Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][CH2:5][C@@:6]1([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[O:11][C:10](=[O:12])[N:9]([C@H:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH3:14])[CH2:8][CH2:7]1)=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1.O>[NH2:1][CH2:4][CH2:5][C@@:6]1([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[O:11][C:10](=[O:12])[N:9]([C@H:13]([C:15]([CH3:18])([CH3:16])[CH3:17])[CH3:14])[CH2:8][CH2:7]1
Reactant: C[C@H](N1CC[C@](CCN=[N+]=[N-])(c2ccc(F)cc2)OC1=O)C(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](N1CC[C@](CCN)(c2ccc(F)cc2)OC1=O)C(C)(C)C
Yield: 70.9 %

Procedure:
To a solution of (S)-6-(2-azidoethyl)-3-((S)-3,3-dimethylbutan-2-yl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (219 mg, 0.63 mmol) in THF (5 mL) and H2O (0.25 mL) was added PPh3 (198 mg, 0.76 mmol), and the mixture was refluxed for 2 h. The solution was concentrated, and the residue was purified by preparative TLC to afford (R)-6-(2-aminoethyl)-3-((S)-3,3-dimethylbutan-2-yl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (144 mg, 71%). 1H NMR (CDCl3): 0.61-0.69 (s, 9H), 1.02-1.08 (d, 3H), 1.98-2.14 (m, 3H), 2.23-2.31 (m, 1H), 2.48-2.56 (m, 1H), 2.58-2.67 (m, 1H), 2.77-2.86 (m, 1H), 3.07-3.12 (m, 1H), 4.33-4.40 (m, 1H), 6.98-7.04 (m, 2H), 7.21-7.24 (m, 2H).
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[CH3:5][O:6][CH:7]1[C:16]2[CH2:15][CH2:14][CH2:13][CH:12]3[CH2:17][CH2:18][O:19][C:10]([C:11]=23)=[CH:9][N:8]1[O:20][CH3:21].[OH-].[Na+]>O1CCOCC1>[C:1]([CH2:2][CH2:3][CH:14]1[CH2:15][C:16]2[CH:7]([O:6][CH3:5])[N:8]([O:20][CH3:21])[CH:9]=[C:10]3[O:19][CH2:18][CH2:17][CH:12]([C:11]=23)[CH2:13]1)#[N:4]
Reactant: COC1C2=C3C(=CN1OC)OCCC3CCC2
Reactant: C=CC#N
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COC1C2=C3C(=CN1OC)OCCC3CC(CCC#N)C2
Reaction time: 24 h

Procedure:
A solution of acrylonitrile (12 ml) and 1,2,3a,4,5,6-hexahydro-7,8-dimethoxypyrano[2,3,4-de]isoquinoline (11 g), described in Example 56, in dioxane (80 ml) and 10% NaOH solution (2.5 ml) is heated and stirred on the steam bath for 24 hr. The mixture is evaporated and the residue is dissolved in a mixture of ether and a little chloroform. The solution is extracted with 2N HCl and the extracts are washed (brine), dried and evaporated. The residue is crystallized from ether and then from benzene-hexane to give the title compound, m.p. 105°-107° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@:12]([C:22]([O:24][CH2:25][CH3:26])=[O:23])([C:19](O)=[O:20])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(OCC(C)C)=O.[NH3:35].Cl>C1COCC1.C(N(CC)CC)C>[CH2:1]([O:8][C:9]([NH:11][C@@:12]([C:19](=[O:20])[NH2:35])([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N
Reactant: CCOC(=O)C[C@@](NC(=O)OCc1ccccc1)(C(=O)O)C(=O)OCC
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C[C@@](NC(=O)OCc1ccccc1)(C(N)=O)C(=O)OCC
Yield: 84 %

