Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:32][O:33][CH3:34])[CH2:10][NH:11][C:12]1[CH:21]=[C:20]([C:22]#[N:23])[C:15]([C:16]([O:18]C)=O)=[C:14]([NH:24][C:25]2[CH:26]=[C:27]([CH3:31])[CH:28]=[CH:29][CH:30]=2)[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C.C(Cl)Cl.[Pt](=O)=O>[CH3:34][O:33][CH2:32][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH2:10][NH:11][C:12]1[N:13]=[C:14]([NH:24][C:25]2[CH:26]=[C:27]([CH3:31])[CH:28]=[CH:29][CH:30]=2)[C:15]2[C:16](=[O:18])[NH:23][CH2:22][C:20]=2[CH:21]=1
Reactant: COC[C@@H](CNc1cc(C#N)c(C(=O)OC)c(Nc2cccc(C)c2)n1)NC(=O)OC(C)(C)C
Agent: O=[Pt]=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC[C@@H](CNc1cc2c(c(Nc3cccc(C)c3)n1)C(=O)NC2)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a round-bottomed flask was added (R)-methyl 6-(2-(tert-butoxycarbonylamino)-3-methoxypropylamino)-4-cyano-2-(m-tolylamino)nicotinate (84.5 mg, 0.180 mmol) in acetic acid (3 mL) and DCM (10 mL). To the resulting yellow solution was added platinum(IV) oxide (4.09 mg, 0.018 mmol). The flask was evacuated and back filled with hydrogen (3×1 atm). The reaction mixture was stirred vigorously at RT for 16 h, subsequently diluted with DCM (10 mL), and filtered through Celite. The filtrate was concentrated to an oil, which was diluted with DCM (10 mL). Potassium carbonate (24.87 mg, 0.180 mmol) was added and the reaction mixture was stirred at RT for 12 h. The crude reaction was diluted with DCM (10 mL), filtered through Celite, and concentrated to give the title compound as a thick yellow oil, which was used without further purification (26.5 mg, 33.4%). [M+H] calc'd for C23H31N5O4, 442. found, 442.
Reaction SMILES: O.Cl.Cl.[CH3:4][N:5]1[C:14]2[C:9](=[CH:10][C:11](N=O)=[C:12]([OH:15])[CH:13]=2)[CH2:8][CH2:7][CH2:6]1>CO>[CH3:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[CH2:8][CH2:7][CH2:6]1
Reactant: CN1CCCc2cc(N=O)c(O)cc21
Agent: Cl
Solvent: CO
Solvent: O
Product: CN1CCCc2ccc(O)cc21

Procedure:
(0.093 mole) was dissolved in a mixture of methanol 105 ml., water 70 ml., and concentrated hydrochloric acid 35 ml. and was filtered into a 500 ml. conical flask. The solution was well cooled to maintain a temperature between 0° and 5° and was rapidly stirred whilst a 10% aqueous solution of sodium nitrite 67 ml. (5% excess) mixed with methanol 67 ml. was slowly dripped in over half an hour and then stirred for another hour. The precipitate was filtered, washed with cold, dilute hydrochloric acid and air-dried to give 11.7 g. (56%) of yellow-brown fine crystals of 1-methyl-1,2,3,4-tetrahydro-6-nitroso-7-hydroxyquinoline hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)=[CH:15][C:14]=1[F:27].[CH3:28][O:29][CH:30](OC)[CH2:31]OC>>[F:27][C:14]1[CH:15]=[C:16]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[CH:17]=[CH:18][C:13]=1[NH:12][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:1][CH2:31][CH2:30][O:29][CH3:28])[CH:3]=2)[N:8]=[CH:7][N:6]=1
Reactant: Nc1ccc2ncnc(Nc3ccc(OCc4ccccn4)cc3F)c2c1
Reactant: COCC(OC)OC
Product: COCCNc1ccc2ncnc(Nc3ccc(OCc4ccccn4)cc3F)c2c1
Yield: 52 %

Procedure:
Using an analogous procedure to that described in Example 43, 6-amino-4-[2-fluoro-4-(2-pyridylmethoxy)anilino]quinazoline was reacted with 2-methoxyacetaldehyde dimethyl acetal to give 4-[2-fluoro-4-(2-pyridylmethoxy)anilino]-6-(2-methoxyethylamino)quinazoline in 52% yield;
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:17][C:16](=[O:18])[NH:15][S:14]1(=[O:20])=[O:19].Cl>CO.O>[O:20]=[S:14]1(=[O:19])[NH:15][C:16](=[O:18])[CH2:17][N:13]1[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[CH2:6][C:5]([OH:21])=[O:4]
Reactant: COC(=O)Cc1ccccc1N1CC(=O)NS1(=O)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)Cc1ccccc1N1CC(=O)NS1(=O)=O
Reaction time: 3 h

