Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:11]([O:15][C:16]([NH:18][CH:19]1[C:25](=[O:26])[NH:24][C:23]2[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=2[NH:21][CH2:20]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].Br[CH2:32][C:33]([O:35][CH3:36])=[O:34]>C1COCC1.C(OCC)(=O)C>[CH3:36][O:35][C:33](=[O:34])[CH2:32][N:24]1[C:25](=[O:26])[C@@H:19]([NH:18][C:16]([O:15][C:11]([CH3:14])([CH3:12])[CH3:13])=[O:17])[CH2:20][NH:21][C:22]2[CH:30]=[CH:29][CH:28]=[CH:27][C:23]1=2
Reactant: COC(=O)CBr
Reactant: CC(C)(C)OC(=O)NC1CNc2ccccc2NC1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CNc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
A 1.0M solution of lithium bis(trimethylsilyl)amide (3.4 ml, 3.4 mmol) in THF was added dropwise to a -78° C. solution of 3-tert-butoxycarbonylamino-1,3,4,5-tetrahydrobenzo[b][1,4]diazepin-2-one (0.94 g, 3.38 mmol) in 20 ml of anhydrous tetrahydrofuran and stirred for 30 minutes. Methyl bromoacetate (0.44 ml, 4 mmol) was added dropwise to the reaction mixture then warmed to room temperature. The reaction was diluted with 100 ml of ethyl acetate and washed with 0.3N potassium hydrogen sulfate (50 ml), water (2×50 ml), and brine. The combined organics were dried over anhydrous sodium sulfate, filtered, and evaporated to afford a gum that was purified by flash chromatography eluting with 3:7 EtOAc/Hex. to give 0.98 g (83%) of the title compound as a white solid. 1H NMR (CDCl3) δ 7.15-7.07 (2H, m), 6.98-6.94 (1H, m), 6.88-6.84 (1H, d), 5.62-5.55 (1H, d), 4.71-4.65 (1H, d), 4.65-4.6 (1H, m), 4.33-4.27 (1H, d), 3.96-3.90 (1H, m), 3.78 (3H, s), 3.44-3.37 (1H, m), 1.4 (9H, s). ##STR161##
Reaction SMILES: CO[C:3]([CH:5]1[CH2:9][CH2:8][CH2:7][C:6]1=[O:10])=O.[F:11][C:12]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:13]=1[C:14]([NH2:16])=[NH:15].[CH2:22](O)C>>[Cl:21][C:18]1[CH:19]=[CH:20][C:12]([F:11])=[C:13]([C:14]2[N:16]=[C:6]([OH:10])[C:5]3[CH2:3][CH2:22][CH2:7][CH2:8][C:9]=3[N:15]=2)[CH:17]=1
Reactant: CCO
Reactant: N=C(N)c1cc(Cl)ccc1F
Reactant: COC(=O)C1CCCC1=O
Product: Oc1nc(-c2cc(Cl)ccc2F)nc2c1CCCC2
Temperature: 80 °C
Yield: 78 %

Procedure:
To a solution of methyl-2-oxocyclopentane carboxylate (2 g, 11.8 mmol, 1 eq), in dry ethanol (20 ml) was added a solution of 2-fluoro-5-chlorobenzamidine (2.04 g, 11.8 mmol, 1 eq) in ethanol (20 ml) and the reaction mixture was heated to 80° C. overnight. The reaction mixture was cooled to r.t. and the solvent was removed in vacuo to afford a crude residue which was purified by recrystallization from hot ethyl acetate to afford 2-(5-chloro-2-fluorophenyl)-5,6,7,8-tetrahydroquinazolin-4-ol (2.56 g, 78%) as a white solid.
Reaction SMILES: C([O:3][P:4]([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])C.Br[CH2:12][CH2:13][CH2:14][N:15]1[C:27]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2>>[CH:17]1[C:16]2[N:15]([CH2:14][CH2:13][CH2:12][P:4](=[O:3])([O:5][CH2:6][CH3:7])[O:8][CH2:9][CH3:10])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]=2[CH:20]=[CH:19][CH:18]=1
Reactant: CCOP(OCC)OCC
Reactant: BrCCCn1c2ccccc2c2ccccc21
Product: CCOP(=O)(CCCn1c2ccccc2c2ccccc21)OCC
Temperature: 130 °C
Reaction time: 18 h
Yield: 92.2 %

