Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:14][C:13]3[CH:15]=[C:16]([O:19]C)[CH:17]=[CH:18][C:12]=3[C:11]=2[C:21]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)=[C:25]([C:38]#[N:39])[CH:24]=2)=[O:22])=[CH:6][CH:5]=1.B(Cl)(Cl)[Cl:41]>ClC(Cl)C>[ClH:41].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:14][C:13]3[CH:15]=[C:16]([OH:19])[CH:17]=[CH:18][C:12]=3[C:11]=2[C:21]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]3[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]3)=[C:25]([C:38]#[N:39])[CH:24]=2)=[O:22])=[CH:6][CH:5]=1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(OCCN3CCCCC3)c(C#N)c2)cc1
Reactant: ClB(Cl)Cl
Agent: Cl
Solvent: CC(Cl)Cl
Product: N#Cc1cc(C(=O)c2c(-c3ccc(O)cc3)sc3cc(O)ccc23)ccc1OCCN1CCCCC1

Procedure:
The title compound was prepared by dissolving 1.6 g (3.04 mmol) of [2-(4-methoxyphenyl)-6-methoxybenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]3-cyanophenyl]methanone hydrochloride in 20 mL of dichloroethane. 2.1 mL of condensed BCl3 was added and sealed in a vessel at room temperature. The reaction was allowed to proceed for sixteen hours. The reaction was quenched by pouring onto ice. The crude product was collected in the organic layer and evaporated to a solid. The product was further purified by chromatography and the hydrochloride prepared as in Preparation 1.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH:4]([NH:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[CH:19][CH:18]=1)=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Li+].[OH-].Cl>CO.O>[F:31][C:28]1[CH:27]=[CH:26][C:25]([O:24][CH2:23][C:20]2[CH:19]=[CH:18][C:17]([CH2:16][O:15][C:13]([NH:12][CH:4]([CH2:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:3]([OH:32])=[O:2])=[O:14])=[CH:22][CH:21]=2)=[CH:30][CH:29]=1
Reactant: COC(=O)C(Cc1ccccc1)NC(=O)OCc1ccc(COc2ccc(F)cc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(NC(Cc1ccccc1)C(=O)O)OCc1ccc(COc2ccc(F)cc2)cc1
Reaction time: 2 h
Yield: 66.5 %

Procedure:
2-[4-(4-Fluoro-phenoxymethyl)benzyloxycarbonyl]amino-3-phenyl-propionic acid methyl ester 38 (115 mg) was dissolved in 10 ml methanol, then treated with 1.1 equiv LiOH in water. After 2 hrs at 60° C., the mixture was poured into water, acidified with HCl, and extracted The organic phase was dried, evaporated and recrystallized to yield about 74 mg of 2-[4-(4-fluorophenoxymethyl) benzyloxycarbonyl]amino-3-phenyl-propionic acid 40, mp. 111.8-113.4° C.
Reaction SMILES: [CH3:1][C:2]1[C:15](=[O:16])[N:14]=[C:13]2[N:4]([C@@H:5]3[O:9][C@H:8]([CH2:10][OH:11])[C@@H:7]([O:12]2)[CH2:6]3)[CH:3]=1.[N-:17]=[N+:18]=[N-:19].[Na+]>CN(C=O)C.O>[N:17]([C@@H:7]1[C@@H:8]([CH2:10][OH:11])[O:9][C@@H:5]([N:4]2[CH:3]=[C:2]([CH3:1])[C:15](=[O:16])[NH:14][C:13]2=[O:12])[CH2:6]1)=[N+:18]=[N-:19]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cn2c(nc1=O)O[C@H]1C[C@H]2O[C@@H]1CO
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cn([C@H]2C[C@H](N=[N+]=[N-])[C@@H](CO)O2)c(=O)[nH]c1=O

