Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][O:19][CH3:20])[N:12]=[CH:11][NH:10][C:9]2=O.CN(C)C=O.C(Cl)(=O)C([Cl:30])=O.O>ClCCl>[Cl:30][C:9]1[C:8]2[C:13](=[CH:14][C:15]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])[CH:7]=2)[N:12]=[CH:11][N:10]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COCCOc1cc2nc[nH]c(=O)c2cc1OCCOC
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: COCCOc1cc2ncnc(Cl)c2cc1OCCOC
Temperature: 25 °C
Reaction time: 12 h
Yield: 126.7 %

Procedure:
To a solution of compound 22 (2.60 g, 8.83 mmol) in dichloromethane (25 mL), was added a drop of N,N-Dimethyl formamide and to that oxalyl chloride (1.52 mL, 17.669 mmol) was added dropwise. This mixture was stirred at room temperature for 12 h. Reaction was monitored by TLC and the reduction continued until TLC indicated no starting material. The reaction mixture was poured in to water. Extracted with ethyl acetate and the combined organic layer were washed with Sat.NaHCO3 and brine and dried over Na2SO4 and evaporated to give the crude compound 23 (3.5 g, crude), which was used in the next reaction without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[N:14][NH:15]3)=[CH:11][CH:10]=2)=[O:7])=[C:4](Cl)[CH:3]=1.[CH2:24]([NH:26][CH2:27][CH3:28])[CH3:25]>CN1C(=O)CCC1.O>[NH2:1][C:2]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[N:14][NH:15]3)=[CH:11][CH:10]=2)=[O:7])=[C:4]([N:26]([CH2:27][CH3:28])[CH2:24][CH3:25])[CH:3]=1
Reactant: Nc1cc(Cl)c(C(=O)Nc2ccc3cn[nH]c3c2)cc1[N+](=O)[O-]
Reactant: CCNCC
Solvent: CN1CCCC1=O
Solvent: O
Product: CCN(CC)c1cc(N)c([N+](=O)[O-])cc1C(=O)Nc1ccc2cn[nH]c2c1
Temperature: 25 °C

Procedure:
A solution 4-amino-2-chloro-N-(1H-indazol-6-yl)-5-nitrobenzamide (1 mmol; see Example 48) in NMP (2 mL) was added with diethylamine (1.0 mL), and the resulting mixture was subjected to microwave irradiation at 70° C. for 1 h. The reaction mixture was cooled to room temperature, diluted with water (20 mL). The solid formed was collected by filtration, washed with water, and dried in vacuo to provide 4-amino-2-diethylamino-N-(1H-indazol-6-yl)-5-nitrobenzamide.
Reaction SMILES: [ClH:1].[CH2:2]1[C:7]2[C:8](=[O:16])[C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[S:11][C:6]=2[CH2:5][CH2:4][NH:3]1.Br[CH2:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[ClH:1].[CH:19]1([CH2:18][N:3]2[CH2:4][CH2:5][C:6]3[S:11][C:10]4[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=4[C:8](=[O:16])[C:7]=3[CH2:2]2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: BrCC1CCCCC1
Reactant: O=c1c2c(sc3ccccc13)CCNC2
Agent: Cl
Product: O=c1c2c(sc3ccccc13)CCN(CC1CCCCC1)C2

Procedure:
Using the procedure of Example 19, 1,2,3,4-tetrahydro-10H-(1)-benzothiopyrano[3,2-c]pyridin-10-one hydrochloride and bromomethylcyclohexane were reacted to obtain 2-cyclohexylmethyl-1,2,3,4-tetrahydro-10H-(1)-benzothiopyrano[3,2-c]pyridin-10-one hydrochloride with the melting point and analysis of Table II.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:41][CH2:42][CH3:43])[C@@H:5]([N:7]([CH2:30][C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][CH:32]=1)[C:8](=[O:29])[C@@H:9]([NH:11]C(=O)OCC1C2C=CC=CC=2C2C1=CC=CC=2)[CH3:10])[CH3:6])[CH3:2].N1CCCCC1.CC(=O)OCC.CO>ClCCl>[NH2:11][C@@H:9]([CH3:10])[C:8]([N:7]([C@@H:5]([CH3:6])[CH:4]([O:41][CH2:42][CH3:43])[O:3][CH2:1][CH3:2])[CH2:30][C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][CH:32]=1)=[O:29]
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@H](C)NC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: C1CCNCC1
Solvent: CO
Solvent: ClCCl
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@H](C)N
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 79.6 %

