Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:10][CH2:11][C:12]([CH3:15])([OH:14])[CH3:13])=[N:4][C:5]([CH3:9])=[N:6][C:7]=1[Cl:8].[Cl:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH:19]=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C1(C)C=CC=CC=1.ClCCl>[Cl:8][C:7]1[N:6]=[C:5]([CH3:9])[N:4]=[C:3]2[C:2]=1[N:1]=[C:19]([C:18]1[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=1[Cl:16])[N:10]2[CH2:11][C:12]([CH3:15])([OH:14])[CH3:13]
Reactant: O=Cc1ccccc1Cl
Reactant: Cc1nc(Cl)c(N)c(NCC(C)(C)O)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Cc1nc(Cl)c2nc(-c3ccccc3Cl)n(CC(C)(C)O)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.9 %

Procedure:
Heat a mixture of 1-(5-amino-6-chloro-2-methylpyrimidin-4-ylamino)-2-methylpropan-2-ol (0.5 g, 0.002 mol), 2-chlorobenzaldehyde (0.6 g, 0.004 mol), p-toluene sulfonic acid (0.1 g) and molecular sieves (1.0 g) in toluene (25 mL) to 130° C. for 16 h. Remove the molecular sieves by filtration through diatomaceous earth, and concentrate the filtrate under reduced pressure to give a residue. Dissolve the residue in dry dichloromethane (5 mL) and add DDQ (0.47 g, 0.002 mol) at 0° C. Stir the reaction mixture at room temperature for 2 h. Dilute the reaction mixture with dichloromethane, wash with 1 N sodium hydroxide solution, water, and brine. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate to give a residue. Purify the residue on a silica gel column eluting with methanol:dichloromethane (2:98) to give the title compound (0.4 g). ES/MS m/z 351 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13](O)=[O:14])=[C:11]([C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[NH:21][N:20]=[CH:19]3)[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:25]([NH2:31])[C@H:26]1[O:30][CH2:29][CH2:28][CH2:27]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH2:1]([N:8]1[C:12]([C:13]([NH:31][CH2:25][C@@H:26]2[CH2:27][CH2:28][CH2:29][O:30]2)=[O:14])=[C:11]([C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[NH:21][N:20]=[CH:19]3)[N:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1c(-c2ccc3[nH]ncc3c2)nnn1Cc1ccccc1
Reactant: NC[C@@H]1CCCO1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NC[C@@H]1CCCO1)c1c(-c2ccc3[nH]ncc3c2)nnn1Cc1ccccc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Into a 20 mL vial, a solution of Example 149C (51 mg, 0.16 mmol) dissolved in dimethylformamide (0.5 mL) was added, followed by the addition of (S)-(+)-tetrahydrofurfurylamine (18.2 mg, 0.18 mmol) dissolved in dimethylformamide (0.9 mL). A solution of HATU (68 mg, 0.18 mmol) dissolved in dimethylformamide (0.5 mL) was added followed by a solution of diisopropylethylamine (0.087 mL, 0.5 mmol) dissolved in dimethylformamide (0.5 mL). The mixture was shaken at 50° C. overnight. The reaction was filtered through a Si-Carbonate cartridge (6 mL-1 g) supplied by Silicycle Chemical Division, and the filtrate was transferred to 20 mL vials. The reaction was checked by LC/MS and concentrated to dryness. The residue was dissolved in 1:1 DMSO/methanol and purified by reverse phase HPLC (Agilent, 5%-100% TFA/water gradient, 8 minute run). 1H NMR (300 MHz, DMSO-d6/D2O) δ ppm 1.35-1.54 (m, 1H) 1.64-1.96 (m, 3H) 3.17-3.26 (m, 1H) 3.32-3.38 (m, 1H) 3.50-3.77 (m, 2H) 3.81-4.00 (m, 1H) 5.58-5.74 (m, 2H) 7.21-7.41 (m, 5H) 7.54-7.66 (m, 1H) 7.68-7.84 (m, 1H) 8.01-8.19 (m, 2H). MS (ESI−) m/z 401 (M−H)−.
