Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]([CH:20]([CH3:22])[CH3:21])[C:3]([O:5]CC1C=CC=C(OC2C=CC=CC=2)C=1)=[O:4].[Cl:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1.[I-].[K+].S(=O)(=O)(O)O>CN(P(N(C)C)(N(C)C)=O)C>[Cl:23][C:24]1[CH:30]=[CH:29][C:27]([NH:28][C@H:2]([C:3]([OH:5])=[O:4])[CH:20]([CH3:22])[CH3:21])=[CH:26][CH:25]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: CC(C)C(Br)C(=O)OCc1cccc(Oc2ccccc2)c1
Agent: O=S(=O)(O)O
Agent: [I-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(C)[C@H](Nc1ccc(Cl)cc1)C(=O)O
Temperature: 0 °C
Reaction time: 96 h

Procedure:
To m-phenoxybenzyl α-bromoisovalerate (5 g, 0.0138 mole) in 9 ml of HMPT, at 24°, is added p-chloroaniline (5.27 g, 0.0413 mole) and a catalytic amount of potassium iodide (60 mg). The reaction mixture is stirred at 70° for four days. The reaction is then poured into ice-water (30 ml) and 10 ml of 2 N sulfuric acid which is extracted with ether (3×30 ml). The combined ether extracts are washed with water (2×30 ml) and brine (10 ml), dried over calcium sulfate, filtered and evaporated. The crude product is purified by preparative TLC to yield the m-phenoxybenzyl ester of N-(p-chlorophenyl)valine.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][CH2:8][CH2:9][N:10]1[C:14]([C:15](OC)=[O:16])=[CH:13][C:12]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[N:11]1.[OH-].[Na+].[H][H]>O1CCCC1>[Cl:7][CH2:8][CH2:9][N:10]1[C:14]([CH2:15][OH:16])=[CH:13][C:12]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[N:11]1
Reactant: COC(=O)c1cc(-c2ccc(F)cc2)nn1CCCl
Reactant: [H][H]
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cc(-c2ccc(F)cc2)nn1CCCl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Under argon and at 0° C., 4 ml of lithium aluminium hydride solution (1M in diethyl ether, 4.00 mmol) are added to a solution of 1.1 g (4.00 mmol) of methyl 1-(2-chloroethyl)-3-(4-fluorophenyl)-1H-pyrazole-5-carboxylate in 20 ml of tetrahydrofuran. The mixture is then stirred at 0° C. for 2 h. At 0° C., 5M of aqueous NaOH solution are then carefully added dropwise to the reaction mixture until the evolution of hydrogen has stopped. The suspension formed is decanted off and the solvent is removed. The crude product obtained is purified by column chromatography on silica gel (cyclohexane/ethyl acetate). This gives 900 mg (86%) of the desired product; log P(HCOOH): 1.84; 1H-NMR (MeCN-d3): δ=7.81-7.77 (m, 2H), 7.16-7.12 (m, 2H), 6.53 (s, 1H), 4.64 (d, 2H), 4.45 (t, 2H), 4.00 (t, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:13])[C:8](Br)=[N:9][C:10]=1[CH3:11])=[O:5])[CH3:2].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]#[CH:22])=[CH:17][CH:16]=1>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:13])[C:8]([C:22]#[C:21][C:18]2[CH:19]=[CH:20][C:15]([Cl:14])=[CH:16][CH:17]=2)=[N:9][C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C)nc(Br)n1C
Reactant: C#Cc1ccc(Cl)cc1
Product: CCOC(=O)c1c(C)nc(C#Cc2ccc(Cl)cc2)n1C

Procedure:
The title compound, MS: m/e=303.0 (M+H+) was prepared in accordance with the general method of example 1b from 2-bromo-3,5-dimethyl-3H-imidazole-4-carboxylic acid ethyl ester and 1-chloro-4-ethynylbenzene.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:11][CH2:10][CH2:9][CH2:8][C:6]=2[N:7]=1.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([C:2]2[N:3]=[C:4]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:5]3[S:11][CH2:10][CH2:9][CH2:8][C:6]=3[N:7]=2)[CH2:21][CH2:20]1
Reactant: Clc1nc2c(c(N3CCOCC3)n1)SCCC2
Reactant: CN1CCNCC1
Product: CN1CCN(c2nc3c(c(N4CCOCC4)n2)SCCC3)CC1
Yield: 69 %

