Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([O:4][CH2:5][C:6]([CH2:16][O:17][N+:18]([O-:20])=[O:19])([CH2:11][O:12][N+:13]([O-:15])=[O:14])[C:7](OC)=[O:8])([O-:3])=[O:2].Cl.[NH2:22][NH2:23].Cl>>[N+:1]([O:4][CH2:5][C:6]([CH2:16][O:17][N+:18]([O-:20])=[O:19])([CH2:11][O:12][N+:13]([O-:15])=[O:14])[C:7]([NH:22][NH2:23])=[O:8])([O-:3])=[O:2]
Reactant: COC(=O)C(CO[N+](=O)[O-])(CO[N+](=O)[O-])CO[N+](=O)[O-]
Reactant: NN
Agent: Cl
Product: NNC(=O)C(CO[N+](=O)[O-])(CO[N+](=O)[O-])CO[N+](=O)[O-]
Yield: 63 %

Procedure:
1 g (3.5 mmol) of methyl 2,2-bis(nitryloxymethyl)-3-nitryloxypropionate is heated with excess aqueous hydrazine hydrochloride solution for 5 hours on a water bath. The mixture is poured onto ice and slightly acidified with hydrochloric acid. After column chromatographic separation of the oil which is produced, 3-nitryloxy-2,2-bis(nitryloxymethyl)propionic acid hydrazide is obtained as a colourless oil. Yield: 63%.
Reaction SMILES: C=O.[C:3](O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH2:21]([O:28][C:29]1[CH:53]=[CH:52][C:51]([CH:54]2[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]2)=[CH:50][C:30]=1[C:31]([NH:33][C:34]1[CH:43]=[C:42]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:41]=[CH:40][C:35]=1[C:36]([O:38][CH3:39])=[O:37])=[O:32])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCCC1>[CH2:21]([O:28][C:29]1[CH:53]=[CH:52][C:51]([CH:54]2[CH2:55][CH2:56][N:57]([CH3:3])[CH2:58][CH2:59]2)=[CH:50][C:30]=1[C:31]([NH:33][C:34]1[CH:43]=[C:42]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:41]=[CH:40][C:35]=1[C:36]([O:38][CH3:39])=[O:37])=[O:32])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(C2CCNCC2)ccc1OCc1ccccc1
Reactant: CC(=O)O
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(C2CCN(C)CC2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 37% formaldehyde aqueous solution (6.3 μL), acetic acid (0.022 mL), and sodium triacetoxyborohydride (0.10 g) were sequentially added to a tetrahydrofuran (3.0 mL) solution of methyl 2-(2-(benzyloxy)-5-(piperidin-4-yl)benzamido)-4-phenylbenzoate (0.10 g), followed by stirring at room temperature for 3 hours and 30 minutes. The solvent was evaporated under reduced pressure, and a saturated aqueous solution of sodium bicarbonate and chloroform were added to the residue. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 98-90% chloroform/methanol] to obtain 0.086 g of methyl 2-(2-(benzyloxy)-5-(1-methylpiperidin-4-yl)benzamido)-4-phenylbenzoate as a white solid.
Reaction SMILES: CCN(C(C)C)C(C)C.[Br:10][C:11]1[CH:12]=[C:13]([C:27]([O:29][CH3:30])=[O:28])[CH:14]=[C:15]2[C:20]=1[O:19][C:18](S(CC)(=O)=O)=[CH:17][C:16]2=[O:26].Cl.[CH3:32][C@H:33]1[O:38][CH2:37][CH2:36][NH:35][CH2:34]1.Cl>C(Cl)Cl.O>[Br:10][C:11]1[CH:12]=[C:13]([C:27]([O:29][CH3:30])=[O:28])[CH:14]=[C:15]2[C:20]=1[O:19][C:18]([N:35]1[CH2:36][CH2:37][O:38][C@H:33]([CH3:32])[CH2:34]1)=[CH:17][C:16]2=[O:26]
Reactant: C[C@@H]1CNCCO1
Reactant: CCS(=O)(=O)c1cc(=O)c2cc(C(=O)OC)cc(Br)c2o1
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(Br)c2oc(N3CCO[C@H](C)C3)cc(=O)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.8 %

