc(F)c1F
Product: CO[C@H]1CO[C@H](c2c(NC(=O)c3csc(-c4c(F)ccc(F)c4F)n3)cnn2C)CC[C@H]1N

Procedure:
Following the procedure for Example 101 starting from tert-butyl ((3R,4R,7S)-7-(4-(2-bromothiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-3-methoxyoxepan-4-yl)carbamate (Intermediate 101), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (2,3,6-trifluorophenyl)boronic acid gave 258. 1H NMR (400 MHz, DMSO-d6) δ 10.15 (s, 1H), 8.69 (s, 1H), 7.95 (s, 1H), 7.77 (qd, J=9.4, 4.9 Hz, 1H), 7.49-7.38 (m, 1H), 5.12 (t, J=5.6 Hz, 1H), 3.91-3.76 (m, 2H), 3.71 (s, 3H), 3.46-3.36 (m, 1H), 3.32-3.21 (m, 1H), 3.01 (s, 3H), 2.49-2.36 (m, 1H), 1.73-1.49 (m, 3H), 1.41 (br, 2H). LCMS (ES+) m/z 482 (M+1).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([OH:13])=O)=[CH:2]1.[CH:14]1([N:20]([CH3:24])[CH2:21][CH2:22][NH2:23])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[CH:14]1([N:20]([CH3:24])[CH2:21][CH2:22][NH:23][C:11](=[O:13])[CH2:10][C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=C(O)Cc1c[nH]c2ccccc12
Reactant: CN(CCN)C1CCCCC1
Product: CN(CCNC(=O)Cc1c[nH]c2ccccc12)C1CCCCC1

Procedure:
Compound 11a was prepared using the amino acid coupling procedure described in Example 10 using (1H-indol-3-yl)-acetic acid and N1-Cyclohexyl-N1-methyl-ethane-1,2-diamine as the starting materials: LC-MS (Method B, retention time=0.516 min. MS calc'd for C19H28N3O (MH+): 314.2. Found 314.5.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[CH2:38][C@@H:37]2[C@:32]([CH3:46])([CH2:33][CH2:34][C@H:35]([O:39][CH:40]3[CH2:45][CH2:44][CH2:43][CH2:42][O:41]3)[CH2:36]2)[C@@H:31]2[C@@H:10]1[C@H:11]1[C@:28]([CH3:47])([CH2:29][CH2:30]2)[C@@H:14]([C@H:15]([CH3:27])[CH2:16][CH2:17][CH2:18][O:19][Si](C(C)(C)C)(C)C)[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH2:1]([O:8][C@@H:9]1[CH2:38][C@@H:37]2[C@:32]([CH3:46])([CH2:33][CH2:34][C@@H:35]([O:39][CH:40]3[CH2:45][CH2:44][CH2:43][CH2:42][O:41]3)[CH2:36]2)[C@@H:31]2[C@@H:10]1[C@H:11]1[C@:28]([CH3:47])([CH2:29][CH2:30]2)[C@@H:14]([C@H:15]([CH3:27])[CH2:16][CH2:17][CH2:18][OH:19])[CH2:13][CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](CCCO[Si](C)(C)C(C)(C)C)[C@H]1CC[C@H]2[C@@H]3[C@H](OCc4ccccc4)C[C@H]4C[C@@H](OC5CCCCO5)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@H](CCCO)[C@H]1CC[C@H]2[C@@H]3[C@H](OCc4ccccc4)C[C@H]4C[C@H](OC5CCCCO5)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 90.4 %