Procedure:
2,3'-Anhydrothymidine (25 O: 0.1115 mol) and NaN3 (29 g, 0.446 mol) was suspended in a mixture of 250 ml DMF and 38 ml H2O. The reaction was refluxed for 5 hours at which time it was poured into 1 liter of H2O. The aqueous solution was extracted with EtOAc (3×700 ml). The EtOAc was dried over Na2SO4, filtered and the EtOAoac was removed in vacuo to yield a viscous oil. This oil was stirred with 200 ml water resulting in a solid 9.15 g (0.0342 mol, 30.7%). mp=116°-118° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15](=[N:22][CH2:23][C:24]([O:26]CC)=O)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:4][CH2:3]1.N>FC(F)(F)C(O)=O>[CH3:1][N:2]1[CH2:3][CH2:4][CH:5]([N:8]2[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:22][CH2:23][C:24]2=[O:26])[CH2:6][CH2:7]1
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1NC1CCN(C)CC1
Agent: N
Solvent: O=C(O)C(F)(F)F
Product: CN1CCC(N2C(=O)CN=C(c3ccccc3)c3ccccc32)CC1
Temperature: 0 °C
Yield: 83.5 %

Procedure:
A solution of 379 mg of the above product 2 in 4 ml of trifluoroacetic acid is refluxed under heating for 16 hours. The reaction mixture is mixed with ice water, basified with ammonia and extracted with methylene chloride. The organic layer is washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue is crystallized from ether-petroleum ether to give 278 mg of 1-(1-methyl-4-piperidinyl)-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one 3 as crystals melting at 158°-159° C. The yield is 87%.
Reaction SMILES: Cl.[CH2:2]([O:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[N:16]1[CH2:22][CH2:21][CH2:20][N:19]([CH2:23][CH2:24][C:25]2([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:29][CH2:28][NH:27][CH2:26]2)[CH2:18][CH2:17]1)[CH3:3].[CH3:36][O:37][C:38]1[CH:46]=[CH:45][C:44]([N:47]2[C:51]([C:52]([F:55])([F:54])[F:53])=[N:50][N:49]=[N:48]2)=[CH:43][C:39]=1[C:40](O)=[O:41]>>[CH3:36][O:37][C:38]1[CH:46]=[CH:45][C:44]([N:47]2[C:51]([C:52]([F:55])([F:53])[F:54])=[N:50][N:49]=[N:48]2)=[CH:43][C:39]=1[C:40]([N:27]1[CH2:28][CH2:29][C:25]([CH2:24][CH2:23][N:19]2[CH2:20][CH2:21][CH2:22][N:16]([C:8]3[N:7]([CH2:6][CH2:5][O:4][CH2:2][CH3:3])[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[N:9]=3)[CH2:17][CH2:18]2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:26]1)=[O:41]
Reactant: COc1ccc(-n2nnnc2C(F)(F)F)cc1C(=O)O
Reactant: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Agent: Cl
Product: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(-n5nnnc5C(F)(F)F)ccc4OC)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 51.1 using 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt(prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt) and 2-methoxy-5-(5-trifluoromethyl-1H-tetrazol-1-yl)benzoic acid to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.[CH3:27][S:28]([N:31]1[CH2:35][CH2:34][CH:33]([NH2:36])[CH2:32]1)(=[O:30])=[O:29]>>[Cl:1][C:2]1[C:3]([NH:36][CH:33]2[CH2:34][CH2:35][N:31]([S:28]([CH3:27])(=[O:30])=[O:29])[CH2:32]2)=[C:4]2[NH:10][C:9]([C:11]3[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)=[CH:15][CH:16]=3)=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: CS(=O)(=O)N1CCC(N)C1
Reactant: Clc1cnc2[nH]c(-c3ccc(OCCN4CCOCC4)cc3)nc2c1Cl
Product: CS(=O)(=O)N1CCC(Nc2c(Cl)cnc3nc(-c4ccc(OCCN5CCOCC5)cc4)[nH]c23)C1
Yield: 19 %

