Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[N:6][CH:5]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[Cl:21])[C:4]=1[C:22]([O:24][CH3:25])=[O:23].[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][C@@H:27]1[CH2:32][OH:33]>>[Cl:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[CH:5]1[C:4]([C:22]([O:24][CH3:25])=[O:23])=[C:3]([CH2:2][N:26]2[CH2:31][CH2:30][O:29][CH2:28][C@@H:27]2[CH2:32][OH:33])[NH:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[N:6]1
Reactant: OC[C@H]1COCCN1
Reactant: COC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Cl
Product: COC(=O)C1=C(CN2CCOC[C@@H]2CO)NC(c2nccs2)=NC1c1ccc(F)cc1Cl
Yield: 39.5 %

Procedure:
Methyl 6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.89 g, 2 mmol) was reacted with (S)-morpholin-3-ylmethanol (0.24 g, 2 mmol) according to the procedure as described in Example 25, Step B to give the title compound as a pale yellow solid (0.38 g, 39%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: C[O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.C([O-])([O-])=O.[K+].[K+].[CH3:19][C:20]1([O:23][CH2:22]1)[CH3:21]>CN(C=O)C>[OH:23][C:20]([CH3:22])([CH3:21])[CH2:19][O:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][C:3]([OH:2])=[O:12])=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1ccc(O)cc1
Reactant: CC1(C)CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(O)COc1ccc(CC(=O)O)cc1
Temperature: 150 °C
Reaction time: 0.5 h
Yield: 69.9 %

Procedure:
Methyl(4-hydroxyphenyl)acetate (500 mg, 3.0 mmol) was dissolved in DMF (3 mL). K2CO3 (829 mg, 6.0 mmol) was added followed by isobutylene oxide (800 μL, 9.0 mmol). The mixture was heated to 150° C. by microwave irradiation for 30 min and concentrated. The residue was dissolved in a 1:1 mixture of methanol and water (20 mL). NaOH (1 g) was added and the mixture was stirred for 30 min. Methanol was removed by rotary evaporation. The aqueous phase was acidified by 4 M HCl and extracted with dichloromethane (2×50 mL). The combined organic phases were extracted with 2 M NaOH (2×50 mL). The combined aqueous phases were subsequently acidified by 4 M HCl and extracted with dichloromethane (2×50 mL). The combined organic phases were dried over Na2SO4, filtered and evaporated to afford [4-(2-hydroxy-2-methylpropoxy)phenyl]acetic acid (106MBT52-D, 470 mg, 70%) as a colourless solid. 1H-NMR (CDCl3): δ 7.19 (m, 2H), 6.88 (m, 2H), 3.78 (s, 2H), 3.57 (s, 2H), 1.34 (s. 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH3:13]C1C=CC(S(O)(=O)=O)=CC=1.[C:24]([O-:27])([O-])=O.[Na+].[Na+]>CC(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:7]([O:27][CH3:24])[O:8][CH3:13])[CH:9]=1
Reactant: O=C([O-])[O-]
Reactant: O=Cc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CC(C)O
Product: COC(OC)c1cc(Cl)ccc1[N+](=O)[O-]
Reaction time: 0.08 h
Yield: 99.7 %

Procedure:
A mixture of 14.7 parts of 5-chloro-2-nitrobenzaldehyde, 13.3 parts of thrimethoxymethane, 0.15 parts of 4-methylbenzenesulfonic acid and 64 parts of 2-propanol was stirred at reflux temperature until completion of the reaction. After cooling, there was added Na2CO3 and stirring was continued for 5 min. The reaction mixture was filtered and the filtrate was evaporated, yielding 18.3 parts (99.7%) of 4-chloro-2-(dimethoxymethyl)-1-nitrobenzene (interm. 8).
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.Br[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1.C([O-])([O-])=O.[Cs+].[Cs+].C1OCCOCCOCCOCCOCCOC1>CC(C)=O.CCCCCC.C(OCC)(=O)C>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][N:2]2[CH2:3][C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:1]2=[O:10])=[CH:14][CH:15]=1
Reactant: O=C1NCc2ccccc21
Reactant: COc1ccc(CBr)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CC(C)=O
Product: COc1ccc(CN2Cc3ccccc3C2=O)cc1
Temperature: 70 °C
Reaction time: 16 h
Yield: 31.6 %