Reaction SMILES: [CH:1]([N:4]([CH3:23])[C:5]1[CH:22]=[CH:21][C:8]2[CH2:9][N:10](C(OC(C)(C)C)=O)[CH2:11][CH2:12][O:13][C:7]=2[CH:6]=1)([CH3:3])[CH3:2].C(OCC)(=O)C.[ClH:30]>>[ClH:30].[ClH:30].[CH:1]([N:4]([CH3:23])[C:5]1[CH:22]=[CH:21][C:8]2[CH2:9][NH:10][CH2:11][CH2:12][O:13][C:7]=2[CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)N(C)c1ccc2c(c1)OCCN(C(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)N(C)c1ccc2c(c1)OCCNC2
Yield: 49.8 %

Procedure:
A solution of tert-butyl 8-[isopropyl(methyl)amino]-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (270 mg, 0.843 mmol) in 4N hydrogen chloride-ethyl acetate (6 ml) was stirred for 1 hr at room temperature, and the solvent was evaporated under reduced pressure. The residue was recrystallized from a mixed solvent of methanol and ether to give the desired product (123 mg, 49.8%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:18])[N:9]([CH3:17])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3I)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:19]([C:21]1([OH:26])[CH2:25][CH2:24][CH2:23][CH2:22]1)#[CH:20]>C(NCC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[C:7]2[C:8](=[O:18])[N:9]([CH3:17])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:20]#[C:19][C:21]3([OH:26])[CH2:25][CH2:24][CH2:23][CH2:22]3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CN1Cc2c(I)ncn2-c2cccc(Cl)c2C1=O
Reactant: C#CC1(O)CCCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Product: CN1Cc2c(C#CC3(O)CCCC3)ncn2-c2cccc(Cl)c2C1=O

Procedure:
9.57 g (25.5 mmol) of 7-chloro-4,5-dihydro-3-iodo-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one was heated to boiling under reflux for 3 hours with 3.52 g (32 mmol) of 1-ethynylcyclopentanol, 170 mg of bis-(triphenylphosphine)-palladium(II) dichloride and 30 mg of copper(I) iodide in 60 ml of diethylamine. The reaction mixture was evaporated and the residue was chromatographed on silica gel while eluting with ethyl acetate. After crystallization from ethyl acetate there was obtained 7-chloro-4,5-dihydro-3-[(1-hydroxycyclopentyl)ethynyl]-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 207°-208°.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:11]2[C:6](=[CH:7][C:8]([C:12]#[CH:13])=[CH:9][CH:10]=2)[N:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:4][CH2:3]1.I[C:22]1[CH:32]=[CH:31][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:24][CH:23]=1.C(N(CC)CC)C>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(Cl)Cl>[CH3:1][C:2]1([CH3:20])[C:11]2[C:6](=[CH:7][C:8]([C:12]#[C:13][C:22]3[CH:32]=[CH:31][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:24][CH:23]=3)=[CH:9][CH:10]=2)[N:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:4][CH2:3]1
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: C#Cc1ccc2c(c1)N(c1ccccc1)CCC2(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)N(c2ccccc2)CCC3(C)C)cc1
Temperature: 40 °C

Procedure:
To a mixture of 0.020 g (0.08 mmol) of 4,4-dimethyl-1,2,3,4-tetrahydro-N-phenyl-7-ethynylquinoline (Compound 8) and 0.51 g (1.8 mmol) of ethyl 4-iodobenzoate were added 1.5 g (2.0 mL, 14 mmol) of triethylamine, 6.2 mg(0.03 mmol) of copper(I)iodide, and 12 mg (0.02 mmol) of bis(triphenylphosphine)palladium(II) chloride, consecutively. The resulting mixture was heated at 40° C. for 5.5 hours. The reaction was cooled, methylene chloride was added, and the reaction mixture was adsorbed onto silica gel. The mixture was purified by flash chromatography (5% ethyl acetate in hexanes) to give the title compound as a yellow oil. PNMR (300 MHz, CDCl3) d 1.36 (6 H, s), 1.39 (3 H, t, J=7.2 Hz), 1.86 (2 H, t, J=6.0 Hz), 3.64 (2 H, t, J=6.0 Hz), 4.36 (2 H, q, J=7.2 Hz), 6.87 (1 H, d, J=1.6 Hz), 6.91 (1 H, dd, J=7.9, 1.6 Hz), 7.14 (1 H, t, J=7.3 Hz), 7.25 (1 H, d, J=7.9 Hz), 7.25 (2 H, d, J=7.3 Hz), 7.39 (2 H, t, J=7.3 Hz), 7.48 (2 H, d, J=8.5 Hz), 7.97 (2 H, d, J=8.5 Hz).