Procedure:
By a procedure similar to that of Example 207 but using 6,7-dichloro-2-[4-(2-morpholin-4-ylethoxy)phenyl]-3H-imidazo[4,5-b]pyridine (Example 206) and 1-(methylsulfonyl)pyrrolidin-3-amine, the title compound was obtained in 19% yield.
Reaction SMILES: [CH:1]1([CH:7]([NH:22][C:23]2[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[CH3:20])[O:10][C:9]=2[CH3:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:32][NH:33][CH2:34][CH2:35][C:36]([O:38]CC)=[O:37]>>[CH:1]1([CH:7]([NH:22][C:23]2[CH:31]=[CH:30][C:26]([C:27]([N:33]([CH3:32])[CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[O:28])=[CH:25][CH:24]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[CH3:20])[O:10][C:9]=2[CH3:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)CCNC
Reactant: Cc1cc(F)ccc1-c1cc(C(Nc2ccc(C(=O)O)cc2)C2CCCCC2)c(C)o1
Product: Cc1cc(F)ccc1-c1cc(C(Nc2ccc(C(=O)N(C)CCC(=O)O)cc2)C2CCCCC2)c(C)o1
Yield: 99 %

Procedure:
An operation similar to that in Example 1 (4) was performed using 4-({cyclohexyl[5-(4-fluoro-2-methylphenyl)-2-methyl-3-furyl]methyl}amino)benzoic acid (464 mg) as well as ethyl 3-(methylamino)propanoate (171 mg) to give the title compound (552 mg, 99%) as an amorphous compound.
Reaction SMILES: C(C1CCC2C(=C(C(=O)C)C=CC=2[F:14])C1=O)(=O)C.[C:19]([NH:22][CH:23]1[CH2:32][CH2:31][C:30]2[C:25](=[C:26]([NH:33]C(=O)C)[CH:27]=[CH:28][CH:29]=2)[C:24]1=[O:37])(=[O:21])[CH3:20]>>[C:19]([NH:22][CH:23]1[CH2:32][CH2:31][C:30]2[C:25](=[C:26]([NH2:33])[CH:27]=[CH:28][C:29]=2[F:14])[C:24]1=[O:37])(=[O:21])[CH3:20]
Reactant: CC(=O)Nc1cccc2c1C(=O)C(NC(C)=O)CC2
Reactant: CC(=O)c1ccc(F)c2c1C(=O)C(C(C)=O)CC2
Product: CC(=O)NC1CCc2c(F)ccc(N)c2C1=O

Procedure:
The reaction was carried out in the same manner as in Example 1-(4), except that 300 mg of the compound prepared in (1) above was used instead of 2,8-diacetylamino-1-tetralone of Example 1-(4), and post-treated to produce 182 mg of the title compound.
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][O:5][C:6]([CH2:8]P(OCC)(OCC)=O)=[O:7].[CH3:17][C:18]1([CH3:29])[C:27](=O)[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[O:19]1>O1CCCC1>[CH2:4]([O:5][C:6]([CH2:8][C:27]1[C:18]([CH3:29])([CH3:17])[O:19][C:20]2[C:25]([CH:26]=1)=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:7])[CH3:3]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: CC1(C)Oc2ccccc2CC1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CC1=Cc2ccccc2OC1(C)C
Reaction time: 1 h

