Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]1[CH:6]=[N:7][CH:8]=[C:9](B2OC(C)(C)C(C)(C)O2)[CH:10]=1)[CH3:2].Br[C:21]1[CH:22]=[C:23]2[C:27](=[C:28]([C:30]([NH2:32])=[O:31])[CH:29]=1)[NH:26][CH:25]=[C:24]2[CH:33]1[CH2:38][CH2:37][N:36]([S:39]([CH2:42][CH3:43])(=[O:41])=[O:40])[CH2:35][CH2:34]1.C(=O)([O-])[O-].[K+].[K+]>>[CH2:1]([NH:3][CH2:4][C:5]1[CH:10]=[C:9]([C:21]2[CH:22]=[C:23]3[C:27](=[C:28]([C:30]([NH2:32])=[O:31])[CH:29]=2)[NH:26][CH:25]=[C:24]3[CH:33]2[CH2:34][CH2:35][N:36]([S:39]([CH2:42][CH3:43])(=[O:40])=[O:41])[CH2:37][CH2:38]2)[CH:8]=[N:7][CH:6]=1)[CH3:2]
Reactant: CCNCc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCNCc1cncc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)c1
Yield: 36 %

Procedure:
Following the general procedure of 5-(5-{[(cyclopropylmethyl)amino]methyl}-3-pyridinyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinecarbaldehyde (30 mg, 0.129 mmol), a 2 M solution of ethylamine in THF (0.065 mL, 0.129 mmol), and NaCNBH3 (16 mg, 0.258 mmol) were reacted to give 19 mg of crude ethyl{[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}amine. The crude ethyl{[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}amine was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (30 mg, 0.0723 mmol), potassium carbonate (60 mg, 0.434 mmol), and chloro-2-(dimethylaminomethyl)-ferrocen-1-yl-(dinorbornylphosphine)palladium(II) (4.4 mg, 0.00723 mmol) to give 12.3 mg of the title compound (36%).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:21])=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[C:6]=2[CH:20]=1.[O:22]1[CH2:26]C[CH2:24][CH2:23]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>COCCO>[Br:1][C:2]1[C:3]([O:21][CH2:24][CH2:23][O:22][CH3:26])=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[C:6]=2[CH:20]=1
Reactant: C1CCOC1
Reactant: O=C1CN=C(c2ccccc2Cl)c2cc(Br)c(O)cc2N1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCO
Product: COCCOc1cc2c(cc1Br)C(c1ccccc1Cl)=NCC(=O)N2
Reaction time: 8 h

Procedure:
To a stirred mixture of 0.300 g (0.00082 mole) 7-bromo-5-(2-chlorophenyl)-1,3-dihydro-8-hydroxy-2H-1,4-benzodiazepin-2-one (Ipp) prepared in Example 28, 60 mL of tetrahydrofuran, 0.070 mL of 2-methoxy ethanol, and 0.2586 g of triphenyl phosphine was added 0.194 mL (0.00099 mole) of diisopropyl azodicarboxylate. The mixture was stirred overnight; then, an additional 0.2586 g of triphenyl phosphine, 0.070 mL of 2-methoxy ethanol and 0.194 mL of diisopropyl azodicarboxylate was added. The mixture stirred for an additional hour and then concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with dichloromethane-methanol (98:2) to yield 0.212 g of 7-bromo-5-(2-chlorophenyl)-1,3-dihydro-8-methoxyethoxy-2H-1,4-benzodiazepin-2-one (Inn). MH+/Z=423.
Reaction SMILES: [H-].[Li+].[CH2:3]([P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])[C:4]([CH3:6])=[O:5].[Cl:15][C:16]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:17]=1[O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]I>>[C:4]([CH:3]([P:7](=[O:14])([O:8][CH2:9][CH3:10])[O:11][CH2:12][CH3:13])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][O:18][C:17]1[CH:25]=[CH:26][C:27]([O:29][CH3:30])=[CH:28][C:16]=1[Cl:15])(=[O:5])[CH3:6]
Reactant: CCOP(=O)(CC(C)=O)OCC
Reactant: COc1ccc(OCCCCCI)c(Cl)c1
Agent: [H-]
Agent: [Li+]
Product: CCOP(=O)(OCC)C(CCCCCOc1ccc(OC)cc1Cl)C(C)=O
Yield: 16.9 %

