Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClCCl.[OH:4][C@H:5]([CH2:18][NH:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][C:27]2=[O:32])=[CH:22][CH:21]=1)[CH2:6][N:7]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]1=[O:17].[C:33](=O)([O-])[O-:34].[K+].[K+]>O1CCCC1>[O:34]=[C:33]1[N:19]([C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][C:27]3=[O:32])=[CH:22][CH:21]=2)[CH2:18][C@H:5]([CH2:6][N:7]2[C:15](=[O:16])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]2=[O:17])[O:4]1
Reactant: O=C([O-])[O-]
Reactant: O=C1c2ccccc2C(=O)N1C[C@H](O)CNc1ccc(N2CCOCC2=O)cc1
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1C[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1
Temperature: 27.5 °C
Reaction time: 5 h
Yield: 90 %

Procedure:
In a four neck round bottom flask, charged dichloromethane (150 ml), 2-((2R)-2-Hydroxy-3-{[4-(3-oxo-4-morpholinyl)phenyl]amino}propyl)-1H-isoindole-1,3(2H)-dione (15 g), N,N′-dicarbonyldiimidazole (9.22 g), and powdered potassium carbonate (5.24 g) at 25 to 30° C. The obtained reaction mass then stirred for 5 h at 25 to 30° C. Reaction mass then filtered and obtained solid is washed the by dichloromethane. Separated filtrate is concentrated under reduced pressure to obtain residue. Added tetrahydrofuran (30 ml) to residue. The obtained mixture is heated to 40 to 45° C. for 30 minutes followed by cooling to room temperature. Finally obtained solid is filtered off and washed by tetrahydrofuran. Yield 90%
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=2[F:16])=[C:6]([CH3:17])[C:5](=[O:18])[N:4]2[CH2:19][CH2:20][O:21][C:3]=12.[CH2:22]([O:29][CH2:30][CH:31]([CH:41]1[CH2:44][CH:43]([S:45](Cl)(=[O:47])=[O:46])[CH2:42]1)[CH2:32][O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>N1C=CC=CC=1>[CH2:34]([O:33][CH2:32][CH:31]([CH:41]1[CH2:42][CH:43]([S:45]([NH:1][C:2]2[C:7]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=3[F:16])=[C:6]([CH3:17])[C:5](=[O:18])[N:4]3[CH2:19][CH2:20][O:21][C:3]=23)(=[O:47])=[O:46])[CH2:44]1)[CH2:30][O:29][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: Cc1c(Nc2ccc(I)cc2F)c(N)c2n(c1=O)CCO2
Reactant: O=S(=O)(Cl)C1CC(C(COCc2ccccc2)COCc2ccccc2)C1
Solvent: c1ccncc1
Product: Cc1c(Nc2ccc(I)cc2F)c(NS(=O)(=O)C2CC(C(COCc3ccccc3)COCc3ccccc3)C2)c2n(c1=O)CCO2
Yield: 71.9 %

Procedure:
Using the same reaction conditions and procedure as described for the preparation of Example 7A, 8-Amino-7-(2-fluoro-4-iodo-phenylamino)-6-methyl-2,3-dihydro-oxazolo[3,2-a]pyridin-5-one (I-7f: 0.22 g, 0.539 mmol) was reacted with 3-(1,3-bis(benzyloxy)propan-2-yl)cyclobutane-1-sulfonyl chloride (0.21 g, 0.539 mmol) in dry pyridine (2 mL) to afford the crude product. Purification by column chromatography on silica gel (80% ethyl acetate in hexane) afforded 0.3 g of the product (71% yield). LCMS: 80%, m/z=773 (M+1)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[SH:9].Br[CH2:11][C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=1)[C:15]([O:17][CH3:18])=[O:16].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9][CH2:11][C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=1)[C:15]([O:17][CH3:18])=[O:16]
Reactant: Nc1cc(Cl)ccc1S
Reactant: COC(=O)c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(CSc2ccc(Cl)cc2N)c1
Yield: 41.7 %

