Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([NH2:14])[S:12][CH:13]=2)=[CH:5][CH:4]=1.Br[CH2:16][C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1.C(N(CC)C(C)C)(C)C.C(OCC)(=O)C>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:10]=[C:11]([NH:14][CH2:16][C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=3)[S:12][CH:13]=2)=[CH:7][CH:8]=1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: COc1ccc(-c2csc(N)n2)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1ccc(-c2csc(NCc3ccc(C#N)cc3)n2)cc1
Temperature: 100 °C
Yield: 34.3 %

Procedure:
5.0 g 4-(4-Methoxyphenyl)-1,3-thiazol-2-amine, 4.29 g 4-bromomethyl-benzonitrile and 6.0 ml N,N-Diisopropylethylamine were suspended in 20 ml dimethylformamide. The reaction mixture was stirred under microwave irradiation at 100° C. for thirty minutes. The cooled reaction mixture was diluted by the addition of 100 ml ethyl acetate and washed 50 ml saturated NaHCO3 solution and the dried over MgSO4. The solvent was removed in vacuo and the resulting residue was purified by chromatography on silica gel with the eluent petroleum ether: ethyl acetate=3:2 to obtain 2.41 g 4-{[4-(4-Methoxy-phenyl)-thiazol-2-ylamino]-methyl}-benzonitrile.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][C:11]=2[F:19])=[C:5]([O:20][CH3:21])[CH:4]=1)[CH3:2].O1CC[CH2:24][CH2:23]1>C(O)C>[CH2:23]([NH:16][C:13]1[CH:14]=[CH:15][C:10]([O:9][C:6]2[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][C:5]=2[O:20][CH3:21])=[C:11]([F:19])[CH:12]=1)[CH3:24]
Reactant: CCc1ccc(Oc2ccc([N+](=O)[O-])cc2F)c(OC)c1
Reactant: C1CCOC1
Solvent: CCO
Product: CCNc1ccc(Oc2ccc(CC)cc2OC)c(F)c1

Procedure:
According to the procedure of example 20 (b) except substituting 4-ethyl-2-methoxy-1-[4-nitro-2-(trifluoromethyl) phenoxy]benzene for 4-ethyl-1-(2-fluoro-4-nitrophenoxy)-2-methoxybenzene (1.16 g; 4.0 mmol) and tetrahydrofurane for ethanol (16 mL), two compounds were obtained after purification on silica gel (gradient cyclohexane/dichloromethane) 4-(4-ethyl-2-methoxyphenoxy)-3-fluoroaniline (466 mg; 45%)
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[F:19][C:20]([F:32])([F:31])[O:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1>>[O:16]=[C:15]1[C:8]2=[CH:7][C:6]3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=[C:2]([C:25]4[CH:24]=[CH:23][C:22]([O:21][C:20]([F:19])([F:31])[F:32])=[CH:27][CH:26]=4)[C:10]=3[N:9]2[CH2:11][CH2:12][CH2:13][NH:14]1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCCNC1=O
Product: N#Cc1cc(-c2ccc(OC(F)(F)F)cc2)c2c(c1)cc1n2CCCNC1=O

Procedure:
The title compound, off-white solid (83 mg, 86%), MS (ISP) m/z=386.4 [(M+H)+], mp 230.5° C., was prepared in accordance with the general method of example 1 from 7-bromo-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 20) (76.0 mg, 0.25 mmol) and commercially available 4-trifluoromethoxy-phenylboronic acid (66.9 mg, 0.325 mmol).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@H:12]2[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13]2)=[C:5]([NH:22][CH2:23][CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:4]=1.[CH:37]([N:40]1[CH2:45][CH2:44][C:43](=O)[CH2:42][CH2:41]1)([CH3:39])[CH3:38].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[C:25]1([CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:23][NH:22][C:5]2[N:4]=[C:3]([CH2:2][NH:1][CH:43]3[CH2:44][CH2:45][N:40]([CH:37]([CH3:39])[CH3:38])[CH2:41][CH2:42]3)[N:11]=[C:10]3[C:6]=2[N:7]=[CH:8][N:9]3[C@H:12]2[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13]2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC(C)N1CCC(=O)CC1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CN)nc32)[C@H](O)[C@@H]1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNC4CCN(C(C)C)CC4)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 36.1 %