Procedure:
DIPEA (51.7 mL, 296.91 mmol) was added dropwise to a stirred solution of methyl 8-bromo-2-(ethylsulfonyl)-4-oxo-4H-chromene-6-carboxylate (44.56 g, 118.77 mmol) and (R)-2-methylmorpholine hydrochloride (22.88 g, 166.27 mmol) in DCM (430 mL) at 5° C. under nitrogen. The resulting suspension was stirred at room temperature for 1 h. The reaction mixture was diluted with water and quenched slowly with HCl 1M (119 mL, 118.77 mmol) (pH 7). The phases were separated and the organic phase was washed with water, brine, dried over MgSO4 and concentrated. The crude product was triturated in EtAc for 1 h, the solid was collected by filtration and dried to afford methyl 8-bromo-2-((R)-2-methylmorpholino)-4-oxo-4H-chromene-6-carboxylate (32.6 g, 67%) as a white solid. Mass Spectrum: m/z [M+H]+=384.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[N:28]4[C:23]([C:24]([NH2:29])=[N:25][CH:26]=[N:27]4)=[CH:22][CH:21]=3)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1.[Br:35]N1C(C)(C)C(=O)N(Br)C1=O.CCOC(C)=O>CN(C=O)C.C([O-])([O-])=O.[Na+].[Na+].[O-]S([O-])=O.[Na+].[Na+].O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[N:28]4[C:23]([C:24]([NH2:29])=[N:25][CH:26]=[N:27]4)=[C:22]([Br:35])[CH:21]=3)[CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(-c3ccc4c(N)ncnn34)c2)CC1
Agent: O=C([O-])[O-]
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(-c3cc(Br)c4c(N)ncnn34)c2)CC1
Reaction time: 1 h
Yield: 165.8 %

Procedure:
The product from step 3 (160 mg. 0.40 mmol) was dissolved in 1 mL of DMF and 1 mL of THF was added. The mixture was cooled to −20° C. (isopropanol/ice/dry ice bath) and 1,3-dibromo-5,5-dimethyl hydantoin (58 mg, 0.20 mmol) was added in 4 portions over 40 minutes. The mixture was stirred for an additional 1 hour during which the internal temp rose to −5° C. It was diluted with a mixture of 1 mL of 2M Na2CO3, 1 mL of sat. Na2SO3 and 6 mL of water and the mixture stirred for 5 minutes. EtOAc (10 mL) was added and the layers were separated. The aqueous layer was extracted with 15 mL of EtOAc and the combined organic fractions were washed with 2M aqueous Na2CO3, water, brine, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by Isco®(Red-sep 12, eluting with 60-100% hexanes/EtOAc) to provide 157 mg (82%) of the title compound as a foamy solid. 1H-NMR (DMSO-d6) 7.98-7.64 (bs, 2H), 7.61 (s, 1H), 7.797 (s, 1H), 7.52 (d, 1H), 7.03 (d, 1H), 7.00-6.93 (m, 2H), (d, 1H), 6.71 (d, 1H), 3.43 (m, 4H), 3.13 (m, 4H), 1.40 (s, 9H); LC-MS [M+H]+=473, 475, RT=2.80 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:20])[C:13]([CH3:15])([CH3:14])[O:12][C:11](OC)=[N:10][S:9]2(=[O:19])=[O:18])=[CH:4][CH:3]=1.[Si:21]([O:28][CH2:29][CH2:30][C@H:31]([NH2:39])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[F:38])([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:20])[C:13]([CH3:15])([CH3:14])[O:12][C:11]([NH:39][C@H:31]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[F:38])[CH2:30][CH2:29][O:28][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:22])[CH3:23])=[N:10][S:9]2(=[O:18])=[O:19])=[CH:4][CH:3]=1
Reactant: COC1=NS(=O)(=O)C(C)(c2ccc(Br)cc2)C(C)(C)O1
Reactant: CC(C)(C)[Si](C)(C)OCC[C@H](N)c1ccccc1F
Solvent: ClCCl
Product: CC1(C)OC(N[C@@H](CCO[Si](C)(C)C(C)(C)C)c2ccccc2F)=NS(=O)(=O)C1(C)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.3 %