Procedure:
Following General Procedure A, the title compound (1.4 g, 42%) was prepared from 2-amino-4-chlorobenzenethiol (1.7 g, 10.90 mmol), methyl 3-(bromomethyl)benzoate (2.5 g, 10.90 mmol) and K2CO3 (7.5 g, 54.50 mmol) in DMF (30 ml).
Reaction SMILES: [F:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:4]([C:17]#[C:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH:3]=1.[NH4+].[Cl-]>CO.C1COCC1.[Zn]>[NH2:8][C:7]1[C:2]([F:1])=[CH:3][C:4]([C:17]#[C:18][Si:19]([CH3:20])([CH3:21])[CH3:22])=[C:5]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:6]=1
Reactant: CCOC(=O)Cc1cc([N+](=O)[O-])c(F)cc1C#C[Si](C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)Cc1cc(N)c(F)cc1C#C[Si](C)(C)C
Reaction time: 1.5 h
Yield: 90.2 %

Procedure:
To a stirring suspension of ethyl 2-(4-fluoro-5-nitro-2-(2-(trimethylsilyl)ethynyl)phenyl)acetate (0.66 g, 2.04 mmol) in MeOH/THF (1:1, 20 mL) was added NH4Cl (1.09 g, 20.4 mmol), followed by Zn dust (1.33 g, 20.4 mmol). After stirring 1.5 h, the mixture was filtered through C elite, and rinsed forward with MeOH. The combined filtrates were concentrated, diluted with brine and extracted with THF (2×). The combined organic layers were washed with brine (1×), dried (MgSO4), filtered and concentrated to afford ethyl 2-(5-amino-4-fluoro-2-(2-(trimethylsilyl)ethynyl)phenyl)acetate (0.54 g, 90% yield). 1H NMR (400 MHz, DMSO-d6): δ 6.86 (d, J=12.0 Hz, 1H), 6.47 (d, J=8.8 Hz, 1H), 5.47 (brs, 2H), 3.88 (d, J= 6.8 Hz, 2H), 3.43 (s, 2H), 1.00 (d, J=6.8 Hz, 3H), 0.00 (s, 9H); MS (ESI) m/z: 294.0 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH:12]=[O:13])[CH:6]=[CH:5]2.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1.[CH:31]([O:33][CH2:34][CH3:35])=[CH2:32]>C(OCC)=C.C(OCC)(=O)C>[CH2:31]([O:33][CH:34]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH:12]=[O:13])[CH:6]=[CH:5]2)[CH3:35])[CH3:32]
Reactant: C=COCC
Reactant: O=Cc1ccc2cc(O)ccc2c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Product: CCOC(C)Oc1ccc2cc(C=O)ccc2c1
Temperature: 25 °C
Yield: 73 %

Procedure:
In a 500 mL three neck flask, equipped with a magnetic stirrer, an addition funnel, and a reflux condenser, were charged 25 g of HNAL (0.1462 mol) and 300 mL of ethyl acetate. 6-Hydroxy-2-naphthaldeyde was not completely soluble even after 3 h stirring at room temperature. To this was added 3.30 g of PPTS (0.0131 mol) and the solution mixture was heated to 70° C. At this temperature, 21 g of ethyl vinyl ether (0.2912 mol) was added dropwise and the reaction mixture became homogeneous upon addition of a few drops of ethyl vinyl ether. After completion of ethyl vinyl ether addition, the reaction temperature was lowered to room temperature and the reaction mixture was stirred overnight. The crude product was purified by column chromatography (silica gel, CH2Cl2) to yield 26 g of pure 6-(1-ethoxy ethoxy)-2-naphthaldehyde (yield: 73%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][C:7](=[O:13])[NH:8]2.[O:14]=[C:15]1[C:20]2=[CH:21][NH:22][C:23]([CH:24]=O)=[C:19]2[CH2:18][CH2:17][O:16]1>>[OH:1][CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[CH:24][C:23]1[NH:22][CH:21]=[C:20]3[C:15](=[O:14])[O:16][CH2:17][CH2:18][C:19]=13)[C:7](=[O:13])[NH:8]2
Reactant: O=C1Cc2c(CCO)cccc2N1
Reactant: O=Cc1[nH]cc2c1CCOC2=O
Product: O=C1Nc2cccc(CCO)c2C1=Cc1[nH]cc2c1CCOC2=O
Yield: 424.3 %

