Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.CN(C)C=O.N1C=CC=CC=1.[CH2:20]([C@H:24]1[CH2:29][CH2:28][C@H:27]([C:30](Cl)=[O:31])[CH2:26][CH2:25]1)[CH2:21][CH2:22][CH3:23]>O>[CH2:20]([C@H:24]1[CH2:25][CH2:26][C@H:27]([C:30]([O:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)=[O:31])[CH2:28][CH2:29]1)[CH2:21][CH2:22][CH3:23]
Reactant: Oc1ccc(Br)cc1
Reactant: CCCC[C@H]1CC[C@H](C(=O)Cl)CC1
Solvent: O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCCC[C@H]1CC[C@H](C(=O)Oc2ccc(Br)cc2)CC1

Procedure:
26 g of 4-bromophenol, 100 ml of dimethylformamide, and 13 g of pyridine were dissolved. 31 g of commercially available trans-4-n-butylcyclohexane carboxylic acid chloride was added dropwise to the solution and the mixture was heated while stirring. The reaction mixture was poured into water to produce crystals. The crystals were collected by filtration, washed with dilute HCl and then water, dried in vacuum, and recrystallized from a mixed solvent of ethyl acetate and methanol to obtain 44 g of 4-bromophenyl trans-4-n-butylcyclohexane carboxylate. To this were added 20 g of 4-ethoxyphenyl acetylene, 0.09 g of bis(triphenylphosphine)-palladium(II) chloride, 0.1 g of copper iodide, 0.79 g of triphenylphosphine, and 260 ml of triethylamine, and the mixture was heated while stirring. After the reaction, the reaction product was poured into water and neutralized with HCl to produce crystals. The crystals were collected by filtration, washed with water, dried in vacuum, and recrystallized from a mixed solvent of ethyl acetate and methanol to obtain 40 g of a compound having the following formula. ##STR43##
Reaction SMILES: [CH:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=2)[C:6]([C:16]([OH:18])=O)=[CH:5]1)([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:55][C:56]1[S:57][CH:58]=[CH:59][N:60]=1>C(Cl)Cl>[S:57]1[CH:58]=[CH:59][N:60]=[C:56]1[NH:55][C:16]([C:6]1[C:7]2[C:12](=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=2)[N:4]([CH:1]([CH3:2])[CH3:3])[CH:5]=1)=[O:18]
Reactant: CC(C)n1cc(C(=O)O)c2ccc([N+](=O)[O-])cc21
Reactant: Nc1nccs1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)n1cc(C(=O)Nc2nccs2)c2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 4.9 %

Procedure:
A solution of 1-isopropyl-6-nitro-1H-indole-3-carboxylic acid (200 mg, 0.81 mmol) in methylene chloride (4 mL) and N,N-diisopropylethylamine (0.32 mL, 1.85 mmol) at 25° C. was treated with benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluoro-phosphate (463 mg, 1.05 mmol). The reaction was stirred at 25° C. for 20 min. At this time, the reaction was treated with 2-aminothiazole (186 mg, 1.85 mmol) and was stirred at 25° C. for 24 h. At this time, the reaction mixture was partitioned between water (50 mL) and ethyl acetate (50 mL) and was treated with a 1N aqueous hydrochloric acid solution (25 mL). The organic layer was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting solid was dissolved in a hot solution of 1/1 hexanes/ethyl acetate and then filtered. The filtrate was cooled in the freezer for 1 h. At this time, the resulting solid was collected by filtration. The filtrate was concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 1/1 hexanes/ethyl acetate) afforded 1-isopropyl-6-nitro-1H-indole-3-carboxylic acid thiazol-2-ylamide (13 mg, 4.9%) as a yellow solid: mp 236-239° C.; EI-HRMS m/e calcd for C15H14N4O3S (M+) 330.0786, found 330.0792.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH2:7])=[C:3]([NH2:8])[CH:2]=1.[CH3:9][C:10]([CH:12]=O)=O.C(OCC)(=O)C>CO>[CH3:12][C:10]1[N:8]=[C:3]2[CH:2]=[N:1][CH:6]=[CH:5][C:4]2=[N:7][CH:9]=1
Reactant: CC(=O)C=O
Reactant: Nc1ccncc1N
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1cnc2ccncc2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.1 %