Procedure:
Compound 2007 (0.0527 g, 0.079 mmol) in anhydrous THF (4 ml) under Ar was treated with tetrabutylammonium fluoride (TBAF) (0.237 ml, 1 M in THF, 0.237 mmol). The solution was stirred until no starting material remained by TLC. The solvent was removed in vacuo, the residue taken up in 5 ml CH2Cl2, washed with 5 ml aqueous saturated NaHCO3 solution, and the aqueous layer was extracted 2×with 5 ml CH2 Cl2. The combined organic layers were dried over anhydrous MgSO4, filtered, and the solvent removed in vacuo. Flash chromatography (SiO2 8:1 hexanes:EtOAc) gave compound 2008 (0.0395 g, 90%) as a white solid foam. 1H NMR (500 MHz, CDCl3) δ: 7.35-7.34 (m, 5H, benzyl Ar-H), 4.71-4.69 (m, 1H, THP ether methine H), 4.585 (d, J=11.8 Hz, 1/2H, benzyl-CH2) , 4.58 (d, J=11.8 Hz, 1/2H, benzyl-CH2), 4.315 (d, J=12.0 Hz, 1/2H, benzyl-CH2), 4.29 (d, J=12.0 Hz, 1/2H, benzyl-CH2) 3.94-3.90 (m, 1H, THP OCH2), 3.62-3.58 (m, 3H, C-24 H & THP OCH2), 3.50-3.48 (m, 1H, C-3 H), 3.45 (s, 1H, 7-H), 0.92 (d, J=6.6 Hz, 3H, C-21 H), 0.81 (s, 3H, C-19 H), 0.63 (s, 3H, C-18 H) (Note: product is a mixture of diastereomers); IR (CHCl3) 3600, 2900 cm -1 ; MS (CI/isobutane) m/z 554 (M+1, 2%), 361 (M+1-THP-HOBn, 42%), 343 (M+1-THP-HPBn, H2O, 100%); m.p. 52°-5° C.; Anal. calcd. for C36H56O4 : C=78.21, H=10.21; Found: C=77.93, H=10.39.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([C:14]([O:16][CH3:17])=[O:15])[CH2:7][C:8]([CH3:13])([CH3:12])[O:9]2)=[CH:4][CH:3]=1.[Br:18]N1C(=O)CCC1=O>CN(C=O)C.C(OCC)(=O)C>[Br:18][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[F:1])[O:9][C:8]([CH3:13])([CH3:12])[CH2:7][CH:6]2[C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)C1CC(C)(C)Oc2cc(F)ccc21
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C1CC(C)(C)Oc2cc(F)c(Br)cc21
Temperature: 50 °C
Yield: 93.2 %

Procedure:
Methyl 7-fluoro-2,2-dimethyl-3,4-dihydro-2H-chromene-4-carboxylate (187 mg, 0.785 mmol) was diluted with DMF (5 mL) followed by the addition of N-bromosuccinimide (154 mg, 0.863 mmol). The reaction was heated at 50° C. for 2.5 hours. The reaction was cooled, diluted with ethyl acetate and washed with water, saturated sodium bicarbonate, water, and brine. The organic layer was dried over MgSO4, filtered and concentrated. The material was purified using a Biotage 40M cartridge, gradient 5% ethyl acetate/hexane to 50% to yield the title compound (232 mg, 93.2% yield).
Reaction SMILES: [NH2:1][C:2]([NH2:19])=[N:3][C:4](=[O:18])[C:5]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[C:8]([O:15]C)=[CH:7][C:6]=1[CH3:17].Cl.N1C=CC=CC=1>N1C=CC=CC=1>[NH2:19][C:2]([NH2:1])=[N:3][C:4](=[O:18])[C:5]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[C:8]([OH:15])=[CH:7][C:6]=1[CH3:17]
Reactant: COc1cc(C)c(C(=O)N=C(N)N)cc1S(C)(=O)=O
Agent: Cl
Solvent: c1ccncc1
Product: Cc1cc(O)c(S(C)(=O)=O)cc1C(=O)N=C(N)N

Procedure:
600 mg of N-diaminomethylene-2-methyl-4-methoxy-5-methylsulfonylbenzamide (obtainable according to Ex. 2) are boiled for 3 hours in 80 ml of pyridine together with 1 g of pyridine hydrochloride. The mixture is cooled and evaporated, and the residue is worked up in the customary manner to give N-diaminomethylene-2-methyl-4-hydroxy-5-methylsulfonylbenzamide, m.p. >260°.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13]COC)[CH:8]=1)[CH3:6])[CH3:2].C(O)(C(F)(F)F)=O.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:1]([O:3][C:4](=[O:17])[CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([OH:13])[CH:8]=1)[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)c1cccc(OCOC)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(C)c1cccc(O)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 2-(3-methoxymethoxy-phenyl)-propionic acid ethyl ester in the dichloromethane was added dropwise TFA (150 mL) at 0□. The reaction mixture was stirred 1 h at 0°, and solid sodium bicarbonate (200 g) was added very slowly. The resulting mixture was poured into ice water very slowly and extracted with EtOAc. The combined organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting residue was chromatographed on silica gel (n-Hex:EtOAc=10:1 to 4:1) to afford the product as colorless oil. (19.0 g, 70.4% 2 steps)
Reaction SMILES: [Cr]([O-])(OCl)(=O)=O.[NH+]1C=CC=CC=1.[OH:13][CH2:14][C:15]1[CH:16]=[C:17]([C:21]2[NH:25][C:24](=[O:26])[O:23][N:22]=2)[CH:18]=[CH:19][CH:20]=1.ClCCl>O1CCCC1>[O:26]=[C:24]1[O:23][N:22]=[C:21]([C:17]2[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=2)[CH:14]=[O:13])[NH:25]1
Reactant: O=c1[nH]c(-c2cccc(CO)c2)no1
Agent: O=[Cr](=O)([O-])OCl
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=Cc1cccc(-c2noc(=O)[nH]2)c1
Yield: 71.9 %

