Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:16]=[C:15]([NH:17][S:18]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH:14]=[C:13]([O:27][C@H:28]([CH3:50])[CH2:29][O:30]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:12]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(OC)C=CC=CC=1>CO>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:16]=[C:15]([NH:17][S:18]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)(=[O:19])=[O:20])[CH:14]=[C:13]([O:27][C@H:28]([CH3:50])[CH2:29][OH:30])[N:12]=1
Reactant: C[C@H](COC(c1ccccc1)(c1ccccc1)c1ccccc1)Oc1cc(NS(=O)(=O)c2ccncc2)nc(SCc2cccc(F)c2F)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: COc1ccccc1
Product: C[C@H](CO)Oc1cc(NS(=O)(=O)c2ccncc2)nc(SCc2cccc(F)c2F)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of N-[2-[[(2,3-difluorophenyl)methyl]thio]-6-[(1R)-1-methyl-2-(triphenylmethoxy)ethoxy]-4-pyrimidinyl]-4-pyridinesulfonamide (the product from step iv). (100 mg) in MeOH (10 mL) was added p-toluenesulfonic acid (31 mg) and anisole (0.15 g). The reaction was then stirred at room temperature for 18 h. The reaction was partitioned between EtOAc (100 mL) and H2O (100 mL). The aqueous layer was then further extracted with EtOAc (2×100 mL). The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by reverse phase HPLC using a TFA (0.2%)/MeCN to give the title compound as a white solid. Yield: 50 mg.
Reaction SMILES: C(N)C1C=CC=CC=1.C(OC([NH:19][C@H:20]([C:24]([NH:26][C@H:27]([C:29]([NH:31][C@H:32]([P:34](=[O:37])([OH:36])[OH:35])[CH3:33])=[O:30])[CH3:28])=[O:25])[CH:21]([CH3:23])[CH3:22])=O)C1C=CC=CC=1>>[NH2:19][C@H:20]([C:24]([NH:26][C@H:27]([C:29]([NH:31][C@H:32]([P:34](=[O:35])([OH:37])[OH:36])[CH3:33])=[O:30])[CH3:28])=[O:25])[CH:21]([CH3:23])[CH3:22]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](C)C(=O)N[C@@H](C)P(=O)(O)O
Solvent: NCc1ccccc1
Product: CC(C)[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](C)P(=O)(O)O

Procedure:
In a manner analogous to that given in Example 35 (b), from the benzylamine salt of (1R)-1-[(N-benzyloxycarbonyl-L-valyl-L-alanyl)amino]-ethylphosphonic acid there was obtained (1R)-1-(L-valyl-L-alanylamino)-ethylphosphonic acid of melting point 263°-265° C (decomposition); [α]D20 = -44.6° (c = 0.5% in water).
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH:6]=[C:5]([CH2:8][C:9]2[CH:33]=[CH:32][C:12]([CH2:13][NH:14][CH:15]3[CH2:20][CH2:19][CH:18]([NH:21]C(=O)OCC4C=CC=CC=4)[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[N:4]2[CH:34]=[C:35]([C:37]3[C:45]4[C:40](=[N:41][CH:42]=[CH:43][CH:44]=4)[NH:39][CH:38]=3)[CH:36]=[C:3]12>FC(F)(F)C(O)=O>[NH2:21][CH:18]1[CH2:19][CH2:20][CH:15]([NH:14][CH2:13][C:12]2[CH:32]=[CH:33][C:9]([CH2:8][C:5]3[N:4]4[CH:34]=[C:35]([C:37]5[C:45]6[C:40](=[N:41][CH:42]=[CH:43][CH:44]=6)[NH:39][CH:38]=5)[CH:36]=[C:3]4[C:2](=[O:1])[NH:7][CH:6]=3)=[CH:10][CH:11]=2)[CH2:16][CH2:17]1
Reactant: O=C(NC1CCC(NCc2ccc(Cc3c[nH]c(=O)c4cc(-c5c[nH]c6ncccc56)cn34)cc2)CC1)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: NC1CCC(NCc2ccc(Cc3c[nH]c(=O)c4cc(-c5c[nH]c6ncccc56)cn34)cc2)CC1

