Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=1)=O.[C:20]([O:27][CH3:28])(=[O:26])[CH2:21][CH2:22][C:23]([CH3:25])=O.Cl[Si](C)(C)C>CN(C=O)C>[CH3:25][C:23]1[N:1]=[C:2]2[S:6][C:5]3[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=3[C:3]2=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[C:22]=1[CH2:21][C:20]([O:27][CH3:28])=[O:26]
Reactant: Nc1sc2c(c1C(=O)c1cccc(Cl)c1)CCCC2
Reactant: COC(=O)CCC(C)=O
Agent: C[Si](C)(C)Cl
Solvent: CN(C)C=O
Product: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1cccc(Cl)c1)CCCC3
Yield: 76.7 %

Procedure:
This compound was prepared according to the procedure B from (2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(3-chlorophenyl)methanone (0.291 g; 1 mmol), methyl levulinate (0.141 mL; 1.1 mmol), chlorotrimethylsilane (0.511 mL; 4 mmol) in DMF (4 mL) for 48 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (3-50%) in heptane furnished 0.296 g (76%) of the title compound as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([CH:15](O)[CH2:16][CH2:17][CH2:18][CH3:19])[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.O=S(Cl)[Cl:25]>C(Cl)Cl>[Cl:25][CH:15]([C:13]1[CH:12]=[CH:11][CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:22])([F:21])[F:1])=[CH:4][CH:5]=2)[N:14]=1)[CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCC(O)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CCCCC(Cl)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 103.8 %

Procedure:
To a solution of 1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}-1-pentanol (1.50 g, 4.85 mmol) in dry DCM was added SOCl2 (3.53 mL, 48.50 mmol), and the resulting solution stirred under nitrogen for 3 hours at rt. The mixture was then reduced under vacuum to afford the title compound as an oily yellow solid (1.65 g).
Reaction SMILES: C1(O[C:8]([N:10]2[CH2:14][CH2:13][C@@H:12]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]2)=[O:9])C=CC=CC=1.[CH2:23]([N:30]1[CH2:34][CH2:33][C@@H:32]([NH2:35])[CH2:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN1C(=O)CCC1>[C:19]([O:18][C:16](=[O:17])[NH:15][C@@H:12]1[CH2:13][CH2:14][N:10]([C:8](=[O:9])[NH:35][C@@H:32]2[CH2:33][CH2:34][N:30]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:31]2)[CH2:11]1)([CH3:20])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(C(=O)Oc2ccccc2)C1
Reactant: N[C@@H]1CCN(Cc2ccccc2)C1
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(C(=O)N[C@@H]2CCN(Cc3ccccc3)C2)C1
Temperature: 100 °C

Procedure:
(R)-3-tert-Butoxycarbonylamino-pyrrolidine-1-carboxylic acid phenyl ester (1 eq.) and (R)-1-benzyl-pyrrolidin-3-ylamine (1 eq.) are dissolved in NMP and heated at 100° C. for 1 hour.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[C:6]=1[F:17])=[O:4].Cl>[Pt]=O.CO>[F:19][C:2]([F:1])([F:18])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[C:6]=1[F:17])=[O:4]
Reactant: O=C(c1cccc(-c2ccncc2)c1F)C(F)(F)F
Agent: O=[Pt]
Agent: Cl
Solvent: CO
Product: O=C(c1cccc(C2CCNCC2)c1F)C(F)(F)F

Procedure:
Preparation according to preparation 9: 2,2,2-trifluoro-1-(2-fluoro-3-pyridin-4-ylphenyl)ethanone (1.26 g, 4.68 mmol), hydrochloric acid (0.2 ml, conc), methanol (20 ml), platinum oxide (0.12 g). Yield: 0.98 g. MS m/z (relative intensity, 70 eV) 275 (M+, 94), 274 (66), 149 (23), 101 (25) 56 (bp).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH3:7])=[CH:3][CH:2]=1>[Pd].C1C=CC=CC=1>[CH3:7][C:4]1[CH:5]=[CH:6][N:1]=[C:2]([C:2]2[CH:3]=[C:4]([CH3:7])[CH:5]=[CH:6][N:1]=2)[CH:3]=1
Reactant: Cc1ccncc1
Agent: [Pd]
Solvent: c1ccccc1
Product: Cc1ccnc(-c2cc(C)ccn2)c1
Reaction time: 24 h

