Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7](Cl)=[N:8][OH:9].[C:12]([C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=1)#[CH:13].N>>[Cl:1][C:2]1[CH:11]=[C:6]([C:7]2[CH:13]=[C:12]([C:14]3[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=3)[O:9][N:8]=2)[CH:5]=[N:4][CH:3]=1
Reactant: ON=C(Cl)c1cncc(Cl)c1
Reactant: C#Cc1cc(F)cc(F)c1
Agent: N
Product: Fc1cc(F)cc(-c2cc(-c3cncc(Cl)c3)no2)c1

Procedure:
The titled compound was prepared according to Method CB using the product of Example 69B (57 mg, 0.3 mmol) and 1-ethynyl-3,5-difluorobenzene (Apollo, 41 mg, 0.3 mmol). 1H NMR (300 MHz, DMSO-d6) δ 7.51 (tt, J=9.3, 2.4 Hz, 1 H), 7.61-7.74 (m, 2H), 7.93 (s, 1H), 8.41 (t, J=2.1 Hz, 1H), 8.82 (d, J=2.4 Hz, 1 H), 9.06 (d, J=1.7 Hz, 1H) ppm; MS (DCI/NH3) m/z 293 (M+H)+, 295 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][NH:14][C@H:13]([C:17]([OH:19])=[O:18])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:27]1([N:33]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:34](Cl)=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:34](=[O:35])[N:33]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@H:13]([C:17]([OH:19])=[O:18])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)[C@@H]1CN(C(=O)OCc2ccccc2)CCN1
Reactant: O=C(Cl)N(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(O)[C@@H]1CN(C(=O)OCc2ccccc2)CCN1C(=O)N(c1ccccc1)c1ccccc1

Procedure:
A solution of 1.03 g (3.90 mmole) of (S)-4-(benzyloxycarbonyl)piperazine-2-carboxylic acid (from Step A) in 12 ml. of DMF was treated with 0.788 g (7.79 mmole) of triethylamine at 25° C. With stirring 0.901 g (3.89 mmole) of diphenylcarbamoyl chloride was added in portions over 2 hours. After 16 hours the mixture was concentrated in vacuo to an orange oil which was chromatographed over an 88×2.5 cm LH 20 column with 11 ml. fractions of methanol. Fractions 35-43 were combined and concentrated to 1.136 g (64%) of pale yellow oil which contained a major spot by TLC (80:18:2 chloroform-methanol-ammonia water, Rf =0.45).
Reaction SMILES: [CH:1](OC)([O:4][CH3:5])[O:2][CH3:3].O.[O-2].[O-2].[O-2].O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.[Al+3].[Al+3].[Cl:26][C:27]1[C:28]([C:37]2[CH:42]=[CH:41][C:40]([Cl:43])=[C:39](C=O)[CH:38]=2)=[N:29][CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1>ClCCl>[Cl:26][C:27]1[C:28]([C:37]2[CH:42]=[CH:41][C:40]([Cl:43])=[C:39]([CH:1]([O:4][CH3:5])[O:2][CH3:3])[CH:38]=2)=[N:29][CH:30]=[C:31]([C:33]([F:35])([F:36])[F:34])[CH:32]=1
Reactant: COC(OC)OC
Reactant: O=Cc1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1Cl
Agent: O=[Si]=O
Agent: [Al+3]
Agent: [O-2]
Solvent: ClCCl
Solvent: O
Product: COC(OC)c1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1Cl

Procedure:
50 ml of trimethyl orthoformate were added to 40.0 g of montmorillonite K-10 in 250 ml of anhydrous dichloromethane, after which a solution of 20.0 g of 3-chloro-2-(4-chloro-3-formylphenyl)-5-trifluoromethylpyridine in 50 ml of dichloromethane was added dropwise while stirring and cooling in ice. After stirring at 23° C. for 20 hours, the clay was removed and thoroughly washed with dichloromethane. The dichloromethane phase was concentrated. The residue was purified by chromatography on silica gel with cyclohexane/ethyl acetate (10:1). Yield: 22.1 g (96%) of a colorless oil.
Reaction SMILES: [C:1]1([CH:7]([CH3:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:10]O>>[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:10])[CH3:9].[C:1]1([C:7]([OH:10])([CH3:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)c1ccccc1
Reactant: OO
Product: CC(=O)c1ccccc1
Product: CC(C)(O)c1ccccc1
Yield: 43.1 %
Yield: 30.6 %