Procedure:
A solution of EXAMPLE 44A (25 mg, 0.04 mmol) in trifluoroacetic acid (2 ml) was stirred at 50° C. for 3 hours. The reaction mixture was then concentrated, and the residue was purified by HPLC (0-100% gradient acetonitrile in water containing 0.1% trifluoroacetic acid) to afford the title compound. MS (DCI/NH3) m/z 467 (M+H)+; 1H NMR (300 MHz, dimethylsulfoxide-d6): δ 1.11-1.54 (m, 4H), 1.55-1.89 (m, 4H), 2.91-3.09 (m, 2H), 4.12 (d, J=4.41 Hz, 2H), 4.18 (s, 2H), 6.52 (d, J=5.76 Hz, 1H), 7.15 (dd, J=7.80, 4.75 Hz, 1H), 7.28 (d, J=1.70 Hz, 1H), 7.45 (d, J=8.81 Hz, 2H), 7.55 (d, J=8.81 Hz, 2H), 7.67 (d, J=1.36 Hz, 1H), 7.83 (d, J=2.37 Hz, 1H), 8.13 (d, J=7.80 Hz, 1H), 8.24 (s, 1H) 10.57 (d, J=5.42 Hz, 1H), 11.76 (s, 1H).
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20][CH2:21][CH3:22]>C(O)C>[CH2:19]([C:4]1([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2][NH:1][CH2:11][CH2:10]1)[CH2:20][CH2:21][CH3:22]
Reactant: CCCCBr
Reactant: CCOC(=O)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCCCC1(C(=O)OCC)CCNCC1
Yield: 113.2 %

Procedure:
A mixture of ethyl isonipecotate (31.8 mmol; 5.0 g), anhydrous potassium carbonate (63.6 mmol; 8.8 g) and 1-bromobutane (31.8 mmol; 4.36 g) in absolute ethanol (63 ml) was stirred at reflux for 3 hours. After cooling, the carbonate was removed by filtration and the filtrate evaporated under reduced pressure. 7.68 g of ethyl 4-butylisonipecotate were obtained in the form of an oil, which was used for the following reaction without further purification. This product was dissolved in anhydrous ethyl ether (32 ml) and added dropwise to a suspension of lithium aluminium hydride (41.3 mmol; 1.57 g) in the same solvent (20 ml) cooled to 0° C. The reaction mixture was stirred at room temperature for 15 hours. After cooling to 0° C., ice was added cautiously and the hydroxides thus formed were removed by filtration. After separating the two phases, the ether phase was dried over anhydrous sodium sulfate and evaporated under reduced pressure to give 5.1 g (94%) of final compound as a clear oil.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH2:12][CH2:13][CH3:14])=[O:3].[CH2:15]([OH:19])[CH2:16][CH2:17][OH:18]>>[CH2:12]([O:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[O:4][C:2]([O:18][CH2:17][CH2:16][CH2:15][OH:19])=[O:3])[CH2:13][CH3:14]
Reactant: CCCOc1ccccc1OC(=O)Cl
Reactant: OCCCO
Product: CCCOc1ccccc1OC(=O)OCCCO

Procedure:
The reaction of 2-propoxyphenol chloroformate with 1,3-propanediol yields 1-(2-propoxyphenoxycarbonyloxy)-3-propanol.
Reaction SMILES: [O:1]([C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[N+:23]([C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][CH2:34][CH2:35][C:36]2([C:49]([NH:51][CH2:52][CH2:53][CH3:54])=[O:50])[C:48]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[C:42]3[C:37]2=[CH:38][CH:39]=[CH:40][CH:41]=3)=[CH:28][CH:27]=1)([O-])=O.C(N(CC)CC)C>CN(C=O)C.C(Cl)Cl>[O:1]([C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([NH:23][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][CH2:34][CH2:35][C:36]2([C:49]([NH:51][CH2:52][CH2:53][CH3:54])=[O:50])[C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][C:42]=3[C:43]3[C:48]2=[CH:47][CH:46]=[CH:45][CH:44]=3)=[CH:28][CH:27]=1)=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCNC(=O)C1(CCCCc2ccc([N+](=O)[O-])cc2)c2ccccc2-c2ccccc21
Reactant: O=C(O)c1ccccc1Oc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCNC(=O)C1(CCCCc2ccc(NC(=O)c3ccccc3Oc3ccccc3)cc2)c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82 %