Procedure:
Freshly distilled 4-picoline (600 ml) was refluxed with palladium on carbon 10% (w/w) for five days. The mixture was then refluxed for a further hour after addition of 100 ml of hot benzene. The palladium on carbon was then removed by filtration (glass-fibre paper). The filtration was repeated until a clear yellow solution was obtained. The volume of the solution was reduced by rotary evaporation to about 200 ml. and was left to stand for 24 hours. White crystals appeared which, after collection, were recrystalised from ethyl acetate. A colourless solid was recovered.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].C(O)(C(F)(F)F)=O.[CH2:35]1[CH2:40][CH2:39][CH:38]([C:41](=[O:46])[CH2:42][C:43](=O)[CH3:44])[CH2:37][CH2:36]1>>[CH:38]1([C:41](=[O:46])/[CH:42]=[C:43](\[NH:1][C@@H:2]([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]3[N:17]=[C:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[O:19][C:20]=3[CH3:21])=[CH:9][CH:8]=2)[C:3]([OH:5])=[O:4])/[CH3:44])[CH2:39][CH2:40][CH2:35][CH2:36][CH2:37]1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C[C@H](N)C(=O)O)cc1
Reactant: CC(=O)CC(=O)C1CCCCC1
Solvent: O=C(O)C(F)(F)F
Product: C/C(=C/C(=O)C1CCCCC1)N[C@@H](Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)O

Procedure:
The title compound was prepared (as described above for the preparation of Example 2) from 428 mg (0.89 mmol) of Intermediate 45 (as the TFA salt) and 150 mg (0.89 mmol) of Intermediate 33 to yield 245 mg (53% yield) of Example 43 as a solid beige-colored glass: TLC (DCM/MeOH (4:1): Rf=0.69; 1H NMR (DMSO-d6, 400 MHz) δ10.79 (d, 1H, J=9.0), 7.89 (m, 2H), 7.50-7.41 (m, 3H), 7.05 (d, 2H, J=8.4), 6.77 (d, 2H, J=8.4), 4.7 (s, 1H), 4.12 (t, 2H, J=6.5), 3.9 (br s, 1H), ), 3.04 (dd, 1H, J=13.6, 4.0), 2.87 (t, 2H, J=6.5), 2.64 (dd, 1H, J=13.6, 8.9), 2.32 (s, 3H), 1.9 (m, 1H), 1.6 (m, 4H), 1.5 (s, 3H), 1.25-1.05 (m, 4H): low resolution MS (ES+)m/e 517.3 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[CH2:5][N:6]=[C:7]=[O:8].[Cl:12][CH2:13][C:14]1[N:18]=[C:17]([NH2:19])[S:16][N:15]=1>CN(C1C=CN=CC=1)C.CN1C(=O)CCC1.CCOC(C)=O>[Cl:12][CH2:13][C:14]1[N:18]=[C:17]([NH:19][C:7]([NH:6][CH2:5][C:4]2[CH:9]=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=2)=[O:8])[S:16][N:15]=1
Reactant: O=C=NCc1cccc(F)c1
Reactant: Nc1nc(CCl)ns1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: O=C(NCc1cccc(F)c1)Nc1nc(CCl)ns1
Temperature: 25 °C
Yield: 72 %

Procedure:
3-Fluorobenzyl isocyanate (1.3 g, 8 mmol) was added into a mixture of Intermediate 38: 3-chloromethyl-[1,2,4]thiadiazol-5-ylamine (0.83 g, 5.5 mmol), and DMAP (22 mg, 0.14 mmol) in NMP (11 mL). The reaction mixture was heated in a microwave reactor for 1 hour at 100 C and then cooled to ambient temperature. The reaction mixture was diluted with EtOAc (75 mL) and washed with water (30 mL×2). The aqueous phase was extracted with EtOAc (40 mL×2). The combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated to give the crude product, which was purified by silica gel column chromatography to afford 1-(3-chloromethyl-[1,2,4]thiadiazol-5-yl)-3-(3-fluoro-benzyl)-urea as an off-white solid (1.2 g, 72%). LC-MS (m/z): 303.0 (M+H)
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])/[CH:2]=[CH:3]\[C:4]([O-:6])=[O:5].[CH2:11](O)[CH3:12]>>[C:4]([O:6][CH2:11][CH3:12])(=[O:5])/[CH:3]=[CH:2]\[C:1]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)/C=C\C(=O)[O-]
Reactant: CCO
Product: CCOC(=O)/C=C\C(=O)OCC

