Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH:6]([F:8])[F:7])=[C:3]([F:5])[F:4].S(=O)(=O)(O)[OH:10]>O>[CH3:1][C:2]([OH:10])([CH:6]([F:8])[F:7])[CH:3]([F:5])[F:4]
Reactant: O=S(=O)(O)O
Reactant: CC(=C(F)F)C(F)F
Solvent: O
Product: CC(O)(C(F)F)C(F)F

Procedure:
As another example, 2-methyl-1,1,3,3-tetrafluoro-2-propanol may be prepared by fluorinating commercially available 1,1-dichloro-2-propanone to form 1,1-difluoro-2-propanone which may then be reacted with CF2 carbene to form 2-methyl-1,1,3,3-tetrafluoro-1-propene. The 2-methyl-1,1,3,3-tetrafluoro-1-propene may then be reacted with sulfuric acid and then water to form 2-methyl-1,1,3,3-tetrafluoro-2-propanol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[C:27]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22][C:21]=4[CH:20]=[CH:19][CH:18]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].C(=O)([O-])[O-].[K+].[K+].Br[CH2:35][CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[C:27]4[CH2:26][CH2:25][N:24]([CH2:35][CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:23][CH2:22][C:21]=4[CH:20]=[CH:19][CH:18]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCNCC4)no2)cc1Cl
Reactant: CC(C)(C)OC(=O)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCN(CCC(=O)OC(C)(C)C)CC4)no2)cc1Cl
Temperature: 100 °C
Yield: 25.4 %

Procedure:
In a 5 ml microwave reaction vessel was added 6-(5-{3-chloro-4-[(1-methyl ethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-2,3,4,5-tetrahydro-1H-3-benzazepine (Free base of Example 8, obtained by standard methods e.g. partitioning between organic and basic aqueous solvents and collecting organic solvent) (70 mg) in DMF (3 ml) to give a brown solution. Then potassium carbonate (101 mg) was added followed by 1,1-dimethylethyl 3-bromopropanoate (38.1 mg, 0.182 mmol). The reaction mixture was heated at 100° C. for 10 minutes. The cooled reaction mixture was diluted with DCM (5 ml) and purified by SCX (washing with methanol and eluting the crude amino ester with methanolic ammonia). Purification by MDAP yielded the amino ester, 1,1-dimethylethyl 3-[6-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1,2,4,5-tetrahydro-3H-3-benzazepin-3-yl]propanoate (25 mg, 0.046 mmol, 25.4% yield) isolated as a light yellow oil. MS (ES) C28H3435ClN3O4 requires 511; found 512 [M+H]+.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]1[C:14]2[C:9](=[CH:10][C:11]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:12]([NH2:15])[CH:13]=2)[N:8]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:7]1)(=[O:3])[CH3:2].Br[CH:32]([CH3:37])[C:33]([O:35][CH3:36])=[O:34].CN(C)C1C2C(=CC=CC=2N(C)C)C=CC=1>C1C=CC=CC=1>[C:1]([O:4][CH2:5][C@H:6]1[C:14]2[C:9](=[CH:10][C:11]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:12]([NH:15][CH:32]([C:33]([O:35][CH3:36])=[O:34])[CH3:37])[CH:13]=2)[N:8]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:7]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1CN(C(=O)OC(C)(C)C)c2cc(OCc3ccccc3)c(N)cc21
Reactant: COC(=O)C(C)Br
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Solvent: c1ccccc1
Product: COC(=O)C(C)Nc1cc2c(cc1OCc1ccccc1)N(C(=O)OC(C)(C)C)C[C@H]2COC(C)=O