Reaction SMILES: Br[C:2]1[C:11]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[C:17]([S:21]([N:23]=[CH:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[O:22])([CH3:20])([CH3:19])[CH3:18].[NH4+].[Cl-]>C1COCC1.O.CCOCC>[O:7]1[CH2:8][CH2:9][O:10][C:11]2[C:2]([CH:24]([NH:23][S:21]([C:17]([CH3:20])([CH3:19])[CH3:18])=[O:22])[CH2:25][CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[CH:3][CH:4]=[CH:5][C:6]1=2
Reactant: Brc1cccc2c1OCCO2
Reactant: COC(=O)CCCC=NS(=O)C(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)CCCC(NS(=O)C(C)(C)C)c1cccc2c1OCCO2
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A cooled (−78° C.) solution of commercially available 5-bromo-2,3-dihydrobenzo[b][1,4]dioxine (500 mg; 2.32 mmol) in anh. THF (5 ml), under nitrogen, was treated dropwise with a solution of 1.6 M n-BuLi in hexanes. The resulting solution was further stirred at −78° C. for 10 min. A solution of methyl 5-((tert-butylsulfinyl)imino)pentanoate (542 mg; 2.32 mmol) in anh. THF (2 ml) was added to the cooled reaction mixture, and stirring at −78° C. was continued for 10 min., and then at −20° C. for 2 h. The resulting reaction mixture was treated successively with aq. sat. NH4Cl (15 ml), Et2O (30 ml) and water (15 ml). The separated organic layer was then washed with brine (15 ml), dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM/MeOH=20/1) afforded methyl 5-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-5-(1,1-dimethylethylsulfinamido)-pentanoate as a yellow oil. LC-MS (conditions A): tR=0.73 min.; [M+H]+: 369.73 g/mol.
Reaction SMILES: [CH2:1](/[C:3](/[C:20]1[S:24][CH:23]=[C:22]([CH:25]=[O:26])[CH:21]=1)=[CH:4]\[CH2:5][CH2:6][C:7]([CH2:18][CH3:19])([O:10][Si:11]([CH2:16][CH3:17])([CH2:14][CH3:15])[CH2:12][CH3:13])[CH2:8][CH3:9])[CH3:2].[BH4-].[Na+].O>C1COCC1.CO>[CH2:1](/[C:3](/[C:20]1[S:24][CH:23]=[C:22]([CH2:25][OH:26])[CH:21]=1)=[CH:4]\[CH2:5][CH2:6][C:7]([CH2:8][CH3:9])([O:10][Si:11]([CH2:16][CH3:17])([CH2:12][CH3:13])[CH2:14][CH3:15])[CH2:18][CH3:19])[CH3:2]
Reactant: CC/C(=C\CCC(CC)(CC)O[Si](CC)(CC)CC)c1cc(C=O)cs1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC/C(=C\CCC(CC)(CC)O[Si](CC)(CC)CC)c1cc(CO)cs1
Reaction time: 1 h

Procedure:
4 g (9.9 mmol) of 5-((E)-1,5-diethyl-5-triethylsilanyloxyhept-1-enyl)thiophene-3-carbaldehyde are dissolved in 50 mL of THF and 50 mL of methanol. 1 g (26 mmol) of sodium borohydride is then added portionwise. The reaction medium is stirred for 1 hour and then poured into 100 mL of water. After purification by chromatography on silica gel, the desired product is obtained in the form of a colourless oil (m=4 g; Y=100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.[Cl:21][C:22]1[CH:27]=[C:26]([C:28]([N:30]2[C:38]3[C:33](=[CH:34][C:35]([F:39])=[CH:36][CH:37]=3)[CH2:32][CH2:31]2)=[O:29])[CH:25]=[C:24](Cl)[N:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:21][C:22]1[N:23]=[C:24]([N:17]2[CH2:18][CH2:19][CH:14]([N:10]3[CH2:9][CH2:8][C:7]4[CH:20]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=4[NH:12][C:11]3=[O:13])[CH2:15][CH2:16]2)[CH:25]=[C:26]([C:28]([N:30]2[C:38]3[C:33](=[CH:34][C:35]([F:39])=[CH:36][CH:37]=3)[CH2:32][CH2:31]2)=[O:29])[CH:27]=1