Procedure:
A solution of (R)-1-ethyl hydrogen 3-benzyloxycarbonylamino-3-ethoxycarbonylsuccinate (1.8 g) in THF (20 mL) was added with triethylamine (0.96 mL) and isobutyl chloroformate (0.84 mL, 0.87 g) in this order at −15° C. with stirring, and the mixture was stirred for 5 minutes. A solution of 25% aqueous ammonia (0.47 mL) was dropped into the reaction mixture at the same temperature. The reaction mixture was stirred at the same temperature for 1 hour, and then poured into diluted hydrochloric acid, the mixture was extracted with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography, in which elution was performed with n-hexane/ethyl acetate (1:1) for purification, and then crystallized from ethyl acetate/n-hexane to obtain the title compound (1.51 g, yield: 84%) as colorless crystals. Optical rotation [α]D25 was −5.7° (c 0.52, ethanol) and optical purity was 96.1% ee.
Reaction SMILES: [Si](OCCC1C=C([N:27]2[C:32]3=[N:33][C:34](NC4C=CC(OCCN(CC)CC)=CC=4)=[N:35][CH:36]=[C:31]3[CH2:30][N:29](C3C=CC(Cl)=CC=3Cl)[C:28]2=[O:60])C=CC=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[NH:27]1[C:32]2=[N:33][CH:34]=[N:35][CH:36]=[C:31]2[CH:30]=[N:29][C:28]1=[O:60]
Reactant: CCN(CC)CCOc1ccc(Nc2ncc3c(n2)N(c2cccc(CCO[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)c2)C(=O)N(c2ccc(Cl)cc2Cl)C3)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=c1ncc2cncnc2[nH]1

Procedure:
A solution of 200 mg (0.23 mmol) of 1-[3-(tert-butyldiphenylsilyloxyethyl)phenyl]-3-(2,4-dichlorophenyl)-7-[4-[2-(diethylamino)ethoxy]anilino]-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one in 5 ml of tetrahydrofuran was treated with 0.5 ml (0.5 mmol) of a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran. After 1 hour the mixture was evaporated and the product purified by chromatography on silica gel using dichloromethane/methanol in a ratio 20:1 as eluting solvent. Evaporation of the product-containing fractions followed by trituration of the residue with hexane and filtration gave 60 mg (42%) 3-(2,4-dichlorophenyl)-7-[4-[2-(diethylamino)ethoxy]anilino]-3,4-dihydro-1-[3-(2-hydroxyethyl))phenyl]pyrimido[4,5-d]pyrimidin-2(1H)-one as a white solid of melting point 110° C.
Reaction SMILES: [Cl:1][C:2]1[N:6]2[N:7]=[C:8](Cl)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[O:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][NH2:21])[CH2:14][CH2:13]1.Cl>CCOCC>[ClH:1].[Cl:1][C:2]1[N:6]2[N:7]=[C:8]([NH:21][CH2:20][CH2:19][CH2:18][N:15]3[CH2:16][CH2:17][O:12][CH2:13][CH2:14]3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: Clc1ccc2ncc(Cl)n2n1
Reactant: NCCCN1CCOCC1
Agent: Cl
Solvent: CCOCC
Product: Clc1cnc2ccc(NCCCN3CCOCC3)nn12
Yield: 57 %

Procedure:
Prepared from 3,6-dichloroimidazo[1,2-b]pyridazine and 3-morpholinopropylamine according to general procedure 3. The free base was converted to the HCl salt with 2N HCl in Et2O to provide the title compound (153 mg, 57%) as a white solid; 1H NMR (500 MHz, CD3OD) δ 7.60 (d, J=9.7 Hz, 1H), 7.39 (s, 1H), 6.70 (d, J=9.7 Hz, 1H), 3.90 (br, 4H), 3.53 (t, J=6.7 Hz, 2H), 3.35-3.27 (m, 6H), 2.20-2.14 (m, 2H): 13C NMR (75 MHz, CD3OD) δ 155.8, 137.2, 127.9, 126.1, 115.6, 114.7, 65.2, 56.8, 53.4, 39.6, 24.5; HPLC tR=8.9 min (Synergi), >99%; ES-MS: (M+H)=332 m/z.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:11])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.Br[CH2:13][C:14]([C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=1)=O>>[F:23][C:18]1[CH:17]=[C:16]([C:14]2[C:6]3[C:7]([O:9][CH3:10])=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[O:11][CH:13]=2)[CH:21]=[C:20]([F:22])[CH:19]=1
Reactant: COc1cc(O)cc(OC)c1
Reactant: O=C(CBr)c1cc(F)cc(F)c1
Product: COc1cc(OC)c2c(-c3cc(F)cc(F)c3)coc2c1
Yield: 68 %