Procedure:
A solution of 2N aqueous NaOH (2.0 mL, 4.0 mmol) is added to a solution of the title compound of Example 40, [2-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-phenyl]-acetic acid methyl ester (57 mg, 0.20 mmol) in MeOH (2.0 mL). The reaction is stirred for 3 h, then neutralized by addition of 2N aqueous HCl (2.0 mL). The mixture is concentrated on a Savant Speedvac to give a yellow solid. The solid is triturated with EtOAc, filtered and the filtrate is evaporated to give a yellow solid. This is dissolved in 2 mL water loaded onto a preparative reverse phase HPLC column (YMC CombiPrep Pro C18, 50×20 mm I.D., particle size S-5 micron, 12 nM) and eluted at 30 mL/min with a gradient of 90:10 (0.1% TFA in water:MeCN) to 10:90 over 5 min. Then held at 10:90 until 7 min. Fractions containing product are combined and concentrated on a Savant Speedvac to yield [2-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-phenyl]-acetic acid as a white solid: [M−1]−=269.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=C[C:11]=2N=N1.C1(C[C@H](N2CC3C(=CC=CC=3S(C)(=O)=O)C2=O)C(O)=O)CCCCC1.C1(C[C@H](N2CC3C(=C(S(C)(=O)=O)C=CC=3)C2=O)C(O)=O)CCCCC1.NC1C=CN=CN=1.[CH:85]1([CH2:91][C@H:92]([N:101]2[CH2:109][C:108]3[C:103](=[CH:104][CH:105]=[CH:106][CH:107]=3)[C:102]2=[O:110])[C:93]([NH:95][C:96]2[S:97][CH:98]=[CH:99][N:100]=2)=[O:94])[CH2:90][CH2:89][CH2:88][CH2:87][CH2:86]1>C(OCC)(=O)C.C(OCC)(=O)C.C(Cl)Cl>[CH:85]1([CH2:91][CH:92]([N:101]2[CH2:109][C:108]3[C:103](=[CH:104][CH:105]=[CH:106][CH:107]=3)[C:102]2=[O:110])[C:93]([NH:95][C:96]2[S:97][CH:98]=[CH:99][N:100]=2)=[O:94])[CH2:86][CH2:87][CH2:88][CH2:89][CH2:90][CH2:11]1
Reactant: O=C(Nc1nccs1)[C@H](CC1CCCCC1)N1Cc2ccccc2C1=O
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CS(=O)(=O)c1cccc2c1C(=O)N([C@@H](CC1CCCCC1)C(=O)O)C2
Agent: CS(=O)(=O)c1cccc2c1CN([C@@H](CC1CCCCC1)C(=O)O)C2=O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(Nc1nccs1)C(CC1CCCCCC1)N1Cc2ccccc2C1=O

Procedure:
BOP coupling of (S)-3-cyclohexyl-2-(4-methylsulfonyl-1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid and regio-isomeric (S)-3-cyclohexyl-2-(7-methylsulfonyl-1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid (200 mg; 0.55 mmol) and 4-aminopyrimidine (89 mg; 0.91 mmol) in a manner similar to that used for the preparation of (S)-3-cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yl-propionamide (outlined in Example 9, Step B) provided after flash chromatography (Biotage 40S; eluent: ethyl acetate/methylene chloride, gradient: 25% to 70% ethyl acetate) to give 83 mg of (S)-3-Cyclohexyl-2-(4-methylsulfonyl-1-oxo-1,3-dihydro-isoindol-2-yl)-N-pyrimidin-4-yl-propionamide as a foam: EI-HRMS m/e calcd for C22H24N4O4SNa (M++Na+) 465.1567, found 465.1568 and 77 mg (S)-3-Cyclohexyl-2-(7-methylsulfonyl-1-oxo-1,3-dihydro-isoindol-2-yl)-N-pyrimidin-4-yl-propionamide as a foam: EI-HRMS m/e calcd for C22H26N4O4SNa (M++Na+) 465.1567, found 465.1572.
Reaction SMILES: Br[CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:3]([OH:5])=[O:4].[Cl-:18].[Ca+2].[Cl-].C(N(CC)CC)C>C(#N)C.[Cl-].C([N+](CC)(CC)CC)C>[Cl:18][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:3]([OH:5])=[O:4]
Reactant: [Cl-]
Reactant: CCCCCCCCCCCCC(Br)C(=O)O
Agent: CC[N+](CC)(CC)CC
Agent: [Ca+2]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCC(Cl)C(=O)O
Temperature: 80 °C
Reaction time: 3 h
Yield: 75.4 %