Procedure:
[II; Ar is 2-Cl-4-CH3OC6H3, Y is O(CH2)5, R is C2H5, R' is CH3CO] was prepared from 0.71 g of lithium hydride, 17.2 g of diethyl acetonylphosphonate and 34 g of 5-(2-chloro-4-methoxyphenoxy)pentyl iodide according to the procedure of Example 12(b). The product was chromatographed on Florisil and further purified by preparative TLC on silica gel to give 6.3 g of diethyl [1-acetyl-6(2-chloro-4-methoxyphenoxy)hexyl]phosphonate as a light yellow oil; MIC vs. herpes simplex type 2=6 mcg/ml. The IR spectrum was consistent with the assigned structure.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:9][CH:8]=[C:7]([O:17][CH3:18])[C:5]=2[N:6]=1.[C:19]([N:22]1[CH2:27][CH2:26][CH:25]([C:28](Cl)=[O:29])[CH2:24][CH2:23]1)(=[O:21])[CH3:20]>>[CH3:18][O:17][C:7]1[C:5]2[N:6]=[C:2]([NH:1][C:28]([CH:25]3[CH2:24][CH2:23][N:22]([C:19](=[O:21])[CH3:20])[CH2:27][CH2:26]3)=[O:29])[S:3][C:4]=2[C:10]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:9][CH:8]=1
Reactant: COc1ccc(N2CCOCC2)c2sc(N)nc12
Reactant: CC(=O)N1CCC(C(=O)Cl)CC1
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)C3CCN(C(C)=O)CC3)nc12

Procedure:
Using 2-amino-4-methoxy-7-morpholin-4-yl-benzothiazol and 1-acetyl-piperidine-4-carbonyl chloride the title compound was obtained as a white solid (22%), MS: m/e=419(M+H+).
Reaction SMILES: [C:1]([O:10][CH2:11][CH3:12])(=[O:9])/[CH:2]=[CH:3]\[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:13]1([NH:19][OH:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)C>[CH2:11]([O:10][C:1](=[O:9])[C@H:2]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[N:19]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[OH:20])[CH3:12]
Reactant: ONc1ccccc1
Reactant: CCOC(=O)/C=C\C(=O)OCC
Solvent: CCO
Product: CCOC(=O)C[C@@H](C(=O)OCC)N(O)c1ccccc1
Temperature: 25 °C
Yield: 113.8 %

Procedure:
A solution of diethyl maleate (20.65 g, 0.117 mol) in ethanol (25.0 g) was added dropwise to a solution of N-phenylhydroxylamine (14.6 g, 0.129 mol) in ethanol (46.3 g). The reaction mixture was stirred at room temperature for an hour. The analysis of the reaction mixture by thin layer chromatography indicated the completion of the reaction. The reaction mixture was concentrated under reduced pressure to give the crude product (37.46 g). The crude product was crystallized from ethylacetate-hexane (28.0 g, 85.0% yield).
Reaction SMILES: [F:1][C:2]1([F:17])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9]C(=O)OC(C)(C)C)[CH2:4][CH2:3]1.C([SiH](CC)CC)C.[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28]>ClCCl>[F:1][C:2]1([F:17])[CH2:7][CH2:6][CH:5]([CH2:8][NH2:9])[CH2:4][CH2:3]1.[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28]
Reactant: CC(C)(C)OC(=O)NCC1CCC(F)(F)CC1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCC1CCC(F)(F)CC1
Reaction time: 24 h