Procedure:
(9H-Fluoren-9-yl)methyl (S)-1-(((S)-1,1-diethoxypropan-2-yl)(naphthalen-1-ylmethyl)amino)-1-oxopropan-2-ylcarbamate (Compound III-10) 15.7 g (27 mmol) and piperidine 22.7 g (270 mmol) were added in DCM (dichloromethane) (90 ml). The mixture was stirred for 1.5 h at room temperature. The mixture was diluted with DCM (200 ml) and washed with water (150 ml×3). The solution was concentrated in vacuo. The residue was purified by column chromatography on silica gel with PE:EA=50:1 to DCM:MeOH=10:1 to give the title compound 7.7 g, (yield 80%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:15])[CH2:9][NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:4][CH:3]=1.[CH3:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1.C(OCC)C>[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:15])[CH2:9][NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:4][CH:3]=2)=[CH:19][CH:18]=1
Reactant: CC(CNS(C)(=O)=O)c1ccc(Br)cc1
Reactant: Cc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccc(C(C)CNS(C)(=O)=O)cc2)cc1
Temperature: 100 °C
Yield: 42.1 %

Procedure:
To a degassed solution of 1.4 g (4.7 mmol) of the product of Example 1, 1.0 g (7.1 mmol) of 4-methylbenzeneboronic acid, 1.0 g (7.1 mmol) of potassium carbonate in 30 mL of toluene, and 10 mL of water was added 0.3 g (0.2 mmol) of tetrakis (triphenylphosphine)palladium(0). The mixture was heated to 100° C. for 2 hr, cooled to ambient temperature and the organic portion was separated. The aqueous portion was extracted three times with ethyl acetate and the combined organic portions were dried (MgSO4), filtered and concentrated in vacuo. The residue was chromatographed on silica gel (30% ethyl acetate/hexane) to afford an off-white solid. The solid was suspended in diethyl ether, filtered and dried in vacuo to afford 0.6 g (43%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:15])([CH3:14])[C:9]([O:11]CC)=[O:10])=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCCC1.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:15])([CH3:14])[C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)(C)c1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C(=O)O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of the product of Example 22A (3.7 g, 13.6 mmoles) in tetrahydrofuran (110.0 ml) and methanol (37.0 ml) was added 2 N sodium hydroxide (19.0 ml) and the solution was stirred at ambient temperature for about 16 hours. The reaction mixture was concentrated in vacuum down to the water layer, was cooled with an ice bath, and was acidified by addition of 2N hydrochloric acid. The precipitate was filtered off and was dried in vacuum to provide the title compound.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:5][CH:6]=[CH:7][CH:8]=1.C([O:17][C:18](=[O:29])[CH:19]([CH3:28])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)C>>[CH:10]1([S:9][C:4]2[C:3]([CH2:2][O:27][C:24]3[CH:23]=[CH:22][C:21]([CH2:20][CH:19]([CH3:28])[C:18]([OH:29])=[O:17])=[CH:26][CH:25]=3)=[CH:8][CH:7]=[CH:6][N:5]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CCOC(=O)C(C)Cc1ccc(O)cc1
Reactant: ClCc1cccnc1SC1CCCC1
Product: CC(Cc1ccc(OCc2cccnc2SC2CCCC2)cc1)C(=O)O
Yield: 40 %

Procedure:
3-Chloromethyl-2-cyclopentylsulfanyl-pyridine (0.056 g, 0.24 mmol) obtained in Step C of Preparation Example 8 and 3-(4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester obtained in Step B of Preparation Example 3 A were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.035 g, 40%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH:5]([O:18][CH2:19][CH3:20])[CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([OH:17])=[CH:9][CH:8]=1)[CH3:2].Cl[CH2:23][C:24]1[N:25]=[C:26]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:27][C:28]=1[CH3:29].[H-].[Na+]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:21])[CH:5]([O:18][CH2:19][CH3:20])[CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([O:17][CH2:23][C:24]2[N:25]=[C:26]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[O:27][C:28]=2[CH3:29])=[CH:9][CH:8]=1)[CH3:2]
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Reactant: CCOC(=O)C(Cc1ccc(O)c2ccccc12)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1ccc(OCc2nc(-c3ccccc3)oc2C)c2ccccc12)OCC