Procedure:
To 2-bromotetradecanoic acid (2 g) dissolved in acetonitrile (100 mg) were added calcium chloride (7.2 g), tetraethylammonium chloride (2.2 g) and triethylamine (0.84 ml), and the mixture was stirred at 80° C. for 3 hours. After precipitates produced by cooling the reaction mixture was removed by filtration, the filtrate was concentrated and the residue was distributed into ethyl acetate and an aqueous citric solution. The ethyl acetate layer was dried and concentrated to give 2-chloro-tetradecanoic acid (1.29 g). To 2-chlorotetradecanoic acid (1.29 g) dissolved in N, N-dimethylformamide (DMF, 50 ml) were added para-nitrophenol (0.68 g) and N,N'-dicyclohexylcarbodiimide (1.1 g), and the mixture was stirred for 12 hours. After precipitates were removed by filtration, the solvent (DMF) was evaporated and the residue was subjected to chromatography on a silica gel column with eluent systems of n-hexane-ethyl acetate (from 200:1 to 50:1) to give the active ester of 2-chlorote tradecanoic acid (11.12 g). To the active ester (500 mg) dissolved in DMF (30 ml) were added 6-(4'-N-glycyl -spicaminyl-amino)purine hydrochloride (500 mg) and triethylamine (2.0 ml). The mixture was stirred for 12 hours. After the solvent was evaporated, the residue was subjected to chromatography on a silica gel column with eluent systems of chloroform-methanol (from 7:1 to 5:1) to give SPK259 in the yield of 202 mg.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[NH:10][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:8][C:6]=2[N:7]=1.[C:18]1([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH3:1][C:2]1[NH:7][C:6]2=[CH:8][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:10][C:5]2=[C:4]([N:27]2[CH2:28][CH2:29][N:24]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:25][CH2:26]2)[N:3]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: Cc1nc(Cl)c2[nH]c(-c3ccccc3)cc2n1
Product: Cc1nc(N2CCN(c3ccccc3)CC2)c2nc(-c3ccccc3)cc-2[nH]1
Temperature: 140 °C
Reaction time: 4 h
Yield: 54 %

Procedure:
A mixture of 2-methyl-4-chloro-6-phenyl-5H-pyrrolo[3,2-d]pyrimidine (Example 1(e)) (0.51 g, 2.45 mmol) and 1-phenylpiperazine (Aldrich Chemical Company) (10 mL) was stirred at 140° C. for 4 h under a N2 atmosphere. After cooling the precipitate was removed by filtration and the filtrate was poured onto a mixture of CH2Cl2 (30 mL) and H2O (40 mL). The mixture was transferred to a separatory funnel where the organic solution was collected, washed with H2O (3×40 mL), saturated NaCl (50 mL), dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel with 97:3 CHCl3/MeOH as eluant to give 483 mg (54%) of 2-methyl-6-phenyl-4-(4-phenylpiperazinyl)pyrrolo[3,2-d]pyrimidine as a tan colored solid. This compound (483 mg, 1.31 mmol) was dissolved in 5:1 EtOAc/MeOH (30 mL) and heated to boiling. To the hot solution was added 1 M ethereal HCl (1.30 mL, 1.30 mmol). The solution was allowed to cool to room temperature. The resulting solid was collected by filtration, washed with EtOAc (2×5 mL), Et2O (2×5 mL) and dried under vacuum at 60° C. to give 404 mg (41%) of the title compound as a beige powder. Mp: 232-234.5° C. 1H NMR (DMSO-d6; 500 MHz): δ 2.55 (s, 3), 3.36 (br s, 4), 4.21 (br s, 4), 6.80 (t, 1, J=7.2), 6.88 (s, 1), 6.99 (d, 2, J=7.8), 7.22 (t, 2, J=7.5), 7.46 (q, 1, J=7.1), 7.51 (t, 2, J=7.3), 7.93 (d, 2, J=7.7), 12.06 (s, 1), 14.46 (s, 1). MS m/z: 370 (M+1 for free base). Anal. Calcd for C23H23N5.2.0HCl.2 .5H2O: C, 56.67; H, 6.20; N, 14.37; Cl, 14.55. Found: C, 56.67; H, 6.23; N, 14.19; Cl, 14.34.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11](O)[CH2:10][C@@:9]1([C:17](=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[CH2:14][CH2:15][CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:27]C(F)(S(F)(=O)=O)C(F)(F)C(F)(F)C(F)(F)F.F.F.F.C(N(CC)CC)C.C(N(CC)CC)C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([F:27])[CH2:10][C@:9]1([C:17](=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[CH2:14][CH2:15][CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CCC[C@]1(C(=O)c2ccc(Cl)c(Cl)c2)CC(O)CN1C(=O)OC(C)(C)C
Agent: F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCC[C@@]1(C(=O)c2ccc(Cl)c(Cl)c2)CC(F)CN1C(=O)OC(C)(C)C
Reaction time: 18 h
Yield: 99.5 %