Procedure:
A mixture of 6.5 g of 2-chloro-4-morpholino-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine and 15 ml of N-methylpiperazine was heated at a bath temperature of 70° to 80° C. for 3 hours. After cooling, the reaction solution was extracted with chloroform, and the extract was washed with water and dried. The solvent was distilled off and the resulting crystals were recrystallized from a mixture of dichloromethane-n-hexane to obtain 5.5 g (69% yield) of 2-(N-methylpiperazino)-4-morpholino-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine as colorless needles having a melting point of 100° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:14][CH3:15])=[CH:4][C:5]2[CH2:11][NH:10][CH2:9][C:8](=[O:12])[NH:7][C:6]=2[CH:13]=1.Cl[C:17]1[N:22]=[C:21]([NH:23][C@@H:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]2[NH:30][S:31]([CH3:34])(=[O:33])=[O:32])[C:20]([Cl:35])=[CH:19][N:18]=1.Cl.O1CCOCC1.CCN(CC)CC>COCCO>[Cl:35][C:20]1[C:21]([NH:23][C@@H:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]2[NH:30][S:31]([CH3:34])(=[O:33])=[O:32])=[N:22][C:17]([NH:1][C:2]2[C:3]([O:14][CH3:15])=[CH:4][C:5]3[CH2:11][NH:10][CH2:9][C:8](=[O:12])[NH:7][C:6]=3[CH:13]=2)=[N:18][CH:19]=1
Reactant: COc1cc2c(cc1N)NC(=O)CNC2
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Agent: Cl
Solvent: COCCO
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COc1cc2c(cc1Nc1ncc(Cl)c(N[C@@H]3CCCC[C@H]3NS(C)(=O)=O)n1)NC(=O)CNC2
Temperature: 120 °C
Yield: 9.8 %

Procedure:
To a solution of 8-amino-7-methoxy-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (66 mg, 0.32 mmol) and N-[(1R,2R)-2-(2,5-dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (100 mg, 0.30 mmol) in 2-methoxyethanol (3 mL) was added 4N HCl-dioxane (50 uL). The mixture was heated under microwave irradiation to 120° C. for 20 minutes. The mixture was adjusted to pH 9 (Et3N) and purified by flash chromatography on silica get (MeOH-DCM) to give 15 mg (9%) of N-{(1R,2R)-2-[5-chloro-2-(7-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamino)-pyrimidin-4-ylamino]-cyclohexyl}-methanesulfonamide as a mustard yellow solid; 1H NMR (400 MHz, DMSO-d6) δ 8.15 (s, 1H), 8.00 (s, 1H), 7.72 (s, 1H), 7.47 (s, 1H), 6.73 (s, 1H), 5.57 (d, J=7 Hz, 1H), 5.46 (d, J=7 Hz, 1H), 4.00 (s, 2H), 3.92 (s, 3H), 3.61 (s, 2H), 3.29 (m, 1H), 2.89 (s, 3H), 2.21 (m, 2H), 1.83 (m, 2H), 1.65 (m, 1H), 1.38 (m, 2H), 1.25 (m, 2H); MS (m/e) 510 (M+1); mp 135° C. (dec.).
Reaction SMILES: [C:1]([NH:4][C@H:5]([PH:21]([OH:23])=[O:22])[C:6]([CH2:17][CH:18]([CH3:20])[CH3:19])([C:12]([O:14]CC)=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:3])[CH3:2].O.[OH-].[Li+].Cl>O>[C:1]([NH:4][C@H:5]([PH:21]([OH:23])=[O:22])[C:6]([CH2:17][CH:18]([CH3:19])[CH3:20])([C:12]([OH:14])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(CC(C)C)(C(=O)OCC)[C@H](NC(C)=O)[PH](=O)O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)C(CC(C)C)(C(=O)O)[C@H](NC(C)=O)[PH](=O)O
Temperature: 25 °C
Reaction time: 72 h
Yield: 92.9 %