Procedure:
A mixture of 2,3-dihydro-isoindol-1-one (0.133 g, 1 mmol), 1-bromomethyl-4-methoxy-benzene (0.222 g, 1.2 mmol,), Cs2CO3 (0.816 g, 2.5 mmol), and 18-crown-6 (0.026 g, 0.1 mmol) in acetone (5 mL) was stirred at 70° C. for 16 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 2-(4-methoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.080 g, 63%). 1H NMR (300 MHz, CDCl3): δ (ppm) 3.80 (s, 3H), 4.24 (s, 2H), 4.76 (s, 2H), 6.88 (d, 2H), 7.25 (d, 2H), 7.36-7.52 (m, 3H), 7.90 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[C:9]([C:11]([O:13]CC)=[O:12])[NH:8][C:7]=12.[OH-].[K+]>O1CCCC1.CO>[Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[NH:8][C:7]=12
Reactant: CCOC(=O)c1cc2ccnc(Cl)c2[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc2ccnc(Cl)c2[nH]1
Temperature: 25 °C
Reaction time: 15.5 h
Yield: 94.6 %

Procedure:
Ethyl 7-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (0.64 g, 2.85 mmol) was dissolved in tetrahydrofuran (5.7 mL) and methanol (6.8 mL). To the mixture was added 3 N KOH (2.85 mL). After stirring overnight (15.5 h) at room temperature, the reaction mixture was concentrated to dryness. The residue was dissolved in water. This aqueous solution was made acidic (pH 3) using 6 N HCl. The precipitate was collected by filtration. The precipitate was dissolved in methanol and concentrated to dryness to afford 7-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (0.53 g, 2.7=mmol, 94%) as a yellow powder: mp 210-214° C.; 1H NMR (300 MHz, CD3OD) δ7.25 (1H, s), 7.65 (1H, d, J=5.4 Hz), 7.94 (1H, d, J=5.4 Hz); ESI MS m/z 195 [C8H5ClN2O2—H]−; HPLC (Method A) >99% (AUC), tR=12.2 min.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]2[CH2:14][CH:9]1[CH2:10][N:11]2[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]2[CH:27]=[CH:26][N:25]=[C:24](Cl)[N:23]=2)[CH:17]=1)=O)(C)(C)C.[NH2:29][CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([Cl:39])[CH:33]=1>>[Cl:39][C:34]1[CH:33]=[C:32]([CH2:31][CH2:30][NH:29][C:24]2[N:23]=[C:22]([C:18]3[CH:19]=[CH:20][CH:21]=[C:16]([CH2:15][N:11]4[CH2:10][CH:9]5[CH2:14][CH:12]4[CH2:13][NH:8]5)[CH:17]=3)[CH:27]=[CH:26][N:25]=2)[CH:37]=[CH:36][C:35]=1[OH:38]
Reactant: NCCc1ccc(O)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CC2CC1CN2Cc1cccc(-c2ccnc(Cl)n2)c1
Product: Oc1ccc(CCNc2nccc(-c3cccc(CN4CC5CC4CN5)c3)n2)cc1Cl