Procedure:
A solution of EXAMPLE 239A (3 g) in dichloromethane (35 mL), trifluoroacetic acid (15 mL), and triethylsilane (1 mL) was stirred for 2 hours. The solution was concentrated, then concentrated from toluene, and left on high vacuum for 24 hours. The semi-solid was taken up in ether/hexane and filtered to provide the title compound as its trifluoroacetic acid salt.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[C:11]1[N:16]=[C:15]([CH3:17])[C:14]([C:18]([O:20]CC)=[O:19])=[C:13]([CH3:23])[N:12]=1.[OH-].[Na+].O>C(O)C>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[C:11]1[N:16]=[C:15]([CH3:17])[C:14]([C:18]([OH:20])=[O:19])=[C:13]([CH3:23])[N:12]=1
Reactant: CCOC(=O)c1c(C)nc(N2CCc3ccccc3C2)nc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1nc(N2CCc3ccccc3C2)nc(C)c1C(=O)O

Procedure:
A mixture of 6c (1.43 g, 4.5 mmol) and an aqueous solution of NaOH (10M, 20 ml) in ethanol (20 ml) was refluxed for 6 hours. To the mixture was added 100 ml of water and then the mixture was washed with dichloromethane (100 ml). The aqueous phase was neutralized with hydrochloric acid to pH=6. Product was precipitated at pH=6. After filtration, 6d was obtained as white powder (1.10 g, 3.88 mmol, 86%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][CH:5]=[CH2:6].[O:7]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>Cl.C(OCC)C>[Cl:1][CH2:2][CH2:3][O:4][CH:5]([O:20][C:17]1[CH:16]=[CH:15][C:14]([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:19][CH:18]=1)[CH3:6]
Reactant: Oc1ccc(Oc2ccccc2)cc1
Reactant: C=COCCCl
Agent: Cl
Solvent: CCOCC
Product: CC(OCCCl)Oc1ccc(Oc2ccccc2)cc1

Procedure:
64 g of freshly distilled 2-chloroethyl-vinyl ether is placed into a flask; one drop of concentrated hydrochloric acid is added, and thereupon an addition is made in portions at room temperature, with stirring, of 93 g of 4-phenoxy-phenol (duration of addition about 1 hour). During the addition of 4-phenoxy-phenol, the temperature rises to about 32°- 34° C, with the 4-phenoxy-phenol completely dissolving. After two further hours' stirring, the reaction mixture is diluted with 300 ml of diethyl ether; the ether solution is washed three times with 10% potassium hydroxide solution and three times with saturated sodium chloride solution. The ether solution is subsequently dried over sodium sulphate, and the ether and the readily volatile constituents (traces of 2-chloroethyl-vinyl ether) are completely removed in vacuo. There is obtained 1-(2-chloroethoxy)-1-[(4-phenoxy)-phenoxy]-ethane in the form of colorless oil having a refractive index of nD20 = 1.5516 (yield 98%).
Reaction SMILES: Br[C:2]1[C:3]([CH2:17][O:18][CH:19]2[CH:24]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][O:35][CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=4[O:43][CH3:44])=[CH:27][CH:26]=3)[CH2:23][CH2:22][N:21](C(OCC3C=CC=CC=3)=O)[CH2:20]2)=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][CH2:12][CH2:13][O:14][CH3:15])[CH:8]=[C:7]2[CH3:16].C(N(CC)CC)C>CO.[Pd]>[CH3:44][O:43][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=1[CH2:36][O:35][CH2:34][CH2:33][CH2:32][O:31][C:28]1[CH:27]=[CH:26][C:25]([CH:24]2[CH2:23][CH2:22][NH:21][CH2:20][CH:19]2[O:18][CH2:17][C:3]2[CH:2]=[C:10]3[C:6]([C:7]([CH3:16])=[CH:8][N:9]3[CH2:11][CH2:12][CH2:13][O:14][CH3:15])=[CH:5][CH:4]=2)=[CH:30][CH:29]=1
Reactant: COCCCn1cc(C)c2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OCCCOCc4ccccc4OC)cc3)c(Br)c21
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: COCCCn1cc(C)c2ccc(COC3CNCCC3c3ccc(OCCCOCc4ccccc4OC)cc3)cc21