Procedure:
7.02 g of diethyl 2-[(R)-(acetamido)(hydroxyphosphinyl)-methyl]-2-isobutylmalonate were suspended in 20 ml of water and 1.76 g of lithium hydroxide monohydrate were added. The mixture was stirred at room temperature for 3 days and was then acidified by the addition of 6 ml of concentrated hydrochloric acid. The solution was then saturated with sodium chloride and extracted ten times with dichloromethane. The combined extracts were dried over anhydrous magnesium sulfate and evaporated to give 6.0 g of ethyl hydrogen 2-[(R)-(acetamido)(hydroxyphosphinyl)methyl]-2(RS)-isobutylmalonate in the form of a white foam as a 3:1 mixture of diastereoisomers; MS: 324 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](C(=O)C)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].ClC1C=CC=C(C(OO)=[O:21])C=1.O[Li].O.O>C(Cl)Cl.CO>[F:1][C:2]1[CH:3]=[C:4]([OH:21])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(C(C)=O)cc1F
Agent: [Li]O
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(O)cc1F
Yield: 72.7 %

Procedure:
A solution of 3′-fluoro-4′-methoxyacetophenone (10 g; 59 mmol) and m-chloroperbenzoic acid (50% purity; 30 g; 89 mmol) in CH2Cl2 (300 mL) was stirred at RT overnight. The solution was washed with saturated aqueous Na2CO3, then filtered through a pad of SiO2 (CH2Cl2 as eluent) and finally chromatographed (SiO2; hex:EtOAc 4:1) to give the crude product (3′-fluoro-4′-methoxy phenyl acetate; 63 g). A solution of this crude material and LiOH.H2O (5 g; 120 mmol) in MeOH:H2O (100 mL of a 9:1 mixture) was stirred at RT overnight. Volatiles were removed in vacuo, and the residue was partitioned between excess aqueous 1 M HCl and EtOAc (aqueous layer pH˜3). The aqueous phase was extracted with EtOAc (2×). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo to give 3-fluoro-4-methoxy phenol (6.1 g; 72%) as an oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([CH:16]3[CH2:25][CH2:24][C:23]4[C:18](=[C:19]([NH2:28])[CH:20]=[CH:21][C:22]=4[O:26][CH3:27])[CH2:17]3)=[O:15])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.Cl.Cl[CH2:31][CH2:32][N:33]([CH2:35][CH2:36]Cl)[CH3:34].C(=O)([O-])O.[Na+].[OH-].[NH4+]>C(O)CCC>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([CH:16]3[CH2:25][CH2:24][C:23]4[C:18](=[C:19]([N:28]5[CH2:36][CH2:35][N:33]([CH3:34])[CH2:32][CH2:31]5)[CH:20]=[CH:21][C:22]=4[O:26][CH3:27])[CH2:17]3)=[O:15])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1
Reactant: COc1ccc(N)c2c1CCC(C(=O)Nc1ccc(N3CCOCC3)cc1)C2
Reactant: CN(CCCl)CCCl
Agent: Cl
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: CCCCO
Product: COc1ccc(N2CCN(C)CC2)c2c1CCC(C(=O)Nc1ccc(N3CCOCC3)cc1)C2
Temperature: 50 °C