Procedure:
Intermediate 143 was coupled with 4-(2-amino-ethyl)-2-chloro-phenol following procedure F. The resulting product was deprotected following procedure G2. LC-MS showed the product had the expected M+H+ of 436. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.38 (s, 1H) 8.26 (d, 2H) 7.87 (d, 1H) 7.72 (m, 1H) 7.48 (d, 1H) 7.20 (s, 1H) 7.00 (d, 1H) 6.79 (d, 1H) 4.62 (s, 2H) 3.92 (d, 2H) 3.74 (d, 2H) 3.61 (t, 2H) 3.24 (t, 2H) 2.88 (t, 2H) 2.76 (d, 1H) 2.37 (d, 1H).
Reaction SMILES: Cl[C:2](=[C:6]([C:9]#[N:10])[C:7]#[N:8])[CH:3]([CH3:5])[CH3:4].Cl.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=1[NH:20][NH2:21].C(N(CC)CC)C>C1COCC1>[NH2:8][C:7]1[N:20]([C:14]2[C:13]([Cl:12])=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:19])[N:21]=[C:2]([CH:3]([CH3:5])[CH3:4])[C:6]=1[C:9]#[N:10]
Reactant: NNc1c(Cl)cccc1Cl
Reactant: CC(C)C(Cl)=C(C#N)C#N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)c1nn(-c2c(Cl)cccc2Cl)c(N)c1C#N
Temperature: 25 °C
Yield: 62.2 %

Procedure:
A solution of (1-chloro-2-methylpropylidene)methane-1,1-dicarbonitrile (9.4 g, 61 mmol) in THF (250 mL) was treated with 2,6-dichlorophenylhydrazine hydrochloride (13.0 g, 61 mmol) followed by triethylamine (12.3 g, 122 mmol). The reaction was then heated to reflux for 18 h. The reaction was then cooled to room temp and partitioned between EtOAc (150 mL) and 1 N NaOH (100 mL). The aqueous layer was extracted with EtOAc (2×150 mL) and the combined organic layers were washed with 10% aq. citric acid (150 mL), sat. aq. NaHCO3 (150 mL), and brine (150 mL). The organic layer was dried (MgSO4), filtered, and evaporated. The crude product was recrystallized from EtOAc/hexane to yield the desired pyrazole (11.2 g, 62%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:43])[NH:4][C@H:5]([C:14](=[O:42])[NH:15][CH2:16][CH2:17][CH2:18][CH2:19][C@H:20]([N:27]([S:32]([C:35]1[CH:40]=[CH:39][C:38]([NH2:41])=[CH:37][CH:36]=1)(=[O:34])=[O:33])[CH2:28][CH:29]([CH3:31])[CH3:30])[CH2:21][O:22][P:23]([OH:26])([OH:25])=[O:24])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1Br.C1C(C[C@H](N)C(O)=O)=CC=C([Br:56])C=1>>[CH3:1][O:2][C:3](=[O:43])[NH:4][C@H:5]([C:14](=[O:42])[NH:15][CH2:16][CH2:17][CH2:18][CH2:19][C@H:20]([N:27]([S:32]([C:35]1[CH:40]=[CH:39][C:38]([NH2:41])=[CH:37][CH:36]=1)(=[O:33])=[O:34])[CH2:28][CH:29]([CH3:30])[CH3:31])[CH2:21][O:22][P:23]([OH:26])([OH:25])=[O:24])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Br:56])=[CH:9][CH:8]=1
Reactant: N[C@@H](Cc1ccc(Br)cc1)C(=O)O
Reactant: COC(=O)N[C@@H](Cc1ccccc1Br)C(=O)NCCCC[C@@H](COP(=O)(O)O)N(CC(C)C)S(=O)(=O)c1ccc(N)cc1
Product: COC(=O)N[C@@H](Cc1ccc(Br)cc1)C(=O)NCCCC[C@@H](COP(=O)(O)O)N(CC(C)C)S(=O)(=O)c1ccc(N)cc1
Yield: 28 %