Procedure:
25 g (0.6 mol) of sodium hydride dispersion (57% in mineral oil) are substantially freed of mineral oil by repeated washing with n-hexane and are then covered with a layer of 500 ml of dried tetrahydrofuran. Under a nitrogen atmosphere and while cooling in an ice bath, 134 g (0.6 mol) of phosphonoacetic acid triethyl ester of formula (H5C2O)2P(=O)CH2C(=O)OC2H5 are added dropwise thereto within a period of 1 hour. The mixture is stirred for a further 1 hour at 0°. To the homogeneous solution there is then added dropwise within a period of 30 minutes a solution of 88.57 g (0.5 mol) of 2,2-dimethyl-3-oxo-chroman [F. Camps et al., J. Heterocyclic Chem. 22, 1421 (1985)] in 300 ml of tetrahydrofuran. The mixture is stirred overnight at room temperature. The solution is then concentrated to approximately 350 ml in vacuo and poured onto 3 liters of ice-cold phosphate buffer solution (pH=6). The mixture is extracted with diethyl ether. The combined organic phases are washed with water and dried over sodium sulfate and then concentrated by evaporation in vacuo. The yellow residue is chromatographed on 4 kg of silica gel (0.040-0.063 mm) with toluene as eluant, yielding 60.3 g (49% of the theoretical yield) of 3-ethoxycarbonylmethyl-2,2-dimethyl-2H-chromene in the form of a light-yellow oil.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[Cl:5][CH2:6][CH2:7][CH2:8][C:9](Cl)=[O:10].[CH3:12][N:13]([CH3:25])[C:14](=[O:24])[C:15]([CH3:23])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16]>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[CH3:25][N:13]([CH3:12])[C:14](=[O:24])[C:15]([C:17]1[CH:18]=[CH:19][C:20]([C:9](=[O:10])[CH2:8][CH2:7][CH2:6][Cl:5])=[CH:21][CH:22]=1)([CH3:23])[CH3:16]
Reactant: O=C(Cl)CCCCl
Reactant: CN(C)C(=O)C(C)(C)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CN(C)C(=O)C(C)(C)c1ccc(C(=O)CCCCl)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 72.4 %

Procedure:
Add AlCl3 (1.129, 8.40 mmol) to carbon tetrachloride (6 mL) under a nitrogen atmosphere at room temperature. Add 4-chlorobutyryl chloride (0.49 mL, 4.37 mmol), stir for 15 minutes and add, by dropwise addition over 3 minutes, a solution of 2-methyl-2-phenyl-propionic acid, dimethylamide (0.64 g, 3.36 mmol) in carbon tetrachloride (6 mL). Stir at room temperature for 17 hours, dilute with methylene chloride (10 mL), pour into ice water (50 mL) and separate the layers. Wash the aqueous layer with methylene chloride (2×70 mL), 51 aqueous sodium hydrogen carbonate, combine the organic layers and dry (Na2SO4). Filter, evaporate the filtrate in vacuo and purify by silica gel chromatography (5:2 hexane/ethyl acetate) to give the title compound (0.72 g, 72%) as a light yellow oil.
Reaction SMILES: [CH2:1]([C@H:8]([NH:19][C:20](=[O:30])[O:21][C@@H:22]1[C@H:29]2[C@H:25]([O:26][CH2:27][CH2:28]2)[O:24][CH2:23]1)[C@H:9]([OH:18])[CH2:10][NH:11][O:12][CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:31]([O:38][C:39]1[CH:44]=[CH:43][C:42]([S:45](Cl)(=[O:47])=[O:46])=[CH:41][CH:40]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(N(C(C)C)CC)(C)C>O1CCCC1.CN(C1C=CC=CN=1)C>[CH2:1]([C@H:8]([NH:19][C:20](=[O:30])[O:21][C@@H:22]1[C@H:29]2[C@H:25]([O:26][CH2:27][CH2:28]2)[O:24][CH2:23]1)[C@H:9]([OH:18])[CH2:10][N:11]([S:45]([C:42]1[CH:41]=[CH:40][C:39]([O:38][CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[CH:44][CH:43]=1)(=[O:47])=[O:46])[O:12][CH:13]([CH2:14][CH3:15])[CH2:16][CH3:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(CC)ONC[C@@H](O)[C@H](Cc1ccccc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21
Reactant: O=S(=O)(Cl)c1ccc(OCc2ccccc2)cc1
Agent: CN(C)c1ccccn1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCC(CC)ON(C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.1 %