Procedure:
This compound was prepared using Method B from 3,5-dimethoxyphenol and 2-bromo-1-(3,5-difluorophenyl)ethanone: Yield 68% following procedures B.2 and B.3; m.p. 102-103° C.; IR 2937, 1591, 1501, 1444, 1354, 1217, 1113 cm−1; 1H-NMR (300 MHz, δ ppm, CDCl3) 7.49 (s, 1H), 7.20-7.11 (m, 2H), 6.75 (tt, J=9.0 Hz, 2.3 Hz, 1H), 6.66 (d, J=1.9 Hz, 1H), 6.36 (d, J=1.9 Hz, 1H), 3.84 (s, 3H), 3.82 (s, 3H); 13C-NMR (75 MHz, δ ppm, CDCl3) 162.8 (dd, J=246.5 Hz, 13.3 Hz), 159.7, 158.2, 154.6, 140.7, 135.8 (t, J=10.6 Hz), 121.5, 112.2 (dd, J=8.1 Hz, 17.4 Hz), 109.2, 102.4 (t, J=25.5 Hz), 95.0, 88.6, 55.9, 55.5.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[CH:7]=[CH:8][O:9][C:4]2=[CH:3][CH:2]=1.C([Li:14])CCC>>[O:9]1[C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][C:5]=2[CH:7]=[C:8]1[Li:14]
Reactant: c1ccc2occc2c1
Reactant: [Li]CCCC
Product: [Li]c1cc2ccccc2o1

Procedure:
To a solution of 2,3-benzofuran (2.0 ml, 18.15 mmol, in 50 ml of anhydrous ether) was added 1.6M n-butyllithium in hexanes (12.5 ml, 20 mmol). To the 2-benzofuranyl lithium formed by stirring the solution at room temp. for 1 hour was added (ice bath) the compound 5(b) (1.62 g, 7.22 mmol) dissolved in anhydrous tetrahydrofuran (70 ml). The reaction was continued at ice-bath temperature for 3 hours then worked-up as described to afford 0.89 g (44%) of product as off-white solids. This material was converted to the dihydrochloride by addition of 1M hydrochloric acid in ether (8 ml) as described. The dihydrochloride obtained was recrystallized from methanol-ether and dried under vacuum at 60° C. overnight to afford the ketone dihydrochloride as off-white crystals (0.82 g). m.p.: 193°-195° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[CH:17]=[CH2:18]>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[O:9][CH2:18][CH:17]=[CH2:16]
Reactant: Cc1ccc(Cl)c(O)c1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCOc1cc(C)ccc1Cl
Yield: 100 %