Procedure:
This derivative was synthesized using the procedure described for the preparation of (1S,5S)-[1-{5-[(4-amino-benzenesulfonyl)-isobutyl-amino]-6-phosphonooxy-hexylcarbamoyl}-2-(2-bromo-phenyl)-ethyl]-carbamic acid methyl ester (example 4, steps A and B) using L-4-bromophenylalanine (Peptech Corp.) instead of L-2-bromophenylalanine. The desired material was obtained in 28% yield (25 mg)
Reaction SMILES: C(OC([NH:8][C@:9]1([C:18]([OH:20])=[O:19])[CH2:11][C@H:10]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O)(C)(C)C.Cl.O1CCOCC1>C(OCC)C>[NH2:8][C@@:9]1([C:18]([OH:20])=[O:19])[CH2:11][C@@H:10]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)N[C@]1(C(=O)O)C[C@H]1c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: N[C@@]1(C(=O)O)C[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.6 %

Procedure:
To commercially available (1R,2S)-1-tert-butoxycarbonylamino-2-phenylcyclopropanecarboxylic acid (130 mg, 0.45 mmol) was added 4N hydrochloric acid—1,4-dioxane solution (2.0 mL, 16 v/w) and the mixture was stirred for 1 hr at room temperature. Diethyl ether (1.0 mL) was added thereto and the mixture was stirred for 5 min, after which the resulting crystals were collected by filtration. The crystals were washed with diethyl ether (1.0 mL) and dried under reduced pressure to give the title compound (81 mg, white powder, yield 84%).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:18]([NH:20][CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[O:19])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:40](Cl)(=[O:42])[CH3:41].C(=O)([O-])O.[Na+]>C1COCC1>[C:40]([N:24]1[CH2:25][CH2:26][CH:21]([NH:20][C:18](=[O:19])[N:17]([CH2:16][CH2:15][CH2:14][N:11]2[CH2:10][CH2:9][CH:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:13][CH2:12]2)[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:22][CH2:23]1)(=[O:42])[CH3:41]
Reactant: CC(=O)Cl
Reactant: O=C(NC1CCNCC1)N(CCCN1CCC(Cc2ccccc2)CC1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)N1CCC(NC(=O)N(CCCN2CCC(Cc3ccccc3)CC2)c2ccccc2)CC1
Reaction time: 1 h
Yield: 69 %

Procedure:
The compound obtained in Example 13 (435 mg, 1.00 mmol), triethylamine (0.335 ml) were dissolved in THF (10 ml), and under ice cooling, to the solution was added acetyl chloride (0.142 ml). The mixture was stirred at the same temperature for 1 hour. To the reaction mixture was added a saturated aqueous solution of sodium hydrogencarbonate (15 ml) under ice cooling, and the mixture was extracted with ethyl acetate (15 ml×3). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate was subjected to column chromatography (silica gel 10 g, ethyl acetate/methanol=1/0 to 9/1 to 4/1), and the desired fraction was concentrated under reduced pressure. To the concentrate was added ethyl acetate and resulting precipitates were collected by filtration. The filtrate was concentrated under reduced pressure. To the concentrate was added diethyl ether, and the resulting precipitates were collected by filtration. The precipitates were washed with diethyl ether, and dried under reduced pressure to give the titled compound (331 mg, 0.69 mmol, Yield 69%) as white crystals.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[Cl:11][C:12]1[CH:13]=[C:14]([C:19](=O)[CH:20]=[C:21](SC)SC)[CH:15]=[CH:16][C:17]=1[Cl:18].O.[NH2:28][NH2:29]>C(O)C>[Cl:11][C:12]1[CH:13]=[C:14]([C:19]2[NH:29][N:28]=[C:21]([N:8]3[CH2:9][CH2:10][C:5]4([O:4][CH2:3][CH2:2][O:1]4)[CH2:6][CH2:7]3)[CH:20]=2)[CH:15]=[CH:16][C:17]=1[Cl:18]
Reactant: NN
Reactant: C1CC2(CCN1)OCCO2
Reactant: CSC(=CC(=O)c1ccc(Cl)c(Cl)c1)SC
Solvent: O
Solvent: CCO
Product: Clc1ccc(-c2cc(N3CCC4(CC3)OCCO4)n[nH]2)cc1Cl
Temperature: 80 °C