Procedure:
Triethylphosphite (13.4 mL, 80.1 mmol) was added via syringe to 9-(3-bromopropyl)-9H-carbazole (7.70 g, 26.7 mmol) in a 50 mL rbf. The reaction was heated and stirred under Argon at 130° C. for 18 hours. Excess triethylphosphite and side-products were removed under vacuum at ˜100° C. to yield a thick yellow oil (8.50 g, 92% yield). 1H NMR (400.14 MHz, CD2Cl2) δ 8.10 (dt, J=7.73, 2.00 Hz, 2H), 7.50-7.44 (m, 4H), 7.27-7.19, m, 2H), 4.43 (t, J=7.00 Hz, 2H), 4.10-3.95 (m, 4H), 2.23-2.09 (m, 2H), 1.74 (dt, J=18.41, 7.80 Hz, 2H), 1.26 (t, J=7.00 Hz, 6H). 13C{1H} NMR (100.62 MHz, CD2Cl2) δ 139.99 (2C), 125.36 (2C), 122.42 (2C), 119.88 (2C), 118.56 (2C), 108.37 (2C), 61.18 (d, J=6.44 Hz), 42.52 (d, J=15.39 Hz), 22.59 (d, J=141.97 Hz), 21.75 (J=4.83 Hz), 15.91 (d, J=5.84 Hz). 31P{1H} NMR (161.97 MHz, CD2Cl2): δ 31.22. Analysis found (calculated) %: C, 65.67 (66.07); H, 7.01 (7.00); N, 4.05 (4.06). MS (EI, m/z): 290 ([M], 100%). Exact mass found (calculated for [M], m/z): 345.14264 (345.14938).
Reaction SMILES: CN(C=O)C.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:23](=[O:24])[C:22]3[C:17](=[C:18]([O:28][CH2:29][CH2:30][CH3:31])[CH:19]=[C:20]4[CH2:27][CH2:26][CH2:25][C:21]4=3)[NH:16][CH:15]=2)=[CH:10][CH:9]=1.[H-].[Na+].Br[CH2:35][CH2:36][CH2:37][Cl:38]>C(OCC)(=O)C.O>[Cl:38][CH2:37][CH2:36][CH2:35][N:16]1[CH:15]=[C:14]([C:11]2[CH:10]=[CH:9][C:8]([O:7][CH3:6])=[CH:13][CH:12]=2)[C:23](=[O:24])[C:22]2[C:17]1=[C:18]([O:28][CH2:29][CH2:30][CH3:31])[CH:19]=[C:20]1[CH2:27][CH2:26][CH2:25][C:21]1=2
Reactant: ClCCCBr
Reactant: CCCOc1cc2c(c3c(=O)c(-c4ccc(OC)cc4)c[nH]c13)CCC2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCOc1cc2c(c3c(=O)c(-c4ccc(OC)cc4)cn(CCCCl)c13)CCC2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 23.8 %