Procedure:
4-(2-Hydroxy-ethyl)-1,3-dihydro-indol-2-one (0.1 g, 0.6 mmol) was condensed with 4-oxo-2,4,6,7-tetrahydro-pyrano[3,4-c]pyrrole-1-carbaldehyde (1.2 eq, 0.06 g) to give 0.5 g (28%) of the title compound as a yellow solid.
Reaction SMILES: [C:1]1([N:7]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([OH:21])(=[O:20])=[O:19])=[CH:15][CH:16]=3)[C:10](=O)[C:8]2=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:22].[K+]>>[S:18]([C:14]1[CH:15]=[CH:16][C:17]2[C:12](=[C:10]([C:8]([OH:22])=[O:9])[C:6]3[C:1]([N:7]=2)=[CH:2][CH:3]=[CH:4][CH:5]=3)[CH:13]=1)([OH:21])(=[O:20])=[O:19]
Reactant: O=C1C(=O)N(c2ccccc2)c2ccc(S(=O)(=O)O)cc21
Reactant: [OH-]
Agent: [K+]
Product: O=C(O)c1c2ccccc2nc2ccc(S(=O)(=O)O)cc12

Procedure:
The title compound can be prepared from N-phenyl isatin 5 sulfonic acid of example 11 and 10% KOH by heating for hours on a steam bath. The solution is filtered, then acidified to pH 1 and product is collected by filtration.
Reaction SMILES: [CH3:1][C:2]1([C:8]([O:10]CC2C=CC=CC=2)=[O:9])[CH2:7][C:4]2([CH2:6][CH2:5]2)[CH2:3]1.[OH-].[Na+]>C1COCC1.O>[CH3:1][C:2]1([C:8]([OH:10])=[O:9])[CH2:7][C:4]2([CH2:6][CH2:5]2)[CH2:3]1
Reactant: CC1(C(=O)OCc2ccccc2)CC2(CC2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C(=O)O)CC2(CC2)C1
Temperature: 50 °C
Reaction time: 12 h
Yield: 98.6 %

Procedure:
To a stirred solution of Intermediate 317A (200 mg, 0.868 mmol) in THF (2 mL) and water (1 mL) was added NaOH (104 mg, 2.61 mmol) at RT and the reaction mixture was warmed to 50° C. and stirred for 12 h. The reaction mixture was concentrated under a reduced pressure, the residue was to pH 2 with a 1.5 N aq. solution of HCl and extracted with Et2O (3×15 mL) The combined organic layer was dried over Na2SO4, filtered and the filtrate concentrated to afford Intermediate 317B as a colorless liquid (0.12 g, 99%). 1H NMR (300 MHz, DMSO-d6) δ ppm 12.38-11.71 (m, 1H), 2.68-2.50 (m, 2H), 1.86-1.66 (m, 2H), 1.43 (s, 3H), 0.62-0.19 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][OH:10])=[CH:5][CH:4]=1.[H-].[Na+].[Br:13][C:14]1[CH:15]=[C:16]([O:21][CH2:22][CH3:23])[C:17](Cl)=[N:18][CH:19]=1>CN(C=O)C>[Br:13][C:14]1[CH:15]=[C:16]([O:21][CH2:22][CH3:23])[C:17]([O:10][CH2:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[N:18][CH:19]=1
Reactant: COc1ccc(CO)cc1
Reactant: CCOc1cc(Br)cnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1cc(Br)cnc1OCc1ccc(OC)cc1
Reaction time: 0.5 h
Yield: 67.7 %