Procedure:
The solution of 0.150 g of benzyl 3-[7-bromo-1-(3-methoxypropyl)-3-methyl-1H-indol-6-ylmethoxy]-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate in 5.0 ml of methanol is admixed with 0.027 ml of triethylamine and hydrogenated in the presence of 30 mg of 5% Pd/C at room temperature over 16 hours. The reaction mixture is clarified by filtration and the filtrate is concentrated by evaporation. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F).
Reaction SMILES: [CH2:1]([S:8][CH:9]1[NH:12][C:11](=[O:13])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH2:17][CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1>[CH2:1]([S:8][CH:9]1[N:12]([CH2:17][CH2:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:11](=[O:13])[CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CC(SCc2ccccc2)N1
Reactant: ICCCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1CC(SCc2ccccc2)N1CCCCc1ccccc1
Reaction time: 18 h
Yield: 14 %

Procedure:
A solution 4-(benzylthio)azetidin-2-one (1.1 g, 5.5 mmol) in dry THF (10 ml) was added dropwise over 10 minutes to a suspension of NaH (0.13 g, 5.6 mmol) in dry THF (5 ml) at -20° C. under a N2 atmosphere. A solution of 1-iodo-4-phenylbutane (1.4 g, 5.5 mmol) in dry THF (10 ml) was added dropwise over 10 minutes at -55° C. After stirring for 18 hours, the mixture was poured onto ice/water (50 g), filtered through hyflo, the THF evaporated under reduced pressure and the residue taken up in ethyl acetate. The solution was washed with brine (×2), dried (MgSO4), evaporated under reduced pressure to a yellow oil which was purified by flash chromatography on silica gel eluted with 5:1, 3:1 then 1:1 petroleun ether/ethyl acetate to give the product as a yellow oil (0.25 g, 14%). 1H NMR δ (CDCl3) 1.5 (4H, m, 2×CH2), 2.6 (2H, m, CH2Ph), 2.85, 3.2 (each 2H, m, H-3 & NCH2), 3.73 (2H, s, SCH2), 4.54 (1H, m, H-4), 7.2 (10H, m, 2×Ph--H)
Reaction SMILES: [F:1][C:2]1[C:8]([F:9])=[C:7]([F:10])[CH:6]=[C:5]([F:11])[C:3]=1N.[CH:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N(OC(C)(C)C)=O>CCCCCCC>[F:1][C:2]1[C:8]([F:9])=[C:7]([F:10])[CH:6]=[C:5]([F:11])[C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: c1ccccc1
Reactant: Nc1c(F)cc(F)c(F)c1F
Agent: CC(C)(C)ON=O
Solvent: CCCCCCC
Product: Fc1cc(F)c(-c2ccccc2)c(F)c1F

Procedure:
A stirred solution of 2,3,4,6-tetrafluoroaniline (50 g, 0.30 mole) in benzene (236.6 g, 3.03 mole) was heated under reflux. During a 45 minute period, t-butyl nitrite (46.8 g, 0.455 mole) was added to the reaction mixture. After complete addition the mixture was heated at reflux for 23/4 hours. n-Heptane (1 l) was added, and the solvent was distilled from the reaction flask until a head temperature of 101° was reached. The pot residue was cooled and subjected to column chromatography on silica gel, elution first with n-heptane, then toluene, to give 2,3,4,6-tetrafluoro-[1,1'-biphenyl] (mp, 89°-90°).
Reaction SMILES: C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[CH3:19][C:20]1[O:21][C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=2[N:24]=1.[Br:29]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OCC)(=O)C>[Br:29][CH2:19][C:20]1[O:21][C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=2[N:24]=1
Reactant: Cc1nc2ccccc2o1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1nc2ccccc2o1
Yield: 37 %