Procedure:
To a DMF solution (6 ml) of 8-(4-methoxyphenyl)-5-propoxy-1,2,3,6-tetrahydro-6-aza-cyclopenta[a]naphthalen-9-one (1.26 g, 3.60 mmol) was added sodium hydride (60% oil base, 189 mg, 4.33 mmol). The mixture was stirred at room temperature for 10 minutes. To the resulting mixture was added 1-bromo-3-chloropropane (1.70 g, 10.8 mmol), followed by stirring at room temperature for 16 hours. Water and ethyl acetate were added to the reaction mixture and the resulting reaction mixture was then subjected to separation. The thus-obtained organic layer was washed with an aqueous saturated sodium chloride solution twice. After being dried over anhydrous sodium sulfate, the organic layer was concentrated under reduced pressure. The residue was purified using silica gel column chromatography (dichloromethane:ethyl acetate=20:1→12:1). The purified product was concentrated under reduced pressure, giving a yellow oily substance of 6-(3-chloropropyl)-8-(4-methoxyphenyl)-5-propoxy-1,2,3,6-tetrahydro-6-aza-cyclopenta[a]naphthalen-9-one (365 mg, yield: 92%).
Reaction SMILES: Cl.[CH3:2][O:3]/[N:4]=[C:5](/[C:9]1[N:10]=[C:11]([NH:14][C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:12][CH:13]=1)\[C:6]([OH:8])=O.CS(Cl)(=O)=O.C(N(C(C)C)CC)(C)C.[NH2:48][C@@H:49]1[C:68](=[O:69])[N:51]2[C:52]([C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])=[C:53]([CH:56]3[CH2:60][CH2:59][O:58][CH2:57]3)[CH2:54][S:55][C@H:50]12>CN(C=O)C.N1C=CC=CC=1>[CH3:2][O:3]/[N:4]=[C:5](/[C:9]1[N:10]=[C:11]([NH:14][C:15]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[S:12][CH:13]=1)\[C:6]([NH:48][C@@H:49]1[C:68](=[O:69])[N:51]2[C:52]([C:61]([O:63][C:64]([CH3:65])([CH3:66])[CH3:67])=[O:62])=[C:53]([CH:56]3[CH2:60][CH2:59][O:58][CH2:57]3)[CH2:54][S:55][C@H:50]12)=[O:8]
Reactant: CC(C)(C)OC(=O)C1=C(C2CCOC2)CS[C@@H]2[C@H](N)C(=O)N12
Reactant: CO/N=C(\C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(C)(C)C)=C(C3CCOC3)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1

Procedure:
2-(Z)-Methoxyimino-2-(2-tritylaminothiazol-4-yl)acetic acid hydrochloride (0.751g) in DMF (5ml) was treated with methanesulphonyl chloride (0.179g, 0.121ml) and diisopropylethylamine (0.404g, 0.544ml) as described in Example 1(g). This was then treated with t-butyl (6R,7R)-7-amino-3-[(RS)-tetrahydrofuran-3-yl]ceph-3-em-4-carboxylate (0.464g) and pyridine (0.112g, 0.114ml) in DMF (5ml). Following work up and purification by flash chromatography with 40, 50 and 60% ethyl acetate/hexane, the title compound was obtained as a yellow foam (0.874g, 82%); vmax (CH2Cl2) 3398, 1783, 1731 (shoulder), 1718 and 1688cm-1 ; δH (CDCl3) 1.53 (9H, s), 1.69-2.43 (3H, m's), 3.29 and 3.46 with 3.34 and 3.48 (2H, 2ABq's, J 17.7 and 17.7Hz), 3.63-4.07 (6H, m's and s), 5.03 and 5.06 (1H, 2d's, J 4.8 and 4.8Hz), 5.84-5.90 (1H, m), 6.73 and 6.74 (1H, 2s), 6.76 and 6.90 (1H, 2d's, J 8.7 and 8.7Hz exchangeable with D2O), 7.02 (1H, br. s, exchangeable with D2O) and 7.31 (15H, s). [Mass spectrum: +ve ion (3NOBA, Na+) MNa+ (774)].
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](=O)[CH2:5][C:6]([O:8]C)=O.C(O)(=O)C.[CH:15]([NH2:17])=[NH:16].C[O-].[Na+]>CO>[CH3:1][O:2][CH2:3][C:4]1[N:17]=[CH:15][N:16]=[C:6]([OH:8])[CH:5]=1
Reactant: COCC(=O)CC(=O)OC
Reactant: N=CN
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COCc1cc(O)ncn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of methyl 4-methoxyacetoacetate (2.0 g, 13.69 mmole) in MeOH (15 mL) was added formamidine acetate (1.57 g, 15.05 mmole) and NaOMe (6.5 mL of a 25% by weight solution in MeOH, 30.11 mmole) then the mixture was heated to reflux. After 18 hours, the mixture was cooled to room temperature and concentrated to dryness. The residue was taken up in H2O and the pH adjusted to 7. The aqueous mixture was extracted with CHCl3 (3×). The combined organic layers were dried (MgSO4), filtered, and concentrated to give the title compound which was sufficiently pure for use in the next step without purification. 1H-NMR (500 MHz, CDCl3) δ 8.17 (s, 1H), 6.60 (s, 1H), 4.38 (s, 2H), 3.50 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.O>C(Cl)Cl.CCN(CC)CC>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:8])=[CH:9][CH:10]=1
Reactant: C1CCNCC1
Reactant: Nc1ccc(C(=O)O)cc1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Nc1ccc(C(=O)N2CCCCC2)cc1
Reaction time: 16 h