Procedure:
To a mixture of (4-methoxyphenyl)methanol (16.71 g, 121 mmol) in DMF (200 mL) was added NaH (3.96 g, 165 mmol) at 0° C. After the mixture was stirred for 30 min, 5-bromo-2-chloro-3-ethoxypyridine (26 g, 110 mmol) was added to above mixture; the mixture was stirred for 12 h at 80-90° C. The mixture was quenched by H2O (20 mL), extracted with DCM (2×200 mL), dried over Na2SO4 and concentrated to give the residue which was purified by via column chromatography (10% EA/90% PE, 360 g silica column). All fractions found to contain product by TLC (EA/PE=5:1, Rf=0.5) were combined and concentrated to yield a white solid of 5-bromo-3-ethoxy-2-((4-methoxybenzyl)oxy)pyridine (36 g, 74.5 mmol, 67.8% yield): 1H NMR (400 MHz, CD3OD) δ 7.71 (d, J=2.0 Hz, 1H), 7.36-7.31 (m, 3H), 6.89-6.87 (m, 2H), 5.27 (s, 2H), 4.05-4.00 (m, 2H) 3.77 (s, 3H), 2.37 (d, J=7.0 Hz, 3H); ES-LCMS m/z 338 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][CH2:16][CH2:17][CH2:18][OH:19])[C:10]=2[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[N:40]1[C:44](=[O:45])[C:43]2=[CH:46][CH:47]=[CH:48][CH:49]=[C:42]2[C:41]1=[O:50].N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[NH2:1][C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][N:40]3[C:44](=[O:45])[C:43]4[C:42](=[CH:49][CH:48]=[CH:47][CH:46]=4)[C:41]3=[O:50])[C:10]=2[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: Nc1nc2c(c3c1ncn3CCCCO)CCCC2
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Nc1nc2c(c3c1ncn3CCCCON1C(=O)c3ccccc3C1=O)CCCC2
Temperature: 25 °C
Reaction time: 5 h
Yield: 38.9 %

Procedure:
A cloudy solution of 4-(4-amino-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl)butan-1-ol (1.0 g, 3.8 mmol), triphenylphosphine (1.49 g, 5.7 mmol) and N-hydroxyphthalimide (0.93 g, 5.7 mmol) in tetrahydrofuran (50 mL) was cooled to approximately 0° C.; then diisopropyl azodicarboxylate (1.33 mL, 6.8 mmol) was added dropwise. The reaction was allowed to warm to ambient temperature and was stirred for 5 hours. The solvent was removed under reduced pressure, and the resulting solid was purified by chromatography on silica gel (gradient elution with 0-10% methanol in dichloromethane with a small amount of concentrated ammonium hydroxide added) to provide 600 mg of 2-[4-(4amino-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl)butoxy]-1H-isoindole-1,3(2H)-dione as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]([NH2:11])[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[N:10](/[N:11]=[CH:12]/[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=Cc1ccccc1
Reactant: Nn1ccc2ncc(Br)cc21
Product: Brc1cnc2ccn(/N=C/c3ccccc3)c2c1
Temperature: 60 °C
Yield: 45.6 %

Procedure:
A mixture of 6-bromo-1H-pyrrolo[3,2-b]pyridin-1-amine (200 mg, 0.95 mmol) and benzaldehyde (120 mg, 1.2 eq) was heated to 60° C. for 10 min. Heptanes (2.0 ml) was added and the mixture was heated to reflux for 10 min. The product was purified by column chromatography (heptane:EtOAc=1:1) to yield a grey solid (130 mg, yield 46%).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([NH:15][C:16]([NH2:18])=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].CO[CH:21]=[C:22]([CH3:27])[C:23]([O:25][CH3:26])=[O:24].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([NH:15][C:16]([NH:18][CH:21]=[C:22]([C:23]([O:25][CH3:26])=[O:24])[CH3:27])=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: CC(C)OC(=O)c1cc(NC(N)=O)c(F)cc1Cl
Reactant: COC=C(C)C(=O)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: COC(=O)C(C)=CNC(=O)Nc1cc(C(=O)OC(C)C)c(Cl)cc1F