Procedure:
In analogy to the procedure described in example 108 c], [rac]-2-ethoxy-3-(4-hydroxy-naphthalen-1-yl)-propionic acid ethyl ester was treated with 4-chloromethyl-5-methyl-2-phenyloxazole and sodium hydride in N,N-dimethylformamide to yield [rac]-2-ethoxy-3-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-naphthalen-1-yl]-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 91 e] to yield [rac]-2-ethoxy-3-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-naphthalen-1-yl]-propionic acid as colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7](=[O:16])[N:8]2[CH2:13][CH:14]=O.[C:17]([O:21][C:22](=[O:41])[N:23]([CH2:30][C:31]1[CH:40]=[CH:39][C:34]2[O:35][CH2:36][CH2:37][O:38][C:33]=2[CH:32]=1)[CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)([CH3:20])([CH3:19])[CH3:18].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C.ClCCl>[C:17]([O:21][C:22](=[O:41])[N:23]([CH2:30][C:31]1[CH:40]=[CH:39][C:34]2[O:35][CH2:36][CH2:37][O:38][C:33]=2[CH:32]=1)[CH:24]1[CH2:29][CH2:28][N:27]([CH2:14][CH2:13][N:8]2[C:9]3[C:4](=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][CH:10]=3)[CH:5]=[CH:6][C:7]2=[O:16])[CH2:26][CH2:25]1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Reactant: COc1cccc2c1ccc(=O)n2CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COc1cccc2c1ccc(=O)n2CCN1CCC(N(Cc2ccc3c(c2)OCCO3)C(=O)OC(C)(C)C)CC1
Reaction time: 0.33 h
Yield: 71.3 %

Procedure:
1H-NMR (CDCl3) δ: 3.96 (3H, s), 5.13 (2H, s), 6.63 (1H, d, J=8.4 Hz), 6.70 (1H, d, J=9.8 Hz), 6.71 (1H, d, J=8.4 Hz), 7.45 (1H, t, J=8.4 Hz), 8.24 (1H, d, J=9.8 Hz), 9.66 (1H, s) (2) To 2.4 mL of dichloromethane solution containing 0.10 g of (5-methoxy-2-oxoquinolin-1(2H)-yl)acetaldehyde, 0.16 g of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate and 24 μL of acetic acid were added, and stirred for 20 min. To the reaction mixture, 0.15 g of sodium triacetoxyborohydride was added, and stirred for 50 min. Chloroform and aqueous saturated sodium hydrogen carbonate solution were added, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=1:3], to give 0.18 g of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(5-methoxy-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a pale yellow oil.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][C:9]([NH:16][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[C:10]([F:15])[CH:11]=2)[N:6]([CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[CH:5]=1.O=[C:29]([CH3:39])[CH2:30][P:31](=[O:38])([O:35][CH2:36][CH3:37])[O:32][CH2:33][CH3:34].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(N(CC)CC)C>C1COCC1.O.C(O)(=O)C>[CH:17]1([NH:16][C:9]2[CH:8]=[C:7]3[C:12]([C:13](=[O:14])[C:4]([CH2:3][NH:2][CH:29]([CH3:39])[CH2:30][P:31](=[O:38])([O:35][CH2:36][CH3:37])[O:32][CH2:33][CH3:34])=[CH:5][N:6]3[CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25])=[CH:11][C:10]=2[F:15])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: CCOP(=O)(CC(C)=O)OCC
Reactant: CCC(CC)n1cc(CN)c(=O)c2cc(F)c(NC3CCCCC3)cc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: CCOP(=O)(CC(C)NCc1cn(C(CC)CC)c2cc(NC3CCCCC3)c(F)cc2c1=O)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
250 mg of 3-(aminomethyl)-7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoroquinolin-4(1H)-one hydrochloride was dissolved in 25 ml of THF, and 0.11 ml of diethyl (2-oxopropyl)phosphonate and 123 mg of sodium triacetoxyborohydride, 0.16 ml of triethylamine and 1.25 ml of acetic acid were added in that order, followed by overnight stirring at room temperature. Water was added, and the insoluble materials were collected by filtration and then purified by silica gel column chromatography to obtain 135 mg of diethyl [2-({[7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]methyl}amino)propyl]phosphonate.
Reaction SMILES: [C:1]([CH:3]([C:11]1[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=1)C(OC(C)(C)C)=O)#[N:2]>FC(F)(F)C(O)C(F)(F)F.C(OCC)C>[CH3:16][N:15]1[C:11]([CH2:3][C:1]#[N:2])=[CH:12][CH:13]=[N:14]1
Reactant: Cn1nccc1C(C#N)C(=O)OC(C)(C)C
Solvent: CCOCC
Solvent: OC(C(F)(F)F)C(F)(F)F
Product: Cn1nccc1CC#N
Yield: 95.9 %