Procedure:
To a solution of 100 mg 4-Amino-benzoic acid in 1 mL DCM and 0.2 mL NEt3, 62 mg piperidine and 184 mg BOP-Cl were added at RT and the mixture was stirred for 16 h. After the addition of 5 mL water the mixture was filtered through a chem elut® cartridge by elution with ethyl acetate and then concentrated under reduced pressure. The residue was directly subjected to the subsequent amide coupling reaction without further purification. Yield: 125 mg.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH3:9])[CH:3]=1.II.FC(F)(F)C(OI([C:25]1[CH:30]=CC=C[CH:26]=1)OC(=O)C(F)(F)F)=O.[Cl:33]CCl>CO>[Cl:33][C:30]1[CH:25]=[CH:26][C:7]2[C:2](=[CH:3][C:4]([CH3:9])=[N:5][C:6]=2[CH3:8])[N:1]=1
Reactant: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Reactant: ClCCl
Reactant: Cc1cc(N)cc(C)n1
Agent: II
Solvent: CO
Product: Cc1cc2nc(Cl)ccc2c(C)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 21.2 %

Procedure:
4-Amino-2,6-dimethylpyridine (2.29 g, 18.7 mmol) was added to a solution of iodine (4.78 g, 18.8 mmol) and [bis(trifluoroacetoxy)iodo]benzene (8.1 g, 18.8 mmol) in dichloromethane (100 mL) and MeOH (30 mL). The mixture was stirred at room temperature for 16 hours. The reaction was quenched by addition of a mixture of saturated sodium metabisulphite solution (70 mL) and saturated sodium carbonate solution (300 mL). The organic phase was separated, washed with brine, and dried over sodium sulfate (Na2SO4). The solvent was removed and the product was purified by silica gel chromatography eluting with 30:1 dichloromethane:MeOH to afford the desired product (998 mg, 21.2%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:6][CH:5]=1)([O-])=O.[NH4+].[Cl-]>CCO.O.[Fe]>[N:11]1([CH2:10][C:7]2[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: O=[N+]([O-])c1ccc(CN2CCOCC2)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1ccc(CN2CCOCC2)cc1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A mixture of 4-[(4-nitrophenyl)methyl]morpholine (220 mg, 1.0 mmol, Step A), iron powder (279 mg, 5.0 mmol) and NH4Cl (39 mg, 0.7 mmol) in EtOH (3 mL) and H2O (3 mL) was stirred for 4 h at 80° C. Filtration and concentration gave the crude 4-(morpholin-4-ylmethyl)-phenylamine, which was used in next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][NH2:8])=[O:6].[CH:12]1([N:15]=[C:16]=[O:17])[CH2:14][CH2:13]1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][NH:8][C:16]([NH:15][CH:12]1[CH2:14][CH2:13]1)=[O:17])=[O:6]
Reactant: NNC(=O)c1cccc(Cl)c1
Reactant: O=C=NC1CC1
Solvent: C1CCOC1
Product: O=C(NNC(=O)c1cccc(Cl)c1)NC1CC1

