Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1([C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[CH3:17][O:18][CH2:19][C:20]1([C:25]([N:27]2[CH2:36][CH2:35][C:34]3[N:33]=[CH:32][C:31]([C:37]([F:40])([F:39])[F:38])=[CH:30][C:29]=3[CH2:28]2)=[O:26])[CH2:24][CH2:23][NH:22][CH2:21]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.C(OCC)(=O)C>[OH:1][C:2]1([C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)[CH2:7][CH2:6][CH:5]([N:22]2[CH2:23][CH2:24][C:20]([C:25]([N:27]3[CH2:36][CH2:35][C:34]4[N:33]=[CH:32][C:31]([C:37]([F:39])([F:38])[F:40])=[CH:30][C:29]=4[CH2:28]3)=[O:26])([CH2:19][O:18][CH3:17])[CH2:21]2)[CH2:4][CH2:3]1
Reactant: COCC1(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)CCNC1
Reactant: COc1ccc(C2(O)CCC(=O)CC2)cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: COCC1(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)CCN(C2CCC(O)(c3ccc(OC)nc3)CC2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The title compound was prepared according to general procedures described in Scheme 2: A mixture of 4-hydroxy-4-(6-methoxypyridin-3-yl)cyclohexanone (71 mg, 0.32 mmol), (3-(methoxymethyl)pyrrolidin-3-yl)(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)methanone VIc (100 mg, 0.29 mmol) and acetic acid (20 μL, 0.34 mmol) in dichloroethane (3 mL) was stirred at room temperature for 0.5 h. Sodium triacetoxyborohydride (123 mg, 0.576 mmol) was added and the reaction mixture was stirred for 2 h at room temperature. After concentration of solvent under reduced pressure, the resulting residue was dissolved in ethyl acetate, then washed with NaHCO3, water and brine. The organic extract was dried, filtered and concentrated. The crude product was obtained as a mixture of isomers which were further separated by reverse phase preparative HPLC to yield isomer A (eluted at 10.092 min) and isomer B (eluted at 11.269 min).
Reaction SMILES: [Br:1][CH2:2][CH2:3]Br.[OH:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[C:8]([O:14][CH3:15])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Br:1][CH2:2][CH2:3][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[C:8]([O:14][CH3:15])[CH:7]=1
Reactant: COc1cc(O)ccc1C=O
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(OCCBr)ccc1C=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 101.8 %

Procedure:
1,2-Dibromoethane (57 mL, 0.66 moles) was added to a mixture of 4-hydroxy-2-methoxybenzaldehyde (10 g, 66 mmoles) and potassium carbonate (45 g, 0.33 moles) in DMF (130 ml) and the resulting mixture was stirred vigorously at room temperature for 16 hours. The mixture was poured into water (0.8 L) and extracted with ethyl acetate (3×300 mL). The combined organic phases were washed with saturated sodium chloride (400 mL), dried over MgSO4 and evaporated in vacuo to afford 17.4 g (99%) of 4-(2-bromoethoxy)-2-methoxybenzaldehyde, M.p. 78-79° C.
Reaction SMILES: [C:1]([C:3]([CH2:13][CH3:14])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4](Cl)=[O:5])#[N:2].[CH2:15]([NH:18][CH2:19][CH:20]=[CH2:21])[CH:16]=[CH2:17]>ClCCl>[CH2:15]([N:18]([CH2:19][CH:20]=[CH2:21])[C:4](=[O:5])[C:3]([C:1]#[N:2])([CH2:13][CH3:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH:16]=[CH2:17]
Reactant: CCC(C#N)(C(=O)Cl)c1ccccc1
Reactant: C=CCNCC=C
Solvent: ClCCl
Product: C=CCN(CC=C)C(=O)C(C#N)(CC)c1ccccc1
Temperature: 5 °C
Reaction time: 2 h
Yield: 327.6 %