Procedure:
Pyridine-3,4-diamine (2.00 g, 18.3 mmol) was dissolved in methanol (100 mL) and cooled in an ice bath. Pyruvic aldehyde (40% wt., 3.36 mL, 22.0 mmol) was added, dropwise, and the solution was allowed to warm to ambient temperature where it was stirred, under nitrogen, for 18 h. The reaction was monitored by LC-MS and pyruvic aldehyde (2.5 mL, 16.4 mmol) was added and the solution stirred at room temperature, under nitrogen for an additional 5 h. The solvent was removed, in vacuo, to give a black liquid which solidified to a black solid (3.58 g) upon standing. This material was adsorbed onto silica gel and purified by column chromatography, eluting with a solution of 1:1 hexane:ethyl acetate to give a brown solid (2.18 g, 82% Yield). 1H NMR 400 MHz (DMSO): δ=9.43 (s, 1H), 9.00 (s, 1H), 8.81 (d, 1H, J=5.9 Hz), 7.91 (dd, 1H, J=5.7 Hz, J=0.8 Hz), 2.79 (s, 3H). HPLC (Column; Xterra RP18, 3.5 μm, 4.6×150 mm, Column temp.=40° C.), Flow=1.2 mL/min., 85/15-5/95, 10 min., 5/95, 5.0 min., (25 mM HCO2NH4 buffer, pH=3.5/AcN/MeOH), No impurities @ 210-370 nM, and no impurities @ 306 nM, retention time =3.5 min. Calculated mass=145.06, [M+H]+=146.
Reaction SMILES: [CH2:1]([C:8]1[C:9]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:10]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[C:11]2[N:12]([CH:14]=[CH:15][CH:16]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:29]N1C(=O)CCC1=O>O1CCCC1>[CH2:1]([C:8]1[C:9]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:10]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[C:11]2[N:12]([C:14]([Cl:29])=[CH:15][CH:16]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)c1c(Cc2ccccc2)nn2cccc2c1-c1ccc(F)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1c(Cc2ccccc2)nn2c(Cl)ccc2c1-c1ccc(F)cc1
Temperature: 20 °C
Reaction time: 2 h
Yield: 35.8 %

Procedure:
To a solution of ethyl 2-benzyl-4-(4-fluorophenyl)pyrrolo[1,2-b]pyridazine-3-carboxylate (730 mg) in tetrahydrofuran (10 ml) was added N-chlorosuccinimide (260 mg) and the mixture was stirred at 20° C. for 2 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with aqueous sodium thiosulfate, water and brine, dried over magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography eluting with a mixture of toluene and ethyl acetate (10:1) to give ethyl 2-benzyl-7-chloro-4-(4-fluorophenyl)pyrrolo[1,2-b]pyridazine-3-carboxylate (285 mg) as an yellow oil.
Reaction SMILES: [CH:1]([S:5][C:6]1[S:7][CH:8]=[C:9]([O:11][S:12]([CH3:15])(=[O:14])=[O:13])[N:10]=1)([CH2:3][CH3:4])[CH3:2].[OH:16]O.O.[OH-].[Na+]>C(O)(=O)C>[CH:1]([S:5]([C:6]1[S:7][CH:8]=[C:9]([O:11][S:12]([CH3:15])(=[O:13])=[O:14])[N:10]=1)=[O:16])([CH2:3][CH3:4])[CH3:2]
Reactant: OO
Reactant: CCC(C)Sc1nc(OS(C)(=O)=O)cs1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CCC(C)S(=O)c1nc(OS(C)(=O)=O)cs1
Yield: 49.7 %