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Reactant: O=C(c1cc(Cl)nc(Cl)c1)N1CCc2cc(F)ccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)N4CCc5cc(F)ccc54)cc(Cl)n3)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.0 g (3.2 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 0.94 g (3.4 mmol) (2,6-dichloro-pyridin-4-yl)-(5-fluoro-2,3-dihydro-indol-1-yl)-methanone and 0.65 mL (3.8 mmol) DIPEA in 10 mL DMF were stirred for 2 h at RT. Then the reaction mixture was evaporated down, the residue was mixed with water and stirred for 30 min at RT. The precipitated solid was suction filtered, stirred with diisopropylether and isopropanol and suction filtered again. After drying the crude product was purified by preparative HPLC-MS. The product-containing fractions were combined and freeze-dried.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH2:20][CH2:21][CH2:22][CH3:23])[C:15]([O:17]CC)=[O:16])[C:10](=[O:24])[CH:9]=2)[CH:7]=1.[OH-].[Li+]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH2:20][CH2:21][CH2:22][CH3:23])[C:15]([OH:17])=[O:16])[C:10](=[O:24])[CH:9]=2)[CH:7]=1
Reactant: CCCCC(C(=O)OCC)n1ccc(-c2cc(Cl)ccc2C#N)cc1=O
Agent: [Li+]
Agent: [OH-]
Product: CCCCC(C(=O)O)n1ccc(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
113 mg (purity 95%, 0.29 mmol) of ethyl 2-[4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]hexanoate (racemate) were hydrolysed with lithium hydroxide according to General Method 6B. Yield: 64 mg (purity 78%, 50% of theory)
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]=[C:10]([C:15](=O)[CH3:16])[C:11]([O:13][CH3:14])=[O:12].[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[SH:25].C(O)(=O)C>CN(C)C=O.CCOCC>[CH3:16][C:15]1[NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[S:25][CH:9]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=2[Cl:1])[C:10]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: Nc1ccccc1S
Reactant: COC(=O)C(=Cc1cccc(Cl)c1Cl)C(C)=O
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COC(=O)C1=C(C)Nc2ccccc2SC1c1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 2-[(2,3-dichlorophenyl)methylene]-3-oxobutanoic acid, methyl ester (1.0 g., 3.66 mmole) in dry dimethylformamide (7 ml.) is treated with 2-aminothiophenol (512 mg., 4.1 mmoles) and the resulting reaction mixcture is stirred at room temperature for 3 hours. Acetic acid (0.1 ml.) is added and the reaction is heated at 75° (oil bath temperature) for 48 hours. It is then cooled to room temperature and diluted with ether. The resulting solution is washed with 1N sodium hydroxide, water, and brine. After drying over anhydrous magnesium sulfate, the solvent is stripped off to provide a yellow solid. It is crystallized from isopropyl ether-dichloromethane to yield 660 mg. of light yellow crystalline product. Recrystallization from isopropyl ether-dichloromethane yields an analytically pure sample of 2,5-dihydro-4-methyl-2-(2,3-dichlorophenyl)-1,5-benzothiazepine-3-carboxylic acid, methyl ester as colorless needles; m.p. 190°-191°. TLC (silica gel; ethyl acetate:hexanes, 40:60) Rf =0.40.