Procedure:
To a stirred solution of (R)-2-(3,4-dichloro-benzoyl)-4-hydroxy-2-propyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.222 g, 0.554 mmol) in THF (3 mL) at ambient temperature under nitrogen was added perfluorobutanesulfonyl fluoride (0.195 mL, 1.11 mmol), triethylamine trihydrofluoride (0.181 mL, 1.11 mmol) and triethylamine (0.46 mL, 3.32 mmol). The reaction mixture was stirred for 18 hours, then filtered through a pad of silica, washed with EtOAc, and concentrated in vacuo to give (S)-2-(3,4-dichloro-benzoyl)-4-fluoro-2-propyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.222 g, 0.551 mmol, 99%) as a yellow foam that was used directly in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](OCC)=[O:10])=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]=[O:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1ccc(Br)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: O=CCc1ccc(Br)cc1
Temperature: -78 °C

Procedure:
To a cold solution (−78° C.) of 15 g (62 mmol) of ethyl (4-bromophenyl)acetate (Compound A) in 150 ml of C12 was added dropwise (over a span of 1 hour) 65 ml (65 mmol) of diisobutylaluminum hydride (DIBAL-H, 1M solution in hexane). After the DIBAL-H addition was complete, the reaction was stirred at −78° C. for an additional hour. The reaction was quenched by the dropwise 13.addition of methanol (10 ml), followed by water (10 ml) and 10% HCl (40 ml). The mixture was then warmed to 0° C., stirred for 10 minutes and then washed with water (15 ml), 10% aqueous NaHCO3 (10 ml) and brine (10 ml). The organic phase was dried over MgSO4 and the solvent distilled off at ambient temperature to give crude (4-bromophenyl)acetaldehyde. To a cold solution (0° C.) of this crude aldehyde in 150 ml of CH2Cl2 was added a solution of 26 g (74.6 mmol) of (carbethoxymethylene)triphenylphosphorane in 50 ml of CH2Cl2. The mixture was stirred for 16 hours, concentrated in vacuo and purified by flash chromatography (silica, 10% EtOAc-hexane) to give ethyl 4-(4-bromophenyl)but-2-enoate as a mixture of E:Z isomers. This isomeric mixture was dissolved in 150 ml of EtOAc and hydrogenated over 1 g of 10% Pd/C for 6 hours. The catalyst was filtered off and the filtrate concentrated in vacuo to give the title compound as a white solid.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:24])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)(C)(C)C.Cl>O1CCOCC1>[NH2:7][CH:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:18]=[CH:19][C:20]([C:23]([N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:24])=[CH:21][CH:22]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2ccc(C(=O)N3CCCCC3)cc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: NC1CCN(S(=O)(=O)c2ccc(C(=O)N3CCCCC3)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.8 %

Procedure:
{1-[4-(Piperidine-1-carbonyl)-benzenesulfonyl]-piperidin-4-yl}-carbamic acid tert-butyl ester (0.17 g, 0.39 mmol) was suspended in a 4M solution of HCl in Dioxane (10 ml). The resulting suspension was stirred at room temperature for 3 hours. After this time the solution was concentrated under vacuum, then azeotroped with methanol and suspended in diethyl ether. The resulting solid precipitate was then collected by filtration, washed with diethyl ether and dried under vacuum to afford the title compound (0.13 g, 100% yield) as a white solid. Tr=1.19 min, m/z (ES+) (M+H)+ 352.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.C([Mg]Br)C.Cl[C:17]([O:19][CH2:20][CH3:21])=[O:18]>C(OCC)C>[CH2:20]([O:19][C:17]([C:6]1[C:5]2[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=2)[NH:8][CH:7]=1)=[O:18])[CH3:21]
Reactant: COc1ccc2[nH]ccc2c1
Reactant: CCOC(=O)Cl
Agent: CC[Mg]Br
Solvent: CCOCC
Product: CCOC(=O)c1c[nH]c2ccc(OC)cc12
Temperature: -5 °C
Reaction time: 1 h
Yield: 33.3 %