Procedure:
A mixture of (3R,3aS, 6aR)hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-1-benzyl-3-[(l-ethylpropoxy)amino]-2-hydroxypropylcarbamate (200 mg, 0.474 mmol), 4-benzyloxybenzenesulphonyl chloride (134 mg, 0.474 mmol), diisoproylethylamine (0.083 mL, 0.474 mmol) and dimethylaminopyridine (1 mg) in anhydrous tetrahydrofuran (3 mL) was stirred at ambient temperature over 16 hours under an Argon atmosphere. The reaction mixture was warmed to 55° C. and an additional quantity of dimethylaminopyridine (˜2 mg) was added. After stirring for 2 hours, the reaction was evaporated in vacuo and the residue was partitioned between dichloromethane and aqueous sodium hydrogen sulfate (1N). After separating the phases, the aqueous layer was extracted with dichloromethane. The combined organic phases were dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The residue was purified on flash grade silica gel eluting with 3:2 ethyl acetate : hexane. Fractions containing the product were combined, evaporated in vacuo, and dried under high vacuum to provide (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-1-benzyl-3-[{[4-(benzyloxy)phenyl]sulfonyl}(1-ethylpropoxy)amino]-2-hydroxypropylcarbamate (235 mg, 74%) as a foam. H1-NMR (chloroform-D3): 0.94 (m, 6H), 1.62 (m, 7H), 3.05 (m, 5H), 3.74 (m, 2H), 3.98 (m, 4H), 4.18 (m, 1H), 4.88 (d, 1H), 5.08 (m, 1H), 5.19 (s, 2H), 5.70 (d, 1H), 7.13 (d, 2H), 7.34 (m, 10H), 7.80 (d, 2H). MS(ESI): 691(M+Na).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH2:11][O:10][C:9]2=[O:18])[CH2:4][CH2:3]1.Cl[C:20]1[CH:36]=[CH:35][C:23]([C:24]([C:26]2[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=2[C:28]([OH:30])=[O:29])=[O:25])=[CH:22][C:21]=1[N+:37]([O-:39])=[O:38].C(N(CC)CC)C>CN(C)C=O>[N+:37]([C:21]1[CH:22]=[C:23]([C:24]([C:26]2[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=2[C:28]([OH:30])=[O:29])=[O:25])[CH:35]=[CH:36][C:20]=1[N:2]1[CH2:3][CH2:4][CH:5]([N:8]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH2:11][O:10][C:9]2=[O:18])[CH2:6][CH2:7]1)([O-:39])=[O:38]
Reactant: O=C1OCc2ccccc2N1C1CCNCC1
Reactant: O=C(O)c1ccccc1C(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(O)c1ccccc1C(=O)c1ccc(N2CCC(N3C(=O)OCc4ccccc43)CC2)c([N+](=O)[O-])c1

Procedure:
A solution of 1-piperidin-4-yl-1,4-dihydro-2H-3,1-benzoxazin-2-one hydrochloride (J.Med. Chem. 1998, 2157) (0.8 g), 2-(4-chloro-3-nitrobenzoyl)benzoic acid (0.9 g) and triethylamine (0.8 ml) in N,N-dimethylformamide (5 ml) was stirred at room temperature for 72 h. The mixture was partitioned between ethyl acetate and dilute hydrochloric acid, the organic layer was evaporated under reduced pressure. Purification was by chromatography eluting with 4% methanol/dichloromethane. The residue was triturated from methanol, yield 0.4 g as a solid.
Reaction SMILES: [NH:1]1[C:6](=[O:7])[C:5](=[O:8])[NH:4][C:3]2[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:15](=[O:16])[C:2]1=2.O.[BH4-].[Na+].Cl>C(O)C>[OH:16][CH:15]1[C:2]2[NH:1][C:6](=[O:7])[C:5](=[O:8])[NH:4][C:3]=2[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:14]1=2
Reactant: O=C1c2ccccc2-c2[nH]c(=O)c(=O)[nH]c21
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=c1[nH]c2c([nH]c1=O)C(O)c1ccccc1-2
Temperature: 25 °C
Reaction time: 18 h
Yield: 91 %