Procedure:
To a suspension of 2-chloro-5-methylphenol (10.0 g, 0.07 mol) and potassium carbonate (11.7 g, 0.08 mol) in acetonitrile (200 mL) at 82° C., was dropwise added a solution of allyl bromide (9.6 mL, 0.11 mol) in acetonitrile (50 mL). The mixture was reflux overnight. Once at room temperature, the mixture was filtered and the precipitate rinsed with diethyl ether. The filtrate was then concentrated in vacuo. The residue was dissolved in diethyl ether (250 mL) and washed with a 2N sodium hydroxide solution (150 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to provide 1-chloro-4-methyl-2-(prop-2-en-1-yloxy)benzene (7a) (12.72 g, 0.07 mol, 99%) which was used without further purification.
Reaction SMILES: [F:1][C:2]1[C:30]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:29][C:5]2[N:6]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=3)[C:7]([CH2:9][O:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:8][C:4]=2[CH:3]=1.[C:37](Cl)(=[O:40])[CH2:38][CH3:39]>ClCCl>[F:1][C:2]1[C:30]([N:31]2[CH2:36][CH2:35][N:34]([C:37](=[O:40])[CH2:38][CH3:39])[CH2:33][CH2:32]2)=[CH:29][C:5]2[N:6]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([O:24][C:25]([F:26])([F:27])[F:28])=[CH:22][CH:23]=3)[C:7]([CH2:9][O:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: CCC(=O)Cl
Reactant: Fc1cc2nc(COc3ccccc3)n(Cc3ccc(OC(F)(F)F)cc3)c2cc1N1CCNCC1
Solvent: ClCCl
Product: CCC(=O)N1CCN(c2cc3c(cc2F)nc(COc2ccccc2)n3Cc2ccc(OC(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
80 mg of 5-fluoro-2-phenoxymethyl-6-piperazin-1-yl-1-(4-trifluoromethoxy-benzyl)-1H-benzoimidazole (0.16 mmol) and 0.033 ml TEA (0.24 mmol) were dissolved in 1.5 ml dichloromethane and treated with 0.018 ml propionyl chloride (0.2 mmol). After 2 h stirring at rt, the reaction mixture was diluted with dichloromethane, washed with water, saturated sodium bicarbonate and brine, dried with magnesium sulfate, filtered and concentrated in vacuo, leading to 87 mg yellow solid (98%). MS (ISP) 557.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@H:27]3[CH2:32][CH2:31][C@H:30]([CH2:33]O)[CH2:29][CH2:28]3)=[N:9][C:10]=2[C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18]3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.[C:35]1(=[O:45])[NH:39][C:38](=[O:40])[C:37]2=[CH:41][CH:42]=[CH:43][CH:44]=[C:36]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@H:27]3[CH2:32][CH2:31][C@H:30]([CH2:33][N:39]4[C:35](=[O:45])[C:36]5[C:37](=[CH:41][CH:42]=[CH:43][CH:44]=5)[C:38]4=[O:40])[CH2:29][CH2:28]3)=[N:9][C:10]=2[C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18]3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Nc1nccn2c1c(-c1ccc3ccc(-c4ccccc4)nc3c1)nc2[C@H]1CC[C@H](CO)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Nc1nccn2c1c(-c1ccc3ccc(-c4ccccc4)nc3c1)nc2[C@H]1CC[C@H](CN2C(=O)c3ccccc3C2=O)CC1
Reaction time: 16 h

Procedure:
trans-{4-[8-Amino-1-(2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexyl}-methanol (290 mg, 0.47 mmol), phthalimide (82 mg, 0.56 mmol), and resin-bound triphenylphosphine (PS-Ph3P [Argonaut, 2.16 mmol/g]) (324 mg) were dissolved in 2.5 mL of THF, evacuated, placed under nitrogen atmosphere and charged with DIAD (0.11 mL, 0.56 mmol). After stirring for 16 h, the resin was filtered, washed with CH2Cl2 (5×) and concentrated to an orange-colored oil. The crude material was purified by silica gel column chromatography [Jones Flashmaster, 10 g/70 mL cartridge, eluting with 1% MeOH/CH2Cl2 to 2%˜7N NH3 in MeOH/CH2Cl2] to afford the desired product as a yellow solid; 1H NMR (CDCl3, 400 MHz) δ 1.17-1.29 (m, 2H), 1.60-1.61 (m, 1H), 1.87-2.07 (m, 4H), 2.12-2.23 (m, 2H), 2.92-3.02 (m, 1H), 3.64 (d, 2H, J=6.8 Hz), 5.25 (s, 2H), 7.11 (d, 1H, J=5.6 Hz), 7.24-7.26 (m, 1H), 7.45-7.49 (m, 1H), 7.52-7.56 (m, 2H), 7.72-7.75 (m, 2H), 7.86-7.95 (m, 5H), 8.17-8.20 (m, 2H), 8.25 (d, 1H, J=8.8 Hz), 8.38-8.39 (m, 1H); MS (ES+): m/z 579.0 [MH+]; HPLC: tR=2.9 min (Micromass Platform II, nonpolar—5 min).
Reaction SMILES: [CH3:1][N:2]1[CH:8]2[CH:3]1[CH2:4][CH2:5][CH2:6][CH2:7]2.[NH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[Cl-].[NH4+]>O>[CH3:1][NH:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]1[N:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CN1C2CCCCC21
Reactant: C1CCNCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: CN[C@@H]1CCCC[C@H]1N1CCCCC1
Yield: 41.8 %