Procedure:
4.95 g (12.0 mmole) of 3S)-3-acetoxymethyl-5-amino-6-benzyloxy-1-t-butoxycarbonylindoline, 1.61 ml (14.4 mmole) of methyl 2-bromopropionate, and 3.09 g (14.4 mmole) of 1,8-bis(dimethylamino)naphthalene were heated to reflux in 18 ml of benzene at 90° C. for 50 hours. The reaction mixture was diluted with benzene, washed with water and saturated brine, dried over anhydrous sodium sulfate, and filtered, followed by condensation to give a residue. The residue was then purified by silica gel column chromatography with changing an eluate from hexane:ethyl acetate (4:1) to hexane:ethyl acetate (2:1) to give 5.82 g of (3S)-3-acetoxymethyl-5-[1-(methoxycarbonyl)ethyl]amino-6-benzyloxy-1-t-butoxycarbonylindoline. Yield, 97%. HRMS: 498.2366 calculated as C27H34N2O7 ; 498.2387 observed.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])[CH3:2].O.C([O-])(O)=O.[Na+]>CCO.[Pd]>[NH2:13][C:10]1[CH:11]=[N:12][C:4]([O:3][CH2:1][CH3:2])=[C:5]([CH:9]=1)[C:6]([OH:8])=[O:7]
Reactant: CCOc1ncc([N+](=O)[O-])cc1C(=O)O
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOc1ncc(N)cc1C(=O)O
Reaction time: 6 h
Yield: 48 %

Procedure:
A solution of 2-ethoxy-5-nitronicotinic acid (12.0 g, 56.6 mmol, prepared by the method described in WO9954333) in a mixture of EtOH (150 ml), H2O (150 ml), NaHCO3 (4.80 g, 57.0 mmol) and 10% palladium on carbon (1.0 g) was hydrogenated at 60 psi and at 60° C. for 6 h. The mixture was cooled, filtered and acidified with AcOH. The mixture was concentrated in vacuo and the residue triturated with DCM/MeOH (95:5) to afford the title compound as a brown/purple solid (5.0 g, 27.5 mmol, 48%); mp 260-262° C.
Reaction SMILES: [Cl:1][C:2]1[C:8]([O:9][CH3:10])=[CH:7][C:5](N)=[C:4]([F:11])[CH:3]=1.N([O-])=O.[Na+].C(Cl)Cl.C(OCC)(=O)C.[BrH:25]>O>[Br:25][C:5]1[CH:7]=[C:8]([O:9][CH3:10])[C:2]([Cl:1])=[CH:3][C:4]=1[F:11]
Reactant: Br
Reactant: COc1cc(N)c(F)cc1Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1cc(Br)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-chloro-2-fluoro-5-methoxyaniline (25.0 g, 0.143 mol) in 10% HBr (250 mL) was cooled to 0° C. and a solution of sodium nitrite (15.0 g, 0.218 mol) in water (20 mL) was slowly added. After addition, methylene chloride (50 mL) and cupric bromide (30.0 g, 0.244 mol) were added slowly. The reaction mixture was then warmed to ambient temperature, stirred for one hour, filtered through a bed of celite, and extracted with methylene chloride (2×100 mL). The combined organic phases were dried and concentrated. Chromatography of the dark oil (5% ethyl acetate in hexanes) gave 1-bromo-4-chloro-2-fluoro-5-methoxybenzene (16.6 g, 0.070 mol): 1H NMR (CDCl3): δ 7.20 (m, 1H), 7.05 (dd, 1H), 4.00 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:49][C:50]1[CH:68]=[CH:67][C:53]2[NH:54][C:55]([CH:57]([NH2:66])[CH2:58][C:59]3[CH:64]=[CH:63][C:62]([OH:65])=[CH:61][CH:60]=3)=[N:56][C:52]=2[CH:51]=1.ClCl>O1CCCC1.ClCCl.CO>[Cl:49][C:50]1[CH:68]=[CH:67][C:53]2[NH:54][C:55]([CH:57]([NH:66][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([C:11]([N:13]4[CH2:17][CH2:16][CH2:15][CH2:14]4)=[O:12])=[C:2]([CH3:1])[CH:3]=3)[CH2:58][C:59]3[CH:60]=[CH:61][C:62]([OH:65])=[CH:63][CH:64]=3)=[N:56][C:52]=2[CH:51]=1
Reactant: NC(Cc1ccc(O)cc1)c1nc2cc(Cl)ccc2[nH]1
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)NC(Cc2ccc(O)cc2)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Yield: 64 %