Procedure:
27.4 g of isopropyl 2-chloro-4-fluoro-5-ureidobenzoate and 13.0 g of methyl 3-methoxy-2-methyl-acrylate are heated under reflux for 2 hours in 250 ml of benzene with 1.9 g of toluene-4-sulphonic acid monohydrate. The reaction mixture is evaporated to dryness under reduced pressure and the residue is stirred with 400 ml of diethyl ether. The insoluble material is filtered off under suction and the filtrate is evaporated to dryness under reduced pressure. The residue is purified by chromatography on 1 kg of silica gel using ethyl acetate/n-hexane (1:3) as the eluent. There is obtained isopropyl 2-chloro-4-fluoro-5-{3-[2-(methoxycarbonyl)propenyl]ureido}-benzoate, m.p. 189°-190° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH2:10])=[O:9])=[N:6][CH:7]=1.CO[CH:13](OC)[N:14]([CH3:16])[CH3:15]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](/[N:10]=[CH:13]/[N:14]([CH3:16])[CH3:15])=[O:9])=[N:6][CH:7]=1
Reactant: COC(OC)N(C)C
Reactant: NC(=O)c1ccc(Br)cn1
Product: CN(C)/C=N/C(=O)c1ccc(Br)cn1
Yield: 95 %

Procedure:
A solution of 5-bromopicolinamide (0.500 g, 2.49 mmol) and dimethylformamide dimethylacetal (20 mL), were heated to 85° C. for 3 h. The reaction was concentrated and the product was used directly in the next step (0.604 g, 95% yield). MS (ESI) m/z 257.1 [M+1]+.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([C:7](Cl)=[O:8])=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:15]1([S:21]([N:24]2[CH:28]=[CH:27][CH:26]=[CH:25]2)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)CCl>[C:15]1([S:21]([N:24]2[CH:25]=[CH:26][C:27]([C:7]([C:4]3[CH:5]=[CH:6][C:1]([CH3:10])=[CH:2][CH:3]=3)=[O:8])=[CH:28]2)(=[O:23])=[O:22])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: O=S(=O)(c1ccccc1)n1cccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: Cc1ccc(C(=O)c2ccn(S(=O)(=O)c3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 105.3 %

Procedure:
A solution of p-toluoyl chloride (4.91 g, 31.8 mmol) in ethylene dichloride (5 ml) was added to a suspension of aluminum chloride (4.62 g, 34.7 mmol) in ethylene dichloride (5 ml) in a 10 minutes period under an atmosphere of nitrogen. After 30 minutes thereto was added a solution of 1-benzenesulfonyl-1H-pyrrole (6.00 g, 28.9 mmol) in ethylene dichloride in a 10 minutes period and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into ice-water and the aqueous layer was extracted with dicloromethane twice. The organic layers were combined, dried and filtered. The filtrate was concentrated and the residue was purified with silica gel chromatography to give the subject compound (9.9 g, 100%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:7])[CH:4]([OH:6])[CH3:5].C(N(CC)CC)C.Cl.CN(C)C.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>CC#N>[CH3:30][C:20]1[CH:25]=[CH:24][C:23]([S:26]([O:6][C@H:4]([CH3:5])[C:3]([O:2][CH3:1])=[O:7])(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: COC(=O)C(C)O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)C
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](C)OS(=O)(=O)c1ccc(C)cc1
Temperature: 5 °C

Procedure:
2-Hydroxy-propanoic acid methyl ester (6.66 g) was dissolved in MeCN (34 mL) and the solution cooled to 5° C. Triethylamine (9.8 mL) was added followed by trimethylamine hydrochloride (0.62 g). A solution of p-toluenesulfonyl chloride (11.6 g) in MeCN (34 mL) (sonicated to complete dissolution) was added over 20 min maintaining the temperature of the reaction below 5° C. The reaction was filtered through Celite and washed through with further MeCN. The filtrate was concentrated almost to dryness (bath 30° C.) and partitioned between diethyl ether and water. The organic layer was separated, dried (MgSO4) and the solvents removed to give the sub titled product as a yellow oil that solidified in the freezer (13.71g).
Reaction SMILES: Cl[C:2]1[C:3]2[S:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[C:4]=2[N:5]=[CH:6][N:7]=1.[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CC(O)C>[CH2:15]([NH:22][C:2]1[C:3]2[S:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[C:4]=2[N:5]=[CH:6][N:7]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Clc1ncnc2c1sc1ccccc12
Reactant: NCc1ccccc1
Solvent: CC(C)O
Product: c1ccc(CNc2ncnc3c2sc2ccccc23)cc1
Yield: 68.6 %