Procedure:
To a solution of 2-phenoxybenzoic acid (Aldrich Chemical Co.) (111 mg, 0.518 mmol) and DMF (2 drops) in CH2Cl2 (1.5 mL) was added oxalyl chloride (389 μL, 2.0M in CH2Cl2, 0.777 mmol). The reaction bubbled for 10 min, then was stirred at RT under argon for 1.5 h. The reaction was concentrated in vacuo, and the resulting residue was dissolved in CH2Cl2 (1.5 mL) and added dropwise to a solution of Example 204 Part A compound (172 mg, 0.432 mmol) and triethylamine (90 μL, 0.648 mmol) in CH2Cl2 (1.5 mL) at 0° C. under argon. The reaction was stirred at 0° C. for 10 min, diluted with CH2Cl2 (20 mL), washed with saturated NaHCO3 (5 mL) and brine (5 mL), then dried over Na2SO4. Evaporation gave a yellow oil, which was dissolved in a minimum amount of CH2Cl2 and purified by flash chromatography on silica gel (50 g) eluting with 30% EtOAc/hexane to provide title compound (211 mg, 82%) as a yellow gum.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]([CH2:8][CH2:9][C:10]([P:16]([OH:19])([OH:18])=[O:17])([P:12]([OH:15])([OH:14])=[O:13])[OH:11])[CH3:7].[OH-].[Na+:21].CC(C)=O>C(#N)C>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]([CH2:8][CH2:9][C:10]([P:16]([O-:19])([OH:18])=[O:17])([P:12]([OH:15])([OH:14])=[O:13])[OH:11])[CH3:7].[Na+:21]
Reactant: CCCCCN(C)CCC(O)(P(=O)(O)O)P(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CC(C)=O
Product: CCCCCN(C)CCC(O)(P(=O)([O-])O)P(=O)(O)O
Temperature: 25 °C
Yield: 65.5 %

Procedure:
A slurry of amorphous ibandronic acid (5 g) in acetonitrile (200 ml) was stirred at reflux temperature. Solid sodium hydroxide (0.63 g) was added, and the reaction mixture was stirred at reflux temperature for an additional 2 hours. Acetone (50 ml) was added dropwise. Then the reaction mixture was cooled to room temperature and stirred for 16 hours. The precipitate was isolated by vacuum filtration, washed with acetone (50 ml), and dried in a vacuum oven at 50° C. for 22 hours to obtain 3.5 g of amorphous ibandronate sodium.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=2[O:19][CH3:20])[C:13](O)=[O:14])=[CH:4][CH:3]=1.Cl.[CH3:22][NH2:23]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=2[O:19][CH3:20])[C:13]([NH:23][CH3:22])=[O:14])=[CH:4][CH:3]=1
Reactant: CN
Reactant: COc1ccc(C(=O)O)cc1/C=C/c1ccc(Cl)cc1
Agent: Cl
Product: CNC(=O)c1ccc(OC)c(/C=C/c2ccc(Cl)cc2)c1

Procedure:
The captioned compound was synthesized from 3-[(E)-2-(4-chlorophenyl)vinyl]-4-methoxy-benzoic acid and methylamine hydrochloride in accordance with the same procedure as in the manufacturing method described in step G of Example 1-2-1.
Reaction SMILES: B(Br)(Br)Br.Cl.[F:6][C:7]([F:41])([F:40])[S:8]([O:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:22]C)[CH:18]=2)[C:13]=1[O:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][N:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)=[CH:27][CH:26]=1)(=[O:10])=[O:9]>ClCCl>[F:40][C:7]([F:6])([F:41])[S:8]([O:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([OH:22])[CH:18]=2)[C:13]=1[O:24][C:25]1[CH:26]=[CH:27][C:28]([O:31][CH2:32][CH2:33][N:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)=[CH:29][CH:30]=1)(=[O:10])=[O:9]
Reactant: COc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Product: O=S(=O)(Oc1ccc2cc(O)ccc2c1Oc1ccc(OCCN2CCCCC2)cc1)C(F)(F)F
Yield: 94 %