Procedure:
Prepared analogously to Example 1g from 3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine, and 1-(5-chloro-1H-benzimidazol-2-yl)-2-(4-hydroxyphenyl)ethylamine in tetrahydrofuran. Yield: 64%; Rf value: 0.14 (silica gel; dichloromethane/methanol=19:1); C28H27ClN4O3 (503.00); mass spectrum: (M+H)+=503/505 (chlorine isotope).
Reaction SMILES: CN(C)[CH2:3][CH2:4][NH:5][C:6](=[O:42])[CH2:7][O:8][C:9]1[CH:10]=[C:11]([C:15]2[N:24]=[C:23]([NH:25][C:26]3[CH:27]=[C:28]4[C:32](=[CH:33][CH:34]=3)[N:31](C(OC(C)(C)C)=O)[N:30]=[CH:29]4)[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)[CH:12]=[CH:13][CH:14]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:31]1[C:32]2[C:28](=[CH:27][C:26]([NH:25][C:23]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]=[C:15]([C:11]4[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:7][C:6]5[O:42][CH:3]=[CH:4][N:5]=5)[CH:10]=4)[N:24]=3)=[CH:34][CH:33]=2)[CH:29]=[N:30]1
Reactant: CN(C)CCNC(=O)COc1cccc(-c2nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c3ccccc3n2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1cc(OCc2ncco2)cc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1

Procedure:
To tert-butyl 5-(2-(3-(2-(2-(dimethylamino)ethylamino)-2-oxoethoxy)-phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate was added a solution of 1:1 TFA:CH2Cl2 (3 mL) and stirred at RT for 2 h. The reaction mixture was concentrated in vacuo and the crude product was purified by prep HPLC (method 20-45—90 mins) to afford N-(1H-indazol-5-yl)-2-(3-(oxazol-2-ylmethoxy)phenyl)quinazolin-4-amine. (12 mg, 0.028 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[CH2:9][CH2:8][CH:7]([N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][N:18]=3)[C:13](=[O:20])[C:12]([C:21]([O:23]CC)=[O:22])=[CH:11]2)[CH2:6]1)=[O:4].[OH-].[Na+]>O1CCCC1.C(O)C.O>[CH3:1][O:2][C:3]([N:5]1[CH2:9][CH2:8][CH:7]([N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][N:18]=3)[C:13](=[O:20])[C:12]([C:21]([OH:23])=[O:22])=[CH:11]2)[CH2:6]1)=[O:4]
Reactant: CCOC(=O)c1cn(C2CCN(C(=O)OC)C2)c2ncccc2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: COC(=O)N1CCC(n2cc(C(=O)O)c(=O)c3cccnc32)C1
Reaction time: 1.5 h
Yield: 95.8 %

Procedure:
To a mixed solution of 269 mg (0.78 mmol) of the compound obtained in Example 2 in 3 ml of tetrahydrofuran and 3 ml of ethanol, 857 μl (0.857 mmol) of 1N sodium hydroxide solution was added at room temperature and the solution was stirred at that temperature for 1.5 hours. Next, this was diluted with water (20 ml) and, after washing with ether (10 ml), 1N hydrochloric acid (0.87 ml) was added to an aqueous layer. After extracting with methylene chloride (40 ml), the extract was dried over anhydrous sodium sulfate, then the solvent was distilled off under vacuum. Thus, 237 mg (96%) of the above-identified compound was obtained as a slightly yellow crystal.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1.[C:13]1(=[O:23])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[N:15][NH:14]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[O:23]=[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[N:15][N:14]1[CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1
Reactant: O=c1[nH]ncc2ccccc12
Reactant: O=Cc1ccc(OCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(OCCn2ncc3ccccc3c2=O)cc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 83.9 %