Procedure:
The procedure of Example III was repeated, but this time cumene (0.056 moles) and hydrogen peroxide (35%, 0.22 moles) were used. The reaction mixture, analysed by HPLC, revealed that 87.4% of the cumene had been consumed, yielding products including acetophenone (43.1% yield) and 2-phenyl-2-propanol (30.6% yield).
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[C:6]([N+:13]([O-])=O)[CH:5]=1)([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[NH2:13][C:6]1[CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: [H][H]
Reactant: CC(C)c1ccc(C(=O)O)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: CC(C)c1ccc(C(=O)O)c(N)c1
Yield: 98 %

Procedure:
The product of Example 431C (0.697 g, 3.332 mmol) was hydrogenated in methanol (30 mL) with 10% palladium-on-carbon (70 mg) at 1 atmosphere hydrogen pressure (balloon) for 2 hours. The reaction was filtered through a 0.45 micron PTFE membrane and the catalyst thoroughly washed with methanol. The filtrate was concentrated by rotary evaporation to give the title compound (0.585 g, 3.264 mmol, 98%). 1H NMR (300 MHz, DMSO-D6) δ ppm 1.15 (d, J=6.62 Hz, 6 H) 2.61-2.92 (m, 1 H) 6.41 (dd, J=8.46, 1.47 Hz, 1 H) 6.58 (d, J=1.84 Hz, 1 H) 7.60 (d, J=8.46 Hz, 1 H) 8.46 (br s, 2 H); MS (ESI+) m/z 180 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][NH2:19].[C:20]([O:24][C:25]([O:27]C(OC(C)(C)C)=O)=O)([CH3:23])([CH3:22])[CH3:21]>O1CCOCC1.CCOCC>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([N:19]([C:25]([O:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:27])[CH3:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CN
Solvent: C1COCCO1
Solvent: CCOCC
Product: CN(C(=O)OC(C)(C)C)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of commercially available 4-oxo-piperidine-1-carboxylic acid benzyl ester (4.67 g, 20 mmol) and methylamine (8 M in EtOH, 12.5 mL, 100 mmol) in dioxane (total volume of 100 mL) is stirred at r.t. for 15 min. NaBHAc3 (6.4 g, 30 mmol) is added and the mixture is stirred for 15 h. The mixture is quenched with 1 M aq. NaOH (30 mL) and stirred at r.t. for 30 min. The mixture is diluted with water (50 mL) and extracted with CH2Cl2 (3×75 mL). The organic extracts are dried (Na2SO4), filtered and evaporated. The residue is dissolved in ether (200 mL) and TEA (1.4 mL, 10 mmol) and, subsequently, a solution of di-tert.butyl-dicarbonat (3.82 g, 17.5 mmol) in ether (10 mL) are added. The mixture is stirred at r.t. for 15 h and quenched with 1 M aq. NaOH (30 mL). The phases are separated and the organic phase is washed with 1 M aq. NaOH (30 mL), 1 M aq. KHSO4 (2×30 mL) and sat. aq. NaCl (30 mL). The organic phase is dried (Na2SO4), filtered and evaporated to provide the title compound.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[Br:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][N:17]=[C:16]2[CH:22]=[O:23].[O:24]1[CH:29]=[CH:28][CH2:27][CH2:26][CH2:25]1>C1COCC1.C(Cl)Cl>[Br:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[N:18]([CH:25]1[CH2:26][CH2:27][CH2:28][CH2:29][O:24]1)[N:17]=[C:16]2[CH:22]=[O:23]
Reactant: C1=COCCC1
Reactant: O=Cc1n[nH]c2ccc(Br)cc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=Cc1nn(C2CCCCO2)c2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 80 %