Reaction SMILES: C([O:3][C:4](=[O:20])[CH2:5][O:6][C:7]1[C:8]2[CH2:9][C:10]3[S:14][C:13]([SH:15])=[N:12][C:11]=3[C:16]=2[CH:17]=[CH:18][CH:19]=1)C.[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:21]([S:15][C:13]1[S:14][C:10]2[CH2:9][C:8]3[C:7]([O:6][CH2:5][C:4]([OH:3])=[O:20])=[CH:19][CH:18]=[CH:17][C:16]=3[C:11]=2[N:12]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)COc1cccc2c1Cc1sc(S)nc1-2
Product: O=C(O)COc1cccc2c1Cc1sc(SCc3ccccc3)nc1-2
Yield: 21 %

Procedure:
Using ethyl[(2-mercapto-8H-indeno[1,2-d]thiazol-7-yl)oxy]acetate and benzyl bromide, the procedure of Example 1 was otherwise repeated to synthesize the title compound. Yield 21%.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:12])[NH:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(Cl)(Cl)C(O)=O.[CH2:20]1[CH:26](O)[NH:25][P:23]([N:28]([CH2:32][CH2:33][Cl:34])[CH2:29][CH2:30][Cl:31])(=[O:24])[O:22][CH2:21]1>CC(C)=O.C(Cl)Cl>[CH2:1]([NH:8][C:9](=[O:12])[N:10]([OH:11])[CH:26]1[CH2:20][CH2:21][O:22][P:23]([N:28]([CH2:32][CH2:33][Cl:34])[CH2:29][CH2:30][Cl:31])(=[O:24])[NH:25]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P1(N(CCCl)CCCl)NC(O)CCO1
Reactant: O=C(NO)NCc1ccccc1
Agent: O=C(O)C(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CC(C)=O
Product: O=C(NCc1ccccc1)N(O)C1CCOP(=O)(N(CCCl)CCCl)N1
Reaction time: 8 h

Procedure:
540 mg (3.25 mmol) of 3-benzyl-1-hydroxyurea in 40 ml of acetone and a catalytic amount of trichloroacetic acid were added to 900 mg (3.25 mmol) of 4-hydroxycyclophosphamide in 1 ml of methylenechloride. The mixture was stored overnight at -25° C., the crystals were then drawn off by suction, washed with acetone and ether and recrystallized from ethyl acetate.
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[CH:9][O:10][C:6]=2[CH:5]=[C:4]([C:11]([OH:13])=[O:12])[C:3]=1[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[F:21].C1C(=O)N([I:29])C(=O)C1>>[F:1][C:2]1[C:7]2[N:8]=[CH:9][O:10][C:6]=2[CH:5]=[C:4]([C:11]([OH:13])=[O:12])[C:3]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([I:29])=[CH:17][C:16]=1[F:21]
Reactant: O=C(O)c1cc2ocnc2c(F)c1Nc1ccccc1F
Reactant: O=C1CCC(=O)N1I
Product: O=C(O)c1cc2ocnc2c(F)c1Nc1ccc(I)cc1F

Procedure:
4-Fluoro-5-((2-fluorophenyl)amino)benzo[d]oxazole-6-carboxylic acid can be reacted with halogenations reagent (such as NIS) under acidic condition in appropriate solvent. The reaction generally is carried out at ambient temperature and normally completes within several hours (1-12 h, prefer 3-10 h). 4-Fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]oxazole-6-carboxylic acid is obtained after conventional workup.