Procedure:
Under an argon atmosphere, 430 mg (2.52 mmol) of 3-chlorobenzoic acid hydrazide are placed in 6 ml tetrahydrofuran. 209 mg (2.52 mmol) of cyclopropyl isocyanate, dissolved in 2 ml tetrahydrofuran is added dropwise and further stirred overnight at room temperature. It is concentrated and purified by stirring the residue with diethyl ether, filtration, further washing with diethyl ether and drying in vacuo. 514 mg (80% of theory) of the target compound are thus obtained.
Reaction SMILES: Br[CH:2]1[CH:7]([CH2:8][CH3:9])[CH2:6][O:5][CH:4]([C:10]2[CH:15]=[CH:14][C:13]([B:16]3[O:20][C:19]([CH3:22])([CH3:21])[C:18]([CH3:24])([CH3:23])[O:17]3)=[C:12]([F:25])[CH:11]=2)[CH2:3]1.[H][H].C(N(CC)CC)C>C1(C)C=CC=CC=1.O.[Pd]>[CH2:8]([CH:7]1[CH2:6][O:5][CH:4]([C:10]2[CH:15]=[CH:14][C:13]([B:16]3[O:17][C:18]([CH3:24])([CH3:23])[C:19]([CH3:22])([CH3:21])[O:20]3)=[C:12]([F:25])[CH:11]=2)[CH2:3][CH2:2]1)[CH3:9]
Reactant: [H][H]
Reactant: CCC1COC(c2ccc(B3OC(C)(C)C(C)(C)O3)c(F)c2)CC1Br
Agent: [Pd]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: CCC1CCC(c2ccc(B3OC(C)(C)C(C)(C)O3)c(F)c2)OC1

Procedure:
18.0 g (36.2 mmol) of 4-bromo-5-ethyl-2-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]tetrahydropyran are hydrogenated for 30 h at a hydrogen pressure of 5 bar and at 80° C. in toluene/water in the presence of Pd/C (5% of Pd) and 12.7 ml (88.1 mmol) of triethylamine. The organic phase is separated off and filtered absorptively (SiO2, toluene). The filtrate is concentrated to dryness, and the residue is recrystallised from ethanol at reduced temperature, giving 5-ethyl-2-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]tetrahydropyran as a colourless solid.
Reaction SMILES: [C:1](N)(=O)/[CH:2]=C/C.CN(N)C.C(NC(=O)/C=C(\O[C:21](=[O:39])[C:22]1[CH:27]=[C:26]([S:28]([CH3:30])=[O:29])[C:25]([Cl:31])=[C:24]([NH:32][CH2:33][C:34]2[O:38][CH:37]=[CH:36][CH:35]=2)[CH:23]=1)/C)(C)(C)C.C([NH:43][NH:44][CH2:45][CH3:46])C>>[CH2:1]([N:44]([CH2:45][CH3:46])[NH:43][C:21](=[O:39])[C:22]1[CH:27]=[C:26]([S:28]([CH3:30])=[O:29])[C:25]([Cl:31])=[C:24]([NH:32][CH2:33][C:34]2[O:38][CH:37]=[CH:36][CH:35]=2)[CH:23]=1)[CH3:2]
Reactant: C/C=C/C(N)=O
Reactant: C/C(=C/C(=O)NC(C)(C)C)OC(=O)c1cc(NCc2ccco2)c(Cl)c(S(C)=O)c1
Reactant: CCNNCC
Agent: CN(C)N
Product: CCN(CC)NC(=O)c1cc(NCc2ccco2)c(Cl)c(S(C)=O)c1

Procedure:
By replacing the crotonamide and the unsymmetrical-dimethylhydrazine employed in Example 38 by equimolar quantities of N-tert-butyl-3-(3-furfurylamino-4-chloro-5-methylsulfinylbenzoyloxy)crotonamide and unsymmetrical-diethylhydrazine respectively and then following substantially the same procedure described in Example 38 there is obtained 3-furfurylamino-4-chloro-5-methylsulfinylbenzoic acid 2,2-diethylhydrazide.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=O)=[C:4]([N:11]([CH2:13][CH2:14][O:15][CH3:16])[CH3:12])[N:3]=1.N1C=CC=CC=1.O=P(Cl)(Cl)Cl.[OH-].[Na+]>C(#N)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]#[N:8])=[C:4]([N:11]([CH2:13][CH2:14][O:15][CH3:16])[CH3:12])[N:3]=1
Reactant: COCCN(C)c1nc(Cl)ccc1C(N)=O
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: COCCN(C)c1nc(Cl)ccc1C#N
Temperature: 55 °C
Yield: 88.6 %