Procedure:
A mixture of 4-(2-bromoethoxy)benzaldehyde (4.97 g), 1(2H)-phthalazinone (3.27 g), potassium carbonate (6.20 g) and N,N-dimethylformamide (50 ml) was stirred at 80° C. for 5 hours. After cooling, the reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated to obtain 4-[2-[1-oxo-2(1H)-phthalazinyl]ethoxy]benzaldehyde (5.36 g, yield 84%) as colorless crystals. This was recrystallized from ethyl acetate-hexane. Melting point: 126–127° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[NH:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]=[CH:17][CH:16]=[CH:15]3)[CH:4]=[CH:3][CH:2]=1>C(O)(=O)C.[Pt](=O)=O>[NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[NH:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[NH:18][CH2:17][CH2:16][CH2:15]3)[CH2:4][CH2:3][CH2:2]1
Reactant: c1cnc2ccc(Nc3cccc4cccnc34)cc2c1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: c1cc2c(c(Nc3ccc4c(c3)CCCN4)c1)NCCC2
Yield: 42.2 %

Procedure:
A solution of 3.68 grams of N-quinolin-8-ylquinolin-6-amine from above in 60 mL of acetic acid containing 0.22 grams of platinum(IV) oxide was hydrogenated at 40 psi for 2.0 hours on a Parr low-pressure hydrogenator. The solution was filtered through diatomaceous earth; concentrated in vacuo; and neutralized with 3N aqueous sodium hydroxide. The aqueous phase was diluted with water and extracted three times with ethyl acetate. The combined ethyl acetate layers were washed with brine; dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to yield 1.6 grams of brown solid. The solid was chromatographed on silica gel, eluting with hexane/ethyl acetate gradient to afford 0.8 grams of the desired product as a purple solid. 1H NMR (CDCl3/D2O) δ 6.4-6.9 (m, 6H), 3.2-3.4 (m, 4H), 2.6-2.9 (m, 4H), 1.8-2.1 (m, 4H).
Reaction SMILES: [C:1]([C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]2[C:12]([CH2:13][C:14]([OH:16])=O)=[CH:11][N:10]=[CH:9]2)=[CH:5][CH:4]=1)#[N:2].Cl.[CH3:20][O:21][C:22](=[O:43])[CH2:23][N:24]([CH2:36][C@@H:37]([NH2:42])[C@@H:38]([CH3:41])[CH2:39][CH3:40])[CH2:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1.C1C=C2C(N(O)N=NC2=CC=1)=O.CN1CCOCC1.C(Cl)CCl>CN(C=O)C.CCOC(C)=O>[CH3:20][O:21][C:22](=[O:43])[CH2:23][N:24]([CH2:36][C@@H:37]([NH:42][C:14](=[O:16])[CH2:13][C:12]1[N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:18][CH:17]=2)[CH:9]=[N:10][CH:11]=1)[C@@H:38]([CH3:41])[CH2:39][CH3:40])[CH2:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: CC[C@H](C)[C@H](N)CN(CC(=O)OC)Cc1cccc2ccccc12
Reactant: N#Cc1ccc(Cn2cncc2CC(=O)O)cc1
Agent: Cl
Agent: O=c1c2ccccc2nnn1O
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CC[C@H](C)[C@@H](CN(CC(=O)OC)Cc1cccc2ccccc12)NC(=O)Cc1cncn1Cc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of [1-(4-cyanobenzyl)-1H-imidazol-5-yl]acetic acid. (4.09 g, 10.24 mmol), the amine hydrochloride salt from step E (5.07 g, 10.24 mmol), HOOBT (1.67 g, 10.24 mmol), and N-methylmorpholine (2.36 ml, 21.5 mmol) in DMF (50 ml) at 0° C., was added EDC (2.16 g, 11.26 mmol). The reaction was stirred at room temperature for 18 hrs, diluted with EtOAc and the organic layer washed with sat. aq NaHCO3, brine, dried (Na2SO4), and the solvent evaporated in vacuo. The residue was chromatographed (SiO2, 3-4% MeOH in CH2Cl2) to afford the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:5]2[CH2:11][CH2:10][N:9](CC3C=CC=CC=3)[CH2:8][C:6]=2[N:7]=1.Cl>C(O)C.[Pd]>[CH3:1][C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:5]2[CH2:11][CH2:10][NH:9][CH2:8][C:6]=2[N:7]=1
Reactant: Cc1nc2c(c(N3CCCCC3)n1)CCN(Cc1ccccc1)C2
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Cc1nc2c(c(N3CCCCC3)n1)CCNC2