Procedure:
p-Toluenesulfonic acid (10 mg, 0.052 mmol) was added to a solution of 5-bromo-indazole-3-carbaldehyde (100 mg, 0.444 mmol) and 3,4-dihydro-2H-pyran (75 mg, 0.891 mmol) in a mixture of THF/CH2Cl2 (1:1, 6 mL). The reaction mixture was stirred for 12 h at room temperature after which the solvent was removed in vacuo. The residue was dissolved in CH2Cl2 (20 mL) and poured in water (20 mL). The organic layer was separated, and the aqueous layer was extracted with CH2Cl2 (20 mL). The combined organic layers were washed with water (40 mL) and brine (40 mL), dried over Na2SO4 and concentrated. Purification by flash chromatography (CH2Cl2) afforded 110 mg, (80% yield) of the title compound as a solid. 1H NMR (400 MHz, CDCl3): δ 10.21 (s, 1H), 8.47 (s, 1H), 7.56 (m, 2H), 5.80 (dd, 1H, J=3.2 and 9.2 Hz), 3.98 (m, 1H), 3.79-3.74 (m, 1H), 2.57-2.49 (m, 1H), 2.20-2.12 (m, 2H), 1.83-1.57 (m, 3H).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16](OS(C(F)(F)F)(=O)=O)=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:5][CH:4]=1.[CH2:28]([OH:31])[C:29]#[CH:30]>>[F:27][C:2]([F:1])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16]([C:30]#[C:29][CH2:28][OH:31])=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:5][CH:4]=1
Reactant: O=S(=O)(Oc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1)C(F)(F)F
Reactant: C#CCO
Product: OCC#Cc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1

Procedure:
In analogy to example 14.1, Trifluoro-methanesulfonic acid 3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl ester and 2-propyn-1-ol were converted to yield 3-[3-(4-Trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-yn-1-ol as off-white solid, MS: 333 (M).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH:13]3[CH2:15][C:16]4([CH2:19][CH:12]3[C:11]2=[O:20])[CH2:18][O:17]4)=[CH:6][CH:5]=1.[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C1(O)C=CC=CC=1>O>[OH:17][C:16]1([CH2:18][NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:19][CH:12]2[C:11](=[O:20])[N:10]([C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:22])([F:21])[F:1])=[CH:9][CH:8]=3)[CH2:14][CH:13]2[CH2:15]1
Reactant: Nc1ccccc1
Reactant: O=C1C2CC3(CO3)CC2CN1c1ccc(OC(F)(F)F)cc1
Solvent: Oc1ccccc1
Solvent: O
Product: O=C1C2CC(O)(CNc3ccccc3)CC2CN1c1ccc(OC(F)(F)F)cc1
Temperature: 60 °C
Reaction time: 24 h
Yield: 24 %