Procedure:
509.8 mg of dibenzoyl peroxide were added to a solution of 56 ml of 2-methylbenzoxazole and 18.73 g of N-bromosuccinimide in 20 ml of carbon tetrachloride at room temperature and the resulting mixture was stirred under reflux for 6 hours. At the end of this time, the reaction mixture was filtered and the resulting filtrate was concentrated by evaporation under reduced pressure to give a crude crystalline solid. This was dissolved in ethyl acetate and then washed consecutively with a saturated aqueous sodium sulfite solution, water and a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. The solvent was then removed by evaporation under reduced pressure to give a crude residue which was purified by column chromatography through silica gel using a 10:1 by volume mixture of hexane and ethyl acetate to give 3.34 g (yield 37%) of the title compound as an oil.
Reaction SMILES: C(OC([NH:8][S:9]([N:12]([CH3:50])[CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][CH2:17][CH:16]1[CH2:20][O:21][C@H:22]1[CH2:29][N:28]2[C:30]3[CH:31]=[C:32]([C:43]([OH:45])=[O:44])[CH:33]=[CH:34][C:35]=3[C:36]([CH:37]3[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]3)=[C:27]2[C:26]2[CH:46]=[CH:47][CH:48]=[CH:49][C:25]=2[O:24][CH2:23]1)(=[O:11])=[O:10])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][S:9]([N:12]([CH3:50])[CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][CH2:17][CH:16]1[CH2:20][O:21][C@H:22]1[CH2:29][N:28]2[C:30]3[CH:31]=[C:32]([C:43]([OH:45])=[O:44])[CH:33]=[CH:34][C:35]=3[C:36]([CH:37]3[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]3)=[C:27]2[C:26]2[CH:46]=[CH:47][CH:48]=[CH:49][C:25]=2[O:24][CH2:23]1)(=[O:11])=[O:10]
Reactant: CN(CCN1CCCC1CO[C@@H]1COc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)O)cc3n2C1)S(=O)(=O)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(CCN1CCCC1CO[C@@H]1COc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)O)cc3n2C1)S(N)(=O)=O
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A solution of (7S)-7-[(1-{2-[{[(tert-butoxycarbonyl)amino]sulfonyl}(methyl)amino]ethyl}-pyrrolidin-2-yl)methoxy]-14-cyclohexyl-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylic acid (7 mM) in DCM was treated with an excess of TFA (>100 eq). The mixture was stirred at RT for 3.5 h. Volatiles were removed in vacuo. The residue was dissolved in toluene and re-evaporated to drive off excess TFA. The material was taken on without further purification. (ES+) m/z 611 (M+H)+.
Reaction SMILES: [CH:1]([NH:4][CH2:5][CH:6]1[CH2:10][O:9][C:8]2([CH:18](Br)[CH2:17][CH2:16][C:15]3[N:14]([S:20]([C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)(=[O:22])=[O:21])[CH:13]=[CH:12][C:11]2=3)[O:7]1)([CH3:3])[CH3:2].C(N(CC)CC)C>ClCCl>[OH:7][CH:6]([CH2:5][NH:4][CH:1]([CH3:3])[CH3:2])[CH2:10][O:9][C:8]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[CH:12]=[CH:13][N:14]2[S:20]([C:23]1[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=1)(=[O:22])=[O:21]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2CCC(Br)C32OCC(CNC(C)C)O2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2ccc3c(OCC(O)CNC(C)C)cccc32)cc1
Temperature: 25 °C
Yield: 67 %

Procedure:
To a solution of 4'-isopropylaminomethyl-5-bromo-1-p-toluenesulfonyl-4,5,6,7-tetrahydroindole-4-spiro-2'-[1,3]dioxolane (100 parts) and triethylamine (143 parts) in dichloromethane (1500 parts) is dropwise added a solution of stannic chloride (80 parts) in dichloromethane (500 parts) at -60° C. with stirring. The mixture is warmed to room temperature, stirred for 5 hours, concentrated and shaken with aqueous 5N-sodium hydroxide and ethyl acetate. The ethyl acetate layer is separated, washed with water, dried over sodium sulfate and concentrated under reduced pressure to give crude product (73 parts) in 87.9% yield. This is triturated in ethyl acetate to give pure 4-(2-hydroxy-3-isopropylaminopropoxy)-1-p-toluenesulfonylindole (56 parts) as amorphous solid in 67% yield. NMR: δCD3SOCD3 0.97d(6.5 Hz)6H, 2.29s3H, 2.56-2.90m3H, 3.76-4.20m3H, 6.71-7.92m9H.
Reaction SMILES: [OH:1][PH:2]([CH2:4][CH:5]([CH2:13][CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[O:3].[C:22](O)([CH3:25])([CH3:24])[CH3:23].O>ClCCl.CN(C)C1C=CN=CC=1>[C:22]([O:3][PH:2]([CH2:4][CH:5]([CH2:13][CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:6]([O:8][C:9]([CH3:10])([CH3:11])[CH3:12])=[O:7])=[O:1])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)CCC(C[PH](=O)O)C(=O)OC(C)(C)C
Reactant: CC(C)(C)O
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CCC(C[PH](=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 70.3 %