Procedure:
(2R,3R,4S,5R)-2-{2-(Aminomethyl)-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl}-5-(methoxymethyl)tetrahydro-3,4-furandiol (example 1) (310 mg, 0.63 mmol) was dissolved (using gentle heating) in dry tetrahydrofuran (20 ml). The resulting solution was cooled to room temperature and, with stirring, treated with a solution of 1-isopropyl-4-piperidinone (90 mg, 0.63 mmol) and acetic acid (45 mg) in dry tetrahydrofuran (5 ml). The mixture was stirred for 1 hr, sodium triacetoxyborohydride (200 mg, 0.94 mmol) added and stirring continued for a further 18 hr. The solvent was then removed under reduced pressure and the residue partitioned between a saturated aqueous solution of sodium hydrogen carbonate and ethyl acetate. The organic phase was separated and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:methanol:ammonia (90:10:0.5) changing to dichloromethane:methanol:ammonia (85:15:0.75) to afford the title compound as a foam (140 mg). MS: 616 (MH+).
Reaction SMILES: [CH2:1]([CH:4]([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:5][OH:6])[CH2:2][CH3:3].CO[C:14]([CH:16]1[CH2:21][CH2:20][CH:19]([C:22]([O:24][CH3:25])=[O:23])[CH2:18][CH2:17]1)=[O:15]>CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4]>[CH2:1]([CH:4]([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:5][O:6][C:14]([CH:16]1[CH2:17][CH2:18][CH:19]([C:22]([O:24][CH2:25][CH:4]([CH2:1][CH2:2][CH3:3])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[O:23])[CH2:20][CH2:21]1)=[O:15])[CH2:2][CH3:3]
Reactant: COC(=O)C1CCC(C(=O)OC)CC1
Reactant: CCCCCC(CO)CCC
Agent: [Ti+4]
Agent: CC(C)[O-]
Product: CCCCCC(CCC)COC(=O)C1CCC(C(=O)OCC(CCC)CCCCC)CC1
Temperature: 185 °C

Procedure:
2-Propylheptyl alcohol (8.1 mol), dimethylcyclohexane-1,4-dicarboxylate (DMCD, cis 81.8%, trans 18.2%, SK NJC, 3.0 mol) and tetraisopropyl titanate catalyst (0.85 g) were added to a 2.5 L reactor equipped with a stirrer and two condensers and heated to 185° C. Di(2-propylheptyl)cyclohexane-1,4-dicarboxylate (cis 81%, trans 19%) was obtained with a purity of 99.3% in the same manner as in Example 1.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH:3]([OH:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH2:10].C(Cl)Cl.C(N(CC)C(C)C)(C)C.[O:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[C:31](Cl)=[O:32]>CCOCC>[F:1][C:2]([F:12])([F:13])[CH:3]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:31]([C:27]1[O:26][CH:30]=[CH:29][CH:28]=1)=[O:32])[OH:11]
Reactant: O=C(Cl)c1ccco1
Reactant: Nc1ccccc1C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccccc1C(O)C(F)(F)F)c1ccco1
Reaction time: 18 h
Yield: 80.1 %