Procedure:
1,4-dioxa-8-azaspiro[4.5]decane (2.2 ml) is added to a solution of 1-(3,4-dichlorophenyl)-3,3-bis(methylthio)prop-2-en-1-one (2.0 g) in ethanol (70 ml) and heated to 80° C. over night. Hydrazine-hydrate (1 ml) is added to the reaction mixture and the mixture is stirred over night at 80° C. The solvent is removed under reduced pressure. The crude product is purified using reverse phase HPLC (Varian C18 Microsorb) eluting with a gradient of 10-100% acetonitrile in water containing 0.2% trifluoroacetic acid to give 8-(5-(3,4-dichlorophenyl)-1H-pyrazol-3-yl)-1,4-dioxa-8-azaspiro[4.5]decane (550 mg). m/z(+) 354/356/358 (M+H+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[O:8])=[CH:3][CH:2]=1.C([O-])([O-])[O:10][CH2:11][CH3:12].C(=O)(O)[O-].[Na+].[C:20](OCC)(=O)[CH3:21]>C(O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:20]([O:8][CH:7]([O:10][CH2:11][CH3:12])[C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)[CH3:21]
Reactant: CCOC(C)=O
Reactant: O=Cc1ccncc1
Reactant: CCOC([O-])[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(OCC)c1ccncc1
Yield: 78 %

Procedure:
4-Pyridinecarboxaldehyde (3.00 mL, 31.4 mmol), ethyl orthoformate (15.7 mL, 94.2 mmol) and p-toluenesulfonic acid (229 mg, 1.57 mmol) were dissolved in ethanol (60.0 mL), and the mixture was heated to reflux under a nitrogen atmosphere for 10 hours. The reaction was stopped by addition of a saturated aqueous sodium bicarbonate solution to the reaction mixture, and extraction with ethyl acetate was performed, followed by washing with brine and drying over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1) to give 4-(diethoxymethyl)pyridine (4.41 g, yield: 78%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.C([Li])CCC.[CH3:14][C:15]([S:18]([N:20]=[C:21]1[CH2:24][O:23][CH2:22]1)=[O:19])([CH3:17])[CH3:16]>C1(C)C=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:21]2([NH:20][S:18]([C:15]([CH3:17])([CH3:16])[CH3:14])=[O:19])[CH2:24][O:23][CH2:22]2)=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: CC(C)(C)S(=O)N=C1COC1
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: CC(C)(C)S(=O)NC1(c2ccc(Br)cn2)COC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 31.3 %