Procedure:
10.5 g (0.05 mole) of 2-cyano-2-ethyl-2-phenylacetyl chloride are dissolved in 50 ml of dichloromethane, the solution is cooled to 5° C., and 9.7 g (0.01 mole) of diallyl amine are added to it under maintaining the temperature of the mixture below 10° C. The reaction mixture is stirred at room temperature for 2 hours, then washed with water, dried over anhydrous magnesium sulfate, and the solvent is removed. 8.79 g (65.5%) of N,N-diallyl-2-cyano-2-ethyl-2-phenylacetic acid amide are obtained; m.p.: 33°-35° C.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[C:5]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:6]([O:16][C:17]2[CH:22]=[CH:21][C:20](/[CH:23]=[CH:24]/[C:25]([OH:27])=[O:26])=[CH:19][CH:18]=2)[C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([O:14]C)=[CH:9][CH:8]=2)[CH3:3].B(Br)(Br)Br>C(Cl)Cl>[OH:14][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[C:6]([O:16][C:17]1[CH:18]=[CH:19][C:20](/[CH:23]=[CH:24]/[C:25]([OH:27])=[O:26])=[CH:21][CH:22]=1)=[C:5]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:4]([CH:2]([CH3:3])[CH3:1])=[CH:13]2
Reactant: COc1ccc2c(Oc3ccc(/C=C/C(=O)O)cc3)c(-c3ccccc3)c(C(C)C)cc2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)c1cc2cc(O)ccc2c(Oc2ccc(/C=C/C(=O)O)cc2)c1-c1ccccc1
Yield: 70.7 %

Procedure:
The methyl ether (75) (0.15 g, 0.34 mmol) was treated with BBr3 in CH2Cl2 to give the crude product as a yellow viscous oil, which was purified by reverse phase preparation HPLC on Agilent 1100 to afford 102 mg (70%) of the title compound (76) as a light yellow solid. mp 198-199° C. 1H NMR (400 MHz, CH3OH-d4): δ 1.18 (d, J=6.8 Hz, 6H), 2.88 (sept, J=6.8 Hz, 1H), 6.26 (d, J=15.9 Hz, 1H), 6.54 (d, J=8.6 Hz, 2H), 6.96 (dd, J1=9.2 Hz, J2=2.4 Hz, 1H), 7.08-7.15 (m, 2H), 7.17 (d, J=2.2 Hz, 1H), 7.18-7.30 (m, 3H), 7.33 (d, J=8.6 Hz, 2H), 7.52 (d, J=15.9 Hz, 1H), 7.56-7.64 (m, 2H). LCMS (ESI): m/z 425 (M+H)+, m/z 423 (M−H)−. HRMS (EI) Calc for C28H24O4: 425.1753 (M+•). Found: 425.1742.
Reaction SMILES: C[O:2][C:3]1[CH:16]=[CH:15][C:6]2[CH:7]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[S:9][C:5]=2[CH:4]=1.C(Cl)Cl.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:16]=[CH:15][C:6]2[CH:7]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[S:9][C:5]=2[CH:4]=1
Reactant: CCOC(=O)c1cc2ccc(OC)cc2s1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCOC(=O)c1cc2ccc(O)cc2s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 33.6 %

Procedure:
To a solution of ethyl 6-methoxy-1-benzothiophene-2-carboxylate (5.58 g, 23.6 mmol) in methylene chloride (50 mL) was added dropwise 1 M boron tribromide methylene chloride solution (71 mL, 70.8 mmol) at −20° C., and the mixture was stirred at room temperature for 3 hr. The reaction mixture was poured into ice, and the mixture was extracted twice with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane to hexane:ethyl acetate=3:2) to give the title compound (1.76 g, yield 34%) as a white solid.
Reaction SMILES: C(OC(=O)C)(=O)C.[CH3:8][C:9](=[CH:15][CH2:16][CH2:17][CH:18]([CH3:21])[CH:19]=[CH2:20])[CH2:10][CH2:11][CH:12]=[N:13]O>>[CH3:8][C:9](=[CH:15][CH2:16][CH2:17][CH:18]([CH3:21])[CH:19]=[CH2:20])[CH2:10][CH2:11][C:12]#[N:13]
Reactant: C=CC(C)CCC=C(C)CCC=NO
Solvent: CC(=O)OC(C)=O
Product: C=CC(C)CCC=C(C)CCC#N

Procedure:
<12> The method for producing 4,8-dimethyl-4,9-decadienenitrile according to the item <11>, wherein the dehydration step is carried out by the acetic anhydride method in which 4,8-dimethyl-4,9-decadienal oxime (an oxime intermediate) is dehydrated by heating in the presence of acetic anhydride to yield 4,8-dimethyl-4,9-decadienenitrile.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]2[C:14]2[CH:19]=[C:18]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:17]=[C:16]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:15]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[S:29]([OH:32])(=[O:31])=[O:30].CC(=O)OCC.O>C1COCC1>[CH:1]1([CH2:7][N:8]2[C:9]([C:14]3[CH:19]=[C:18]([C:20]([CH3:21])([CH3:23])[CH3:22])[CH:17]=[C:16]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:15]=3)=[CH:10][C:11]([S:29]([OH:32])(=[O:31])=[O:30])=[C:12]2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccc(-c2cc(C(C)(C)C)cc(C(C)(C)C)c2)n1CC1CCCCC1
Reactant: O=S(=O)(O)Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(S(=O)(=O)O)cc(-c2cc(C(C)(C)C)cc(C(C)(C)C)c2)n1CC1CCCCC1
Temperature: -78 °C
Reaction time: 3 h
Yield: 83 %