Procedure:
To a solution of 5-methoxyindole (10.0 g, 67.9 mmol) in anhydrous diethyl ether (200 cm3) being maintained at 0° C. under a nitrogen atmosphere was added a solution of ethyl magnesium bromide in diethyl ether (3.0 M, 22.65 cm3, 67.95 mmol) over a period of ca. 10 min. The reaction was heat to reflux for 45 min, cooled to −5° C. and ethyl chloroformate (6.5 cm3, 67.9 mmol) was added. After stirring at this temperature for 1 h, the mixture was heated to reflux for 30 min, cooled and added to ice containing sat. aqueous ammonium chloride solution (150 cm3). This mixture was extracted into ethyl acetate (150 cm3), washed with water (3×150 cm3), dried (MgSO4) and evaporated under reduced pressure to afford a brown oil (13.21 g), crystallisation from diethyl-ether/heptane afforded the title compound (4.95 g, 33%). Positive ion ESI (M+H)+ 220.0.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C@H:9]([CH3:17])[C@:10]([CH3:16])([OH:15])[C:11]([F:14])([F:13])[F:12])C1C=CC=CC=1.O>CO>[NH2:8][C@H:9]([CH3:17])[C@:10]([CH3:16])([OH:15])[C:11]([F:14])([F:13])[F:12]
Reactant: C[C@@H](N(Cc1ccccc1)Cc1ccccc1)[C@](C)(O)C(F)(F)F
Solvent: O
Solvent: CO
Product: C[C@@H](N)[C@](C)(O)C(F)(F)F
Reaction time: 8 h
Yield: 80.4 %

Procedure:
(2S,3R)-3-(Dibenzylamino)-1,1,1-trifluoro-2-methylbutan-2-ol (Example 52B) (1.94 g, 5.75 mmol) was dissolved in MeOH (50 mL) and an then treated with the catalyst (0.612 g, 10% dry weight, 50% water). The reaction vessel was then purged with alternating vacuum and N2 (7×). H2 was introduced and then the vessel was purged again with vacuum alternated with H2 (3×). The reaction vessel was then finally charged with H2 (90 psi). The pressure was allowed to drop to ca. 80 psi and allowed to stay there overnight (H2 uptake appeared to stop). After 15 h, the reaction was purged with N2/vacuum cycles and the catalyst/carbon was removed by filtration through celite. The celite cake was rinsed with MeOH and the resulting filtrate was carefully concentrated to a white solid by rotavap followed by finishing the last part of the liquid volume with an N2 blow down. The resulting grey solid/film was dissolved in CH2Cl2 and then filtered through a microfilter to remove remaining Pd/C. The resulting pale yellow filtrate was then blown down and exposed to light vacuum to afford a pale yellow solid (0.726 g, 80%) PMR of this material showed excellent purity and no remaining sm: 1H NMR (400 MHz, DMSO-d6) δ 2.95 (q, J=6.7 Hz, 1H), 1.60 (bs, 2H), 1.13-1.11 (m, 3H), 0.96-0.94 (m, 3H).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[NH:7])[CH2:4][S:3]1.[NH:8]=[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=N)[NH:10]1.C(O)CO>CO>[NH:8]=[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[C:4]2[S:3][C:2](=[O:1])[NH:6][C:5]2=[NH:7])[NH:10]1
Reactant: N=C1CSC(=O)N1
Reactant: N=C1NC(=N)c2ccccc21
Solvent: CO
Solvent: OCCO
Product: N=C1NC(=O)SC1=C1NC(=N)c2ccccc21

Procedure:
17.5 parts of 2-oxo-4-iminothiazolidine and 32 parts of the adduct of 1,3-diiminoisoindoline and ethylene glycol, in 400 parts of methanol, are refluxed for 5 hours. After the mixture has cooled, the product is filtered off, washed with methanol and dried. 33 parts of 1-imino-3-(2'-oxo-4'-iminothiazolidinylidene)-isoindoline (formula II, Z=°O) are obtained as a yellowish brown powder.
Reaction SMILES: [H][H].[C]=O.[CH:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>[Pd]>[CH:5]1([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: [H][H]
Reactant: c1ccccc1
Agent: [Pd]
Agent: [C]=O
Product: c1ccc(C2CCCCC2)cc1