Procedure:
A mixture of tert-butyl 2-cyano-2-(1-methyl-1H-pyrazol-5-yl)acetate (130 mg, 0.588 mmol) in hexafluoroisopropanol (1 mL) was submitted to microwave radiation at 130° C. for 15 minutes. The reaction mixture was diluted with diethyl ether (30 mL), washed with water (5 mL) and brine (5 mL), dried over magnesium sulfate, filtered, concentrated under reduced pressure and dried under high vacuum to afford 2-(1-methyl-1H-pyrazol-5-yl)acetonitrile (68.3 mg) as a pale yellow oil. 1H NMR (500 MHz, CDCl3) δ 3.77 (s, 2H), 3.89 (s, 3H), 6.30 (s, 1H), 7.45 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH3:8])[N:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[F:12][C:13]([F:25])([F:24])[C:14]([NH:16][C@H:17]1[CH2:23][CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=[O:15]>>[CH2:7]([N:6]1[C:2]([N:20]2[CH2:21][CH2:22][CH2:23][C@H:17]([NH:16][C:14](=[O:15])[C:13]([F:24])([F:12])[F:25])[CH2:18][CH2:19]2)=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=[N:5]1)[CH3:8]
Reactant: O=C(N[C@H]1CCCNCC1)C(F)(F)F
Reactant: CCn1ncc([N+](=O)[O-])c1Cl
Product: CCn1ncc([N+](=O)[O-])c1N1CCC[C@H](NC(=O)C(F)(F)F)CC1
Yield: 44 %

Procedure:
Following the procedure for Example 503 starting with 5-chloro-1-ethyl-4-nitro-1H-pyrazole and (S)-2,2,2-trifluoro-N-(hexahydro-1H-azepin-4-yl)-acetamide gave (S)-N-(1-(1-ethyl-4-nitro-1H-pyrazol-5-yl)azepan-4-yl)-2,2,2-trifluoroacetamide as a pale yellow gum (0.12 g, 44%). 1H-NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 6.42-6.40 (m, 1H), 4.22-4.18 (m, 1H), 4.12 (q, J=7 Hz, 2H), 3.42-3.35 (m, 1H), 3.27-3.18 (m, 3H), 2.25-2.05 (m, 2H), 2.00-1.75 (m, 4H), 1.47 (t, J=7 Hz, 3H).
Reaction SMILES: CN(C)C=O.C(Cl)(=O)C(Cl)=O.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:24]3[C:25](=[O:42])[N:26]([C:29]4[CH:34]=[CH:33][C:32]([N:35]5[CH:40]=[CH:39][CH:38]=[CH:37][C:36]5=[O:41])=[CH:31][CH:30]=4)[CH2:27][CH2:28][C:23]=3[C:22]([C:43]([NH2:45])=O)=[N:21]2)=[CH:16][CH:15]=1.N1C=CC=CC=1>CC#N>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:24]3[C:25](=[O:42])[N:26]([C:29]4[CH:34]=[CH:33][C:32]([N:35]5[CH:40]=[CH:39][CH:38]=[CH:37][C:36]5=[O:41])=[CH:31][CH:30]=4)[CH2:27][CH2:28][C:23]=3[C:22]([C:43]#[N:45])=[N:21]2)=[CH:16][CH:15]=1
Reactant: COc1ccc(-n2nc(C(N)=O)c3c2C(=O)N(c2ccc(-n4ccccc4=O)cc2)CC3)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: CC#N
Product: COc1ccc(-n2nc(C#N)c3c2C(=O)N(c2ccc(-n4ccccc4=O)cc2)CC3)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To dimethylformamide (0.2 mL, 2.6 mmol) in CH3CN (20 mL) at 0° C. was added oxalyl chloride (0.23 mL, 2.6 mmol) and the reaction was stirred 0.5 h. The amide from Example 27 was added and the reaction was stirred cold 0.5 h. Pyridine (0.37 mL, 4.6 mmol) was added and the reaction was allowed to warm to rt and stirred for 24 h. The solvent was stripped, the residue was partitioned between CH2CO2 and 1N HCl, and the layers separated. The aqueous layer was basified with 1N NaOH and extracted with EtOAc. The organic layers were combined and dried (MgSO4). Purification by chromatography on silica gel using 3% MeOH in CH2Cl2 and recrystallization from CH2Cl2/hexanes afforded 117 mg (89%); 1H NMR (CDCl3) δ 7.50 (d,j=8.8 Hz, 2H), 7.44 (m, 5H), 7.31 (m, 1H), 6.97 (d,j=9.2 Hz, 2H), 6.71 (d,j=9.5 Hz, 2H), 6.28 (m, 1H), 4.24 (t,j=6.6 Hz, 2H), 3.85 (s, 3H), 3.24 (t,j=6.6 Hz, 2H) ppm; LRMS (M+H)+ 438.4.
Reaction SMILES: [O:1]=[CH:2]C(Cl)(Cl)Cl.[NH2:7][CH2:8][C:9]1([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>C(Cl)(Cl)Cl>[CH:2]([NH:7][CH2:8][C:9]1([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:1]
Reactant: O=CC(Cl)(Cl)Cl
Reactant: NCC1(N2CCCCC2)CCCCC1
Solvent: ClC(Cl)Cl
Product: O=CNCC1(N2CCCCC2)CCCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.6 %