Procedure:
Add pyrdinium chloro chromate (5.22 g, 24.2 mmol) to a solution of 3-(3-hydroxymethyl-phenyl)-4H-[1,2,4]oxadiazol-5-one (3.10 g, 16.1 mmol) in tetrahydrofuran:dichloromethane (125 mL:125 mL) and stir. After 4 hours concentrate under reduced pressure to give a residue. Purify the residue by flash chromatography eluting with ethyl acetate:hexanes:acetic acid (50%:50%:0.1%) to yield the title product as a white solid (2.20 g, 72%): 1H NMR (DMSO-d6) δ 7.83 (t, 1H), 8.10-8.17 (m, 2H), 8.35 (m, 1H), 10.09 (s, 1H), 13.15 (bs, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:15]([O:17]CC)=[O:16])=[CH:4][NH:5][C:6]=1[C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-].[Na+]>CO>[CH3:1][C:2]1[C:3]([C:15]([OH:17])=[O:16])=[CH:4][NH:5][C:6]=1[C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)c1c[nH]c(C(=O)c2ccccc2)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(C(=O)O)c[nH]c1C(=O)c1ccccc1
Yield: 88.4 %

Procedure:
Ethyl 4-methyl-5-benzoylpyrrole-3-carboxylate (0.8 g.) was combined with 20 ml. of methanol and 15 ml. of 1 N sodium hydroxide and boiled in an open flask for 1.5 hours on a steam bath. The aqueous residue was cooled, extracted with 10 ml. of ether, and acidified with conc. hydrochloric acid to yield crystalline 4-methyl-5-benzoylpyrrole-3-carboxylic acid (630 mg., m.p. 241°-243° C., m/e 229).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][NH:8][CH2:7]1)=[O:5])[CH3:2].C(N(C(C)C)C(C)C)C.C1(C)C=CC(S(O[CH2:31][CH2:32][CH:33]2[CH2:42][CH2:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[O:34]2)(=O)=O)=CC=1>CN(C)C=O>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:31][CH2:32][CH:33]2[CH2:42][CH2:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[O:34]2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)OCCC2CCc3ccccc3O2)cc1
Reactant: CCOC(=O)C1CCCNC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CCCN(CCC2CCc3ccccc3O2)C1
Reaction time: 16 h
Yield: 71.7 %

Procedure:
First 1.57 g (10 mmol) of piperidine-3-carboxylic acid ethyl ester and then 2.07 g (16 mmol) of N-ethyl-N,N-diisopropylamine are added to a solution of 2.66 g (8 mmol) of 2-[2-(p-toluenesulphonyloxy)ethyl]chroman in 35 ml of absolute dimethylformamide. The mixture is stirred for 16 hours at 60° and, after cooling, is concentrated by evaporation under a high vacuum. Water is added to the oily residue and extraction is carried out with diethyl ether. The combined organic phases are washed with water and extracted with 2N hydrochloric acid. The combined hydrochloric acid extracts are rendered alkaline, while cold, with sodium hydroxide solution (30% strength) and extracted with dichloromethane. The combined dichloromethane phases are dried over sodium sulphate and concentrated by evaporation in vacuo. 2.28 g (90.1%) of crude product are obtained and are chromatographed on 120 g of silica gel (0.040-0.063 mm) using ethyl acetate as the eluant. 1.82 g (72.2%) of 1-[2-(chroman- 2-yl)ethyl]-piperidine-3-carboxylic acid ethyl ester are then obtained in the form of a yellow oil. The 1-[2-(chroman-2-yl)ethyl]-piperidine-3-carboxylic acid ethyl ester hydrochloride produced therefrom using hydrochloric acid in diethyl ether crystallises from ethanol/diethyl ether and melts at 148°-151°.