Procedure:
rac-(3aR,5S,6aS)-2-[4-(trifluoromethoxy)phenyl]hexahydro-1H-spiro[cyclopenta[c]pyrrole-5,2′-oxiran]-1-one (80 mg, 0.25 mmol), aniline (5 mL) and PhOH (23 mg, 0.24 mmol) were mixed together, and the mixture was stirred for 24 h at 60° C. The solution was then poured into water (25 mL) and extracted with ether (3×20 mL). The combined ether was washed with sodium hydroxide (10%, 3×10 mL), with water (30 mL) and dried over Na2SO4. The solvent was removed and the residue was purified by prep-TLC (petroleum ether:ethyl acetate=1:1) to yield the title compound (25 mg, 24%). 1H NMR (300 MHz, CDCl3): δ 7.57-7.55 (m, 2H), 7.27-7.13 (m, 4H), 7.00-6.93 (m, 3H), 5.26 (bs, 1H), 4.07 (t, 1H, J=9.3 Hz), 3.75-3.73 (m, 1H), 3.34-2.22 (m, 3H), 3.05-2.90 (m, 1H), 2.46-2.42 (m, 1H), 2.02-1.90 (m, 3H); LC-MS: 407.1 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C@H:7]2[CH2:13][C@H:12]3[N:14]([CH2:15][CH2:16][C@H:17]([NH:24][C:25]([CH:27]4[CH2:32][CH2:31][C:30]([F:34])([F:33])[CH2:29][CH2:28]4)=[O:26])[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[C@H:9]([CH2:10][CH2:11]3)[CH2:8]2)[C:5]([CH:35]([CH3:37])[CH3:36])=[N:4][N:3]=1.[P:38](=[O:42])([OH:41])([OH:40])[OH:39]>C(O)C>[CH3:1][C:2]1[N:6]([C@H:7]2[CH2:13][C@H:12]3[N:14]([CH2:15][CH2:16][C@H:17]([NH:24][C:25]([CH:27]4[CH2:28][CH2:29][C:30]([F:34])([F:33])[CH2:31][CH2:32]4)=[O:26])[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C@H:9]([CH2:10][CH2:11]3)[CH2:8]2)[C:5]([CH:35]([CH3:37])[CH3:36])=[N:4][N:3]=1.[P:38]([O-:42])([O-:41])([O-:40])=[O:39]
Reactant: O=P(O)(O)O
Agent: Cc1nnc(C(C)C)n1[C@@H]1C[C@H]2CC[C@@H](C1)N2CC[C@H](NC(=O)C1CCC(F)(F)CC1)c1ccccc1
Solvent: CCO
Product: O=P([O-])([O-])[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Maraviroc (10 gm) was dissolved in ethanol (900 ml), and stirred for 30 minutes at room temperature. To the solution was added phosphoric acid (20 gm) and then cooled to 0 to 5° C. The reaction mass was stirred for 11 hours at 0 to 5° C. and filtered. The solid obtained was dried to obtain 10 gm of crystalline form 4 of maraviroc phosphate.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.C(Cl)Cl.CS(C)=O.[N:14]1([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]2[OH:25])[CH2:18][CH2:17][CH2:16][CH2:15]1>CCN(CC)CC>[N:14]1([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][C:20]2=[O:25])[CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: OC1CCCCC1N1CCCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C1CCCCC1N1CCCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 71.5 %

Procedure:
A solution of oxalyl chloride (50 mL, 0.5732 mol) in 200 mL of freshly distilled CH2Cl2 was cooled down to -70° C. and DMSO (80 mL, 1.1274 mol) was carefully added dropwise. After 15 min., 2-(1-pyrrolidinyl)cyclohexanol (a) (70 g, 0.4142 mol) was added to the reaction mixture, followed by Et3N (350 mL). The cold bath was then removed, and the mixture was stirred at room temperature for two and a half hours. Progress of the reaction was followed by gas chromatography. The solvent was partially removed in vacuo and ethyl ether (200 mL) was added. This organic layer was washed with brine (3×100 mL), dried (Na2SO4), and the solvent removed in vacuo. The crude product was distilled under high vacuum (BP: 84° C./0.5 mmHg) to yield 49.5 g of the ketone (b) as a colorless oil (72%). Rf : 0.49 (CHCl3 :MeOH:NH4OH=92:7:1); B.P: 84° C. (0.5 mmHg); IR (neat) 2940, 2860, 2800, 1715, 1440 cm-1 ; 1H-NMR (CDCl3) d 1.53-1.63 (m, 1H), 1.72 (m, 4H), 1.76-1.93 (m, 4H), 1.94-2.04 (m, 1H), 2.21, (m, 1H), 2.52 (m, 5H), 2.83 (dd, 1H, J1 =8.6, J2 =4.5 Hz); Mass Spectrum Calcd. for C10H17NO: 167.1310, Found: 167.1310.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([S:19]([NH2:22])(=[O:21])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:23]([N:25]1[CH2:30][CH2:29][CH:28]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1)=[O:24].[C:38](O)(=[O:41])[CH2:39][CH3:40]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([S:19]([NH:22][C:38](=[O:41])[CH2:39][CH3:40])(=[O:21])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:23]([N:25]1[CH2:30][CH2:29][CH:28]([C:31]2[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=2)[CH2:27][CH2:26]1)=[O:24]
Reactant: CCC(=O)O
Reactant: NS(=O)(=O)c1cnn2c(Nc3cc(F)ccc3F)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Product: CCC(=O)NS(=O)(=O)c1cnn2c(Nc3cc(F)ccc3F)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Yield: 87.1 %