Procedure:
To a solution of 1,1,1-trifluoro-2-hydroxy-2-(2-aminophenyl)ethane from Step 2 (600 mg, 3.14 mmol), methylene chloride (10 mL) was added N,N,-diisopropylethylamine (893 mg, 6.91 mmol) followed by 2-furoyl chloride (902 mg, 6.91 mmol) dropwise over 5 min under an argon atmosphere at 23° C. After 18 h, the reaction was diluted with ether (100 mL), washed with KHSO4 (1N, 1×80 mL), sat'd NaHCO3 (1×80 mL), brine (1×80 mL) and dried (MgSO4). After concentration in vacuo, the crude residue was taken on to the next step. The residue was dissolved in ethyl acetate (300 mL), washed with KHSO4 (2×50 mL) and with brine (1×50 mL), dried (Na2SO4), and concentrated in vacuo. To a solution of the residue and methanol (3 mL) was added NaOH (1.5 N, 3 mL) at 23° C. under argon. After 2 h at 23° C., the reaction was concentrated in vacuo, diluted with ether (150 mL), washed with brine (100 mL) and dried (MgSO4). After concentration in vacuo, the residue was purified by flash chromatography (ethyl acetate:hexane 1:3) to afford N-[2-(2,2,2-trifluoro-1-hydroxyethyl)phenyl]furan-2-carboxamide (717 mg, 80%) as an oil: 1H NMR (CDCl3) δ5.14 (q, J=6 Hz), 6.55 (m), 7.16-7.58 (m), 8.25 (m); 13C NMR (CDCl3) 72.7 (q, J=33 Hz), 112.2, 115.0, 122.7,123.1, 126.5 (q, J=280 Hz), 129.7, 136.8, 144.7, 149.5, 169.6. MS (EI) 285 (M+), 245, 216. IR (neat) 3500-3000, 1650 cm−1. Anal. Calc'd. for C13H10NO3F3: C, 54.74; H, 3.53; N, 4.91. Found: C, 54.63; H, 3.50; N, 4.90.
Reaction SMILES: [C:1]([OH:6])(=O)[CH2:2][CH2:3][CH3:4].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:40][C:41]1[C:42]([NH:59][CH:60]2[CH2:65][CH2:64][N:63]([CH2:66][CH2:67][C:68]#[N:69])[CH2:62][CH2:61]2)=[C:43]2[CH:49]=[CH:48][N:47]([S:50]([C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)(=[O:52])=[O:51])[C:44]2=[N:45][CH:46]=1>CN(C=O)C.C(Cl)Cl>[C:53]1([S:50]([N:47]2[C:44]3=[N:45][CH:46]=[C:41]([NH:40][C:1](=[O:6])[CH2:2][CH2:3][CH3:4])[C:42]([NH:59][CH:60]4[CH2:61][CH2:62][N:63]([CH2:66][CH2:67][C:68]#[N:69])[CH2:64][CH2:65]4)=[C:43]3[CH:49]=[CH:48]2)(=[O:51])=[O:52])[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1
Reactant: N#CCCN1CCC(Nc2c(N)cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Reactant: CCCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCC(=O)Nc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1NC1CCN(CCC#N)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Butyric acid (0.029 ml, 0.321 mmol), diisopropylethylamine (0.065 ml, 0.375 mmol), and HATU (0.122 g, 0.321 mmol) were added sequentially to a solution of 3-[4-(5-amino-1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-piperidin-1-yl]-propionitrile (0.130 g, 0.306 mmol, prepared as described in Example 118) in a 4:1 mixture of CH2Cl2 and DMF (5 ml) at 25° C. The reaction mixture was stirred for 15 h at 25° C., then was partitioned between saturated NaHCO3 (6 ml) and CH2Cl2 (2 ml). The phases were separated using a phase separation column (Biotage) and the organic layer was concentrated under reduced pressure to give crude N-{1-benzenesulfonyl-4-[1-(2-cyano-ethyl)-piperidin-4-ylamino]-1H-pyrrolo[2,3-b]pyridin-5-yl}-butyramide as a brown oil. LCMS (Method G, ESI): RT=0.59 min, m+H=495.3. This material was used in the next step below without additional purification or characterization.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11](=[O:27])[CH2:12][C:13](=[O:26])[CH2:14][O:15][C:16]23[CH2:25][CH:20]4[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]4)[CH2:17]2)[CH2:23]3)[CH:5]=1.O.[N:30]([O-])=[O:31].[Na+]>C(O)(=O)C.C1COCC1>[CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11](=[O:27])[C:12](=[N:30][OH:31])[C:13](=[O:26])[CH2:14][O:15][C:16]23[CH2:25][CH:20]4[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]4)[CH2:17]2)[CH2:23]3)[CH:5]=1
Reactant: COC(=O)c1cccc(NC(=O)CC(=O)COC23CC4CC(CC(C4)C2)C3)c1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cccc(NC(=O)C(=NO)C(=O)COC23CC4CC(CC(C4)C2)C3)c1
Temperature: 5 °C
Reaction time: 1 h
Yield: 94.9 %