Procedure:
To a solution of 6-chloro-2-[(2-methoxy-ethyl)-methyl-amino]-nicotinamide (3) (14 g, 58 mmol) in acetonitrile (anhydrous, 360 mL) were added pyridine (37.5 mL, 463.8 mmol) and POCl3 (21.2 mL, 232 mmol). The reaction was heated at 55° C. for 3 hours. After cooling to room temperature, NaOH solution (10% aq.) was slowly added till pH 9. The solution was extracted with EtOAc (3×200 mL). The combined organic layer was dried over MgSO4, filtered, and evaporated in vacuo. Purification was accomplished by silica gel chromatography, eluting with 5%-30% EtOAc/hexanes gradient, to afford 11.6 g (90% yield) of the desired product. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.61 (d, J=7.4 Hz, 1 H), 6.58 (d, J=7.8 Hz, 1 H), 3.87 (t, J=5.3 Hz, 2 H), 3.64 (t, J=5.3 Hz, 2 H), 3.38 (s, 3 H), 3.36 (s, 3 H).
Reaction SMILES: ON=[CH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)=[O:5].[OH:14]S(O)(=O)=O>>[CH3:13][C:10]1[CH:9]=[C:8]2[C:7](=[CH:12][CH:11]=1)[NH:6][C:4](=[O:5])[C:3]2=[O:14]
Reactant: O=S(=O)(O)O
Reactant: Cc1ccc(NC(=O)C=NO)cc1
Product: Cc1ccc2c(c1)C(=O)C(=O)N2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Hydroxyimino-N-p-tolyl-acetamide (14 g, 0.0078 mol) was added portion wise to a preheated (60° C.) conc. H2SO4 (70 mL) over a period of 30 min. After the addition, the mixture was stirred at the same temperature for another 1 h. The reaction mixture was cooled to room temperature and was poured into crushed ice. The precipitate was collected by filtration and washed with chilled water several times. Finally it was dried in a vacuum oven to get the required product as brick red coloured solid.
Reaction SMILES: [CH:1]12[O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2.[C:8]([K])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:10])[CH3:9]>>[CH3:9][C:8]([C@@H:2]1[CH2:3][CH2:4][CH2:5][CH2:6][C@H:1]1[OH:7])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:10]
Reactant: CC(C)([K])c1ccccc1
Reactant: C1CCC2OC2C1
Product: CC(C)(c1ccccc1)[C@@H]1CCCC[C@H]1O

Procedure:
The next step in the synthesis was the addition of cyclohexene oxide to α-cumylpotassium to produce trans-2-cumylcyclohexanol. Dropwise addition of 105 mL (1.0 mol) of cyclohexene oxide (available from Lancaster Synthesis, Ltd., Windham, N.H., U.S.A.) followed; as before, the cyclohexene oxide addition was controlled so that the bath temperature did not rise above 30° C. As cyclohexene oxide was added, the reaction mixture thinned and became black. After this addition, the mixture was stirred for 3 hours. The reaction flask was cooled in an ice bath and 750 mL of saturated aqueous ammonium chloride was added slowly to the reaction mixture, which changed in color from light brown to bright orange to light brown again; concurrently, a white precipitate that had formed during the initial stages of the addition dissolved.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[N:19]=[C:20]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[O:21][C:22]=3[CH3:23])=[CH:12][CH:11]=2)[C:5]([CH2:30][C:31]#N)=[CH:4][CH:3]=1.C(O)C.[OH-:36].[Na+].Cl.[OH2:39]>>[CH3:1][C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[N:19]=[C:20]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[O:21][C:22]=3[CH3:23])=[CH:12][CH:11]=2)[C:5]([CH2:30][C:31]([OH:39])=[O:36])=[CH:4][CH:3]=1
Reactant: O
Reactant: Cc1ccc(CC#N)c(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)n1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(CC(=O)O)c(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)n1
Yield: 82 %