Procedure:
A solution of 70 mg of 5-(4-bromophenyl)-2-methoxy-5,6,6-trimethyl-5,6-dihydro-1,4,3-oxathiazine 4,4-dioxide and 66 mg of (S)-3-(tert-butyldimethylsilanyloxy)-1-(2-fluorophenyl)propylamine in 1 ml of methylene chloride was stirred under a gentle argon stream, such that the solvent evaporated gradually. After stirring at room temperature overnight, the residue was dissolved in 20 ml of dichloromethane and extracted with 10 ml of 0.5 N aqueous hydrochloric acid and 10 ml of water. The organic phase was dried using a phase separator cartridge (Chromabond® PTS), concentrated by rotary evaporation and dried under high vacuum. This gave the product (113 mg) with a molecular weight of 613.7 g/mol (C27H38BrFN2O4SSi); MS (ESI): m/e=614 (M+H+).
Reaction SMILES: [C:1]([NH:20][C@H:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C@@H:22]1[OH:27])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH3:28][C:29]1([CH3:45])[O:34][CH:33]([C:35]([NH:37][CH2:38][CH2:39][C:40](O)=[O:41])=[O:36])[C:32]([CH3:44])([CH3:43])[CH2:31][O:30]1>>[CH3:28][C:29]1([CH3:45])[O:34][CH:33]([C:35]([NH:37][CH2:38][CH2:39][C:40]([O:27][C@@H:22]2[CH2:23][CH2:24][CH2:25][CH2:26][C@H:21]2[NH:20][C:1](=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:41])=[O:36])[C:32]([CH3:44])([CH3:43])[CH2:31][O:30]1
Reactant: CC1(C)OCC(C)(C)C(C(=O)NCCC(=O)O)O1
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)N[C@H]1CCCC[C@@H]1O
Product: CCCCCCCC/C=C\CCCCCCCC(=O)N[C@@H]1CCCC[C@H]1OC(=O)CCNC(=O)C1OC(C)(C)OCC1(C)C
Yield: 56.8 %

Procedure:
(1S,2S)-2-(N-Oleoylamino)cyclohexanol (3.79 g) and 2.59 g of 3-[N-(2,2,5,5-tetramethyl-1,3-dioxane-4-carbonyl)amino]propionic acid were reacted in the same manner as in Example 15 to obtain 3.52 g of the title compound (yield: 57%)
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14](=[O:28])[C:15]2[CH:20]=[C:19]([N+:21]([O-])=O)[C:18]([NH:24][CH3:25])=[C:17]([O:26][CH3:27])[CH:16]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[F:30][C:31]([F:45])([F:44])[CH2:32][N:33]1[C:37]2=[N:38][CH:39]=[CH:40][CH:41]=[C:36]2[CH:35]=[C:34]1[CH:42]=O.S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(O)C.O.C(Cl)Cl>[C:1]([O:5][C:6](=[O:29])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]([C:15]2[CH:16]=[C:17]([O:26][CH3:27])[C:18]3[N:24]([CH3:25])[C:42]([C:34]4[N:33]([CH2:32][C:31]([F:45])([F:44])[F:30])[C:37]5=[N:38][CH:39]=[CH:40][CH:41]=[C:36]5[CH:35]=4)=[N:21][C:19]=3[CH:20]=2)=[O:28])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CNc1c(OC)cc(C(=O)N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)cc1[N+](=O)[O-]
Reactant: O=Cc1cc2cccnc2n1CC(F)(F)F
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: COc1cc(C(=O)N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)cc2nc(-c3cc4cccnc4n3CC(F)(F)F)n(C)c12
Temperature: 100 °C
Yield: 83.9 %