Procedure:
4.0 g of 2-sec-butylthio-4-methylsulfonyloxy-1,3-thiazole was dissolved in 15 ml of acetic acid, and 2.2 ml of 35% aqueous hydrogen peroxide was added to the solution at room temperature, followed by reaction at 30° to 40° C. for 4 hours. The reaction mixture was poured into chilled water, neutralized by 5% aqueous solution of sodium hydroxide, and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of common salt, dried over anhydrous sodium sulfate and concentrated to obtain an oil, which was purified by silica-gel column chromatography to 2.1 g of the objective compound as a pale yellow oil (yield: 49.7%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[NH:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][NH:27][C:28]3[N:33]=[CH:32][CH:31]=[CH:30][N:29]=3)[CH2:21][CH2:20]2)=[CH:4][CH:3]=1.[C:34]([O:37][C:38](=[O:40])[CH3:39])(=[O:36])[CH3:35].[C:41]([OH:44])(=[O:43])[CH3:42]>>[C:38]([OH:37])(=[O:40])/[CH:39]=[CH:42]/[C:41]([OH:44])=[O:43].[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[NH:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][N:27]([C:28]3[N:29]=[CH:30][CH:31]=[CH:32][N:33]=3)[C:34](=[O:36])[CH3:35])[CH2:21][CH2:20]2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(Cn2c(NC3CCN(CCNc4ncccn4)CC3)nc3ccccc32)cc1
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)O
Product: CC(=O)N(CCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1)c1ncccn1
Product: O=C(O)/C=C/C(=O)O
Yield: 16.5 %

Procedure:
A mixture of 4.5 parts of 1-[(4-fluorophenyl)methyl]-N-[1-[2-[(2-pyrimidinyl)amino]ethyl]-4-piperidinyl]-1H-benzimidazol-2-amine, 15 parts of acetic acid anhydride and 140 parts of acetic acid was stirred and refluxed overnight. The reaction mixture was evaporated. The residue was taken up in water and the whole was alkalized with ammonium hydroxide. The product was extracted with dichloromethane. The extracft was dried, filtered and evaporated. The residue was purified by HPLC over silica gel using a mixture of methylbenzene and ethanol (90:10 by volume) as eluent. The second fraction was collected and the eluent was evaporated. The residue was converted into the (E)-2-butenedioate salt in methanol. The salt is filtered off and dried, yielding 1.2 parts (16.5%) of N-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]-N-(2-pyrimidinyl)acetamide (E)-2-butenedioate (1:2); mp. 191.1° C. (compound 99).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4]2=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:11][C:3]=12.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C([O-])([O-])=O.[K+].[K+]>O.CCOC(C)=O>[CH3:8][C:6]1[NH:5][C:4]2=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:11][C:3]2=[C:2]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[N:7]=1
Reactant: Cc1nc(Cl)c2nc(-c3ccccc3)cc-2[nH]1
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1nc(N2CCNCC2)c2nc(-c3ccccc3)cc-2[nH]1
Temperature: 25 °C
Yield: 29.1 %