Procedure:
To a solution of di-tert-butyl 2-[(hydroxy-phosphinyl)methyl]pentane-1,5-dioate (315 g, 0.977 mol) in dichloromethane (1000 ml) cooled in an ice bath and under nitrogen were added tert-butanol (123.1 g, 1.66 mol), 4-dimethylaminopyridine (1 g, 8.2 mmol), andl-ethyl-3-(3-dimethylaminopropyl) carbodiimide (281 g, 1.47 mol). The reaction was allowed to stir overnight. Water was added to the reaction mixture and the dichloromethane layer was retained and dried, and the solvent was removed under reduced pressure. The resulting residue was purified by column chromatography and the desired product was eluted with 1:1 to 2:3 hexane/ethyl acetate. The fractions containing product were concentrated under reduced pressure leaving a clear oil (260 g, 70%). 1H NMR (CDCl3) : δ 1.4 (m, 27H), 1.8 (m, 1H), 1.9 (m, 2H), 2.1 (m, 1H), 2.3 (m, 2H), 2.7-2.8 (m, 1H), 6.7 & 8.0 (d, 1H, the P-H).
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:7]2[CH2:8][CH2:9][CH2:10][C:6]=2[C:5]2[C:11]([OH:24])=[CH:12][C:13]([CH:15]([CH3:23])[CH:16]([CH3:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:14][C:4]=2[O:3]1.[C:26](OC(=O)C)(=[O:28])[CH3:27]>N1C=CC=CC=1>[C:26]([O:24][C:11]1[C:5]2[C:6]3[CH2:10][CH2:9][CH2:8][C:7]=3[C:2]([CH3:1])([CH3:25])[O:3][C:4]=2[CH:14]=[C:13]([CH:15]([CH3:23])[CH:16]([CH3:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:12]=1)(=[O:28])[CH3:27]
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CCC1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCCCCC(C)C(C)c1cc(OC(C)=O)c2c(c1)OC(C)(C)C1=C2CCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4,4-dimethyl-9-hydroxy-7-(1,2-dimethylheptyl)-1,2,3,4-tetrahydrocyclopenta[ c][l]benzopyran (6.85 g., 0.02 mole) and acetic anhydride (3.06 g., 0.03 mole) in 20 ml. of pyridine was warmed over a steam bath with stirring for 2 hours. The reaction mixture was allowed to cool to room temperature and the pyridine was removed by evaporation under reduced pressure. Water was added to the residue and this aqueous mixture was extracted with three portions of ether. The ether extracts were washed several times with water, 6N HCl, again with water, and dried over Na2SO4. Solvent evaporation in vacuo left 7.59 g. (99%) of crude acetate. The ir and nmr were in agreement with the proposed structure.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH2:31][N:10]2[C:11]3[CH:12]=[C:13]([C:24]([O:26]C(C)(C)C)=[O:25])[CH:14]=[CH:15][C:16]=3[C:17]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]2[C:8]2[CH:32]=[CH:33][C:34]([O:36][CH3:37])=[CH:35][C:7]=2[CH:6]=1)=[O:4].FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]([C:5]1[CH2:31][N:10]2[C:11]3[CH:12]=[C:13]([C:24]([OH:26])=[O:25])[CH:14]=[CH:15][C:16]=3[C:17]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]2[C:8]2[CH:32]=[CH:33][C:34]([O:36][CH3:37])=[CH:35][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)C1=Cc2cc(OC)ccc2-c2c(C3CCCCC3)c3ccc(C(=O)OC(C)(C)C)cc3n2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1=Cc2cc(OC)ccc2-c2c(C3CCCCC3)c3ccc(C(=O)O)cc3n2C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 96.8 %