Procedure:
The bottom product from flash distillation column 417 is taken in line 449 to a secondary esterification reactor 450. This is provided with a stirrer 451 and a sparger 452 which is connected to a line 453 through which ethanol vapour is supplied to reactor 450. Further reaction of monoethyl maleate and ethanol occurs in reactor 450, resulting in formation of additional diethyl maleate. A stream containing recycled ethanol is returned to reactor 450 in line 454.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[N:19]([CH3:28])[C:18]2=[O:29])=[CH:12][C:3]=1[O:4][C:5]1[NH:10][C:9](=[O:11])[CH:8]=[CH:7][CH:6]=1.Br[CH:31]([CH3:36])[C:32]([O:34][CH3:35])=[O:33].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>O>[Cl:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[N:19]([CH3:28])[C:18]2=[O:29])=[CH:12][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([O:11][CH:31]([C:32]([O:34][CH3:35])=[O:33])[CH3:36])[N:10]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3cccc(=O)[nH]3)c(Cl)cc2F)c1=O
Reactant: COC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(C)Oc1cccc(Oc2cc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc2Cl)n1
Temperature: 50 °C
Reaction time: 1 h
Yield: 120.1 %

Procedure:
To a mixture of 50 mg of 6-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-pyridone, 21 mg of methyl 2-bromopropionate and 1 ml of N,N-dimethylformamide was added 21 mg of potassium carbonate, and the mixture was stirred for 1 hour at 50° C. The solution was cooled to room temperature, poured into water, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 72 mg of 2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-6-{1-(methoxycarbonyl)ethoxy}pyridine [present compound 2-42].
Reaction SMILES: Br[C:2]1[Se:3][CH:4]=[CH:5][CH:6]=1.[F:7][C:8]1[C:13]([F:14])=[C:12](B(O)O)[CH:11]=[CH:10][C:9]=1[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH3:25])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:24]([C:21]1[CH:22]=[CH:23][C:18]([C:9]2[CH:10]=[CH:11][C:12]([C:2]3[Se:3][CH:4]=[CH:5][CH:6]=3)=[C:13]([F:14])[C:8]=2[F:7])=[CH:19][CH:20]=1)[CH3:25]
Reactant: Brc1ccc[se]1
Reactant: CCc1ccc(-c2ccc(B(O)O)c(F)c2F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCc1ccc(-c2ccc(-c3ccc[se]3)c(F)c2F)cc1