Procedure:
To a solution of (R)-tert-butyl(1-(3-methoxy-4-(methylamino)-5-nitrobenzoyl)piperidin-3-yl)carbamate (3.58 g, 8.76 mmol) and 1-(2,2,2-trifluoroethyl)-1H-pyrrolo[2,3-b]pyridine-2-carbaldehyde (2.61 g, 11.44 mmol) in ethanol (140 ml) was added portionwise a solution of sodium hydrosulfite (3.18 g, 15.53 mmol) in water (70 ml). The mixture was flushed with nitrogen then heated at 100° C. overnight (16 hours). The reaction mixture was concentrated under vacuum then diluted with DCM (150 ml) and water (150 ml). The organic layer was collected and the aqueous layer washed with DCM (3×100 ml). Organic layers were collected, dried with Na2SO4, filtered through a hydrophobic frit and concentrated under vacuum to yield 5.5 g of crude product as white solid. This was dissolved in a minimum volume of DCM and purified using Biotage SP4 on a 100 g SNAP silica cartridge. The column was eluted with a gradient of 70-100% ethyl acetate in DCM for 10CV. Appropriate fractions were collected and concentrated under vacuum to yield the title compound as a white solid (4.31 g).
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C([O-])([O-])=O.[Na+].[Na+]>CC(O)C.O>[F:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]2[N:6]3[N:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]3=[N:4][C:3]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=2)=[CH:26][CH:25]=1
Reactant: COc1ccc2nc(-c3ccc(C)c([N+](=O)[O-])c3)c(Br)n2n1
Reactant: OB(O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: COc1ccc2nc(-c3ccc(C)c([N+](=O)[O-])c3)c(-c3ccc(F)cc3)n2n1
Temperature: 80 °C
Yield: 88.4 %

Procedure:
To a stirred mixture of 3-bromo-6-methoxy-2-(4-methyl-3-nitrophenyl)imidazo[1,2-b]pyridazine (0.100 g, 0.275 mmol), 4-fluorophenylboronic acid (0.412 mmol), Na2CO3 (0.825 mmol) in 2-propanol (6 mL) and water (2 mL) that has been degassed with N2 (5 minutes) is added PdCl2(PPh3)2(0.0275 g). The reaction mixture is heated at 80° C. for 6 hours, cooled, diluted with sat. aqueous NaHCO3 (50 mL) and extracted with EtOAc (3×25 mL). Organic layer is collected, dried over Na2SO4, filtered and concentrated to dryness. The crude product is purified via chromatography (hexanes to EtOAc) to afford 0.092 g (88%) of the title compound as a yellow solid: Rf 0.47 (1:1 EtOAc:hexanes); LCMS (m/z)=379.4 [M+H]+, tR=3.07 min.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][C:11](O)=[O:12])=[CH:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[S:1]1[CH:2]=[C:3]([CH2:10][CH2:11][OH:12])[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2
Reactant: O=C(O)Cc1csc2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCc1csc2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-benzothienylacetic acid (5.2 mmol) in 10 mL of anhydrous THF was slowly added to a stirred solution of LAH (10.4 mmol) in 50 mL of THF at 0° C. The ice bath was removed and the solution was stirred overnight, while it was allowed to warm to room temperature. The reaction was quenched by addition of water, 10% aqueous NaOH. The mixture was filtered over Celite and the filtrate was concentrated to give 2-(benzo[b]thiophen-3-yl)ethanol, which was used for tosylation.
Reaction SMILES: C[Al](C)C.[NH2:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][N:7]=1.[Si:14]([O:31][CH2:32][CH2:33][O:34][CH2:35][C@H:36]([O:41][C:42]1[N:47]=[CH:46][N:45]=[C:44]2[N:48]([C:51]3[CH:56]=[CH:55][CH:54]=[C:53]([Cl:57])[C:52]=3[Cl:58])[N:49]=[CH:50][C:43]=12)[C:37](OC)=[O:38])([C:27]([CH3:30])([CH3:29])[CH3:28])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C=CC=CC=1>[Si:14]([O:31][CH2:32][CH2:33][O:34][CH2:35][C@H:36]([O:41][C:42]1[N:47]=[CH:46][N:45]=[C:44]2[N:48]([C:51]3[CH:56]=[CH:55][CH:54]=[C:53]([Cl:57])[C:52]=3[Cl:58])[N:49]=[CH:50][C:43]=12)[C:37]([NH:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][N:7]=1)=[O:38])([C:27]([CH3:28])([CH3:29])[CH3:30])([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)[C@H](COCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)Oc1ncnc2c1cnn2-c1cccc(Cl)c1Cl
Reactant: N#Cc1ccc(N)nc1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](OCCOC[C@H](Oc1ncnc2c1cnn2-c1cccc(Cl)c1Cl)C(=O)Nc1ccc(C#N)cn1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 93.4 %