Procedure:
A solution of 2-methyl-7-(phenylmethyl)-4-piperidin-1-yl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (Preparation 88, 12 g) in ethanol (200 ml) was adjusted to pH 2 with concentrated hydrochloric acid, palladium (5% on carbon) was added and the reaction mixture was hydrogenated at 60 psi. The reaction mixture was filtered, and the filtrate concentrated in vacuo. Chloroform and sodium hydroxide (2 M solution) were added and the organic extracts were dried, and concentrated in vacuo. The crude residue was dissolved in petroleum ether (30-40) and cooled in ice, the title compound was collected as a solid.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[C:11]2[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=2[Se:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SH:18][CH2:19][CH:20]([OH:23])[CH2:21][OH:22]>>[CH2:1]([NH:8][C:12]([C:11]1[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=1[Se:9][S:18][CH2:19][CH:20]([OH:23])[CH2:21][OH:22])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCC(O)CS
Reactant: O=c1c2ccccc2[se]n1Cc1ccccc1
Product: O=C(NCc1ccccc1)c1ccccc1[Se]SCC(O)CO

Procedure:
Prepared similar to example 1 from 2,88 g (10,0 mmol) of 2-benzyl-1,2-benzisoselenazole-3(2H)-one and 1,1 g (10,2 mmol) of 3-mercapto-1,2-propanediol.
Reaction SMILES: [OH:1][C:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH2:11][OH:12])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].N1C=CC=CC=1.[Cl:25][CH2:26][CH2:27][C:28](Cl)=[O:29].C(OCC)(=O)C>CC(C)=O.O>[C:13]1([C:2]([OH:1])([C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:4])[CH2:11][O:12][C:28](=[O:29])[CH2:27][CH2:26][Cl:25])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(c1ccccc1)C(O)(CO)c1ccccc1
Reactant: O=C(Cl)CCCl
Solvent: O
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: O=C(CCCl)OCC(O)(C(=O)c1ccccc1)c1ccccc1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
10.2 g (42 mmol) 2,3-dihydroxy-1,2-diphenyl-1-propanone was dissolved in 130 ml acetone. 6.6 g (84 mmol) pyridine was added and the reaction mixture was cooled to −10° C. 10.7 g (84 mmol) 3-chloropropionyl chloride was added drop wise, while the temperature was kept below 0° C. The reaction was allowed to continue for 30 minutes at 0° C., followed by 5 hours at room temperature. 150 ml ethyl acetate and 200 ml water were added to the reaction mixture. The organic fraction was isolated and the aqueous fraction was extracted for a second time with 200 ml ethyl acetate. The pooled organic fractions were dried over MgSO4 and evaporated under reduced pressure. (2,3-diphenyl-2-hydroxy-3-oxopropyl)-3-chloro-propionate was isolated by preparative column chromatography on a Prochorm LC80 column, using Kromasil Si60A 10μ and methylene chloride as eluent at a flow rate of 150 ml/min. 8 g of (2,3-diphenyl-2-hydroxy-3-oxopropyl)-3-chloro-propionate (60%) was isolated as a white crystalline product. (TLC on Merck Kieselgel 254F60, eluent methylene chloride, Rf: 0.19)