Procedure:
To a solution of compound 5b (1.0 g, 2.7 mmol) in THF (10 mL) was added dropwise ClSO3H (3 mL) at −78° C. This mixture was stirred at −78° C. for 3 h, then EA and cooled water was added and extracted with EA. The organic layer was washed with aq. NaHCO3, dried and concentrated to afford compound 5c (1.0 g, 83%) as yellow oil.
Reaction SMILES: S(=O)(=O)(O)O.Cl.[CH2:7]([O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21]N)=[CH:17][CH:16]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O=[C:24]([CH3:30])[C:25]([O:27][CH2:28][CH3:29])=[O:26]>C(O)C>[CH2:7]([O:14][C:15]1[CH:20]=[C:19]2[C:18](=[CH:17][CH:16]=1)[NH:21][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:30]2)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NNc1ccc(OCc2ccccc2)cc1
Reactant: CCOC(=O)C(C)=O
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CCOC(=O)c1cc2cc(OCc3ccccc3)ccc2[nH]1
Temperature: 45 °C
Reaction time: 2 h
Yield: 68.8 %

Procedure:
To a mixture of sulfuric acid (80.0 mL, 1.50 mol) dissolved in Ethanol (450 mL) at 0° C. was added (4-(benzyloxy)phenyl)hydrazine hydrochloride (90.0 g, 359 mmol) to form a suspension. To the suspension was added ethyl 2-oxopropanoate (43.9 mL, 395 mmol) in EtOH (90 mL) and mechanically stirred for 2 h using a mechanical stirrer. The mixture was heated to 45° C. and maintained for 16 h. The mixture was cooled to room temperature and cold EtOH (200 mL) was added. The mixture was filtered through a course frit. The collected solid was washed sequentially with cold EtOH, hexanes, and water. The solid was dried in a vacuum oven (45° C., 2 Ton) to give ethyl 5-(benzyloxy)-1H-indole-2-carboxylate (73.1 g, 247 mmol, 69% yield). Exact mass calculated for C18H17NO3: 295.1, found: LCMS m/z=296.2, [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.41 (t, J=7.1 Hz, 3 H), 4.40 (q, J=7.1 Hz, 2 H), 5.10 (s, 2 H), 7.08 (dd, J1=8.9, J2=2.4 Hz, 1 H), 7.14 (d, J=1.6 Hz, 1 H), 7.20 (d, J=2.3 Hz, 1 H), 7.32 (m, 2 H), 7.39 (m, 2 H), 7.47 (m, 2 H), 8.75 (bs, 1 H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].Cl[CH2:11][C:12]([OH:14])=[O:13].Cl>[OH-].[Na+]>[CH:5]([C:4]1[CH:3]=[C:2]([CH:9]=[CH:8][CH:7]=1)[O:1][CH2:11][C:12]([OH:14])=[O:13])=[O:6]
Reactant: O=C(O)CCl
Reactant: O=Cc1cccc(O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=Cc1cccc(OCC(=O)O)c1

Procedure:
A solution of 3-hydroxybenzaldehyde and 0.3 mol of chloroacetic acid in 300 ml of 2N sodium hydroxide was refluxed for 6 hours. After cooling, the solution was acidified with hydrochloric acid and the precipitate was filtered off and crystallized from ethyl acetate/petroleum ether 60-80.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[CH2:4][P:5]([OH:7])[OH:6].[OH-].[Na+:16]>>[NH2:1][CH2:2][CH:3]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[CH2:4][PH:5](=[O:6])[O-:7].[Na+:16]
Reactant: NCC(CP(O)O)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Product: NCC(C[PH](=O)[O-])c1ccc(Cl)cc1