Procedure:
To a mixture of 2-[6-methyl-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-3-pyridyl]acetonitrile. (0.58 g), ethanol (10 mL) was added a 2N aqueous sodium hydroxide solution (10 mL) and the mixture was heated under reflux for 24 hrs. 1N Hydrochloric acid (20 mL) and water were added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give crystals (0.51 g, 82%) of 2-[6-methyl-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-3-pyridyl]acetic acid. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 138-139° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=O.[CH3:22][O:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28](=[O:33])[CH2:27]2>>[CH3:22][O:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28](=[O:33])[C:27]2=[CH:20][C:3]1[NH:4][C:5]2[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)[C:7](=[O:19])[C:6]=2[C:2]=1[CH3:1]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCOCC1)CC2
Reactant: COc1ccc2c(c1)CC(=O)N2
Product: COc1ccc2c(c1)C(=Cc1[nH]c3c(c1C)C(=O)N(CCN1CCOCC1)CC3)C(=O)N2
Yield: 33.3 %

Procedure:
The title compound was prepared under the same conditions as described in Example 13 with 3-methyl-5-(2-morpholin-4-yl-ethyl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 5-methoxy-1,3-dihydro-indol-2-one (prepared according to U.S. Pat. No. 6,114,371) as starting materials to give 2-(5-methoxy-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-5-(2-morpholin-4-yl-ethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (30 mg, 33.3%) as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([Br:26])=[CH:24][CH:23]=[C:22](Cl)[N:21]=3)[C@H:14]2[CH3:28])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl.[F:32][CH:33]1[CH2:36][NH:35][CH2:34]1.C(=O)(O)[O-].[Na+]>CS(C)=O>[F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([Br:26])=[CH:24][CH:23]=[C:22]([N:35]4[CH2:36][CH:33]([F:32])[CH2:34]4)[N:21]=3)[C@H:14]2[CH3:28])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: FC1CNC1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1nc(Cl)ccc1Br
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1nc(N2CC(F)C2)ccc1Br
Temperature: 150 °C
Reaction time: 8 h

Procedure:
To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(3-bromo-6-chloropyridin-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one (INTERMEDIATE 24, 2.0 g, 3.86 mmol) in DMSO (25 mL), under nitrogen, were added 3-fluoroazetidine hydrochloride (2.16 g, 19.3 mmol) and sodium bicarbonate (1.95 g, 23.2 mmol). The resulting mixture was stirred at 150° C. overnight. The reaction mixture was quenched with water, then extracted 3 times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate in hexanes to afford the titled compound. 1H NMR (500 MHz, CDCl3): δ 7.92 (s, 1H); 7.81 (s, 2H); 7.60 (d, J=8.5 Hz, 1H); 6.20 (d, J=8.6 Hz, 1H); 5.79 (d, J=8.6 Hz, 1H); 5.52 (m, 0.5H); 5.40 (m, 0.5H); 4.90 (d, J=16.9 Hz, 1H); 4.40-4.24 (m, 4H); 4.20-4.09 (m, 2H); 0.82 (d, J=6.6 Hz, 3H).
Reaction SMILES: CO[C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1.[H-].[Na+].[C:15](#[N:17])[CH3:16]>C1(C)C=CC=CC=1>[CH3:11][O:10][C:7]1[CH:6]=[CH:5][C:4]([C:3]([CH2:16][C:15]#[N:17])=[O:12])=[CH:9][CH:8]=1
Reactant: CC#N
Reactant: COC(=O)c1ccc(OC)cc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1ccc(C(=O)CC#N)cc1
Reaction time: 20 h

Procedure:
166.2 grams (1 mole) of 4-methoxybenzoic acid methyl ester and 60 grams (2 moles) of sodium hydride (80 weight % suspension in white oil) were heated to 65° C. in 750 ml of dry toluene. Within 2 hours there were dropped in 82.1 grams (2 moles) of acetonitrile at 85° C. and then stirring was continued for a further 20 hours at 90° C. The precipitate was filtered off with suction, 200 ml of glacial acetic acid slowly stirred in with cooling and subsequently the mixture was added to 1 liter of ice water. The precipitated crystal mass was filtered off with suction, post washed with water and recrystallized from acetone. There were thus obtained 149 grams (85% of theory) or 4-methoxybenzoylacetonitrile having a melting point of 127°-129° C.