Procedure:
To a toluene (20 ml) solution of 2,5-dibromopyridine (1.93 g, 8.16 mmol) that is cooled to −78° C. in an atmosphere of nitrogen is added n-butyllithium (2.5 M in hexanes, 3.6 ml, 8.98 mmol) dropwise via syringe over a period of five minutes. The reaction mixture is stirred at −78° C. for ten minutes more before 2-methyl-N-(oxetan-3-ylidene)propane-2-sulfinamide (1.43 g, 8.16 mmol) is added all at once as a concentrated solution in toluene. The reaction is stirred for 30 minutes at −78° C. and for 20 minutes at 0° C. before it is quenched with saturated aqueous ammonium chloride (5 ml). The volatiles were removed by rotary evaporation at reduced pressure. The residual material is partitioned between water (20 ml) and methylene chloride (50 ml). The aqueous is extracted once more with methylene chloride (30 ml). The combined extracts were concentrated and the residual material is subjected to flash column chromatography using a gradient of acetone in hexanes (20% to 75% over 5 column volumes) to provide N-(3-(5-bromopyridin-2-yl)oxetan-3-yl)-2-methylpropane-2-sulfinamide (850 mg): 1H NMR (400 MHz, CDCl3) 1.32 (s, 9H) 4.91-4.97 (m, 2H) 5.13 (d, 1H) 5.34 (d, 1H) 7.78 (d, 1H) 8.04 (m, 1H) 8.68 (d, 1H); m/z (CI) 333, 335 [m+H]+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([O:9][C:10]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:11]=1[C:12](=[O:15])[CH2:13]Br)[CH3:8].[CH3:21][C:22]1[C:23]([CH3:31])=[N:24][C:25]([SH:30])=[C:26]([CH:29]=1)[C:27]#[N:28]>CN(C=O)C.C(OCC)(=O)C>[CH3:21][C:22]1[CH:29]=[C:26]2[C:27]([NH2:28])=[C:13]([C:12](=[O:15])[C:11]3[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:10]=3[O:9][CH2:7][CH3:8])[S:30][C:25]2=[N:24][C:23]=1[CH3:31]
Reactant: CCOc1ccc(F)cc1C(=O)CBr
Reactant: Cc1cc(C#N)c(S)nc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOc1ccc(F)cc1C(=O)c1sc2nc(C)c(C)cc2c1N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A suspension of potassium carbonate (0.189 g, 1.37 mmol), 2-ethoxy-5-fluorophenacyl bromide (1.02 g, 3.95 mmol) and 5,6-dimethyl-2-mercaptonicotine nitrile (0.50 g, 3.04 mmol) in dry DMF (10 ml) is stirred at room temperature for 16 h. The resulting mixture is diluted with ethyl acetate and washed with water. Drying over sodium sulfate, filtering, evaporating the solvent and purification of the residue by silicagel column chromatography yields the title compound, having a m.p. of 170° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].Cl[C:13]1[C:14]2[C:27]([CH3:28])=[CH:26][S:25][C:15]=2[N:16]=[C:17]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[N:18]=1>>[N:21]1[CH:22]=[CH:23][CH:24]=[C:19]([C:17]2[N:18]=[C:13]([NH:8][CH2:7][C:6]3[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[C:14]3[C:27]([CH3:28])=[CH:26][S:25][C:15]=3[N:16]=2)[CH:20]=1
Reactant: Cc1csc2nc(-c3cccnc3)nc(Cl)c12
Reactant: NCc1cccc([N+](=O)[O-])c1
Product: Cc1csc2nc(-c3cccnc3)nc(NCc3cccc([N+](=O)[O-])c3)c12

Procedure:
With the procedure of Example 1, the reaction of 3-nitrobenzylamine with 4-chloro-2-(pyridin-3-yl)-5-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-(3-nitrobenzylamino)-5-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [OH2:1].O.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].[C:14]([O:17][C:18](=[O:20])[CH3:19])(=[O:16])[CH3:15].[C:21]([NH:24][C:25]1[CH:35]=[C:34]([Cl:36])[C:33]2[C:37]3C=1CC[C:29]=3[CH:30]=[CH:31][C:32]=2[Cl:38])(=[O:23])[CH3:22].O>C(O)(=O)C>[C:21]([NH:24][C:25]1[CH:35]=[C:34]([Cl:36])[C:33]2[C:37](=[CH:29][CH:30]=[CH:31][C:32]=2[Cl:38])[C:15]=1[C:14]([O:17][C:18]([C:19]1[C:37]2[C:33](=[C:32]([Cl:38])[CH:31]=[CH:30][CH:29]=2)[C:34]([Cl:36])=[CH:35][C:25]=1[NH:24][C:21](=[O:23])[CH3:22])=[O:20])=[O:16])(=[O:1])[CH3:22]
Reactant: O
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)Nc1cc(Cl)c2c(Cl)ccc3c2c1CC3
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)Nc1cc(Cl)c2c(Cl)cccc2c1C(=O)OC(=O)c1c(NC(C)=O)cc(Cl)c2c(Cl)cccc12
Temperature: 25 °C
Yield: 83 %