Procedure:
Using 7-(2,5-difluorophenylamino)-6-[4-(4-fluorophenyl)piperidine-1-carbonyl]pyrazolo[1,5-a]pyrimidine-3-sulfonamide (0.050 g, 0.094 mmol) obtained in Example 35 step 5 and propionic acid (0.035 mL, 0.471 mmol) instead of cyclopropanecarboxylic acid, and in the same manner as in Example 1 step 6, the title compound (0.048 g, 86%) was obtained.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].OS(O)(=O)=O.[C:10]1([CH:16]([CH2:19][CH3:20])[C:17]#[N:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[N+:1]([C:13]1[CH:14]=[CH:15][C:10]([CH:16]([CH2:19][CH3:20])[C:17]#[N:18])=[CH:11][CH:12]=1)([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: CCC(C#N)c1ccccc1
Agent: O=S(=O)(O)O
Product: CCC(C#N)c1ccc([N+](=O)[O-])cc1
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
A 3-necked round-bottomed flask was charged with conc. HNO3 (240 ml) and cooled to 10° C. with the aid of an ice/acetone bath. Conc. H2SO4 (240 ml) was then added slowly so as to maintain the temperature below 30° C. 2-Phenylbutyronitrile (Aldrich, 110 ml) was introduced dropwise to the stirred solution over a period of 1 hour, maintaining the temperature below 20° C. The ice/acetone bath was then removed and the mixture stirred for a further 30 minutes at ambient temperature before pouring it onto crushed ice (100 g). The resulting mixture was extracted with ethyl acetate (1500 ml×2) and the extracts pooled, washed with saturated bicarb. (1000 ml) and water (500 ml). After drying over MgSO, the ethyl acetate was evaporated under reduced pressure to give crude 2-(4-nitrophenyl)butyronitrile as a yellow oil, crude yield 138 g, 98%. Analysis by GC.MS indicated a para:meta ratio of 3.5:1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([OH:13])=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:47]([O:50][C:51]([C@H:53]1[CH2:58][CH2:57][C@H:56]([CH:59]([NH:62][C:63]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64])[CH2:60][NH2:61])[CH2:55][CH2:54]1)=[O:52])[CH2:48][CH3:49]>CN(C=O)C>[CH2:47]([O:50][C:51]([C@H:53]1[CH2:58][CH2:57][C@H:56]([CH:59]([NH:62][C:63]([O:65][C:66]([CH3:67])([CH3:69])[CH3:68])=[O:64])[CH2:60][NH:61][C:11]([C:8]2([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[CH2:9][CH2:10]2)=[O:13])[CH2:55][CH2:54]1)=[O:52])[CH2:48][CH3:49]
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CC1
Reactant: CCCOC(=O)[C@H]1CC[C@H](C(CN)NC(=O)OC(C)(C)C)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCOC(=O)[C@H]1CC[C@H](C(CNC(=O)C2(c3ccc(Cl)cc3)CC2)NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1-(4-Chlorophenyl)cyclopropanecarboxylic acid (527 mg, 2.68 mmol, 1.0 eq) was dissolved in anhydrous DMF (20 mL) in a 250 mL RB flask, under argon. HBTU (1.32 g, 3.48 mmol, 1.3 eq), and DIPEA (0.95 mL, 5.36 mmol, 2.0 eq) were added to this solution. The reaction mixture was stirred at RT for 15 minutes. To this mixture was charged cis-/trans-4-(2-Amino-1-tert-butoxycarbonylamino-ethyl)-cyclohexanecarboxylic acid propyl ester (1-7) (880 mg, 2.68 mmol. 1.0 eq) in anhydrous DMF (20 mL) solution. The reaction mixture was stirred at RT for 2 hours. LC/MS indicated the absence of the starting material. DMF was removed under vacuum. The residue was treated with 1:1 brine/EtOAc (300 mL). The aqueous layer was extracted with EtOAc (2×150 mL). The combined EtOAc extracts were washed with brine (1×150 mL), dried over Na2SO4 and the solvent evaporated to dryness. The crude product was purified on a silica gel column, eluting with EtOAc/Hexanes (20˜25%) to give 1.26 g (92% yield) of 1-9. The 1H NMR (DMSO-d6) data is depicted in FIG. 6.
Reaction SMILES: Cl.[Br:2][C:3]1[N:7]2[CH:8]=[C:9]([C:12]([OH:14])=O)[N:10]=[CH:11][C:6]2=[CH:5][CH:4]=1.[C:15]1([NH2:26])[C:20](F)=[C:19](F)[C:18](F)=[C:17](N)C=1F.Cl.Cl.[CH3:29][CH2:30][N:31](C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C1COCC1>[N:26]12[CH2:17][CH2:18][CH:19]([CH2:20][CH2:15]1)[C@@H:30]([NH:31][C:12]([C:9]1[N:10]=[CH:11][C:6]3[N:7]([C:3]([Br:2])=[CH:4][CH:5]=3)[CH:8]=1)=[O:14])[CH2:29]2
Reactant: O=C(O)c1cn2c(Br)ccc2cn1
Reactant: CCN(C(C)C)C(C)C
Reactant: Nc1c(F)c(N)c(F)c(F)c1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(N[C@H]1CN2CCC1CC2)c1cn2c(Br)ccc2cn1
Reaction time: 16 h