Procedure:
To a solution of 3-[4-(adamantan-1-yloxy)-3-oxo-butyrylamino]-benzoic acid methyl ester (9.95 g, 25.8 mmol) in acetic acid (100 mL) and THF (90 mL) was added water (12 mL). The mixture was cooled to 5° C. and an aqueous solution (16 mL) of sodium nitrite (2.31 g, 35.0 mmol) was added dropwise while maintaining the temperature below 10° C. Upon completion of the addition, the reaction mixture was allowed to warm to room temperature and stirred for 1 h. The solvent was removed under reduced pressure and the residue was partitioned between saturated aqueous NaHCO3 and ethyl acetate. The aqueous phase was discarded and the organic phase was washed with further saturated aqueous NaHCO3 and brine. The organic phase was dried (MgSO4) and the solvent was evaporated at reduced pressure to afford the title product as a yellow foam (10.15 g, 95%). 1H NMR (CDCl3) 11.06 (1H, br s), 8.25 (1H, s), 7.93-7.90 (1H, m), 7.84-7.81 (1H, m), 7.51-7.41 (1H, m), 4.83 (2H, s), 3.95 (3H, s), 2.20 (3H, s), 1.82-1.57 (12H, m).
Reaction SMILES: [N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH:4]3[C:11](Cl)=[O:12])[CH2:2]1)[CH2:8]2.[NH2:14][C@H:15]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH2:16]1>>[F:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][CH2:20][N:17]2[CH2:18][CH2:19][CH:15]([NH:14][C:11]([CH:4]3[CH:5]4[CH2:10][N:1]5[CH2:8][CH:7]([CH2:9][C@@H:3]3[CH2:2]5)[CH2:6]4)=[O:12])[CH2:16]2)=[CH:23][CH:24]=1
Reactant: O=C(Cl)C1C2CC3CC1CN(C3)C2
Reactant: N[C@H]1CCN(CCc2ccc(F)cc2)C1
Product: O=C(NC1CCN(CCc2ccc(F)cc2)C1)C1C2CC3C[C@@H]1CN(C3)C2

Procedure:
1-Azaadamantane-4-carbonyl chloride and (S)-3-amino-1-(2-(4-fluorophenyl)ethyl)pyrrolidine were reacted under the same conditions as in Example 53 to give (S)-N-(1-(2-(4-fluorophenyl)ethyl)pyrrolidin-3-yl)-1-azaadamantane-4-carboxamide.
Reaction SMILES: [C:1]([C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])#[N:2].Cl.[NH2:19][OH:20].C([O-])([O-])=O.[Na+].[Na+]>C(O)C.O>[OH:20][NH:19][C:1]([C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])=[NH:2]
Reactant: NO
Reactant: N#C[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N=C(NO)[C@@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 100 °C
Yield: 74.9 %