Procedure:
This compound was prepared according to the method described in Example 26 by employing 4-chloro-2-methyl-6-phenylpyrrolo[3,2-d]pyrimidine (Example 1(e)) (0.10 g, 0.41 mmol), piperazine (Aldrich Chemical Company) (0.382 g, 4.43 mmol) and K2CO3 (0.34 g, 2.50 mmol) in H2O (2.5 mL) to give crude pink solids. These solids were taken up in hot EtOAc, cooled to room temperature, and the impurities were removed by filtration. The filtrate was concentrated to give 0.035 g (29%) of the title compound as an off-white solid. Mp: 236° C. 1H NMR (DMSO-d6; 500 MHz): δ 2.42 (s, 3), 2.85 (t, 4, J=5.2), 3.62 (t, 4, J=5.2), 6.77 (s, 1), 7.36 (m, 1), 7.45 (t, 2, J=7.8), 7.95 (d, 2, J=7.6), 10.96 (s, 1); MS m/z: 294 (M+1). Anal. Calcd for C17H19N5O.0.5H2O: C, 67.53; H, 6.67; N, 23.16. Found: C, 67.35; H, 6.59; N, 23.01.
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:15]([OH:17])=O)[C:9]([OH:11])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:26][C@H:27]1[CH2:33][CH2:32][S:31][C@H:30]2[CH2:34][CH2:35][CH2:36][C@@H:37]([C:38]([NH:40][CH2:41][CH2:42][CH3:43])=[O:39])[N:29]2[C:28]1=[O:44]>>[CH2:18]([C@@H:14]([CH2:13][CH2:12][C@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]([NH:26][C@H:27]1[CH2:33][CH2:32][S:31][C@H:30]2[CH2:34][CH2:35][CH2:36][C@@H:37]([C:38](=[O:39])[NH:40][CH2:41][CH2:42][CH3:43])[N:29]2[C:28]1=[O:44])=[O:11])[C:15]([NH:26][C@H:27]1[CH2:33][CH2:32][S:31][C@H:30]2[CH2:34][CH2:35][CH2:36][C@@H:37]([C:38](=[O:39])[NH:40][CH2:41][CH2:42][CH3:43])[N:29]2[C:28]1=[O:44])=[O:17])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCCNC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](N)C(=O)N21
Reactant: O=C(O)[C@H](CC[C@H](Cc1ccccc1)C(=O)O)Cc1ccccc1
Agent: Cl
Product: CCCNC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)N[C@H]3CCS[C@H]4CCC[C@@H](C(=O)NCCC)N4C3=O)Cc3ccccc3)C(=O)N21

Procedure:
(2R,5R)-2,5-Dibenzyl-N1,N6-bis((4S,7S,10aS)-5-oxo-7-(propylcarbamoyl)octahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-yl)hexanediamide was synthesized as described in General Procedure F using Intermediate 3 (7.9 mg, 0.024 mmol) and Intermediate 38 (18 mg, 0.056 mmol) to give a light yellow solid (15 mg, 70% yield). Anal. Calcd. for C46H64N6O6S2 m/z 860.7. found: 861.6 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.24-7.13 (m, 10H), 5.31 (m, 2H), 4.94 (m, 4H), 3.33-3.13 (m, 6H), 2.76 (m, 6H), 2.35 (m, 4H), 2.08 (m, 4H), 1.70-1.47 (m, 18H), 0.90 (m, 6H).
Reaction SMILES: [C:1](=O)([O-])[O-].[Cs+].[Cs+].IC.[O:9]=[C:10]1[CH:24]([CH2:25][C:26]([O:28]C(C)(C)C)=[O:27])[C:23]2[N:22]=[CH:21][N:14]3[CH2:15][C:16](=[O:20])[CH2:17][CH2:18][NH:19][C:12]([C:13]=23)=[CH:11]1>CN(C=O)C>[CH3:1][CH:15]1[N:14]2[CH:21]=[N:22][C:23]3[CH:24]([CH2:25][C:26]([OH:28])=[O:27])[C:10](=[O:9])[CH:11]=[C:12]([C:13]=32)[NH:19][CH2:18][CH2:17][C:16]1=[O:20]
Reactant: CC(C)(C)OC(=O)CC1C(=O)C=C2NCCC(=O)Cn3cnc1c32
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: CC1C(=O)CCNC2=CC(=O)C(CC(=O)O)c3ncn1c32
Reaction time: 18 h