Procedure:
A stirred mixture of 7-methyl-7-azabicyclo[4.1.0]heptane (5.0 ml, 39 mmol), piperidine (3.9 ml, 39 mmol) and 0.2 g of ammonium chloride dissolved in 0.4 ml of water was heated under reflux for 5.5 hours. Normal work-up of the reaction mixture followed by bulb-to-bulb distillation yielded 3.2 g (42%) of trans-N-methyl-2-(1-piperidinyl)cyclohexanamine as a colorless liquid, bp 210° C. (at a pressure of 2666 Pascal).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:11][CH2:12][CH3:13])[C:6]=2[C:5](=[O:14])[NH:4][C:3]1=[O:15].Cl[CH2:17][CH2:18][CH2:19][CH2:20][P:21]([O:26][CH2:27][CH3:28])(=[O:25])[O:22][CH2:23][CH3:24]>>[CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:11][CH2:12][CH3:13])[C:6]=2[C:5](=[O:14])[N:4]([CH2:17][CH2:18][CH2:19][CH2:20][P:21](=[O:25])([O:26][CH2:27][CH3:28])[O:22][CH2:23][CH3:24])[C:3]1=[O:15]
Reactant: CCOP(=O)(CCCCCl)OCC
Reactant: CCCn1cnc2c1c(=O)[nH]c(=O)n2C
Product: CCCn1cnc2c1c(=O)n(CCCCP(=O)(OCC)OCC)c(=O)n2C

Procedure:
The title substance was prepared from 0.072 mol of 3-methyl-7-propyl-xanthine and 0.072 mol of diethyl 4-chlorobutanephosphonate analogously to Example 23, chromatographed on silica gel (eluent: dichloromethane/methanol 20:1) and crystallized from diisopropyl ether.
Reaction SMILES: ClC1C=C([CH2:8][CH2:9][CH2:10][N:11]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)C=CC=1.[F:32][C:33]1[CH:38]=[CH:37][C:36]([C:39](=[O:45])CCC(O)=O)=[CH:35][CH:34]=1.C(OC(=O)CSC1SC(N)=NC=1)C>>[F:32][C:33]1[CH:38]=[CH:37][C:36]([CH:39]([OH:45])[CH2:8][CH2:9][CH2:10][N:11]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)=[CH:35][CH:34]=1
Reactant: C[C@H]1CC[C@H](N(CCCc2cccc(Cl)c2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1
Reactant: O=C(O)CCC(=O)c1ccc(F)cc1
Agent: CCOC(=O)CSc1cnc(N)s1
Product: C[C@H]1CC[C@H](N(CCCC(O)c2ccc(F)cc2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of {2-[-3-[3-(3-chloro-phenyl)-propyl]-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid using 4-(4-fluoro-phenyl)-4-oxo-butyric acid and (2-aminothiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: [CH:1]1[N:9]2[C:4]([C:5]3([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[O:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=32)=[CH:3][CH:2]=1.[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][C:21]=1[C:29]([F:32])([F:31])[F:30].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([N:16]2[CH2:17][CH2:18][C:5]3([O:6][C:7]4[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=4[N:9]4[CH:1]=[CH:2][CH:3]=[C:4]34)[CH2:14][CH2:15]2)=[O:25])=[CH:22][C:21]=1[C:29]([F:30])([F:31])[F:32]
Reactant: c1ccc2c(c1)OC1(CCNCC1)c1cccn1-2
Reactant: O=C(O)c1ccc(F)c(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(c1ccc(F)c(C(F)(F)F)c1)N1CCC2(CC1)Oc1ccccc1-n1cccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.7 %