Procedure:
To a suspension of 6-bromopyrrolo[1,2-a]pyrazine-3-carboxylic acid hydrochloride (1.67 mmol), (R)-3-aminoquinulidine dihydrochloride (0.34 g, 1.67 mmol), DIEA (1.5 mL, 8.35 mmol) in DMF (20 mL) and THF (10 mL) is added HATU (0.64 g, 1.67 mmol). The resulting suspension is stirred for 16 h at which time it is concentrated to dryness under reduced pressure. The resulting material is absorbed to silica gel and purified with silica gel chromatography (9% MeOH/1%NH3OH/CH2Cl2 as the eluent) salted with fumeric acid, and crystallized from EtOH/acetone/Et2O to give an off white spheres. Yield 45%. HRMS (FAB) calcd. for C15H17BrN4O+H 349.0664, found 349.0647.
Reaction SMILES: [CH:1]1([C:4](=O)[CH2:5][C:6]#[N:7])[CH2:3][CH2:2]1.O.[NH2:10][NH2:11]>C(O)C>[CH:1]1([C:4]2[CH:5]=[C:6]([NH2:7])[NH:11][N:10]=2)[CH2:3][CH2:2]1
Reactant: N#CCC(=O)C1CC1
Reactant: NN
Solvent: O
Solvent: CCO
Product: Nc1cc(C2CC2)n[nH]1
Yield: 80 %

Procedure:
5 g (0.046 mol) of 3-cyclopropyl-3-oxo-propanenitrile were dissolved in 200 ml of ethanol and 2.26 ml (0.046 mol) of hydrazine hydrate were added. The solution was maintained at reflux for 5 hours and then the solvent evaporated under vacuum. The residue was re-dissolved with methylene chloride and washed several times with brine. The organic layer was dried over anhydrous sodium sulfate and the solvent evaporated to give 4.53 g (80% yield) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:19]([O:20]C(=O)C)=[CH:18][C:5]2[CH:6]=[C:7]([C:9](=[O:17])[CH2:10][N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[O:8][C:4]=2[C:3]=1[CH3:24].C(=O)(O)[O-].[Na+]>CO>[OH:20][C:19]1[C:2]([CH3:1])=[C:3]([CH3:24])[C:4]2[O:8][C:7]([C:9](=[O:17])[CH2:10][N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:6][C:5]=2[CH:18]=1
Reactant: CC(=O)Oc1cc2cc(C(=O)CN3CCOCC3)oc2c(C)c1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Cc1c(O)cc2cc(C(=O)CN3CCOCC3)oc2c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.8 %