Procedure:
Cesium carbonate (214 mg, 0.66 mmol) and iodomethane (93 mg, 0.66 mmol) were added to a solution of tert-butyl (2,7-dioxo-5,6,7,8-tetrahydro-4H-imidazo[1,5,4-fg][1,6]benzodiazocin-1(2H)-yl)acetate (109 mg, 0.33 mmol, described in Intermediate 13) in DMF (5 mL). After 18 h, the mixture was purified directly 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=346(M+1).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[N:21]=[C:20]([NH:22][C:23]3[NH:24][N:25]=[C:26]([CH3:28])[CH:27]=3)[C:19]3[C:14](=[CH:15][C:16]([N+:29]([O-])=O)=[CH:17][CH:18]=3)[N:13]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]>CCO.O.CC(O)=O.[Fe]>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([S:11][C:12]2[N:21]=[C:20]([NH:22][C:23]3[NH:24][N:25]=[C:26]([CH3:28])[CH:27]=3)[C:19]3[C:14](=[CH:15][C:16]([NH2:29])=[CH:17][CH:18]=3)[N:13]=2)=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(Sc2nc(Nc3cc(C)n[nH]3)c3ccc([N+](=O)[O-])cc3n2)cc1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CC(=O)Nc1ccc(Sc2nc(Nc3cc(C)n[nH]3)c3ccc(N)cc3n2)cc1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
[2-(4-Acetamido-phenylsulfanyl)-7-nitroquinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine (182 mg, 4.18.10−4 mol) is dissolved in a mixture EtOH/water/AcOH (25/10/1, 36 mL) and the reaction is heated at 90° C. Iron powder (93 mg) is added and the mixture is stirred at 90° C. for 4 hours, cooled to room temperature and filtered through a pad of celite. The pad is washed with methanol and the combined filtrate is concentrated in vacuo. The residue is purified by flash chromatography (SiO2, DCM/MeOH gradient) to give the desired [2-(4-acetamido-phenylsulfanyl)-7-aminoquinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine.
Reaction SMILES: C([C:3]1[CH:12]=[CH:11][C:10]2[CH:9]([N:13]([CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[O:31]C)[CH2:14][CH2:15][CH2:16]CC(OCC)=O)[CH2:8][CH2:7][CH2:6][C:5]=2[N:4]=1)#N.[C:33]([O:36][CH2:37][CH3:38])(=[O:35])[CH3:34]>Br>[CH2:37]([O:36][C:33](=[O:35])[CH2:34][CH2:16][CH2:15][CH2:14][N:13]([CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[OH:31])[CH:9]1[CH2:8][CH2:7][CH2:6][C:5]2[N:4]=[C:3]([C:33]([O:36][CH2:37][CH3:38])=[O:35])[CH:12]=[CH:11][C:10]1=2)[CH3:38]
Reactant: CCOC(C)=O
Reactant: CCOC(=O)CCCCN(CCc1ccccc1OC)C1CCCc2nc(C#N)ccc21
Agent: Br
Product: CCOC(=O)CCCCN(CCc1ccccc1O)C1CCCc2nc(C(=O)OCC)ccc21
Temperature: 120 °C
Reaction time: 5 h

Procedure:
Under nitrogen, 23.23 g (0.05 mol) of ethyl 5-{(2-cyano-5,6,7,8-tetrahydroquinolin-5-yl)[2-(2-methoxyphenyl)ethyl]amino}pentanoate were taken up in 175 ml of hydrobromic acid (48% in water). The syrup-like solution was then heated to 120° C. and stirred at this temperature for 5 hours. The clear yellow reaction solution was then cooled to room temperature and concentrated to dryness. Subsequently, 350 ml of anhydrous ethanol and 25 ml of a 4 N solution of hydrogen chloride in dioxane were added to the residue obtained, and the mixture was stirred at 65° C. overnight. The reaction mixture was then concentrated on a rotary evaporator to about 50 ml, 550 ml of saturated aqueous sodium bicarbonate solution were carefully added and the mixture was extracted three times with in each case 150 ml of ethyl acetate. The combined organic phases were dried over sodium sulphate, filtered and concentrated to dryness. The residue obtained (brown oil) was dissolved in 100 ml of ethyl acetate, 65 g of silica gel were added and the mixture was once more concentrated to dryness. The residue was then purified by column chromatography on silica gel (metal column 58×8 cm, 1600 ml of silica gel; mobile phase: ethyl acetate/petroleum ether 1:5, after about 3 liters 1:4, after about 3.5 liters 1:3). This gave 9.43 g (0.02 mol, 38% of theory) of the target compound as a colourless oil.
Reaction SMILES: [O:1]=[C:2](Cl)OC(Cl)(Cl)Cl.[F:9][C:10]1([F:33])[O:15][C:14]2[CH:16]=[C:17]([F:28])[C:18]([NH:20][NH:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:19][C:13]=2[N:12]([CH2:29][C:30]#[CH:31])[C:11]1=[O:32]>C1(C)C=CC=CC=1>[CH:14]([O:15][CH:10]([CH3:11])[CH3:2])([CH3:16])[CH3:13].[C:23]([C:22]1[O:27][C:2](=[O:1])[N:20]([C:18]2[C:17]([F:28])=[CH:16][C:14]3[O:15][C:10]([F:9])([F:33])[C:11](=[O:32])[N:12]([CH2:29][C:30]#[CH:31])[C:13]=3[CH:19]=2)[N:21]=1)([CH3:24])([CH3:25])[CH3:26]
Reactant: C#CCN1C(=O)C(F)(F)Oc2cc(F)c(NNC(=O)C(C)(C)C)cc21
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: C#CCN1C(=O)C(F)(F)Oc2cc(F)c(-n3nc(C(C)(C)C)oc3=O)cc21
Product: CC(C)OC(C)C
Temperature: 25 °C
Yield: 140.7 %