Reaction SMILES: [Br-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)C=CC=CC=1.[H-].[Na+].[CH:34]([O:36][CH:37]1[CH2:42][CH2:41][N:40]([C:43]([O:45][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[O:44])[CH2:39][CH2:38]1)=O.O>CS(C)=O>[F:19][C:16]([F:17])([F:18])[C:13]1[CH:12]=[CH:11][C:10]([CH:9]=[CH:34][O:36][CH:37]2[CH2:42][CH2:41][N:40]([C:43]([O:45][CH2:46][C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)=[O:44])[CH2:39][CH2:38]2)=[CH:15][CH:14]=1
Reactant: FC(F)(F)c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=COC1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(OCc1ccccc1)N1CCC(OC=Cc2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Triphenyl-(4-trifluoromethylbenzyl)-phosphonium bromide (3.00 g, 5.98 mmol) was dissolved in DMSO (50 ml). To the solution, sodium hydride (0.239 g, 5.98 mmol) was added with cooling on ice-bath followed by stirring at room temperature for 1 hour. To the solution, a solution of benzyl 4-formyloxypiperidine-1-carboxylate (1.497 g, 5.69 mmol) in DMSO (10 ml) was added dropwise followed by stirring at 60° C. for 7 hours. The reaction mixture was added water and extracted with ethyl acetate twice. The organic phases were combined, washed with water and a saturated saline solution, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=4/1) and then purified by silica gel column chromatography (methylene chloride/ethyl acetate=9/1) to afford benzyl 4-[2-(4-trifluoromethylphenyl)-vinyloxy]piperidin-1-carboxylate as a colorless oil.
Reaction SMILES: [CH3:1][CH:2]1[CH:9]2[CH2:10][CH:5]([C:6]([CH3:11])=[CH:7][CH2:8]2)[CH:4]([OH:12])[CH2:3]1.[Na].[CH3:14]I>O1CCCC1>[CH3:14][O:12][CH:4]1[CH2:3][CH:2]([CH3:1])[CH:9]2[CH2:10][CH:5]1[C:6]([CH3:11])=[CH:7][CH2:8]2
Reactant: CI
Reactant: CC1=CCC2CC1C(O)CC2C
Agent: [Na]
Solvent: C1CCOC1
Product: COC1CC(C)C2CC=C(C)C1C2
Temperature: 40 °C
Yield: 71.9 %

Procedure:
To a solution of 10 g (60.2 mmol) of 4,8-dimethylbicyclo[3.3.1]nona-7-en-2-ol [IA] in 60 ml of tetrahydrofuran were added 1.3 g (56.5 mmol) of sodium and the resulting mixture was heated with stirring at 40° C. After the sodium was dissolved, 12.8 g (90 mmol) of methyl iodide were added dropwise and the resulting mixture was heated with stirring at 40° C. for 10 hours. After cooling, the tetrahydrofuran was distilled off under reduced pressure, the residue was subjected to column chromatography and eluate with toluene gave 7.8 g of the title compound, which had a refrigerant and camphor-like smell.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([Br:10])[C:7](F)=[C:6]([F:12])[C:5]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21].[N-:23]=[N+:24]=[N-:25].[Na+]>CC(N(C)C)=O.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([Br:10])[C:7]([N:23]=[N+:24]=[N-:25])=[C:6]([F:12])[C:5]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21]
Reactant: COC(=O)c1cc(Br)c(F)c(F)c1Nc1ccc(Cl)cc1Cl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: COC(=O)c1cc(Br)c(N=[N+]=[N-])c(F)c1Nc1ccc(Cl)cc1Cl
Temperature: 50 °C
Yield: 96.2 %