Procedure:
Chloral (4.65 g.) was added dropwise to a cooled solution of 1-[1-(aminomethyl)cyclohexyl]piperidine (5.9 g) in dry chloroform (30 ml). The mixture was stirred at room temperature for 16 hrs. and then heated under reflux for 30 mins. The solution was evaporated to dryness and the oily residue re-evaporated with ether. This residual brown oil (7.9 g) was distilled under high vacuum to give a viscous pale yellow oil of 1-[1-(formamidomethyl)cyclohexyl]piperidine (5.1 g.) b.p. 170°-2°C at 1.7 mm.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=O)=[CH:4][CH:3]=1.[C:17]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])#[N:18].C1C=CC=CC=1.NCCC(O)=O>O.C(O)(=O)C>[C:17]([C:19](=[C:6]([C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)[C:5]1[CH:15]=[CH:16][C:2]([F:1])=[CH:3][CH:4]=1)[C:20]([O:22][CH2:23][CH3:24])=[O:21])#[N:18]
Reactant: CCOC(=O)CC#N
Reactant: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: NCCC(=O)O
Solvent: c1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C(C#N)=C(c1ccc(F)cc1)c1ccc(F)cc1
Reaction time: 336 h
Yield: 56.2 %

Procedure:
A mixture of 20.0 g (92 mmoles) of 4,4'-difluorobenzophenone, 11.0 g (97 mmoles) of ethyl cyanoacetate in a mixed solvent of 100 mL of dry benzene and 20 mL of glacial acetic acid containing a catalytic amount of β-alanine (0.9 g) was refluxed with separation of water using a Dean-Stark water trap. Separation of water was rapid during the first 2 hours (0.4 mL aqueous layer collected) but slower afterward. Azeotropic distillation was continued for a period of 14 days. Analytical TLC eluted with 10% EtOAc in hexanes (v/v) (Merck plate, 0.25 mm Silica gel-F) showed two spots at Rf =0.2 (desired product) and at Rf =0.45 (4,4'-difluorobenzophenone starting material). Crude reaction mixture was washed with water (40 mL×2), and the combined aqueous washes were extracted with EtOAc (150 mL×2). The organic layers were combined, dried over MgSO4 and concentrated under reduced pressure to crystallize the product as pale cubic crystals. The crude product was collected, washed with 1:1 EtOAc in hexanes (v/v) then recrystallized from 8:1 (hexanes:ethyl acetate v/v) to give 16.2 g (56.3%) of analytical pure title compound; m.p.=114°-116° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([OH:17])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH3:19].[H-].[Na+]>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([O:17][CH3:19])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: N#Cc1ccc(OCc2ccccc2)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(OCc2ccccc2)ccc1C#N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a magnetically stirred solution of 4-benzyloxy-2-hydroxybenzonitrile (1-A, WO 00/69841) (7.95 g, 35.3 mmol) and iodomethane (5.43 mL, 87.2 mmol) in DMF (90 mL) cooled to −5° was added all at once sodium hydride (60% dispersion, 2.17 g, 54.2 mmol). The mixture was stirred for 30 min, warmed to room temperature and stirred for an additional 2 h. Most of the DMF was removed in vacuo, and the residue was partitioned between water and ethyl acetate. The aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with water and saturated brine and dried (MgSO4). The residue after removal of the solvent in vacuo was triturated with hexane and chromatographed on silica gel with hexanes-CH2Cl2 (2:3) to give 4-benzyloxy-2-methoxybenzonitrile (1-B). MS: m/z 240 (M+1); 1H NMR (500 MHz, CDCl3): δ 7.47 (d, 1H, J=8.4 Hz), 7.36-7.45 (m, 5H), 6.58 (dd, 1H, J=2.3, 8.4 Hz), 6.57 (d, 1H, J=2.3 Hz), 5.10 (s, 2H), 3.88 (s, 3H) ppm.
Reaction SMILES: C([O:3][C:4]([C:6]12[CH2:23][CH:22]1[CH:21]=[CH:20][CH2:19][CH2:18][CH2:17][CH2:16][NH:15][C:14](=[O:24])[N:13]1[CH:9]([CH2:10][CH:11]([O:25][C:26]3[C:35]4[C:30](=[CH:31][C:32]([O:36][CH3:37])=[CH:33][CH:34]=4)[N:29]=[C:28]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH:27]=3)[CH2:12]1)[C:8](=[O:44])[NH:7]2)=[O:5])C.[OH-].[Na+]>CO>[CH3:37][O:36][C:32]1[CH:31]=[C:30]2[C:35]([C:26]([O:25][CH:11]3[CH2:10][CH:9]4[N:13]([C:14](=[O:24])[NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20]=[CH:21][CH:22]5[C:6]([C:4]([OH:5])=[O:3])([NH:7][C:8]4=[O:44])[CH2:23]5)[CH2:12]3)=[CH:27][C:28]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)=[N:29]2)=[CH:34][CH:33]=1
Reactant: CCOC(=O)C12CC1C=CCCCCNC(=O)N1CC(Oc3cc(-c4ccccc4)nc4cc(OC)ccc34)CC1C(=O)N2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCNC(=O)N4C3)cc(-c3ccccc3)nc2c1
Temperature: 60 °C
Yield: 64.9 %