Procedure:
Diphosgene (0.445 ml, 3.69 mmol) was added dropwise to a stirred solution of N′-(2,2,7-trifluoro-3-oxo-4-(prop-2-ynyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)pivalohydrazide (1311 mg, 3.69 mmol) in dry toluene (30 ml) at room temperature under nitrogen. The resulting mixture was stirred at reflux for 4 hours. It was then cooled to room temperature and evaporated in vacuo to yield 1.7 g of crude product. Trituration of this with diisopropyl ether afforded 990 mg of the title compound as a white powder (purity>95%).
Reaction SMILES: [O:1]=[S:2]1(=[O:15])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH2:16]([CH:26]1[CH2:28][O:27]1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C>[O:15]=[S:2]1(=[O:1])[CH2:3][CH2:4][N:5]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:28][CH:26]([OH:27])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:12][CH:13]=2)[CH2:6][CH2:7]1
Reactant: O=S1(=O)CCN(c2ccc(O)cc2)CC1
Reactant: CCCCCCCCCCC1CO1
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: CCCCCCCCCCC(O)COc1ccc(N2CCS(=O)(=O)CC2)cc1
Yield: 38.9 %

Procedure:
4-(1,1-dioxo-thiomorpholin-4-yl)phenol (2.3 g, 10 mmol), 2-(decyl)-oxirane (1.9 g, 10 mmol) and ethyltriphenylphosphonium bromide (0.2 g) are reacted and purified as described for compound 102 to afford a light browm solid 1.6 g (38%), m.p. 84° C.
Reaction SMILES: [CH:1]([O-:3])=O.[Na+].[H][H].O.[C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=O)C>C(O)=O>[CH:14]1[CH:13]=[CH:12][C:11]([CH2:8][CH2:1][OH:3])=[CH:16][CH:15]=1
Reactant: CC(=O)c1ccccc1
Reactant: O=C[O-]
Reactant: [H][H]
Agent: [Na+]
Solvent: O=CO
Solvent: O
Product: OCCc1ccccc1

Procedure:
Then Non-patent Literature 3 suggested a method to use sodium formate as the hydrogen source under a condition of a two-phase reaction system where water is employed as the solvent. In this method, although there is a large increase in the reaction rate and an improvement in the S/C ratio (substrate/catalyst molar ratio) compared to the reaction using formic acid, the optical purity of the alcohol is decreased. For example, a reaction of an acetophenone gives phenylethanol at 97% ee using formic acid, whereas a two-phase reaction system gives phenylethanol at 95% ee.
Reaction SMILES: [F:1][CH:2]([F:26])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([CH3:18])[C:4]=1[S:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1C=C(Cl)C=C(C(OO)=[O:35])C=1.C1C=C(Cl)C=C(C(O)=O)C=1>>[F:26][CH:2]([F:1])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:10])[F:11])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([CH3:18])[C:4]=1[S:19]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:35]
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(Sc2ccccc2)c1C
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C(O)c1cccc(Cl)c1
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(S(=O)c2ccccc2)c1C