Reaction SMILES: Cl.[C:2]([C:4]1[CH:23]=[CH:22][C:7]([CH2:8][N:9]2[CH2:18][CH2:17][C:16]3[C:11](=[CH:12][C:13]([C:19](O)=[O:20])=[CH:14][CH:15]=3)[CH2:10]2)=[CH:6][CH:5]=1)#[N:3].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[NH2:50][CH:51]1[CH2:56][CH2:55][N:54]([CH2:57][C:58]2[CH:63]=[CH:62][C:61]([C:64]#[N:65])=[CH:60][CH:59]=2)[CH2:53][CH2:52]1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>CN(C=O)C>[C:2]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][N:9]2[CH2:18][CH2:17][C:16]3[C:11](=[CH:12][C:13]([C:19]([NH:50][CH:51]4[CH2:56][CH2:55][N:54]([CH2:57][C:58]5[CH:63]=[CH:62][C:61]([C:64]#[N:65])=[CH:60][CH:59]=5)[CH2:53][CH2:52]4)=[O:20])=[CH:14][CH:15]=3)[CH2:10]2)=[CH:22][CH:23]=1)#[N:3]
Reactant: N#Cc1ccc(CN2CCC(N)CC2)cc1
Reactant: N#Cc1ccc(CN2CCc3ccc(C(=O)O)cc3C2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#Cc1ccc(CN2CCC(NC(=O)c3ccc4c(c3)CN(Cc3ccc(C#N)cc3)CC4)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.9 %

Procedure:
To a solution of 2-(4-cyanobenzyl)-1,2,3,4-tetrahydroisoquinoline-7-carboxylic acid hydrochloride (50 mg, 0.17 mmol) in DMF (2 mL), HATU (78 mg, 0.21 mmol), 4-amino-1-(4-cyanobenzyl)piperidine dihydrochloride (52 mg, 0.18 mmol) and triethylamine (125 uL, 91 mg, 0.9 mmol) were added. The resulting reaction mixture was allowed to stir at room temperature overnight and poured into saturated sodium bicarbonate solution (30 mL) to give a white precipitate which was filtered and dried under vacuum. The resulting solid was triturated with ethyl ether to provide 2-(4-cyanobenzyl)-N-(1-(4-cyanobenzyl)piperidin-4-yl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide (compound 37) as a white crystalline solid (69 mg, 82%). 1H NMR (DMSO-d6): δ 8.08 (1H, d, J=7.7 Hz); 7.79 (4H, dd, J=8.5, 6.9 Hz); 7.60-7.54 (3H, m); 7.49 (3H, d, J=8.8 Hz); 7.16 (1H, d, J=8.3 Hz); 3.78-3.66 (3H, m); 3.55 (4H, br s); 2.86 (2H, t, J=5.2 Hz); 2.82-2.66 (4H, m); 2.04 (2H, t, J=11.3 Hz); 1.75 (2H, d, J=11.3 Hz); 1.55 (2H, q, J=11.8 Hz). MS (M+H)+=490.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:7]2[CH2:8][NH:9][CH2:10][CH2:11][N:6]2[N:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[C:20](Cl)(=[O:24])[CH:21]([CH3:23])[CH3:22]>ClCCl>[CH3:22][CH:21]([CH3:23])[C:20]([N:9]1[CH2:10][CH2:11][N:6]2[N:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[C:7]2[CH2:8]1)=[O:24]
Reactant: CC(C)C(=O)Cl
Reactant: O=[N+]([O-])c1cc2n(n1)CCNC2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C(=O)N1CCn2nc([N+](=O)[O-])cc2C1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2-nitro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine 124d (160 mg, 0.952 mmol) in dichloromethane (10 mL) was added triethylamine (197 mg, 1.90 mmol). After stirring at room temperature for 5 minutes, a solution of isobutyryl chloride (111.0 mg, 1.047 mmol) in dichloromethane (2 mL) was added and the mixture was stirred for 1 h. Analysis of the reaction mixture by LCMS showed complete conversion to the desired product. It was then concentrated under reduced pressure to afford 148a as a white solid (220 mg, 97%), which was used in the next step without further purification. MS-ESI: [M+H]+ 239.0
Reaction SMILES: [OH-].[Fe+2:2].[OH-].[C:4]([OH:7])(=[O:6])[CH3:5]>>[C:4]([O-:7])(=[O:6])[CH3:5].[Fe+2:2].[C:4]([O-:7])(=[O:6])[CH3:5]
Reactant: CC(=O)O
Agent: [Fe+2]
Agent: [OH-]
Product: CC(=O)[O-]

Procedure:
Iron(II) acetate was prepared using the same method as the Example 1 except that 1 g of iron hydroxide prepared in the Example 1 and 100 g of acetic acid were put into a three-neck round bottom flask and reacted at a temperature of 25° C. for 24 hour.