Procedure:
A mixture of 56.0 g (0.27 mol) of 2-bromoselenophene, 70.0 g (0.27 mol) of 2,3-difluoro-4′-ethylbiphenyl-4-ylboronic acid, 22.0 g (19.0 mmol) of tetrakis(triphenylphosphine)palladium(0) and 800 ml of 2 N sodium carbonate soln. in 2.5 l of toluene/ethanol (1:1) is heated at 90° C. for 17 h. After cooling, the organic phase is separated off, and the aqueous phase is extracted with toluene. The combined organic phases are washed with water, and the solution is dried using sodium sulfate. The solution is concentrated to dryness, and the residue is purified by column chromatography (SiO2, toluene). The further purification is carried out by recrystallisation from ethanol and n-heptane. 2-(4′-Ethyl-2,3-difluorobiphenyl-4-yl)-selenophene is obtained as a yellowish solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=1[NH2:27]>>[NH2:27][C:26]1[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=1[C:6]1[CH:5]=[CH:4][C:3]([C:17]2[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=2)=[C:2]([F:1])[CH:7]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Reactant: Nc1ccccc1Br
Product: Nc1cnc(-c2ccc(-c3ccccc3N)cc2F)cn1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 6 utilizing 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amine and 2-bromoaniline. MS (ESI): mass calcd. for C16H13FN4, 280.11; m/z found, 281.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.36 (s, 1H), 8.02 (s, 1H), 7.91 (m, 1H), 7.31 (d, J=12.7, 2H), 7.04 (d, J=7.3, 2H), 6.82-6.58 (m, 4H), 4.94 (s, 2H).
Reaction SMILES: C(O)(C(F)(F)F)=O.[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][O:15][C:16](=[O:48])[NH:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([NH:27][C:28]2[C:33]([NH:34]C(OC(C)(C)C)=O)=[CH:32][CH:31]=[C:30]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[N:29]=2)=[O:26])=[CH:21][CH:20]=1>ClCCl>[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][O:15][C:16](=[O:48])[NH:17][CH2:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]([NH:27][C:28]2[C:33]([NH2:34])=[CH:32][CH:31]=[C:30]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[N:29]=2)=[O:26])=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)nc1NC(=O)c1ccc(CNC(=O)OCc2ccccn2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccc(-c2ccccc2)nc1NC(=O)c1ccc(CNC(=O)OCc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
TFA (1 mL, 12.98 mmol) was added to a flask containing pyridin-2-ylmethyl{4-[({3-[(tert-butoxycarbonyl)amino]-6-phenylpyridin-2-yl}amino)carbonyl]benzyl}carbamate (100 mg, 0.181 mmol) in dichloromethane (2 ml) and the mixture stirred at room temperature for 1 hour. The reaction was quenched by the addition of saturated sodium bicarbonate until bubbling stopped. The aqueous layer was extracted (3×) with EtOAc and dried over sodium sulfate. The organic product was purified using HPLC. LCMS of the major UV absorbant fraction indicated the presence of the desired product. 1H NMR (DMSO-d6) δ: 10.36 (s, 1H), 8.51 (d, J=4 Hz, 1H), 7.96-8.05 (m, 3H), 7.88-7.94 (m, 2H), 7.76-7.82 (m, 1H), 7.65 (d, J=8.3 Hz 1H), 7.32-7.45 (m, 5H), 7.18-7.32 (m, 3H), 5.12 (s, 2H), 5.09 (s, 2H), 4.28 (d, J=6.2 Hz, 2H) MS: cal'd 454 (MH+), exp 454 (MH+). The in vitro HDAC1 IC50 of this compound is 35 nM. The IC50 of this compound in HCT-116 cells is 560 nM. Percent Cyp inhibitions at 10 μM are 27, 47 and 24%, for Cyp3A4, 2C9, and 2D6, respectively. The inflection point for MK-499 binding is 2535 μM.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[N:11]=[C:10]([CH2:12][NH2:13])[CH:9]=[CH:8][C:6]=2[N:7]=1.[CH3:20][C:21]([CH3:26])([CH3:25])[C:22](O)=[O:23].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>CN(C)C=O>[Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)[C:5]2[N:11]=[C:10]([CH2:12][NH:13][C:22](=[O:23])[C:21]([CH3:26])([CH3:25])[CH3:20])[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: CC(C)(C)C(=O)O
Reactant: NCc1ccc2nc(Cl)nc(N3CCOCC3)c2n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)NCc1ccc2nc(Cl)nc(N3CCOCC3)c2n1
Reaction time: 8 h

Procedure:
(2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methanamine (0.1 g) was added to a pre-stirred (15 minutes) solution of trimethylacetic acid (1.2 eq), 1-hydroxybenzotriazole (1.1 eq.), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.1 eq.), triethylamine (2 eq.) in N,N-dimethylformamide (2.77 mL). The reaction was stirred overnight then extracted with ethyl acetate and brine. The organic layer was dried (Mg2SO4), filtered and concentrated to give quantitative yield of N-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)pivalamide.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[N:17][C:5]2[NH:6][C:7]([N:12]3[CH:16]=[CH:15]N=C3)=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.[CH2:19](N)C=C>>[CH2:16]([NH:12][C:7]1[NH:6][C:5]2[N:17]=[CH:18][C:2]([Cl:1])=[CH:3][C:4]=2[S:9](=[O:11])(=[O:10])[N:8]=1)[CH:15]=[CH2:19]
Reactant: O=S1(=O)N=C(n2ccnc2)Nc2ncc(Cl)cc21
Reactant: C=CCN
Product: C=CCNC1=NS(=O)(=O)c2cc(Cl)cnc2N1