Procedure:
Trimethylaluminium (2M in toluene) (0.638 mL, 1.28 mmol) was added to 6-aminonicotinonitrile (152 mg, 1.28 mmol) in toluene (2 mL) under nitrogen. The resulting solution was stirred at room temperature for 15 minutes. (2S)-methyl 3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-(1-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanoate (Intermediate AR1) (425 mg, 0.64 mmol) in toluene (8 mL) was added sealed into a 20 mL microwave tube. The reaction was heated to 120° C. for 4 hours in the microwave reactor and cooled to RT. The reaction mixture was allowed to cool and concentrated in vacuo. The residue was neutralised with citric acid (1M, aq) and then diluted with water (30 mL) and extracted with EtOAc (2×50 mL). The combined organics were dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 50% EtOAc in isohexane to afford (2S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-N-(5-cyanopyridin-2-yl)-2-(1-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanamide (450 mg, 94%).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH:10]([CH2:12][C:13]([OH:15])=O)=[CH2:11].N1C2C=CC=C(O[P+](N(C)C)(N(C)C)N(C)C)C=2N=N1.F[P-](F)(F)(F)(F)F.Cl.Cl.[N:45]1[C:53]2[CH2:52][CH2:51][NH:50][CH2:49][C:48]=2[S:47][C:46]=1[NH:54][C:55]([NH2:57])=[NH:56].[OH-].[Na+]>CN(C)C=O>[C:13]([N:50]1[CH2:51][CH2:52][C:53]2[N:45]=[C:46]([NH:54][C:55]([NH2:57])=[NH:56])[S:47][C:48]=2[CH2:49]1)(=[O:15])[CH2:12][CH:10]=[CH2:11]
Reactant: N=C(N)Nc1nc2c(s1)CNCC2
Reactant: C=CCC(=O)O
Agent: CN(C)[P+](Oc1cccc2[nH]nnc12)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CCC(=O)N1CCc2nc(NC(=N)N)sc2C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Diisopropylethylamine (0.22 mmol), vinyl acetic acid (0.11 mmol) and benzotriazolyloxy-tris-(dimethylamino)phosphonium-hexafluorophosphate (0.11 mmol) are added successively to a stirred suspension of N-(4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridine-2-yl)-guanidine-dihydrochloride (0.1 mmol) in dimethylformamide (0.7 mL), and the reaction mixture is stirred for 16 hours at room temperature. After the addition of 2M caustic soda solution (1 ml) there is extraction with ethyl acetate. The combined organic phases produce the pure title compound after drying over sodium sulphate and concentrating to dryness.
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:19][OH:20]>>[O:1]([CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][C:14](=[N:19][OH:20])[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCN(CCCOc2ccccc2)CC1
Reactant: NO
Agent: Cl
Product: ON=C1CCN(CCCOc2ccccc2)CC1