Procedure:
A suspension of sodium dichromate dihydrate (7.5 g, 25 mmol) in 50 mL of acetic acid was heated to reflux and treated with acetic anhydride (6.6 g, 65 mmol). The reaction was stirred at reflux and treated portionwise with 3-acetylamino-5,6-dichloroacenapthene (1.4 g, 5.0 mmol, from Example E4). The reaction was refluxed for 5 hours, cooled to room temperature and poured into a mixture of ice and water. The resulting precipitate was removed by filtration, washed with water and dried in vacuo to give 1.2 g of the title compound.
Reaction SMILES: [N:1]#[C:2]Br.[N:4]#[C:5]Br.CC(C)=[O:9].[OH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)([CH3:20])[CH3:19])=[CH:14][CH:13]=1.C(N(CC)CC)C>CC(C)=O.O>[O-:9][C:2]#[N:1].[O-:11][C:5]#[N:4].[OH:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]([C:21]2[CH:22]=[CH:23][C:24]([OH:27])=[CH:25][CH:26]=2)([CH3:20])[CH3:19])=[CH:16][CH:17]=1
Reactant: N#CBr
Reactant: CC(C)=O
Agent: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Solvent: O
Solvent: CCN(CC)CC
Product: N#C[O-]
Reaction time: 0.33 h

Procedure:
A quantity of 222.45 grams (2.10 moles) of cyanogen bromide was added to a reactor containing 350 milliliters of stirred acetone under a nitrogen atmosphere. The cyanogen bromide-acetone solution was cooled to -5° C., then 228.30 grams (1.00 mole) of Bisphenol A dissolved in 700 milliliters of chilled acetone was added to the reactor. The stirred solution was allowed to equilibrate at -5° C., then 203.39 grams (2.01 moles) of triethylamine was added to the reactor over a 25-minute (1500 s) period and so as to maintain the reaction temperature at -5° to 0° C. After completion of the triethylamine addition, the reaction temperature was maintained at -6° to 7° C. for an additional 45 minutes (2700 s), followed by addition of the reaction product to chilled water (1 gallon, 3.78 liters) with agitation. After 20 minutes (1200 s), the water and product mixture was added to a separatory funnel and the resulting slurry of crystals was filtered. The recovered crystalline product was dissolved in methylene chloride (400 milliliters), washed with 5 percent hydrochloric acid (500 milliliters), washed with water (1000 milliliters) and then dried over anhydrous sodium sulfate. The dry methylene chloride solution was filtered and solvent removed by rotary evaporation under vacuum. Bisphenol A dicyanate (245.3 grams) was recovered in 88.1 percent yield as a light tan colored crystalline solid. Infra-red spectrophotometric analysis confirmed the product structure.
Reaction SMILES: Cl.[O:2]1[CH2:6][CH2:5][NH:4][C:3]1=[NH:7].Br[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[F:19])=O.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[F:19][C:13]1[CH:14]=[C:15]([F:18])[CH:16]=[CH:17][C:12]=1[C:10]1[N:7]=[C:3]2[N:4]([CH:9]=1)[CH2:5][CH2:6][O:2]2
Reactant: O=C(CBr)c1ccc(F)cc1F
Reactant: N=C1NCCO1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1ccc(-c2cn3c(n2)OCC3)c(F)c1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 26.7 %

Procedure:
The oxazolidin-2-imine hydrochloride (TCI, 5.00 g, 40.8 mmol) and 2-bromo-1-(2,4-difluorophenyl)ethanone (7.99 g, 34.0 mmol, Example #8, Step A) were dissolved in DMF (34.7 mL) then Na2CO3 (9.01 g, 85.0 mmol) was added. The mixture was stirred for about 15 min and then it was heated to about 80° C. for about 5 h. The mixture was cooled then filtered and the filtrate was concentrated under reduced pressure. The material was purified by flash chromatography on silica gel using DCM/EtOAc (gradient 1:0 to 0:1) to give the title compound (2.02 g, 26%): LC/MS (Table 1, Method g) Rt=1.94 min; MS m/z: 223.1 (M+H)+.