Procedure:
Add a solution of boron tribromide in dichloromethane (4 M, 5 mL, 20.00 mmol) to a solution of 6-methoxy-1-(4-(2-(piperidin-1-yl)ethoxy)phenoxy)naphthalen-2-yl trifluoromethanesulfonate hydrochloride (2.8 g, 4.98 mmol) and dichloromethane (100 ml). Stir the reaction for 2 hours and then quench with aqueous sodium bicarbonate. Extract the mixture 3 times with dichloromethane. Combine the extracts, dry over sodium sulfate, filter and concentrate to obtain the title compound (2.4 g, 4.68 mmol).
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:10][N:11]([CH2:13][CH2:14][OH:15])[CH3:12]>>[C:1]1([NH:7][C:8](=[O:9])[O:15][CH2:14][CH2:13][N:11]([CH3:12])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C=Nc1ccccc1
Reactant: CN(C)CCO
Product: CN(C)CCOC(=O)Nc1ccccc1
Reaction time: 0.5 h

Procedure:
With cooling, 128 g of phenyl isocyanate are added dropwise to 96 g of dimethylaminoethanol at 60°-70° C. in the course of 45 minutes. After a further 30 minutes at 65° C., low boiling constituents are removed at a pressure of 0.02 torr and a bath temperature of 90° C. The residue (218.4 g=97.6%) is a light yellow fluid and consists substantially of the above ester. Titration: 1 equivalent=208.4 g (theory 208.2). IR spectrum 3320 cm-1NH, 1720 cm-1C=O; no bands between 2000 and 2500 cm-1, i.e. isocyanate is no longer present. Small amounts of 5-10 g can be distilled in a bulb tube at 135° C./0.015 torr; larger amounts decompose on distillation.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:11][O:10][CH2:9][CH:8]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[C:6]=2[N:7]=1.Cl.[CH3:21][NH2:22]>>[Cl:1][C:2]1[N:3]=[C:4]([NH:22][CH3:21])[C:5]2[CH2:11][O:10][CH2:9][CH:8]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[C:6]=2[N:7]=1
Reactant: CN
Reactant: Clc1ccc(C2COCc3c(Cl)nc(Cl)nc32)cc1
Agent: Cl
Product: CNc1nc(Cl)nc2c1COCC2c1ccc(Cl)cc1
Yield: 30.6 %

Procedure:
2,4-dichloro-8-(4-chlorophenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine (Preparation K) (500 mg, 1.584 mmol) and methanamine hydrochloride (160 mg, 2.377 mmol) were combined and purified as per Preparation Ha to give 2-chloro-8-(4-chlorophenyl)-N-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine (150 mg, 0.484 mmol, 30.5% yield). LC-MS (M+H)+=310.0. 1H NMR (500 MHz, CDCl3) δ ppm 7.22-7.31 (2H, m), 7.13 (2H, d, J=8.55 Hz), 4.46-4.64 (1H, m), 4.43 (1H, br. s.), 3.97-4.14 (1H, m), 3.91 (1H, d, J=3.36 Hz), 3.09 (3H, d, J=4.88 Hz).
Reaction SMILES: C([O:5][C:6]([C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:39])[CH2:14][O:15][C:16]1[CH:21]=[C:20]([OH:22])[CH:19]=[C:18]([O:23][CH2:24][C:25]([N:27]2[CH2:31][CH2:30][CH2:29][C@@H:28]2[C:32]([O:34]C(C)(C)C)=[O:33])=[O:26])[CH:17]=1)=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[C:32]([C@H:28]1[CH2:29][CH2:30][CH2:31][N:27]1[C:25](=[O:26])[CH2:24][O:23][C:18]1[CH:17]=[C:16]([CH:21]=[C:20]([OH:22])[CH:19]=1)[O:15][CH2:14][C:13]([N:9]1[CH2:10][CH2:11][CH2:12][C@@H:8]1[C:6]([OH:7])=[O:5])=[O:39])([OH:34])=[O:33]
Reactant: CC(C)(C)OC(=O)[C@H]1CCCN1C(=O)COc1cc(O)cc(OCC(=O)N2CCC[C@@H]2C(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)[C@H]1CCCN1C(=O)COc1cc(O)cc(OCC(=O)N2CCC[C@@H]2C(=O)O)c1
Reaction time: 8 h
Yield: 95.5 %