Reaction SMILES: C(=O)([O-])[O-].[Ca+2].[Br:6][C:7]1[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=1.[CH3:17][C:18]1[CH:19]=[C:20]([CH:22]=[C:23]([CH3:32])[C:24]=1[S:25]([CH2:28][N+:29]([O-:31])=[O:30])(=[O:27])=[O:26])[NH2:21].O>O1CCCC1>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([NH:21][C:20]2[CH:19]=[C:18]([CH3:17])[C:24]([S:25]([CH2:28][N+:29]([O-:31])=[O:30])(=[O:27])=[O:26])=[C:23]([CH3:32])[CH:22]=2)(=[O:15])=[O:14])=[CH:9][CH:8]=1
Reactant: Cc1cc(N)cc(C)c1S(=O)(=O)C[N+](=O)[O-]
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(NS(=O)(=O)c2ccc(Br)cc2)cc(C)c1S(=O)(=O)C[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 20 h
Yield: 24.2 %

Procedure:
2.0 g (20.0 mmol) of calcium carbonate and 3.8 g (14.9 mmol) of 4-bromobenzenesulphonyl chloride are successively added to a mixture of 2.4 g (9.83 mmol) of 3,5-dimethyl-4-[(nitromethyl)sulphonyl]aniline in 45 ml of anhydrous tetrahydrofuran. The reaction medium is stirred for 20 h at room temperature and is then refluxed for 48 h. After cooling, it is poured into 400 ml of water and extracted with methylene chloride. The combined organic extracts are dried over sodium sulphate and concentrated to dryness under reduced pressure. The oily residue obtained is purified by chromatography on a column of silica (eluent: methylene chloride) to give 1.1 g (24%) of 4-bromo-N-[3,5-dimethyl-4-[(nitromethyl)sulphonyl]phenyl]benzenesulphonamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH:10]([CH3:13])[CH2:11][OH:12])[CH:5]=[CH:6][C:7]=1[F:8].[BH3-]C#N.[Na+].[OH:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=O>ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]([CH2:22][C:21]2[CH:20]=[C:19]([OH:18])[CH:26]=[CH:25][CH:24]=2)[CH:10]([CH3:13])[CH2:11][OH:12])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(CO)Nc1ccc(F)c(Cl)c1
Reactant: O=Cc1cccc(O)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCCl
Product: CC(CO)N(Cc1cccc(O)c1)c1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2-[(3-chloro-4-fluorophenyl)amino]propan-1-ol (1-4, 0.030 g, 0.147 mmol) in DCE (1.0 mL) was treated with NaCNBH3 (0.019 g, 0.295 mmol), and 3-hydroxylbenzaldehyde (0.036 g, 0.295 mmol). The resulting mixture stirred at 25° C. for 24 h then concentrated. The reaction was purified by reverse phase liquid chromotography (Semi-prep YMC C-18 Column 5% CH3CN/H2O up to 95% CH3CN/H2O) to give 3-{[(3-chloro-4-fluorophenyl)(2-hydroxy-1-methylethyl)amino]methyl}phenol (1-5). 1H NMR (300 MHz, CDCl3) δ 7.15 (m, 3H), 6.89 (m, 2H), 6.71 (m, 2H), 4.44 (d, J=10.0 Hz, 2H), 4.00 (m, 1H), 3.73 (s, 2H), 1.19 (d, J=6.7 Hz, 3H). MS 310.3 found, 310.7 (M+H+) required.