Procedure:
13-Cyclohexyl-3-methoxy-7H-benzo[3,4]azepino[1,2-a]indole-6,10-dicarboxylic acid 10-tert-butyl ester 6-methyl ester 1a (1 g, 1 eq) was dissolved in dry dichloromethane under N2, followed by the addition of trifluoroacetic acid (TFA) (8.88 ml, 60 eq). The solution was stirred at RT for 24 h. The solvent was then removed under reduced pressure. The crude product was triturated with diethyl ether. The crystals were filtered off and dried under vacuum overnight to afford the title product 13-Cyclohexyl-3-methoxy-7H-benzo[3,4]azepino[1,2-a]indole-6,10-dicarboxylic acid 6-methyl ester 13a (89%, 0.86 g); LC-MS: Rt. 3.19 min., m/z 446 [M+H]+.
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[CH:5][C:4]([N:7]2[CH:11]=[C:10]([OH:12])[CH:9]=[N:8]2)=[CH:3][CH:2]=1.[H-].[Na+].F[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1.O>CN(C)C=O>[N+:23]([C:20]1[CH:21]=[CH:22][C:17]([O:12][C:10]2[CH:9]=[N:8][N:7]([C:4]3[CH:3]=[CH:2][C:1]([CH3:13])=[CH:6][CH:5]=3)[CH:11]=2)=[CH:18][CH:19]=1)([O-:25])=[O:24]
Reactant: Cc1ccc(-n2cc(O)cn2)cc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(-n2cc(Oc3ccc([N+](=O)[O-])cc3)cn2)cc1
Reaction time: 0.5 h

Procedure:
1-p-Tolyl-1H-pyrazol-4-ol (1.0 g, 5.75 mmol) in dimethylformamide was added to the cold slurry of sodium hydride (344 mg, 8.61 mmol). Reaction mixture was stirred for 0.5 hour followed by addition of 4-fluoro nitro benzene (810 mg, 5.74 mmol) in cold condition. Reaction mixture was stirred at 20-35° C. for 20 minutes. Water was then added to quench the reaction. The aqueous layer was extracted with diethylether and the combined organic layer was washed with brine solution and dried over anhydrous Na2SO4. The solvent was evaporated under vacuum at 40° C. and the product was purified by column chromatography using mixture of petroleum ether and ethyl acetate.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([CH3:16])[N:10]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)=[CH:19][C:18]=1[O:32][CH2:33][CH2:34][F:35])[C:9]2=[O:36])=[O:5])C.C[O-].[Na+]>CO>[F:35][CH2:34][CH2:33][O:32][C:18]1[CH:19]=[C:20]([O:23][CH2:24][CH2:25][CH2:26][N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[CH:21]=[CH:22][C:17]=1[N:10]1[C:9](=[O:36])[C:8]2[C:13](=[CH:14][CH:15]=[C:6]([C:4]([O:3][CH3:1])=[O:5])[CH:7]=2)[N:12]=[C:11]1[CH3:16]
Reactant: CCOC(=O)c1ccc2nc(C)n(-c3ccc(OCCCN4CCCC4)cc3OCCF)c(=O)c2c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc2nc(C)n(-c3ccc(OCCCN4CCCC4)cc3OCCF)c(=O)c2c1

Procedure:
6-ethoxycarbonyl-3-(2-fluoroethoxy-4-[3-(1-pyrrolidinyl)propoxy]-phenyl)-2-methyl-4(3H)-quinazolinone synthesized in Example 205 was treated by sodium methoxide in dry methanol, and the title compound was thus obtained.