Procedure:
1-(3-Phenoxypropyl)-4-piperidone oxime is prepared from 1-(3-phenoxypropyl)-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:22]=[CH:21][C:8]([O:9][CH2:10][C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])=[CH:7][CH:6]=1)=[O:4].[N:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1.C(OCC)C>C(#N)C>[N:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:30][CH2:31][N:32]([CH2:2][C:3]([C:5]3[CH:22]=[CH:21][C:8]([O:9][CH2:10][C:11]([NH:13][CH2:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[O:12])=[CH:7][CH:6]=3)=[O:4])[CH2:33][CH2:34]2)=[CH:25][CH:24]=1
Reactant: O=C(COc1ccc(C(=O)CBr)cc1)NCc1ccccc1
Reactant: c1cc(N2CCNCC2)ccn1
Solvent: CCOCC
Solvent: CC#N
Product: O=C(COc1ccc(C(=O)CN2CCN(c3ccncc3)CC2)cc1)NCc1ccccc1
Reaction time: 8 h

Procedure:
A solution of 2-[4-(bromoacetyl)phenoxy]-N-(phenylmethyl)-acetamide (1.40 g) (preparation described in EP0 052442) in acetonitrile (5 ml) was added to a stirred solution of 1-(4-pyridyl)piperazine (1.14 g) in acetonitrile (20 ml). After stirring overnight the liquors were decanted from the residual gum, then concentrated in vacuo. Purification by flash chromatography on silica, eluting with 2 to 5% v/v methanol/dichloromethane, gave a solid. Trituration of this solid with diethyl ether gave the title compound, 95 mg: m.p. 150°-151° C.; NMR (d6DMSO) δ 8.67 (1H, bt), 8.15 (2H, d), 8.00 (2H, d), 7.26 (5H, m), 7.06 (2H, d), 6.81 (2H, d), 4.66 (2H, s), 4.34 (2H, d), 3.84 (2H, s), 3.33 (4H, t), 2.54 (4H, t); m/e 445 (M+H)+ ; Calculated for C26H28N4O3.0.25H2O: C, 69.5; H, 6.4; 12.5. found: C, 69.6; H, 6.4; N, 12.3%.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]([CH3:19])[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1.[NH:22]1[CH:26]=[CH:25][N:24]=[C:23]1[CH:27]=O.C(OC)(OC)OC.[BH4-].[Na+]>CO>[NH:22]1[CH:26]=[CH:25][N:24]=[C:23]1[CH2:27][NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]([CH3:19])[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:20][CH:21]=1
Reactant: O=Cc1ncc[nH]1
Reactant: CN(CCCCN1CCCCC1)Cc1ccc(CN)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: CO
Product: CN(CCCCN1CCCCC1)Cc1ccc(CNCc2ncc[nH]2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 36.7 %

Procedure:
The compound (248.5 mg) obtained in Example 44-5 was dissolved in methanol (12.4 ml) and added with 2-imidazole carboxaldehyde (123.7 mg) and trimethyl orthoformate (0.282 ml) and the whole was stirred at room temperature for 2.5 hours. Subsequently, sodium borohydride (97.4 mg) was added thereto under ice-cooling and the whole was stirred at room temperature for additional 30 minutes. The reaction solution was concentrated under reduced pressure. The residue was added with water and the whole was subjected to extraction with chloroform. The organic layer was washed with a saturated saline solution and dried with anhydrous sodium sulfate, followed by concentration under reduced pressure. The residue was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (116.3 mg) as a yellow oily substance.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[N:7]([CH3:12])[C:8](=[S:11])[NH:9][N:10]=1.Br[CH2:14][CH:15]1[CH2:17][CH2:16]1.ClCCl.C([O-])(O)=O.[Na+]>CN(C)C=O>[CH:15]1([CH2:14][S:11][C:8]2[N:7]([CH3:12])[C:6]([CH2:5][CH2:4][CH2:3][CH2:2][OH:1])=[N:10][N:9]=2)[CH2:17][CH2:16]1
Reactant: Cn1c(CCCCO)n[nH]c1=S
Reactant: BrCC1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cn1c(CCCCO)nnc1SCC1CC1
Temperature: 60 °C