Procedure:
Part A. Benzyl (S)-2-cyanopyrrolidine-1-carboxylate (500 mg, 2.17 mmol) was dissolved in aqueous ethanol (3 mL) and water (1 mL). Hydroxylamine hydrochloride (152 mg, 2.17 mmol) and Na2CO3 (115 mg, 1.08 mmol) were added and the reaction mixture heated to 100° C. for 1 h. The ethanol was removed and the aqueous residue was extracted with dichloromethane (3×25 mL), dried over Na2SO4 decanted and concentrated yielding benzyl (S)-2-(N-hydroxycarbamimidoyl)pyrrolidine-1-carboxylate as a pale yellow gum (428 mg, 75% yield): HPLC (method 1) tR=1.40 min, Purity 76%; LCMS (method 4) tR=0.81 min, m/z 264 (M+H).
Reaction SMILES: [C:1]([C:9]1[CH:26]=[CH:25][C:12]2[N:13]=[C:14]([CH2:16][S:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)=[O:18])[NH:15][C:11]=2[CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].S(OC)(O[CH3:33])(=O)=O>C(O)C.O>[C:1]([C:9]1[CH:26]=[CH:25][C:12]2[N:13]([CH3:33])[C:14]([CH2:16][S:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)=[O:18])=[N:15][C:11]=2[CH:10]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[C:1]([C:9]1[CH:26]=[CH:25][C:12]2[N:13]=[C:14]([CH2:16][S:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)=[O:18])[N:15]([CH3:33])[C:11]=2[CH:10]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COS(=O)(=O)OC
Reactant: O=C(c1ccccc1)c1ccc2nc(CS(=O)c3ccccn3)[nH]c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cn1c(CS(=O)c2ccccn2)nc2cc(C(=O)c3ccccc3)ccc21
Product: Cn1c(CS(=O)c2ccccn2)nc2ccc(C(=O)c3ccccc3)cc21
Yield: 12.5 %
Yield: 40 %

Procedure:
A mixture of 3.61 g of 5-benzoyl-2-(2-pyridylsulfinylmethyl)benzimidazole (0.01 mole), 0.40 g of sodium hydroxide (0.01 mole) and 2 ml of dimethyl sulfate (0.02 mole) in 50 ml of ethanol and 5 ml of water is maintained under reflux for 3 hours. The ethanol is evaporated off and the residue diluted with water and extracted with chloroform. The organic phase is washed with water, dried and evaporated. The residue is chromatographed with silica gel, using chloroform/methanol (99:1) and subsequently chloroform/methanol (95:5) as eluant. On fractional crystallization of the final fraction in ethyl acetate, 0.47 g (12.5%) of 5-benzoyl-1-methyl-2-(2-pyridylsulfinylmethyl)benzimidazole, melting point 174°-177° C., and 1.5 g (40%) of 6-benzoyl-1-methyl-2-(2-pyridylsulfinylmethyl)benzimidazole, melting point 181°-183° C., are obtained.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[F:9][C:10]1[CH:11]=[CH:12][C:13]2[N:19]3[CH:20]=[N:21][CH:22]=[C:18]3[CH2:17][N:16]([CH3:23])[C:15](=[O:24])[C:14]=2[CH:25]=1.O>CN(C)C=O>[Br:1][C:22]1[N:21]=[CH:20][N:19]2[C:13]3[CH:12]=[CH:11][C:10]([F:9])=[CH:25][C:14]=3[C:15](=[O:24])[N:16]([CH3:23])[CH2:17][C:18]=12
Reactant: CN1Cc2cncn2-c2ccc(F)cc2C1=O
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: CN1Cc2c(Br)ncn2-c2ccc(F)cc2C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3.58 g of N-bromosuccinimide are added to 4.62 g (20 mmol) of 8-fluoro-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one in 100 ml of dimethylformamide and the mixture is stirred at room temperature for 2 hours. Subsequently, the mixture is poured into 500 ml of water and extracted several times with chloroform. The combined chloroform extracts are washed with water, dried over magnesium sulphate and evaporated. After recrystallization of the residue from ethyl acetate, there is obtained 3-bromo-8-fluoro-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 200°.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:20]=[C:19]2[C:14]([CH2:15][NH:16][C:17](=O)[NH:18]2)=[CH:13][C:12]=1[O:22][CH3:23])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:24]([O:30][CH2:31]Cl)(=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26].Cl.CN(C=[O:38])C>C(OCC)(=O)C.O>[CH2:3]([O:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15](=[O:38])[N:16]([CH2:31][O:30][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[CH:17]=[N:18]2)=[CH:13][C:12]=1[O:22][CH3:23])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COc1cc2c(cc1OCc1ccccc1)NC(=O)NC2
Reactant: CN(C)C=O
Reactant: CC(C)(C)C(=O)OCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCc1ccccc1
Reaction time: 1.5 h