Procedure:
A solution of 0.25 g of 3-amino-2-(4-chlorophenyl)propylphosphonous acid in 10 ml of 0.1M sodium hydroxide solution is stirred at room temperature for a period of 1 hour, and then concentrated under reduced pressure to give sodium 3-amino-2-(4-chlorophenyl)propylphosphinate as a hygroscopic solid, 31P=+26.0 ppm (D2O).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:13][C@H:12]1[C:21](=O)[NH:22][CH2:23][C:24](=[O:26])[CH3:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(Cl)(Cl)C(Cl)(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>ClCCl.O>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:13][C@H:12]1[C:21]1[O:26][C:24]([CH3:25])=[CH:23][N:22]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)CNC(=O)[C@@H]1C[C@@H](OC(C)(C)C)CN1C(=O)OCc1ccccc1
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cnc([C@@H]2C[C@@H](OC(C)(C)C)CN2C(=O)OCc2ccccc2)o1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 42 %

Procedure:
To a stirred solution of (2S,4R)-4-tert-butoxy-2-(2-oxo-propylcarbamoyl)-pyrrolidine-1-carboxylic acid benzyl ester (2.5 g, 6.65 mmol) and hexachloroethane (3.148 g, 13.3 mmol) in dichloromethane (16 mL) was added triphenyl phosphine (3.458 g, 13.3 mmol). The mixture was stirred at 0° C. for 20 min. Then triethylamine (1.36 mL, 13.3 mmol) was added and the reaction mixture was stirred at room temp. for 14 h. Water was then added to the reaction mixture, extracted with dichloromethane and the combined organic layer was washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated. The crude was then purified by column chromatography to give (2S,4R)-4-tert-butoxy-2-(5-methyl-oxazol-2-yl)-pyrrolidine-1-carboxylic acid benzyl ester (1 g, 42% yield) as an off-white solid. MS calcd. for C20H27N2O4 [(M+H)+] 359.0, obsd. 359.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]([CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]2)[S:9]1(=[O:33])=[O:32].Cl>ClCCl.O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]([CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[S:9]1(=[O:32])=[O:33]
Reactant: CC(C)(C)OC(=O)N1CCN(CCN2c3ccccc3N(c3ccccc3Cl)S2(=O)=O)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=S1(=O)N(CCN2CCNCC2)c2ccccc2N1c1ccccc1Cl
Yield: 79.2 %

Procedure:
In an analogous manner as general procedure II, step 2, a solution of tert-butyl 4-{2-[3-(2-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethyl}piperazine-1-carboxylate (0.22 g, 0.45 mmol) in dichloromethane (10 mL) was treated with hydrogen chloride (3.0 mL of a 4 M solution in dioxane), resulting in a white precipitate that was evaporated and dried under vacuum to provided 1-(2-chlorophenyl)-3-(2-piperazin-1-ylethyl)-1,3-dihydro-2,1,3-benzothiadiazole2,2-dioxide (0.14 g, 81%) as a white solid:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:19]([NH:21]N)=[O:20])[CH2:13][C:14]1[N:18]=[CH:17][NH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N([O-])=O.[Na+].C(=O)([O-])[O-].[K+].[K+].[CH2:33]([O:40][C:41](=[O:47])[C@@H:42]1[CH2:46][CH2:45][CH2:44]N1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>Cl.C(OCC)(=O)C>[CH2:33]([O:40][C:41](=[O:47])[C@@H:42]1[CH2:46][CH2:45][CH2:44][N:21]1[C:19](=[O:20])[C@H:12]([CH2:13][C:14]1[N:18]=[CH:17][NH:16][CH:15]=1)[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: NNC(=O)[C@H](Cc1c[nH]cn1)NC(=O)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Solvent: CCOC(C)=O
Product: O=C(N[C@@H](Cc1c[nH]cn1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)OCc1ccccc1
Yield: 49.9 %