Procedure:
A solution of N-(4-morpholinophenyl)-8-amino-5-methoxy-1,2,3,4-tetrahydronaphthalene-2-carboxamide (1.4 g, 3.5 mmol), bis(2-chloroethyl)-methylamine hydrochloride (960 mg, 5 mmol) and sodium hydrogen carbonate (420 mg, 5 mmol) in n-butanol (30 mL) was heated at 90° C. for 5 h. After cooling, 2 M ammonium hydroxide (30 mL) was added and the mixture heated at 50° C. for 1 h. The phases were separated, evaporated in vacuo and purified by flash chromatography on a silica gel column with chloroform/ethanol/conc. ammonium hydroxide 90/10/0.3 as eluent. Yield: 320 mg (20%) of the title compound: mp 230-232° C.; EIMS (70 eV) m/z (relative intensity) 464 (75, M+).
Reaction SMILES: [CH2:1]([C:13]1[CH:17]=[CH:16][S:15][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Li+].CC([N-]C(C)C)C.[CH3:26][Sn:27](Cl)([CH3:29])[CH3:28]>C1COCC1>[CH3:26][Sn:27]([CH3:29])([CH3:28])[C:16]1[S:15][CH:14]=[C:13]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH:17]=1
Reactant: C[Sn](C)(C)Cl
Reactant: CCCCCCCCCCCCc1ccsc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCc1csc([Sn](C)(C)C)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a stirred degassed homogeneous solution of 3-dodecyl thiophene (19) (2 g, 7.92 mmol) in THF at −78° C. was added LDA (4.75 ml, 9.51 mmol) drop wise. The mixture was stirred at −78° C. for 1 h, then trimethylstannylchloride dissolved in 9.5 ml of THF was added, and the solution warmed to room temperature. Stirring was continued for 2 h at room temperature. The mixture was washed with saturated NaHCO3 and extracted with diethylether. The organic layer was separated and dried over anhydrous sodium sulphate and concentrated under reduced pressure to give desired product 20 in 90% yield. 1H-NMR (CD2Cl2, 400 MHz) δ 7.19 (s, 1H), 7.02 (s, 1H), 2.63 (t, 2H), 1.62 (m. 2H), 1.2-1.4 (m, 18H), 0.88 (t, 3H), 0.34 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.[C:14]1(C)C=CC=CC=1>CO>[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([O:8][CH3:14])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: Cc1ccccc1
Solvent: CO
Product: COC(=O)c1cc(Cl)c(N)cc1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-amino-5-chloro-2-methoxybenzoic acid (1.008 g, 5.0 mmol) in a mixture of toluene (9 mL) and methanol (1 mL) at 0° C. was added(trimethylsilyl)diazomethane (2.0 M in hexane, 3.0 mL, 6.0 mmol) dropwise. The reaction mixture was then warmed to room temperature and stirred for 16 h. Excess(trimethylsilyl)diazomethane was quenched by adding acetic acid until the bright yellow color of the reaction mixture disappeared. The mixture was then concentrated in vacuo to give the title compound as an off-white solid, which was used without further purification.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]1[C:21]([CH2:22][CH:23]([CH3:25])[CH3:24])=[C:20]2[C:11]([C:12]([NH2:26])=[N:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=32)=[N:10]1.Cl[C:28]([O:30][CH2:31][CH3:32])=[O:29]>ClCCl>[CH2:22]([C:21]1[N:9]([CH3:8])[N:10]=[C:11]2[C:20]=1[C:19]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:13]=[C:12]2[NH:26][C:28](=[O:29])[O:30][CH2:31][CH3:32])[CH:23]([CH3:24])[CH3:25]
Reactant: CC(C)Cc1c2c(nn1C)c(N)nc1ccccc12
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)Nc1nc2ccccc2c2c(CC(C)C)n(C)nc12
Temperature: 4 °C
Yield: 46.7 %