Procedure:
Sodium hydride (60% dispersion in mineral oil, 1.44 g) was added portionwise during 20 minutes to a solution of 7-benzyloxy-6-methoxy-3,4-dihydroquinazolinone (8.46 g) in DMF (70 ml) and the mixture was stirred for 1.5 hours. Chloromethyl pivalate (5.65 g) was added dropwise and the mixture was stirred at ambient temperature for 2 hours. The mixture was diluted with ethyl acetate (100 ml) and poured onto a mixture of ice and water (400 ml) containing 2N aqueous hydrochloric acid (4 ml). The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic extract was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulphate and evaporated. The residue was triturated under a mixture of petroleum ether (b.p. 60-80° C.) and diethyl ether. The solid so obtained was isolated and dried under vacuum to give 7-benzyloxy-6-methoxy-3-pivaloyloxymethyl-3,4dihydroquinazolin-4-one (10 g); NMR Spectrum: (DMSOd6) 1.11 (s, 9H), 3.89 (s, 3H), 5.3 (s, 2H), 5.9 (s, 2H), 7.27 (s, 1H), 7.35 (m, 1H), 7.47 (t, 2H), 7.49 (d, 2H), 7.51 (s, 1H), 8.34 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([CH2:10]/[CH:11]=[C:12](/[CH2:14][CH2:15][C:16]([OH:18])=[O:17])\[CH3:13])[C:5]([OH:19])=[C:4]2[C:20]([O:22][CH2:23][C:3]=12)=[O:21].O.O.[Sn](Cl)Cl.C(OCC(C)C)(=O)C.O[CH2:38][CH2:39][N:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1>>[CH3:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([CH2:10]/[CH:11]=[C:12](/[CH2:14][CH2:15][C:16]([O:18][CH2:38][CH2:39][N:40]2[CH2:45][CH2:44][O:43][CH2:42][CH2:41]2)=[O:17])\[CH3:13])[C:5]([OH:19])=[C:4]2[C:20]([O:22][CH2:23][C:3]=12)=[O:21]
Reactant: COc1c(C)c2c(c(O)c1C/C=C(\C)CCC(=O)O)C(=O)OC2
Reactant: OCCN1CCOCC1
Agent: Cl[Sn]Cl
Solvent: CC(=O)OCC(C)C
Solvent: O
Product: COc1c(C)c2c(c(O)c1C/C=C(\C)CCC(=O)OCCN1CCOCC1)C(=O)OC2
Temperature: 25 °C
Reaction time: 11 h

Procedure:
A mixture of mycophenolic acid (192 g, 0.6 mol) and 4-(2-hydroxyethyl)-morpholine (440 ml, 6 molar equivalents) was stirred at 150-155° C. for 4 hours in the presence of tin(II) chloride dihydrate (20.4 g, 0.15 molar equivalents) under nitrogen atmosphere. After the completion of the reaction, the reaction mixture was allowed to cool to room temperature. The obtained dark liquid was poured into isobutyl acetate (4.0 l). The solution was extracted with 2% of aqueous sodium bicarbonate solution (1.2 l, then 2×0.4 l). After the first addition of sodium bicarbonate solution the formed two-phase system was treated with charcoal (40 g) and filtrated (an emulsion was filtered off). The solution was extracted with water (1 l). -After phase separation the organic phase was washed with water (1 l) and evaporated to dryness at 40-50° C. under vacuum. To the solid material acetone (400 ml) and isopropanol (3.8 l) were added and the mixture was warmed to 40-45° C. (the material was dissolved). The solution was cooled to −5° C. during 6 hours and it was stirred at this temperature for 10-12 hours. After filtration, the crystals were washed with 2:19 acetone/isopropanol mixture (420 ml). The crude compound was dried in vacuum at 60° C. The yield was 169-195 g (65-75%). HPLC impurity profile: MPA=0.1%. Assay: 99.85%.
Reaction SMILES: [C:1]([C:4]1[S:5][C:6]2[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=2[C:8]=1[CH3:9])(=[O:3])[CH3:2].[Se](=O)=[O:15]>O1CCOCC1.O>[CH3:9][C:8]1[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[S:5][C:4]=1[C:1](=[O:3])[CH:2]=[O:15]
Reactant: O=[Se]=O
Reactant: CC(=O)c1sc2ccccc2c1C
Solvent: O
Solvent: C1COCCO1
Product: Cc1c(C(=O)C=O)sc2ccccc12