Procedure:
In 99 ml of an aqueous solution of 1N hydrochloric acid was dissolved 10.01 g of Nα -benzyloxycarbonyl-L-histidine hydrazide (3). After adding thereto 132 ml of ethyl acetate, 8.25 ml of an aqueous solution of 2.313 g of sodium nitrite was added to the mixture with stirring vigorously under ice-cooling. After performing the reaction at 0° C. for 5 minutes, 39.6 ml of an aqueous 50% potassium carbonate solution was added to the reaction mixture under ice-cooling to alkalify the solution. The reaction mixture was placed in a separation funnel and an organic layer thus formed was collected. Furthermore, the aqueous layer was extracted by 20 ml of ethyl acetate and the extract was combined with the foregoing organic layer. The mixture was dried over anhydrous sodium sulfate under ice-cooling for 10 minutes. By removing anhydrous sodium sulfate by filtration, 152 ml of an ethyl acetate solution of Nα -benzyloxycarbonyl-L-histidine azide (4) was obtained. The product was ice-cooled and 20 ml of an ethyl acetate solution of 5.703 g of L-proline benzyl ester (5) was added thereto. The mixture was reacted overnight at 0° C. and then the reaction mixture was concentrated to dryness. The residue was dissolved in 22 ml of chloroform-methanol (10:1) and subjected to silica gel column chromatography. The eluate by chloroform-methanol (95:5) was concentrated to dryness to provide 6.602 g of Nα -benzyloxycarbonyl-L-histidyl-L-proline benzyl ester (6).
Reaction SMILES: [F:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N+:4]([O-])[CH:5]=[CH:6][CH:7]=1.[ClH:15].S(=O)=O>C(O)(=O)C>[ClH:15].[ClH:15].[F:1][C:2]1[C:3]([N:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: [O-][n+]1cccc(F)c1N1CCNCC1
Agent: Cl
Agent: O=S=O
Solvent: CC(=O)O
Product: Fc1cccnc1N1CCNCC1

Procedure:
A solution of 3-fluoro-2-piperazinylpyridine N-oxide (2 mmol) in 10 ml of glacial acetic acid is warmed to about 85° C. saturated with anhydrous hydrogen chloride gas and treated with a fine stream of sulfur dioxide for 1 hour. The acetic acid is removed under reduced pressure and the residue is crystallized from an ethanol-ethyl acetate mixture to give the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].CS(O[CH2:14][CH:15]1[CH2:18][O:17][CH2:16]1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl-].[NH4+]>C(#N)C>[N+:1]([C:4]1[CH:5]=[N:6][N:7]([CH2:14][CH:15]2[CH2:18][O:17][CH2:16]2)[CH:8]=1)([O-:3])=[O:2]
Reactant: CS(=O)(=O)OCC1COC1
Reactant: O=[N+]([O-])c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CC#N
Product: O=[N+]([O-])c1cnn(CC2COC2)c1
Temperature: 100 °C
Yield: 99.3 %

Procedure:
A mixture of 4-nitropyrazole (1000 mg, 8.80 mmol), oxetan-3-ylmethyl methanesulfonate (1.90 g, 11.0 mmol), cesium carbonate (8.70 g, 27.0 mmol) and acetonitrile (13 mL) was heated at 100° C. for 3 h. The mixture was cooled to room temperature, saturated ammonium chloride was added. The mixture was extracted with methylene chloride 3×. Combined organics were dried (Na2SO4) and the solvent removed under reduced pressure. The crude product was purified by flash chromatography eluting with 0 to 70% ethyl acetate in heptane to give 4-nitro-1-(oxetan-3-ylmethyl)pyrazole (1.60 g, 99%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[C:20]4[N:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][N:21]4[C:28]=3[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C.Cl.[OH-].[Na+]>C(Cl)Cl.CO.O1CCOCC1>[CH3:27][O:26][C:24]1[CH:23]=[CH:22][N:21]2[C:28]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[C:18]([C:15]3[CH:14]=[CH:13][C:12]([C:8]4([NH2:7])[CH2:9][CH2:10][CH2:11]4)=[CH:17][CH:16]=3)[N:19]=[C:20]2[N:25]=1
Reactant: COc1ccn2c(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1ccn2c(-c3ccccc3)c(-c3ccc(C4(N)CCC4)cc3)nc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.8 %

Procedure:
To a mixture of crude {1-[4-(7-methoxy-3-phenyl-imidazo[1,2-a]pyrimidin-2-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (550 mg) in DCM (3 mL) and methanol (1.9 mL) was added a solution of 4 M hydrogen chloride in dioxane (5.8 mL) and the mixture was stirred for 2 hours at rt. The mixture was poured onto ice, made alkaline with aqueous sodium hydroxide (2 N) and extracted three times with a mixture of DCM/methanol. The combined organic phases were washed with brine, dried and concentrated in vacuo. Purification was achieved by chromatography [silica; gradient elution: DCM to 8:2 DCM/ethanol] to give the title compound (220 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[O:8][C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:6][C:5]2=[C:15]([C:17]([OH:19])=O)[CH:16]=1.Cl.Cl.[NH2:22][CH:23]1[CH2:30][CH:29]2[N:31]([CH3:32])[CH:25]([CH2:26][CH2:27][CH2:28]2)[CH2:24]1.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH3:32][N:31]1[CH:25]2[CH2:26][CH2:27][CH2:28][CH:29]1[CH2:30][CH:23]([NH:22][C:17]([C:15]1[CH:16]=[C:2]([Cl:1])[CH:3]=[C:4]3[O:8][C:7]([C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=4)=[N:6][C:5]=13)=[O:19])[CH2:24]2
Reactant: O=C(O)c1cc(Cl)cc2oc(-c3ccccc3)nc12
Reactant: CN1C2CCCC1CC(N)C2
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1C2CCCC1CC(NC(=O)c1cc(Cl)cc3oc(-c4ccccc4)nc13)C2
Temperature: 25 °C
Reaction time: 18 h
Yield: 14.2 %