Procedure:
Triethylamine (0.49 mL, 3.53 mmol) was added to a suspension of 2-methyl-1-(2-methylpropyl)-2H-pyrazolo[3,4-c]quinolin-4-amine (prepared as described in Example 3) (0.75 g, 2.95 mmol) in dichloromethane (30 mL) and cooled to 4° C. Ethyl chloroformate (0.352 g, 3.24 mmol) was added in dichloromethane (5 mL) dropwise over 5 minutes to the reaction mixture and maintained at ambient temperature for 16 hours. The reaction mixture was diluted with dichloromethane (25 mL) and washed sequentially with water (25 mL), 4% sodium bicarbonate (2×25 mL), water (25 mL), and brine (25 mL). The combined organic layers were concentrated under reduced pressure and the residue was purified via column chromatography on silica gel (80 g, eluting with 0-10% CMA/chloroform), concentrated under reduced pressure, and recrystallized from diethyl ether to afford 0.45 g of ethyl 1-isobutyl-2-methyl-2H-pyrazolo[3,4-c]quinolin-4-ylcarbamate as white crystals, mp 120-121° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](Cl)=[O:5].[CH3:12][O:13][C:14]1[CH:22]=[C:21]2[C:17]([CH2:18][CH2:19][CH2:20]2)=[CH:16][C:15]=1[C:23]1[N:24]=[CH:25][C:26]([NH2:29])=[N:27][CH:28]=1.CCN(C(C)C)C(C)C>ClCCl.O1CCCC1.CO.[OH-].[Na+]>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([NH:29][C:26]1[CH:25]=[N:24][C:23]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][C:14]=2[O:13][CH3:12])[CH2:20][CH2:19][CH2:18]3)=[CH:28][N:27]=1)=[O:5]
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: COc1cc2c(cc1-c1cnc(N)cn1)CCC2
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CO
Product: COc1cc2c(cc1-c1cnc(NC(=O)c3c(F)cccc3F)cn1)CCC2
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 37.8 %

Procedure:
Under an atmosphere of argon, 2,6-difluorobenzoyl chloride (29 mg, 0.2 mmol) was added to a stirred solution of 130 (20 mg, 0.1 mmol) and Hünig's base (90 μL, 64 mg, 0.5 mmol) in dichloromethane (0.5 mL) at room temperature. The reaction was stirred for 0.5 h. The solution was diluted with tetrahydrofuran (0.6 mL), methanol (0.4 mL) and 2 M sodium hydroxide solution (0.2 mL). The mixture was stirred and heated to 60° C. for 60 min then cooled to room temperature, diluted with dichloromethane (5 mL), dried with sodium sulfate and concentrated under reduced pressure. Flash chromatography (ISCO system, silica, 0-20% ethyl acetate in hexane) provided 131 (14.4 mg, 30%) as a solid: LRESIMS m/z 381.1 [M+H]+, calcd. for C21H18F2N3O2 382.1.
Reaction SMILES: BrN1C(=O)CCC1=O.[CH2:9]([CH:16]1[CH:20]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[O:19][C:18](=[O:28])[O:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(Cl)(Cl)(Cl)Cl.[W]>[CH:21](=[C:20]1[C:16](=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:17][C:18](=[O:28])[O:19]1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C1OC(Cc2ccccc2)C(Cc2ccccc2)O1
Agent: [W]
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: O=c1oc(=Cc2ccccc2)c(=Cc2ccccc2)o1
Reaction time: 3 h
Yield: 63.5 %