Procedure:
In addition, U.S. Pat. No. 5,146,024 discloses that benzene can be reacted with hydrogen in the presence of carbon monoxide and a palladium-containing zeolite X or Y to produce cyclohexylbenzene, which can then be converted in high yield to phenol and cyclohexanone by autooxidation with subsequent acid treatment. The hydroalkylation reaction is carried out at a liquid hourly space velocity (LHSV) of the benzene feed of about 1 to about 100 hr−1, a total reaction pressure of about 345 to about 10,350 kPa, a molar ratio of H2 to benzene of about 0.1:1 to about 10:1, a molar ratio of carbon monoxide to H2 of about 0.01:1 to about 0.3:1, and a temperature of about 100 to about 250° C. Preferred operating conditions are said to include a LHSV of the benzene feed of about 5 to about 30 hr−1, a total reaction pressure of about 1,380 to about 4,830 kPa, a molar ratio of H2 to benzene of about 0.2:1 to about 1:1, a molar ratio of CO to H2 of about 0.02:1 to about 0.1:1, and a reaction temperature of about 140 to about 200° C.
Reaction SMILES: [C:1]1([CH:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B.C1C[O:21]CC1.[OH-].[Na+].OO>CCOCC.O>[C:1]1([C@@H:7]2[C@@H:16]([OH:21])[CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[O:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C1CCOC1
Reactant: C1=CC(c2ccccc2)Oc2ccccc21
Agent: B
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: O[C@H]1Cc2ccccc2O[C@@H]1c1ccccc1
Temperature: 23 °C
Reaction time: 12 h
Yield: 63 %

Procedure:
A solution of 2-phenyl-2H-chromene (2a) (167 mg, 0.8 mmol) and 1 molar BH3-THF (16 mL) was stirred for 2 h at 23° C. Solution was cooled to 0° C. before a 20% (w/w) aqueous solution of NaOH (4.8 mL) and 30% (w/w) aqueous solution of H2O2 (4.9 mL) were added. The reaction was slowly warmed to 23° C. and stirred for 12 h. The solution was then diluted with Et2O and H2O followed by acidification with 10% (w/w) aqueous HCl and extraction with Et2O. The organics were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Purification by flash chromatography with 10% EtOAc/hexanes afforded 7 as a white solid (115 mg, 63%). Spectroscopic data was consistent with those previously reported.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[Br:17]N1C(=O)CCC1=O>N(C(C)(C)C#N)=NC(C)(C)C#N.C(Cl)(Cl)(Cl)Cl>[Br:17][CH2:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:16][CH:15]=2)=[O:7])=[CH:9][CH:10]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C(=O)c2ccc(F)cc2)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(c1ccc(F)cc1)c1ccc(CBr)cc1
Temperature: 25 °C
Yield: 91.4 %

Procedure:
A carbon tetrachloride solution (200 ml) of 4-fluoro-4'-methylbenzophenone (16 g), N-bromosuccinimide (14.2 g) and 2,2'-azodi-isobutyronitrile (0.1 g) was heated for 16 hours with refluxing. After the mixture was cooled to a room temperature, the precipitates were collected by filtration, and the solvent was distilled off to obtain 4-bromomethyl-4'-fluorobenzophenone (20 g).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:3]=1[CH2:4][NH:5][N:6]1[C:10]2[CH:11]=[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[OH:20].[CH3:26]I>CN(C=O)C>[Cl:1][C:2]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:3]=1[CH2:4][NH:5][N:6]1[C:10]2[CH:11]=[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:13]=[CH:14][C:9]=2[N:8]([CH3:26])[C:7]1=[O:20]
Reactant: CI
Reactant: CCOC(=O)c1ccc2nc(O)n(NCc3ccc(Cl)cc3Cl)c2c1
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2c(c1)n(NCc1ccc(Cl)cc1Cl)c(=O)n2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.8 %

Procedure:
Sodium hydrite (0.080 g, 60% suspension in oil) was added to a solution of 1-(2,4-dichlorobenzylamino)-2-hydroxy-6-(ethoxycarbonyl)benzimidazole (0.396 g) in N,N′-dimethylformamide (4 ml), and the mixture was stirred at room temperature for 1 hr. Methyl iodide (0.307 g) was added, and the mixture was stirred for 2 hr. The precipitated crystals were collected by filtration, washed with water and ethanol and dried to give the objective compound (0.348 g).