Procedure:
4-Chlorobenzothieno[3,2-d]pyrimidine (111 mg, 0.5 mmol), (see following experimental) and benzylamine (114 mg, 1.0 mmol) (111 mg, 1.1 mmol) in stirred 2-propanol (2 mL) are heated at reflux under N2 for 26 h. The mixture is allowed to cool, and the precipitate is collected by Buchner filtration, rinsed with 2-propanol and water and dried in an oven to give 4-benzylaminobenzothieno[3,2-d]pyrimidine (100 mg, 68%) as a white powder. 1H NMR (DMSO) δ8.60 (1H, s), 8.51 (1H, t, J=5.9 Hz), 8.31 (1H, ddd, J=0.7, 1.4, 8.0 Hz), 8.17 (1H, ddd, J=0.7, 1.8, 8.1 Hz), 7.68 (1H, ddd, J=1.2, 7.0, 8.1 Hz), 7.59 (1H, ddd, J=1., 7.0, 8.1 Hz), 7.36 (2H, d, J=7.4 Hz), 7.33 (2H, t, J=7.3 Hz), 7.24 (1H, t, J 7.2 Hz), 4.79 (2H, d, J=6.0 Hz).
Reaction SMILES: [F:1][C:2]([C:5]1[N:6]=[C:7]([CH2:10][N:11]2[N:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)[S:8][CH:9]=1)([F:4])[CH3:3].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([C:25]2[O:29][CH:28]=[N:27][C:26]=2[C:30](O)=[O:31])[CH:22]=[CH:23][CH:24]=1>>[F:1][C:2]([C:5]1[N:6]=[C:7]([CH2:10][N:11]2[N:15]=[C:14]([NH:16][C:30]([C:26]3[N:27]=[CH:28][O:29][C:25]=3[C:21]3[CH:22]=[CH:23][CH:24]=[C:19]([O:18][CH3:17])[CH:20]=3)=[O:31])[CH:13]=[N:12]2)[S:8][CH:9]=1)([F:4])[CH3:3]
Reactant: COc1cccc(-c2ocnc2C(=O)O)c1
Reactant: CC(F)(F)c1csc(Cn2ncc(N)n2)n1
Product: COc1cccc(-c2ocnc2C(=O)Nc2cnn(Cc3nc(C(C)(F)F)cs3)n2)c1

Procedure:
Following general procedure Z2, starting from 2-[4-(1,1-difluoro-ethyl)-thiazol-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-(3-methoxy-phenyl)-oxazole-4-carboxylic acid.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[NH2:13][C:14]1[CH:19]=[C:18]([O:20][CH2:21][CH2:22][CH3:23])[CH:17]=[CH:16][C:15]=1[S:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:34])[CH3:33])=[CH:27][CH:26]=1>C(O)C>[CH3:12][C:6]1[N:7]=[C:8]2[C:3]([C:2]([NH:13][C:14]3[CH:19]=[C:18]([O:20][CH2:21][CH2:22][CH3:23])[CH:17]=[CH:16][C:15]=3[S:24][C:25]3[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:34])[CH3:33])=[CH:27][CH:26]=3)=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:5]=1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Reactant: CCCOc1ccc(Sc2ccc(NC(C)=O)cc2)c(N)c1
Solvent: CCO
Product: CCCOc1ccc(Sc2ccc(NC(C)=O)cc2)c(Nc2ccnc3nc(C)ccc23)c1