Procedure:
Prepared from product of example 7 (6.0 g, 15.3 mmol) and MCPBA (3.11 g of an 85% mixture with MCBA, (ether/petroleum ether) afforded the product as a white solid (4.85 g).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([CH2:23][CH2:24][Cl:25])[P:5]([N:16]([CH2:20][CH2:21][Cl:22])[CH2:17][CH2:18][Cl:19])(=[O:15])[O:6][CH2:7][CH2:8][S:9]([CH2:12][CH2:13]O)(=[O:11])=[O:10].[CH:26]([N:29](CC)[CH:30](C)[CH3:31])(C)[CH3:27].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C(NCC)C>ClCCl.C(OC(C)C)(=O)C>[ClH:1].[Cl:1][CH2:2][CH2:3][N:4]([CH2:23][CH2:24][Cl:25])[P:5]([N:16]([CH2:20][CH2:21][Cl:22])[CH2:17][CH2:18][Cl:19])(=[O:15])[O:6][CH2:7][CH2:8][S:9]([CH2:12][CH2:13][N:29]([CH2:30][CH3:31])[CH2:26][CH3:27])(=[O:11])=[O:10]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=P(OCCS(=O)(=O)CCO)(N(CCCl)CCCl)N(CCCl)CCCl
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CC(=O)OC(C)C
Solvent: CCNCC
Product: CCN(CC)CCS(=O)(=O)CCOP(=O)(N(CCCl)CCCl)N(CCCl)CCCl
Product: Cl
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 36 %

Procedure:
2-{[2-(Hydroxy)ethyl]sulfonyl}ethyl N,N,N′,N′-tetrakis(2-chloroethyl)phosphorodiamidate (150 mg, 0.31 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0° C., and N,N-diisopropylethylamine (108 μL, 0.62 mmol) and trifluoromethanesulfonic anhydride (55 μL, 0.33 mmol) were added, and the reaction mixture allowed to stand for 15 minutes. The reaction mixture was added to a solution of diethylamine (64 μL, 0.62 mmol) in isopropyl acetate (2 mL), and this was allowed to stand for 30 minutes. The reaction mixture was diluted with isopropyl acetate (10 mL) and washed with 5% aqueous NaHCO3 (2×10 mL) and 1M aqueous HCl (2×5 mL). The aqueous acidic fractions were combined, washed with dichloromethane (10 mL), and solid NaHCO3 was added to pH>9. The mixture was extracted with isopropyl acetate (2×10 mL), and the isopropyl acetate extracts combined, dried over MgSO4, filtered, diluted with HCl (4.0M in dioxane, 1 mL), and concentrated under vacuum to give 2-{[2-(diethylamino)ethyl]sulfonyl}ethyl N,N,N′,N′-tetrakis(2-chloroethyl)phosphorodiamidate hydrochloride as a pale brown oil (32 mg, 19% yield). MS (ES+): m/z=536 [C16H34Cl4N3O4PS+H].
Reaction SMILES: [CH3:1][C:2]1[O:10][C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=1.[NH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:14]=1[N+:22]([O-:24])=[O:23].C(OCC)C>C(#N)C>[N+:22]([C:14]1[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:13]=1[O-:12])([O-:24])=[O:23].[NH2:11][N+:6]1[CH:7]=[CH:8][C:9]2[O:10][C:2]([CH3:1])=[CH:3][C:4]=2[CH:5]=1
Reactant: NOc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: Cc1cc2cnccc2o1
Solvent: CC#N
Solvent: CCOCC
Product: Cc1cc2c[n+](N)ccc2o1
Product: O=[N+]([O-])c1ccc([O-])c([N+](=O)[O-])c1
Temperature: 30 °C
Reaction time: 22 h
Yield: 81.7 %

Procedure:
A mixture of 2-methylfuro[3,2-c]pyridine (1.20 g, 8.99 mmol) and 1-(aminooxy)-2,4-dinitrobenzene (1.79 g, 8.99 mmol) in acetonitrile (9.0 mL) was stirred at 30° C. for 22 hr, and diethyl ether was added. The resulting precipitate was collected by filtration to give the title compound (2.44 g, yield 82%).