Procedure:
m.p. 224°-227° C. from 7-chloro-3-(imidazol-1-yl)-4H-pyrido[2,3-e]-1,2,4-thiadiazine 1,1-dioxide and allylamine. (Compound 16).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[Na+].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([O-:20])=[O:19])=[CH:14][CH:13]=1>CS(C)=O.O>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([C:2]2[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: O=Cc1cccnc1Cl
Reactant: O=S([O-])c1ccc(Cl)cc1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=Cc1cccnc1S(=O)(=O)c1ccc(Cl)cc1
Temperature: 100 °C
Yield: 46.9 %

Procedure:
2-Chloro-3-pyridinecarboxaldehyde (5.0 g, 35.0 mmol) and 4-chlorobenzenesulfinic acid sodium salt (7.75 g, 38.8 mmol) were dissolved in DMSO (120 ml) and the mixture was heated at 100° C. for 72 h under nitrogen. Upon cooling to ambient the mixture was diluted with water (500 ml) and extracted with EtOAc (3×). The combined organics were washed with water, brine, dried (MgSO4) and evaporated to dryness to afford 8.1 g of crude material. The crude compound was pre-absorbed onto silica and purified by dry pad suction column chromatography, eluting with heptane using an EtOAc gradient, to afford 4.62 g (61%) of the desired product as a white powdery solid (MP=100.5-101° C.; IR=1698 cm−1; HPLC=8.00 min>99%).
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:28]=[C:29]([NH:33][C:34]([CH:36]3[CH2:38][CH2:37]3)=[O:35])[CH:30]=[CH:31][CH:32]=2)[CH2:23][CH2:22]1>>[C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([NH:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]3[CH:28]=[C:29]([NH:33][C:34]([CH:36]4[CH2:38][CH2:37]4)=[O:35])[CH:30]=[CH:31][CH:32]=3)[CH2:23][CH2:22]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCCCN1CCC(c2cccc(NC(=O)C3CC3)c2)CC1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Product: O=C(Nc1cccc(C2CCN(CCCNC(=O)C(c3ccccc3)c3ccccc3)CC2)c1)C1CC1

Procedure:
Example 17 was prepared from diphenylacetyl chloride and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}cyclo propanecarboxamide according to the procedures described in Scheme 8: 1H NMR (400 MHz, CDCl3) δ 9.26–9.09 (br, 1H), 8.12–7.91 (br, 1H), 7.69 (d, 1H, J=7.2 Hz), 7.63–7.42 (br, 1H), 7.43–7.12 (m, 11H), 6.88 (d, 1H, J=7.2 Hz), 5.03 (s, 1H), 3.53–3.27 (m, 4H), 2.99–2.84 (m, 2H), 2.84–2.58 (m, 3H), 2.40–2.16 (m, 2H), 2.16–1.98 (m, 2H), 1.98–1.83 (m, 2H), 1.78–1.64 (m, 1H), 1.10–0.97 (m, 2H), 0.90–0.76 (m, 2H); ESMS m/e: 496.3 (M+H)+.
Reaction SMILES: N[C:2](N)=[S:3].[Cl:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])CBr.[OH-].[Na+].Cl>C(O)C.C(OCC)C>[Cl:5][C:6]1[CH:7]=[C:8]([CH2:2][SH:3])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: COc1ccc(CBr)cc1Cl
Reactant: NC(N)=S
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Product: COc1ccc(CS)cc1Cl
Temperature: 80 °C
Yield: 83 %

Procedure:
Thiourea (3.04 g, 0.04 mol) was added to a solution of 3-chloro-4-methoxybenzyl bromide (4.0 g, 0.02 mol) in ethanol (200 ml) and refluxed for 16 hours. The reaction mixture was concentrated in vacuo and the residue was subsequently dissolved in aqueous sodium hydroxide solution (30 g, 0.75 mol in 300 ml water) and heated at 80° C. for one hour. The reaction mixture was cooled with an ice bath and acidified by addition of concentrated hydrochloric acid. The product was isolated by extraction three times into diethyl ether. The combined organic phases were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo, to give the sub-title compound as a colourless oil in 83% yield (3.0 g).
Reaction SMILES: [C:1]([O:5][C:6](OC=CC1C=CC=CC=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=1.C(OC(OC(OC(C)(C)C)=O)=O)(C)(C)C>>[C:1]([O:5][C:6]([O:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=Cc1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)OC=Cc1ccccc1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)Oc1ccc(C=O)cc1