Procedure:
5-(4-hydroxybutyl)-4-methyl-2,4-dihydro-3H-1,2,4-triazole-3-thione (0.3 g), (bromomethyl)cyclopropane (0.17 ml) and triethyl ammine (0.27 ml) were dissolved in dimethylformamide (2 ml). Reaction was heated at 60° C. for 2 h. Dichloromethane and NaHCO3 saturated solution were added. Solvent was removed, under reduced pressure to give a crude that was purified by Silica column (eluting with DCM/MeOH from 0 to 10%) to give the title compound (0.2 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14]3[CH:15]=[CH:16][C:17]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])=[CH:18][C:13]=3[O:12][C:11]([CH3:25])([CH3:24])[C:10]2=[O:26])[CH:5]=[CH:6][C:7]=1[F:8].N1C=CC=CC=1.[C:33](Cl)(=[O:35])[CH3:34]>ClCCl>[CH3:25][C:11]1([CH3:24])[C:10](=[O:26])[N:9]([C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([NH:1][C:33](=[O:35])[CH3:34])[CH:3]=2)[C:14]2[CH:15]=[CH:16][C:17]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])=[CH:18][C:13]=2[O:12]1
Reactant: CC1(C)Oc2cc(NS(C)(=O)=O)ccc2N(c2ccc(F)c(N)c2)C1=O
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1cc(N2C(=O)C(C)(C)Oc3cc(NS(C)(=O)=O)ccc32)ccc1F
Reaction time: 1 h

Procedure:
To a solution of N-[4-(3-amino-4-fluorophenyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl]methanesulfonamide (compound obtained in Example 44; 13 mg) and pyridine (5.5 μL) in dichloromethane (5 mL) was added acetyl chloride (3.6 μL) under ice-cooling, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was purified by column chromatography on silica gel (solvent; chloroform to chloroform/methanol (9/1) and triturated with diisopropylether to give N-(5-{2,2-dimethyl-7-[(methanesulfonyl)amino]-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl}-2-fluorophenyl)acetamide (10 mg) as a pale yellow powder.
Reaction SMILES: [CH3:1][C:2]1([CH3:34])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([O:14][CH2:15][CH2:16][O:17][C:18]3[CH:33]=[CH:32][C:21]([CH:22]=[C:23]([C:28]([O:30][CH3:31])=[O:29])[C:24]([O:26][CH3:27])=[O:25])=[CH:20][CH:19]=3)[CH:5]=[CH:4][C:3]1=2.[H][H]>CO.O1CCOCC1.[Pd]>[CH3:1][C:2]1([CH3:34])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([O:14][CH2:15][CH2:16][O:17][C:18]3[CH:19]=[CH:20][C:21]([CH2:22][CH:23]([C:24]([O:26][CH3:27])=[O:25])[C:28]([O:30][CH3:31])=[O:29])=[CH:32][CH:33]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: COC(=O)C(=Cc1ccc(OCCOc2ccc3c(c2)C(C)(C)CCC3(C)C)cc1)C(=O)OC
Reactant: [H][H]
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)C(Cc1ccc(OCCOc2ccc3c(c2)C(C)(C)CCC3(C)C)cc1)C(=O)OC
Yield: 95.6 %

Procedure:
To a solution of dimethyl 4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthoxy)ethoxy]benzylidenemalonate (2.55 g, 5.47 mmol) in a mixture of methanol (20 ml) and 1,4-dioxane (150 ml) is added 5% palladium on charcoal (1.20 g). Then the mixture is stirred under an atmosphere of hydrogen at room temperature until hydrogen uptake ceased. The solution is filtered through Celite, and the filtrate is evaporated under a vacuum. The residue is crystallized from ethyl acetate to give the title compound (2.45 g, 96%). HRMS calcd for C28H36O6: 468.5902. Found: 468.5905. MA calcd for C28H36O6: C, 71.77%; H, 7.74%. Found: C, 71.52%; H, 7.76%.