Procedure:
To a stirred suspension of 9H-indeno[1,2-b]pyrazine-2,3,9(1H,4H)-trione. 1H2O (5.0 g, 21.5 mmol) in 200 ml of ethanol and 30 ml of water was added sodium borohydride (1.76 g, 46.5 mmol) in four portions over 2 hours, then 200 ml of water was added and the mixture was stirred for 18 hours at room temperature. The reaction mixture was acidified with hydrochloric acid (70 ml, 1N) to pH 1.5 and the precipitate was filtered off, washed with water and dried to give 4.59 g (91%) of the title compound. M.p. >300° C. 1H-NMR (DMSO-d6, δ): 5.1 (d, 1H), 5.72 (d, 1H), 7.15 (t, 1H), 7.28 (t, 1H), 7.41 (d, 1H), 7.48 (d, 1H), 12.0 (s, 1H), 12.25 (s, 1H).
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14](Br)[CH:15]=1.C(N(CC)CC)C>C(OCC)(=O)C.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Br:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([C:8]#[C:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:15]=1
Reactant: Brc1cncc(Br)c1
Reactant: C#Cc1ccccc1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Brc1cncc(C#Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 31.8 %

Procedure:
Add phenylacetylene (1.11 mL, 10.10 mmol) dropwise to a mixture of 3,5-dibromopyridine (2.05 g, 8.65 mmol), bis(triphenylphosphine)palladium (II) dichloride (300 mg, 0.427 mmol), and copper (I) iodide (160 mg, 0.840 mmol) in triethylamine (8.50 mL, 60.98 mmol) and stir for 3 h at room temperature. Dilute the reaction mixture with ethyl acetate and wash with a saturated aqueous solution of sodium chloride. Dry (sodium sulfate), filter and concentrate. Purify the residue by silica gel chromatography, eluting with a gradient of 100:0 to 90:10 hexanes:ethyl acetate, to give the title compound (710 mg, 32%).
Reaction SMILES: C[Si]([C:5]#[CH:6])(C)C.C([Li])CCC.[OH:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1.[Cl-].[NH4+]>C1COCC1.O>[OH:18][CH:17]([C:16]1[CH:19]=[CH:20][C:13]([OH:12])=[CH:14][CH:15]=1)[C:5]#[CH:6]
Reactant: C#C[Si](C)(C)C
Reactant: O=Cc1ccc(O)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: C#CC(O)c1ccc(O)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of trimethylsilylacetylene (1.00 g, 10 mmol) (Aldrich) in dry THF (100 mL) under argon at −78° C. was added n-butyllithium (4.4 mL, 11 mmol, 2.5 M solution in hexanes) (Aldrich) dropwise. The reaction was stirred for 30 min at −78° C., after which time 4-hydroxybenzaldehyde (0.50 g, 4 mmol) (Aldrich) was added and the reaction was allowed to slowly warm to room temperature. A saturated solution of ammonium chloride (5 mL) was then added and the reaction was stirred at room temperature for 2 h. The solution was then diluted by the addition of 30 mL water, and THF was removed in vacuo. The product was extracted with ethyl acetate (3×50 mL) and the combined organic layers were dried over magnesium sulfate and concentrated in vacuo to give clean 3-hydroxy-3-(4-hydroxyphenyl)-1-propyne which was used directly, without further purification. (Yield 501 mg, 84%).
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[N:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8](O)=[O:9]>>[Cl:5][C:6]1[C:7]([C:8]([Cl:3])=[O:9])=[CH:11][CH:12]=[CH:13][N:14]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cccnc1Cl
Product: O=C(Cl)c1cccnc1Cl
Temperature: 90 °C
Reaction time: 1 h
Yield: 100.6 %

Procedure:
1131 g (9.5 mol) of thionyl chloride were slowly added dropwise at 90° C. to 500 g (3.17 mol) of 2-chloronicotinic acid. The reaction mixture was stirred for 1 hour at 90° C. and freed from thionyl chloride under reduced pressure (“high vacuum”) at approximately 40° C. This gave 561 g (100%) of the title compound as colorless crystals.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].[C:10](Cl)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>ClCCl.C(N(CC)CC)C>[C:10]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: NCCCCCC(=O)O
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)CCCCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 36 h
Yield: 58.2 %