Procedure:
U.S. Pat. No. 4,461,628 of Ito et al., issued Jan. 1, 1985 teaches the preparation of t-butoxycarbonyloxystyrene by reaction of p-hydroxybenzaldehyde with di-t-butyldicarbonate in the presence of base to yield p-t-butoxycarbonyloxybenzaldehyde, which is then reacted with methyltriphenylphosphonium bromide and potassium t-butoxide to yield the desired product.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:16]([O-])=O)=[C:6]([S:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])(=[O:10])=[O:9])[CH:7]=1.[H][H]>CO.[Pd]>[NH2:16][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][C:6]=1[S:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])(=[O:10])=[O:9]
Reactant: COC(=O)CS(=O)(=O)c1cc(C)ccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)CS(=O)(=O)c1cc(C)ccc1N
Yield: 98.8 %

Procedure:
Palladium (10%) on carbon is added to a solution of methyl ((5-methyl-2-nitro-phenyl)sulfonyl)acetate (Preparation 37, 2.0 g) in MeOH (60 mL) and the solution is shaken on a Parr apparatus under 30 psi of hydrogen. After 3 hours the solution is filtered through Celite and the filter cake eluted with MeOH (60 mL). The combined MeOH eluant is evaporated and the remaining residue placed under high vacuum overnight to obtain 1.76 g (99%) of the title compound as a dark solid. Physical characteristics: MS (ESI+) m/z 244 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]3([CH2:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([N+:19]([O-])=O)[CH:16]=4)[CH2:11]3)[C:9](=[O:22])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(N(CC)CC)C.[H][H]>CCOC(C)=O.[Pd]>[NH2:19][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[CH2:11][C:10]1([C:3]3[C:2]([Cl:1])=[N:7][CH:6]=[N:5][C:4]=3[NH:8][C:9]1=[O:22])[CH2:18]2
Reactant: O=C1Nc2ncnc(Cl)c2C12Cc1ccc([N+](=O)[O-])cc1C2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Nc1ccc2c(c1)CC1(C2)C(=O)Nc2ncnc(Cl)c21
Reaction time: 2 h

Procedure:
To a solution of (±)-4′-chloro-5-nitro-1,3-dihydrospiro[indene-2,5′-pyrrolo[2,3-d]pyrimidin]-6′(7′H)-one (40 mg, 0.126 mmol, described in Intermediate 4) in EtOAc (10 mL) was added triethylamine (0.026 mL, 0.189 mmol). The mixture was hydrogenated at 30 psi hydrogen over 10% Pd/C (10 mg). After 2 h, the reaction mixture was filtered through a pad of Celite and concentrated in vacuo. The residue was purified by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. Lyophilization provided the title compound. MS: m/z=287 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9](=[O:10])[CH2:8][CH2:7][C@@H:6]1[C:11]([NH:13][CH:14]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH:15]([OH:19])[C:16](O)=[O:17])=[O:12].[CH3:31][O:32][NH2:33]>>[F:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9](=[O:10])[CH2:8][CH2:7][C@@H:6]1[C:11]([NH:13][CH:14]([CH:15]([OH:19])[C:16]([NH:33][O:32][CH3:31])=[O:17])[CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:12]
Reactant: O=C(O)C(O)C(Cc1ccccc1)NC(=O)[C@H]1CCC(=O)N1Cc1ccccc1F
Reactant: CON
Product: CONC(=O)C(O)C(Cc1ccccc1)NC(=O)[C@H]1CCC(=O)N1Cc1ccccc1F

Procedure:
The reaction can be carried out in analogy to reaction step 20.3 by reacting 3-((R)-1-(2-fluorobenzyl)-5-oxopyrrolidine-2-carboxamido)-2-hydroxy-4-phenylbutanoic acid with O-methylhydroxylamine.