Procedure:
Compound 139 (55 mg, mol) was dissolved in 2 ml of methanol and mixed with 3 eq. of aqueous NaOH and heated for 2 h at 60° C. in a closed vial. The reaction mixture was then extracted into ethyl acetate. The water solution was collected and acidified with 1N HCl solution to pH 2. The resulting solution was concentrated by rotary evaporation, dissolved in methanol and purified by preparative HPLC (acetonitrile-water) to give 34 mg of the title product. Yield 65%. MS (M+H+) 571.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]([CH3:13])[C:10]([OH:12])=O.ClC1C=CC=CC=1Cl>O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[CH2:8][CH:9]([CH3:13])[C:10]2=[O:12]
Reactant: CC(Cc1ccccc1Br)C(=O)O
Solvent: Clc1ccccc1Cl
Solvent: O
Product: CC1Cc2c(Br)cccc2C1=O
Temperature: 140 °C
Reaction time: 6 h
Yield: 56.4 %

Procedure:
To 52.5 g of 3-(2-bromophenyl)-2-methylpropionic acid (215 mmole) were added 210 g of polyphosphoric acid and 250 ml of o-dichlorobenzene, and the mixture was stirred at 140° C. for 6 hours. The mixture was diluted with 300 ml of water, and the product was extracted with n-hexane and ether, dried and concentrated, and the residual concentrate thus obtained was distilled to give 27.3 g of 4-bromo-2-methylindan-1-one as a colorless oil (yield, 56%).
Reaction SMILES: C([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][C:20](=[O:24])[N:21]([CH3:23])[CH3:22])[C:11]=2[C:12]=1[CH3:13])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[CH3:22][N:21]([CH3:23])[C:20]([CH2:19][O:18][C:14]1[C:11]2[C:12]([CH3:13])=[C:8]([C:6]([OH:7])=[O:5])[O:9][C:10]=2[CH:17]=[CH:16][CH:15]=1)=[O:24]
Reactant: Cc1c(C(=O)OC(C)(C)C)oc2cccc(OCC(=O)N(C)C)c12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(C(=O)O)oc2cccc(OCC(=O)N(C)C)c12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The above 4-dimethylcarbamoylmethoxy-3-methyl-benzofuran-2-carboxylic acid tert-butyl ester was dissolved into a 40% TFA/methylene chloride solution, and stirred at room temperature for four hours. Evaporation of solvent gave 4-dimethylcarbamoylmethoxy-3-methyl-benzofuran-2-carboxylic acid in quantitative yield.