Procedure:
A 15-mL, round bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with 6-chloro-2-phenyl-benzoxazole-4-carboxylic acid (0.075 g, 0.274 mmol), 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride (0.063 g, 0.411 mmol) 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride (0.079 g, 0.411 mmol), 1-hydroxybenzotriazole (0.037 g, 0.274 mmol), diisopropylethylamine (0.141 g, 1.09 mmol), and DMF (1.0 mL). After stirring at ambient temperature for 18 h, the reaction was concentrated under reduced pressure and purified by preparative HPLC to afford 0.016 g (14% yield) of N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-6-chloro-2-phenylbenzoxazole-4-carboxamide as an off-white solid: 1H NMR (500 MHz, CDCl3) δ 8.95 (br s, 1H), 8.23 (d, J=6.9 Hz, 2H), 8.20 (d, J=2.0 Hz, 1H), 7.71 (d, J=2.0 Hz, 1H), 7.65-7.57 (m, 3H), 4.58 (q, J=7.1 Hz, 1H), 3.18 (br s, 2H), 2.58 (m, 5H), 2.25-2.02 (m, 3H), 1.55 (s, 3H), 1.23 (m, 3H); MS (APCI) m/z 409 [M+H]+
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH2:8][C:7]([CH3:11])([CH3:10])[C:6]=2[CH:12]=1.[I:13]Cl.[OH-].[Na+].C([O-])([O-])=O.[Na+].[Na+]>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([I:13])[C:5]2[O:9][CH2:8][C:7]([CH3:10])([CH3:11])[C:6]=2[CH:12]=1
Reactant: CC1(C)COc2ccc(Br)cc21
Reactant: ClI
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC1(C)COc2c(I)cc(Br)cc21
Temperature: 0 °C
Yield: 56 %

Procedure:
5-Bromo-3,3-dimethyl-2,3-dihydro-benzofuran (example 1f) (10 g, 44 mmol) was dissolved in glacial acetic acid (40 mL), iodine monochloride (10.86 g, 66.9 mmol) was added and the reaction mixture was heated at reflux for 72 hours then cooled to 0° C., and 1N NaOH was slowly added until pH=8 followed by Na2CO3 until the solution become colorless. The solution was extracted with ethyl acetate and the organic layer further washed with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified on silica gel (10% ethyl acetate in hexane) to give 8.7 g of 5-bromo-7-iodo-3,3-dimethyl-2,3-dihydro-benzofuran (56%). 1H NMR (300 MHz; CDCl3): 1.34 (s, 6H), 4.32 (s, 2H), 7.13 (d, J=2 Hz, 1H), 7.58 (d, J=2 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9](Cl)[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:19]C)[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:21][S:22][CH2:23][CH2:24][OH:25].[Na].Cl.N>>[NH2:1][C:2]1[N:10]=[C:9]([O:25][CH2:24][CH2:23][S:22][CH3:21])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CSCCO
Reactant: COc1nc2c(N)nc(Cl)nc2n1Cc1ccccc1
Agent: Cl
Agent: N
Agent: [Na]
Product: CSCCOc1nc(N)c2nc(O)n(Cc3ccccc3)c2n1
Yield: 27 %

Procedure:
6-amino-9-benzyl-2-chloro-8-methoxypurine (190 mg, 0.56 mmol) was added to 2-methylthioethanol (3 ml) containing sodium (110 mg, 4.78 mmol). The mixture was heated for 2 hours. Thereto were added 2N hydrochloric acid and 28% aqueous ammonia in order. The mixture was extracted with 3% methanol/chloroform and the organic layer was dried on sodium sulfate. After removal of the solvent in vacuo, the residue was purified by silica gel chromatography (3% methanol/chloroform) to give the subject compound (59 mg, yield 27%).