Procedure:
N-Bromosuccinimide (0.1033 g, 0.58 mmole) was added to a refluxing solution of 4,5-dibenzyl-1,3-dioxolan-2-one (75 mg, 0.28 mmole) in CCl4 (30 ml) under argon. The refluxing mixture was irradiated with a 75 watt unfrosted tungsten light for 0.5 h. Refluxing was continued for 3 h, then the solution was cooled, filtered, and the solvent removed in vacuo (20° C./15 mm Hg). Flash chromatography (ethyl ether-hexane eluent) gave 4,5-dibenzylidene-1,3-dioxolan-2-one (47 mg, 63%): mp115° C. (rapid heating); IR (AgCl) 3023, 1812, 1493, 1453, 1365, 1156, 1087, 910, 697 cm-1 ; 'H NMR (CDCl3) 7.39(s, 10H), 4.95(s, 2H).
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[Cl:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1C=O>CCCCCC.O1CCCC1>[Cl:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH:8]1[O:7][C:1](=[O:6])[CH:2]=[C:3]([OH:4])[CH2:5]1
Reactant: COC(=O)CC(C)=O
Reactant: O=Cc1ccccc1Cl
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C1C=C(O)CC(c2ccccc2Cl)O1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
The title compound was prepared as described in General Method 1 using 2.5 mL of methyl acetoacetate, 1.0 g of NaH 60% dispersion in oil, 12.5 mL of 2.0M n-butyl lithium in hexane, 3.3 mL of 2- chlorobenzaldehyde and 75 mL of tetrahydrofuran. After addition of the aldehyde, the reaction was stirred for 10 minutes at 0° C. then stirred for 2 hours at room temperature. The crude product was triturated from diethyl ether to afford a solid (m.p. 124°-125° C.). 1H NMR (CDCl3) δ 2.63 (dd, 1 H), 3.10 (dd, 1 H), 3.68 (dd, 2 H), 6.07 (dd, 1 H), 7.3-7.65 (m, 4 H).
Reaction SMILES: C(OC([N:8]1[C@@H:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)=[CH:16][CH:15]=2)[CH2:11][O:10]C1(C)C)=O)(C)(C)C.[ClH:31].O1CCOCC1>CO>[ClH:31].[NH2:8][C@@H:12]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)=[CH:16][CH:15]=1)[CH2:11][OH:10]
Reactant: COc1ccc(Oc2ccc(C[C@H]3COC(C)(C)N3C(=O)OC(C)(C)C)cc2)cc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COc1ccc(Oc2ccc(C[C@H](N)CO)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of crude product obtained from step 1 (100 mg, 0.25 mmol, 1 eq.) in methanol (2 ml) was added 4N HCl in dioxane (2 ml, 8 mmol, 32 eq.). The resulting mixture was stirred at room temperature for 2 hr. And then the volatile material was removed under reduced pressure. The residue thus obtained was washed with ether (3×15 ml) to remove non-acidic impurities. After dried, 75 mg of desired product (HCl salt) was obtained as white solid (99% isolated yield). 1H NMR (400 MHz, DMSO-d6) 62.87 (m, 2H), 3.27-3.30 (m, 1H), 3.36-3.41 (m, 1H), 3.50-3.55 (m, 1H), 3.93 (s, 2H), 6.91-6.95 (m, 4H), 7.19-7.30 (m, 9H), 7.93 (s, brs, 2H); LCMS (UV, ESI), 274 (M+1), 95% purity.
Reaction SMILES: [CH:1](=[N:9][OH:10])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].ClN1C(=O)CCC1=O.[CH:19]([P:21](=[O:26])([O:24][CH3:25])[O:22][CH3:23])=[CH2:20].C(N(CC)CC)C>ClCCl.N1C=CC=CC=1>[OH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]1[CH2:20][CH:19]([P:21](=[O:26])([O:24][CH3:25])[O:22][CH3:23])[O:10][N:9]=1
Reactant: ON=Cc1ccccc1O
Reactant: C=CP(=O)(OC)OC
Agent: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: COP(=O)(OC)C1CC(c2ccccc2O)=NO1
Temperature: 0 °C
Yield: 63.4 %

Procedure:
41.1 g (0.3 mol) of salicylaldoxime in dichloromethane are refluxed with 40.1 g (0.3 mol) of N-chlorosuccinimide and 1.5 ml of pyridine for 3 hours. Ice-water is added and the mixture is extracted, and the hydroxamoyl chloride is recrystallized from dichloromethane/petroleum ether. 25.5 g (0.15 mol) of this are reacted with 20.4 g (0.15 mol) of dimethyl vinylphosphonate and 22.9 ml (0.165 mol) of triethylamine in dichloromethane in analogy to Example 5 to give 25.8 g of oily product.
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N+](C1C=CC=CC=1)([O-])=O.C(=O)([O-])[O-].[K+].[K+].[F:26][C:27]1[CH:28]=[C:29]([OH:33])[CH:30]=[CH:31][CH:32]=1.Cl>O.[Cu]>[F:26][C:27]1[CH:28]=[C:29]([CH:30]=[CH:31][CH:32]=1)[O:33][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1ccccc1I
Reactant: Oc1cccc(F)c1
Agent: [Cu]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C(O)c1ccccc1Oc1cccc(F)c1