Procedure:
The product from Example 1d (30 mg, 0.17 mmol) was reacted in ethanol (1 mL) with the product from Example 235a (55 mg, 0.17 mmol) for 18 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid salt (14 mg, 30%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 0.97 (t, J=7.35 Hz, 3 H) 1.59-1.83 (m, 2 H) 2.02 (s, 3 H) 2.75 (s, 3 H) 3.97 (t, J=6.43 Hz, 2 H) 6.31 (d, J=7.35 Hz, 1 H) 7.04-7.18 (m, 4 H) 7.25-7.45 (m, J=8.64, 3.86 Hz, 3 H) 7.77 (d, J=8.46 Hz, 1 H) 8.35 (d, J=7.35 Hz, 1 H) 8.94 (d, J=8.82 Hz, 1 H) 9.96 (s, 1 H) 10.99 (s, 1 H) 14.31 (s, 1 H); MS (ESI+) m/z 459 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]([CH2:8][P:9](=[O:12])([OH:11])[OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:15]([C:19]([CH2:24][CH3:25])([CH2:22]O)[CH2:20]O)[CH2:16][CH2:17][CH3:18]>>[CH2:15]([C:19]1([CH2:24][CH3:25])[CH2:22][O:11][P:9](=[O:10])([CH2:8][C:7]2[CH:13]=[CH:14][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[O:12][CH2:20]1)[CH2:16][CH2:17][CH3:18]
Reactant: O=[N+]([O-])c1ccc(CP(=O)(O)O)cc1
Reactant: CCCCC(CC)(CO)CO
Product: CCCCC1(CC)COP(=O)(Cc2ccc([N+](=O)[O-])cc2)OC1

Procedure:
With 4-nitrobenzylphosphonic acid and 2-butyl-2-ethyl-1,3-propanediol, the same procedure as in Reference Example 11 was followed, to yield 5-butyl-5-ethyl-2-(4-nitrobenzyl)-1,3,2-dioxaphosphorinane-2-oxide, which was then recrystallized from ethanol-hexane to yield colorless prisms having a melting point of 111° to 112° C.
Reaction SMILES: [CH2:1]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23]C)=[CH:19][CH:18]=3)[CH:15]=2)[N:10]([CH3:25])[C:9]=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[CH2:1]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[CH:15]=2)[N:10]([CH3:25])[C:9]=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(-c2ccc3c(c2)c(Cc2ccccc2)c(-c2ccccc2)n3C)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cn1c(-c2ccccc2)c(Cc2ccccc2)c2cc(-c3ccc(O)cc3)ccc21

Procedure:
The desired product was prepared using a procedure similar to step 4 of example 3. Thus, 3-benzyl-5-(4-methoxy-phenyl)-1-methyl-2-phenyl-1H-indole (0.757 g, 1.876 mmol) was reacted with BBr3 (2.3 ml of a 1M solution in CH2Cl2) to give the product (0.371 g, 0.953 mmol, 51%) as a solid, mp 133-135° C. 1H NMR (DMSO-d6) δ 3.61 (s, 3H), 4.03 (s, 2H), 6.80 (d, J=8.6 Hz, 2H), 7.07-7.10 (m, 3H), 7.18 (t, J=7.9 Hz, 2H), 7.38-7.39 (m, 3H), 7.44-7.55 (m, 7H), 9.36 (s, 1H); IR (solid) 3290, 3020, 1605, 1520, 1480, 1430, 1370, and 1230 cm−1; [ESI(+)], m/z 390 (M+H)+; Anal. Calcd. for C28H23NO-0.25H2O: C, 85.36; H, 6.01; N, 3.55; Found: C, 85.52, H, 5.94; N, 3.32.
Reaction SMILES: [F:1][C:2]([F:10])=[CH:3][CH:4]1[CH2:8][NH:7][C:6](=[O:9])[CH2:5]1.[BrH:11]>O>[Br:11][C:2]([F:10])([F:1])[CH2:3][CH:4]1[CH2:8][NH:7][C:6](=[O:9])[CH2:5]1
Reactant: O=C1CC(C=C(F)F)CN1
Reactant: Br
Solvent: O
Product: O=C1CC(CC(F)(F)Br)CN1
Temperature: 25 °C
Yield: 49 %

Procedure:
In a 50 ml three necked flask fitted with a magnetic stirrer, under inert atmosphere, 0.1 g of 4-(2,2-difluoro-vinyl)-pyrrolidin-2-one a5 (0.6 mmol) is heated in HBr (62% w/w in H2O, 10 ml) for 0.75 h at reflux. The reaction mixture is cooled down to room temperature, diluted with water and extracted with CH2Cl2 (3 times), dried over MgSO4, filtered and concentrated in vacuo to afford 0.076 g of 4-(2-bromo-2,2-difluoro-ethyl)-pyrrolidin-2-one a6 (49%).