Procedure:
A solution of 46 mg (0.084 mmol) (R)-1-[[3-[2-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethoxy]-5-hydroxy-phenoxy]-acetyl]-pyrrolidine-2-carboxylic acid tert-butyl ester in 1 ml trifluoroacetic acid was stirred for 4 h at room temperature. The solvent was removed in vacuo and the residue suspended in 5 ml ether. The resulting suspension was stirred overnight. Filtration and drying gave 35 mg (96%) of the title compound as a light brown powder.
Reaction SMILES: C1(C#C)C=CC=CC=1.[C:9]1([CH2:15][CH2:16][CH2:17][C:18]#[CH:19])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[N:20]([C:23]1[S:24][C:25]([C:29]([NH:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])=[C:26]([CH3:28])[N:27]=1)=[N+:21]=[N-:22]>>[CH2:32]([NH:31][C:29]([C:25]1[S:24][C:23]([N:20]2[CH:19]=[C:18]([CH2:17][CH2:16][CH2:15][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[N:22]=[N:21]2)=[N:27][C:26]=1[CH3:28])=[O:30])[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: Cc1nc(N=[N+]=[N-])sc1C(=O)NCc1ccccc1
Reactant: C#CCCCc1ccccc1
Solvent: C#Cc1ccccc1
Product: Cc1nc(-n2cc(CCCc3ccccc3)nn2)sc1C(=O)NCc1ccccc1
Yield: 32 %

Procedure:
Following the procedure as described in Example 10, making variations as necessary to replace phenylacetylene with 5-phenyl-1-pentyne to react with 2-azido-N-benzyl-4-methylthiazole-5-carboxamide, the title compound was obtained as a white solid in 32% yield: mp 94-97° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.12 (s, 1H), 7.38-7.18 (m, 10H), 6.14 (t, J=6.0 Hz, 1H), 4.62 (d, J=6.0 Hz, 2H), 2.81 (t, J=9.0 Hz, 2H), 2.79-2.68 (m, 5H), 2.09-2.04 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 160.9, 155.7, 153.3, 149.2, 141.5, 137.4, 128.9, 128.4, 128.3, 127.9, 127.8, 125.9, 123.9, 118.4, 44.3, 35.2, 30.6, 24.9, 17.4; MS (ES+) m/z 418.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([O:12]P(N3CCOCC3)(N3CCOCC3)=O)[CH2:9][N:8]=[C:7]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:6]=2[CH:33]=1.C(N(CC)CC)C.[CH2:41](O)[CH2:42][OH:43]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([O:12][CH2:41][CH2:42][OH:43])[CH2:9][N:8]=[C:7]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:6]=2[CH:33]=1
Reactant: O=P(OC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1)(N1CCOCC1)N1CCOCC1
Reactant: OCCO
Solvent: CCN(CC)CC
Product: OCCOC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1

Procedure:
A suspension of 1.95 g (4.0 mmoles) of 7-chloro-2-di-(morpholino)phosphinyloxy-5-phenyl-3H-1,4-benzodiazepin in 10 ml of ethylene glycol containing 4 ml of triethylamine was heated on a steam bath for 2 hrs. A clear solution formed soon after heating began. Triethylamine was removed in vacuo. The ethylene glycol solution was poured into ice water precipitating solids which were collected and washed thoroughly with water. Remaining water was removed from the solid by dissolving in solid in ether, drying over sodium sulfate and evaporation of ether. Crystallization of the residue from ether-hexane gave colorless prisms, mp 142°-144°.
Reaction SMILES: C[O-].[Na+].[CH3:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C@@H:13]2[C@H:18]3[CH2:19][O:20][C@H:16]([O:17]3)[C@@H:15]([O:21]C(=O)C3C=CC=CC=3)[C@H:14]2[O:30][CH3:31])=[CH:8][CH:7]=1>ClCCl.CO.ClCCl>[CH3:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][C@@H:13]2[C@H:18]3[CH2:19][O:20][C@H:16]([O:17]3)[C@@H:15]([OH:21])[C@H:14]2[O:30][CH3:31])=[CH:10][CH:11]=1
Reactant: COc1ccc(O[C@H]2[C@H](OC)[C@H](OC(=O)c3ccccc3)[C@@H]3OC[C@H]2O3)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(O[C@H]2[C@H](OC)[C@H](O)[C@@H]3OC[C@H]2O3)cc1
Reaction time: 1 h
Yield: 59 %