Procedure:
A solution of acetic acid 6,7-dimethyl-2-(2-morpholin-4-yl-acetyl)-benzofuran-5-yl ester (23 mg), prepared as in Example 17, in MeOH (10 mL) was stirred while sodium bicarbonate (10 mg) was added. Then the mixture was stirred at RT overnight, followed by evaporation to dryness. The residue was purified by silica gel column, eluting with 5% MeOH in dichloromethane to give 11 mg of 1-(5-hydroxy-6,7-dimethyl-benzofuran-2-yl)-2-morpholin-4-yl-ethanone as an oil. Conversion into HCl salt gave a yellow solid. 1H NMR (CD3OD, 300 MHz) δ:: 7.60 (s, 1H), 7.20 (s, 1H), 3.78(m, 6H), 2.64(m, 4H), 2.50(s, 3H), 2.40(s, 3H) ppm. 13C NMR (CDCl3, 75 MHz)δ: 187.98, 170.20, 153.31, 152.29, 146.58, 130.44, 124.53, 122.80, 114.36, 113.15, 64.69, 53.79, 21.28, 13.47, 12.86 ppm. M/S 290 (M+H+).
Reaction SMILES: O[CH2:2][C:3]1[CH:16]=[N:15][C:6]2[C:7]3[N:8]([CH:12]=[CH:13][CH:14]=3)[C:9](=[O:11])[NH:10][C:5]=2[CH:4]=1.Cl.Cl.[CH2:19]([NH:21][C:22](=[O:36])[C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[C:25]([CH3:35])[CH:24]=1)[CH3:20].[I-].C(C[P+](C)(C)C)#N.C(N(C(C)C)C(C)C)C>C(#N)CC>[CH2:19]([NH:21][C:22](=[O:36])[C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:30][CH2:31][N:32]([CH2:2][C:3]3[CH:16]=[N:15][C:6]4[C:7]5[N:8]([CH:12]=[CH:13][CH:14]=5)[C:9](=[O:11])[NH:10][C:5]=4[CH:4]=3)[CH2:33][CH2:34]2)=[C:25]([CH3:35])[CH:24]=1)[CH3:20]
Reactant: CCNC(=O)c1ccc(N2CCNCC2)c(C)c1
Reactant: O=c1[nH]c2cc(CO)cnc2c2cccn12
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: CCNC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)[nH]c(=O)n3cccc43)CC2)c(C)c1
Temperature: 95 °C
Reaction time: 18 h
Yield: 30.3 %

Procedure:
To a suspension of 3-(hydroxymethyl)pyrido[2,3-e]pyrrolo[1,2-c]pyrimidin-6(5H)-one (7.20 mg, 0.033 mmol), N-ethyl-3-methyl-4-(piperazin-1-yl)benzamide dihydrochloride (13.40 mg, 0.042 mmol) and (cyanomethyl)trimethylphosphonium iodide (13.02 mg, 0.054 mmol) in Propiononitrile (Volume: 0.5 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.029 mL, 0.167 mmol) at 23° C. The reaction was stirred at 95° C. for 18 hr. The suspension was cooled to 23° C., filtered, rinsed with ACN (3×1 mL) and dried in vacuo to provide N-ethyl-3-methyl-4-(4-((6-oxo-5,6-dihydropyrido[2,3-e]pyrrolo[1,2-c]pyrimidin-3-yl)methyl)piperazin-1-yl)benzamide (0.004 g, 0.01 mmol, 27.0% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.10 (t, J=7.20 Hz, 3H) 2.26 (s, 3 H) 2.53-2.65 (m, 4 H) 2.84-2.99 (m, 4 H) 3.20-3.27 (m, 2 H) 3.65 (s, 2 H) 6.71-6.76 (m, 1H) 7.02 (d, J=8.34 Hz, 1 H) 7.07 (dd, J=3.54, 1.26 Hz, 1H) 7.57-7.60 (m, 1 H) 7.60-7.66 (m, 2 H) 7.67 (dd, J=3.03, 1.52 Hz, 1 H) 8.22 (t, J=5.56 Hz, 1 H) 8.36 (d, J=1.52 Hz, 1 H) 11.58 (s, 1 H). ESI-MS: m/z 445.4 (M+H)+. mp=254.8-258.5° C.