Procedure:
6-Aminocaproic acid (26 g, 0.2 mole) was dissolved in dichloromethane (200 mL) by the addition of triethylamine (100 mL). Trityl chloride (120 g, 0.45 mole) was added and the solution stirred for 36 hr. The resulting solution was extracted with 1N HCl and the organic layer evaporated to dryness. The residue was suspended in 2-propanol/1N NaOH (300 mL/100 mL) and refluxed for 3 hr. The solution was evaporated to a thick syrup and added to dichloromethane (500 mL). Water was added and acidified. The phases were separated, and the organic layer dried over sodium sulfate and evaporated to dryness. The residue was suspended in hot 2-propanol, cooled, and filtered to give 43.5 g (58%) of 6-(trityl-amino)caproic acid, useful as an intermediate compound.
Reaction SMILES: C1O[C:4]2([CH2:9][CH2:8][C:7]([CH2:11][CH2:12][CH2:13][OH:14])(O)[CH2:6][CH2:5]2)[O:3]C1.C(N(C(C)C)CC)(C)C.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O>C(Cl)Cl>[O:14]1[C:7]2([CH2:6][CH2:5][C:4](=[O:3])[CH2:9][CH2:8]2)[CH2:11][CH2:12][CH2:13]1
Reactant: OCCCC1(O)CCC2(CC1)OCCO2
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCC2(CCCO2)CC1

Procedure:
A mixture of 4-(3-Hydroxypropyl)-4-hydroxy-cyclohexanone ethylene ketal (1.4 g) and diisopropylethylamine (3.37 mL) in methylene chloride (100 mL) at -78° C. was treated with triflic anhydride (1.64 mL). After 30 min the reaction mixture was washed with water, the solvent was dried over magnesium sulfate and removed in vacuo. The residue was dissolved in 30 mL of tetrahydrofuran and 15 mL of 3% HCl. After 5 h at room temperature the reaction mixture was diluted with water and the product was extracted with ether. After drying over magnesium sulfate the solvent was removed in vacuo to afford 1-Oxaspiro[4.5]decan-8-one as an oil.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:3]1.Cl.[Br:20][C:21]1[C:29]([F:30])=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[C:23]([NH:31]N)[CH:22]=1>C(O)(=O)C>[Br:20][C:21]1[C:29]([F:30])=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[C:23]2[C:22]=1[C:7]1[CH2:6][CH2:5][CH:4]([CH:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:3][C:2]=1[NH:31]2
Reactant: NNc1cc(Br)c(F)cc1C(=O)O
Reactant: CCOC(=O)C(C(=O)OCC)C1CCCC(=O)C1
Agent: Cl
Solvent: CC(=O)O
Product: CCOC(=O)C(C(=O)OCC)C1CCc2c([nH]c3c(C(=O)O)cc(F)c(Br)c23)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.5 %

Procedure:
A solution of diethyl 2-(3-oxocyclohexyl)malonate (15.26 g, 59.5 mmol) and 4-bromo-5-fluoro-2-hydrazinylbenzoic acid hydrochloride [Intermediate 24B] (17.0 g, 59.5 mmol) in acetic acid (120 mL) was heated at reflux for 2 h, then was stirred overnight at room temperature. The precipitate which formed was collected by filtration to provide a white solid. The filtrate was concentrated and purified by column chromatography on silica gel (80 g), eluting with EtOAc-hexanes (gradient from 0-100%). The resulting oily product was crystallized from a mixture of EtOAc, ether and hexanes to provide additional solid, which was combined with the first solid to provide 5-bromo-2-(1,3-diethoxy-1,3-dioxopropan-2-yl)-6-fluoro-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid as a white solid (10.5 g, 49% yield). Mass spectrum m/z 470, 472 (M+H)+.