Procedure:
o-Iodobenzoic acid (12.4 g.) and nitrobenzene (5 ml.) were treated under stirring at 140°-150° with 3.4 g. of anhydrous potassium carbonate; the mixture was stirred for 10 minutes at 160°, and 3-fluorophenol (7 g.) was added, followed by portionwise addition of potassium carbonate (7 g.) and copper powder (0.1 g.) The mixture was stirred at 160°-165° for 45 minutes, cooled, diluted with water, and treated with 5 N HCl to give the title compound, m.p. 122°. ##STR9##
Reaction SMILES: [F:1][C:2]([F:19])([CH2:13][CH2:14][C:15]([F:18])([F:17])[F:16])[C:3]([F:12])([F:11])[C:4]([Si:7](Cl)([Cl:9])[Cl:8])([F:6])[F:5].C[SiH](C)Cl.Cl[SiH3].C[Si](C)(Cl)Cl>[Cl-].C([P+](CCCCCC)(CCCCCC)CCCCCC)CCCCCCCCCCCCC>[F:19][C:2]([F:1])([CH2:13][CH2:14][C:15]([F:16])([F:17])[F:18])[C:3]([F:12])([F:11])[C:4]([SiH:7]([Cl:9])[Cl:8])([F:6])[F:5]
Reactant: FC(F)(F)CCC(F)(F)C(F)(F)C(F)(F)[Si](Cl)(Cl)Cl
Agent: CCCCCCCCCCCCCC[P+](CCCCCC)(CCCCCC)CCCCCC
Agent: C[SiH](C)Cl
Agent: C[Si](C)(Cl)Cl
Product: FC(F)(F)CCC(F)(F)C(F)(F)C(F)(F)[SiH](Cl)Cl
Temperature: 80 °C
Yield: 92.8 %

Procedure:
Under a nitrogen atmosphere, a 1-liter 3-necked flask equipped with a heating mantle, magnetic stirrer, pot thermometer, addition funnel and dry-ice condenser was charged with nonafluorohexyltrichlorosilane (457.8 g) and tetradecyl(trihexyl)phosphonium chloride (15.4 g). The mixture was heated to 80° C. and dimethylchlorosilane (124.9 g) was added to the mixture via addition funnel over 1 hr. The pot temperature dropped due to light chlorosilane refluxing. Upon completion of the addition, the reaction was refluxed for 6-8 hrs. The pot temperature slowly increased to 75° C., which indicates the conversion of dimethylchlorosilane to dimethyldichlorosilane. The reaction was cooled to room temperature and GC analysis (low-temp. method) of the mixture indicated about 84% completion. The pot was vented carefully under the protection of nitrogen. Distillation provided 386.6 g of crude product (63.5% pure, 58.0% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]([CH2:11][CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]3)[C:7](=O)[CH2:8][O:9][C:4]=2[CH:3]=1.B.O1CCCC1.Cl.[OH-].[Na+]>O.CO.C1COCC1>[CH3:20][N:17]1[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][CH2:11][N:6]2[C:5]3[CH:21]=[CH:22][C:2]([NH2:1])=[CH:3][C:4]=3[O:9][CH2:8][CH2:7]2)[CH2:15][CH2:16]1
Reactant: CN1CCN(CCCN2C(=O)COc3cc(N)ccc32)CC1
Agent: B
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CN1CCN(CCCN2CCOc3cc(N)ccc32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.9 %

Procedure:
To a mixture of 7-amino-4-[3-(4-methylpiperazin-1-yl)propyl]-2H-1,4-benzoxazine-3(4H)-one (Preparation Example 435) (300 mg) and THF (9 mL), gradual dropwise addition of borane-tetrahydrofuran complex (3.0 mL, 1M THF solution) was conducted under ice cooling under an argon atmosphere. After the dropwise addition was completed, the mixture was stirred at room temperature for 1 hour and further stirred at 70° C. for 3 hours. After methanol (10 mL) was gradually added to the reaction liquid under ice cooling, 1M hydrochloric acid (5 mL) and thereafter 1M aqueous sodium hydroxide (10 mL) were added and stirred at room temperature for 1 hour. After dilution with water, the reaction liquid was extracted with ethyl acetate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (eluent; chloroform:methanol=100:0 to 20:1) to give 4-[3-(4-methylpiperazin-1-yl)propyl]-3,4-dihydro-2H-1,4-benzoxazine-7-amine (120 mg).