Procedure:
Spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine] (100 mg, 0.361 mmol), 4-fluoro-3-(trifluoromethyl)benzoic acid (75.2 mg, 0.361 mmol), and triethylamine (110 mg, 151 μL, 1.08 mmol) were combined in DMF (3 mL) and HATU (137 mg, 0.361 mmol) was added. The reaction was stirred at room temperature for 1 h and was concentrated. The residue was purified by column chromatography (silica gel: 0-50% ethyl acetate in hexanes) to give (4-fluoro-3-(trifluoromethyl)phenyl)(spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)methanone (113 mg, 73%). ESI-MS m/z calc. 430.1, found 431.1 (M+1)+; Retention time: 2.24 minutes (4 min run).
Reaction SMILES: [C:1]([NH:4][C:5]1[N:13]=[C:12]2[C:8]([N:9]=[CH:10][N:11]2[CH2:14][O:15][CH2:16][CH2:17][Se]C2C=CC=CC=2)=[C:7]([C:25](=[O:39])[N:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:6]=1)(=[O:3])[CH3:2].OO.C(=O)(O)[O-].[Na+].C(N(C(C)C)CC)(C)C>O1CCOCC1>[C:1]([NH:4][C:5]1[N:13]=[C:12]2[C:8]([N:9]=[CH:10][N:11]2[CH2:14][O:15][CH:16]=[CH2:17])=[C:7]([C:25](=[O:39])[N:26]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc(C(=O)N(c2ccccc2)c2ccccc2)c2ncn(COCC[Se]c3ccccc3)c2n1
Agent: O=C([O-])O
Agent: OO
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: C=COCn1cnc2c(C(=O)N(c3ccccc3)c3ccccc3)nc(NC(C)=O)nc21
Temperature: 60 °C

Procedure:
To a solution of 2-acetamido-6-diphenylcarbamoyl-9-[2-(phenylselenyl)ethoxymethyl]purine (4.92 g, 8.16 mmol) in dioxane (80 mL) was added 30% H2O2 (4 mL, 35 mmol) and sodium bicarbonate (2.1 g, 24.5 mmol). The mixture was heated at 60° C. for 20 min. The reaction was then concentrated to about 10 mL, diluted with ethyl acetate (100 mL), dried (MgSO4) and the solvents were removed in vacuo. The residue was dissolved in dioxane (40 mL), diisopropylethylamine (1.27 g, 10 mmol) was added and the solution was heated at 80° C. for 30 min under nitrogen. The solvent was evaporated in vacuo and the residual oil was chromatographed on silica gel using CH2Cl2 -ethyl acetate (1:1) as eluent to give the title compound as a yellowish powder: yield 2.3 g (65%).
Reaction SMILES: [CH3:1][C:2]([C:5]([CH2:7]Cl)=O)([CH3:4])[CH3:3].[CH3:9][N:10]1[CH2:15][CH2:14][N:13]([C:16]([NH2:18])=[S:17])[CH2:12][CH2:11]1.C(OCC)C>C(O)C>[CH3:9][N:10]1[CH2:15][CH2:14][N:13]([C:16]2[S:17][CH:7]=[C:5]([C:2]([CH3:4])([CH3:3])[CH3:1])[N:18]=2)[CH2:12][CH2:11]1
Reactant: CC(C)(C)C(=O)CCl
Reactant: CN1CCN(C(N)=S)CC1
Solvent: CCOCC
Solvent: CCO
Product: CN1CCN(c2nc(C(C)(C)C)cs2)CC1