Procedure:
A mixture of 5-bromo-2-(2,4-dichlorophenylamino)-3,4-difluorobenzoic acid methyl ester (2.02 g, 4.91 mmol) and NaN3 (379 mg, 5.83 mmol) in DMA (40 mL) was heated at 50° C. for 3 hours. The reaction mixture was diluted with EtOAc, and washed with water (5×). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to give the desired product (2.05 g, 96%) that was used directly without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH2:9][CH2:10][C:11](=O)[NH:12][N:13]=2)[CH:5]=[CH:6][CH:7]=1.ClC1C=C(C2[N:27]=[N:26][C:25](NN)=[CH:24]C=2)C=CC=1.C(Cl)(=O)C>>[CH3:24][C:25]1[N:12]2[N:13]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[CH:9]=[CH:10][C:11]2=[N:27][N:26]=1
Reactant: O=C1CCC(c2cccc(Cl)c2)=NN1
Reactant: NNc1ccc(-c2cccc(Cl)c2)nn1
Solvent: CC(=O)Cl
Product: Cc1nnc2ccc(-c3cccc(Cl)c3)nn12

Procedure:
Following the general procedure of Example 12, 6-(m-chlorophenyl)-4,5-dihydro-3(2H)-pyridazinone is converted to 6-(m-chlorophenyl)-3-hydrazinopyridazine which is treated with acetyl chloride to give the title compound, m.p. 165°-167° C.
Reaction SMILES: [C:1]1([CH:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:8][CH:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[CH2:12][CH2:11][NH:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:29][C:30](N)=[O:31]>>[C:30]([N:10]1[CH2:11][CH2:12][C:13]2[C:18](=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[CH:9]1[CH2:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:31])[NH2:29]
Reactant: COc1cc2c(cc1OC)C(CC(c1ccccc1)c1ccccc1)NCC2
Reactant: NC(N)=O
Product: COc1cc2c(cc1OC)C(CC(c1ccccc1)c1ccccc1)N(C(N)=O)CC2
Reaction time: 3 h

Procedure:
A solution of 1-(2,2-diphenyleth-1-yl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (1.0598 g, 2.838 mmoles) and urea (1.704 g, 10 equiv.) was heated at reflux. After 3 hours, TLC indicated less than 15% conversion. More urea (15.5 g, 90 equiv.) was added. Reflux continued for 24 hours. The solvent was then evaporated and the residue dissolved in water (80 mL). A white solid formed. After 1 hour, the solid was collected by filtration, washed with water, and dried in vacuo overnight (1.0554 g, 89%). 1H-NMR (CDCl3) δ 2.49 (m, 1H), 2.69 (m, 2H), 2.90 (m, 1H), 3.37 (m, 1H), 3.82 (s, 3H), 3.86 (s, 3H), 3.89 (m, 2H), 4.05 (t, 1H), 4.38 (m, 1H), 6.41 (s, 1H), 6.60 (s, 1H), 7.29 (m, 10H). Mass spec. 417.3 (MH)+. Anal. Calc. for C26H28N2O3: C-74.98, H-6.78, N-6.73. Found: C-74.72, H-6.74, N-6.45.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([CH:22]=[CH:23][C:24]=1[Cl:25])[O:12][CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][NH2:21])[CH2:15][CH2:14]1.[NH2:26][C:27]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][C:28]=1[C:29](O)=[O:30].Cl>>[NH2:26][C:27]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][C:28]=1[C:29]([NH:21][CH2:20][CH2:19][N:16]1[CH2:15][CH2:14][CH:13]([O:12][C:11]2[CH:22]=[CH:23][C:24]([Cl:25])=[C:9]([Cl:8])[CH:10]=2)[CH2:18][CH2:17]1)=[O:30]
Reactant: COc1ccc(N)c(C(=O)O)c1
Reactant: NCCN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(N)c(C(=O)NCCN2CCC(Oc3ccc(Cl)c(Cl)c3)CC2)c1
Yield: 75.4 %

Procedure:
Prepared by the method of Example 2 using the product from Example 1 step (iv) (1.0 g) and 2-amino-5-methoxybenzoic acid (0.418 g) without the addition of 1.0M ethereal hydrogen chloride solution to give an oil which was purified by chromatography (dichloromethane:methanol, 95:5) to give the sub-titled product as an oil (0.82 g).