Procedure:
A 52.9 g portion of 2-acetyl-3-methylbenzothiophene was added to a solution of 36.9 g of selenium dioxide in 95 ml of dioxane and 13 ml of water at 55°-60° C. The mixture was refluxed overnight, filtered, washed with dioxane and evaporated. The residue was purified by flash column chromatography, eluting with hexane:ethyl acetate (8:2), giving 5.1 g of 3-methyl-a-oxobenzo[b]thiophene-2-acetaldehyde.
Reaction SMILES: [C:1]1([C:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][NH2:15])[N:10]=[CH:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.Cl[CH2:38][C:39]([NH:41][C:42]1[C:51]2[C:46](=[CH:47][CH:48]=[C:49]([O:52][S:53]([CH3:56])(=[O:55])=[O:54])[CH:50]=2)[CH:45]=[CH:44][CH:43]=1)=[O:40]>C(#N)C>[CH3:56][S:53]([O:52][C:49]1[CH:50]=[C:51]2[C:46]([CH:45]=[CH:44][CH:43]=[C:42]2[NH:41][C:39](=[O:40])[CH2:38][NH:15][CH2:14][CH2:13][C:11]2[N:10]=[CH:9][N:8]([C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:12]=2)=[CH:47][CH:48]=1)(=[O:55])=[O:54]
Reactant: CS(=O)(=O)Oc1ccc2cccc(NC(=O)CCl)c2c1
Reactant: NCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)Oc1ccc2cccc(NC(=O)CNCCc3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the product from Step B (25.6 g, 72.7 mmol) in 200 mL of acetonitrile was added diisopropylethylamine (50 mL, 303 mmol), followed by the product from Step D (19.0 g, 60.5 mmol). The reaction was stirred at room temperature overnight, then concentrated in vacuo. The resulting material was partitioned between EtOAc and water, washed with brine, dried (MgSO4), filtered, and concentrated in vacuo to provide the titled product.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#N.[CH2:10]([Mg]Br)[CH3:11].Cl.[O:15]1CCCC1>>[NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4](=[O:15])[CH2:10][CH3:11]
Reactant: C1CCOC1
Reactant: N#Cc1ccccc1N
Reactant: CC[Mg]Br
Agent: Cl
Product: CCC(=O)c1ccccc1N
Reaction time: 4 h
Yield: 56 %

Procedure:
2-Aminobenzonitrile (1 mmol) was disposed in anhydrous tetrahydrofuran (5 ml) is followed by adding ethylmagnesium bromide (10 equivalent weights) at 0° C. under nitrogen gas atmosphere and reacting for 4 hours to obtain a reaction product. The pH of the reaction product was adjusted to be in the range of 3 to 4 using 1N HCl, followed by partitioning using ethyl acetate and saturated NaHCO3 for three times. The ethyl acetate layer was collected and purified using a silica gel column (n-hexane/acetone=4:1), thereby obtaining [1-(2-aminophenyl)propan-1-one] (83.5 mg, yield 56%).