Procedure:
1.34 g of chloropinacoline are dissolved in 15 cc of absolute ethanol. After the addition of 1.6 g of 4-methyl-1-piperazinyl-thiocarboxamide, the mixture is heated to the boil on a water bath for 1 hour. Cooling is then effected and diethyl ether is added until the mixture remains turbid. The precipitated crystals are filtered off and recrystallized from ethanol. The resulting 2-(4-methyl-1-piperazinyl)-4-tert.butyl-thiazole hydrochloride has an M.P. of 206°. The base liberated from its hydrochloride in known manner by treatment with an aqueous sodium hydroxide solution has a B.P. of 97°-99°/0.2 mm Hg.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=1.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>CS(C)=O>[O:14]1[CH2:15][CH2:16][N:11]([C:2]2[CH:3]=[C:4]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:6][CH:7]=2)[CH2:12][CH2:13]1
Reactant: O=[N+]([O-])c1cccc(F)c1
Reactant: C1COCCN1
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cccc(N2CCOCC2)c1

Procedure:
Using 1-fluoro-3-nitrobenzene (10 g, 0.07M) and morpholine (33.5 g, 0.38M) in DMSO (116 ml) is prepared using the method described by Brown G. R. et al., Tet. Lett. 40 (1999) 1219-1222. Filtration of the precipitated product yields the product; mp 113.8-115.5° C.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[CH:21][C:20]([S:23][CH:24]5[CH2:29][CH2:28][N:27]([C:30]([CH3:35])([CH3:34])[C:31]([OH:33])=O)[CH2:26][CH2:25]5)=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].CC[N:38](C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.N.CCN=C=NCCCN(C)C>CN(C=O)C>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[CH:21][C:20]([S:23][CH:24]5[CH2:29][CH2:28][N:27]([C:30]([CH3:34])([CH3:35])[C:31]([NH2:38])=[O:33])[CH2:26][CH2:25]5)=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:2])[CH3:3]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(SC3CCN(C(C)(C)C(=O)O)CC3)ccc1OCC2
Reactant: CCN(C(C)C)C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: N
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(SC3CCN(C(C)(C)C(N)=O)CC3)ccc1OCC2
Yield: 78.5 %

Procedure:
To a suspension of 2-{4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-9-ylsulfanyl]piperidin-1-yl}-2-methylpropionic acid (20 mg, 0.0411 mmol) in DMF (1.5 mL) was added DIPEA (21 ul, 0.123 mmol), HOBt.NH3 (9 mg, 0.0616 mmol) and EDCI (12 mg, 0.0616 mmol) and the reaction mixture was stirred at RT for 18 h. The mixture was then partitioned between EtOAc and water. The aqueous layer was further extracted with EtOAc and the combined organic layers were washed with water, followed by brine, then dried and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 2-8% 2M NH3/MeOH in DCM) affording 2-{4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-9-ylsulfanyl]piperidin-1-yl}isobutyramide as a colorless gum (16 mg, 77%). LCMS: RT 2.16/2.19 min [M+H]+ 496.1
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[NH2:8].C(N(C(C)C)C(C)C)C.[C:19](Cl)(Cl)=[S:20]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[N:8]=[C:19]=[S:20]
Reactant: Nc1c(Cl)cncc1Cl
Reactant: S=C(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: S=C=Nc1c(Cl)cncc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20.3 %

Procedure:
To a solution of 3,5-dichloropyridin-4-amine (4.0 g, 24.53 mmol) in DCM (20 mL), was added N-ethyl di-isopropyl amine (6.3 g, 48.83 mmol). The reaction mixture was stirred at RT for 30 minutes. The reaction mixture was cooled at 0° C. and thiophosgene (2.76 g, 24.00 mmol) was added drop wise. The reaction mixture was stirred at 0° C. to RT for 3-4 h. The reaction mixture was diluted with DCM and the obtained crude was purified by column chromatography to afford 1.0 g of the desired product. 1HNMR (DMSO-d6): δ 8.77 (s, 2H); MS [M+H]+: 205.20.