Procedure:
Sodium methoxide (13.5 g, 250 mmol) is added to a solution of the above crude residue 90 in dichloromethane/methanol (540 ml, 1/1). After stirring for 1 h, the reaction medium is diluted with dichloromethane (500 ml) and then washed with aqueous 3% hydrochloric acid solution and water. After drying, filtration and concentration, the residue is purified on silica to give compound 91 (10.5 g, 59% over two steps).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Cl[CH2:14][CH2:15][CH2:16][O:17][CH3:18]>>[CH3:18][O:17][CH2:16][CH2:15][CH2:14][O:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COCCCCl
Reactant: COC(=O)c1ccc(C)cc1O
Product: COCCCOc1cc(C)ccc1C(=O)OC

Procedure:
Analogously to Method F, 103.7 g of methyl 2-hydroxy-4-methylbenzoate are reacted with 95.8 g of 1-chloro-3-methoxypropane. The title compound is obtained as slightly beige oil. Rf=0.27 (1:2 EtOAc-heptane); Rt=4.22.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH:15]=O)[O:10][N:9]=2)=[CH:4][CH:3]=1.[CH2:17]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][N:27]3[CH2:28][CH2:29][N:24]([CH2:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:25][CH2:26]3)[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: O=CCCc1cc(-c2ccc(F)cc2)no1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Fc1ccc(-c2cc(CCCN3CCN(Cc4ccccc4)CC3)on2)cc1
Yield: 75 %

Procedure:
About 2 min after dissolving 3-[3-(4-fluorophenyl)isoxazol-5-yl]propanal (20 mg, 0.09 mmol) and 1-benylpiperazine (15.9, 0.09 mmol) in 2 mL of dry methylene chloride, were added NaBH(OAc)3 (58 mg, 0.27 mmol) and molecular sieves (5 beads). The reaction mixture was reacted for 22.5 hr and followed the same processes as in Example 1 to obtain 25.6 mg (74.0%) of the target compound.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=O)[C:6]1=[O:15].C[C:21]1[CH:26]=[CH:25][CH:24]=[C:23](C)[C:22]=1[OH:28]>FC(F)(F)S(O)(=O)=O>[Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:25]2[CH:26]=[CH:21][C:22]([OH:28])=[CH:23][CH:24]=2)([C:25]2[CH:24]=[CH:23][C:22]([OH:28])=[CH:21][CH:26]=2)[C:6]1=[O:15]
Reactant: O=C1C(=O)N(Cc2ccccc2Cl)c2ccccc21
Reactant: Cc1cccc(C)c1O
Agent: O=S(=O)(O)C(F)(F)F
Product: O=C1N(Cc2ccccc2Cl)c2ccccc2C1(c1ccc(O)cc1)c1ccc(O)cc1

Procedure:
Using a method similar to Example 12, 1-(2-chloro-benzyl)-1H-indole-2,3-dione (300 mg, 1.1 mmol) and 2,6-dimethylphenol (831 mg, 8.83 mmol) in trifluoromethanesulfonic acid (5 mL) gives a crude brown oil. Purify by flash chromatography (CH2Cl2, 10% EtOAc/CH2Cl2, 25% EtOAc/CH2Cl2) and recrystallize the resulting oil from diethyl ether/CH2Cl2/hexanes to give after drying under house vacuum 145 mg (30%) of the title compound as an off-white powder. MS (ES): m/z=442 (M+1), 440 (M−1); 1H NMR(DMSO-d6): δ9.46 (s, 2H), 7.52 (dd, J=1.2 Hz, J=7.8 Hz, 1H), 7.36-7.24 (m, 4H), 7.10 (t, J=7.3 Hz, 1H), 7.01-6.91 (m, 6H), 6.71 (d, J=8.7 Hz, 4H), 5.06 (s, 2H).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH3:22])[CH:8]=[C:9](/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)[CH:10]=1)=[O:5])C.C1COCC1.O.[OH-].[Na+]>C(O)C>[CH3:22][N:7]1[CH:8]=[C:9](/[CH:11]=[CH:12]/[C:13]2[CH:14]=[CH:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=2)[CH:10]=[C:6]1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1cc(/C=C/c2ccc([N+](=O)[O-])cc2)cn1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: Cn1cc(/C=C/c2ccc([N+](=O)[O-])cc2)cc1C(=O)O
Temperature: 25 °C
Yield: 55.2 %

Procedure:
Ethyl-1-methyl-4-[(E)-2-(4-nitrophenyl)ethenyl]-1H-pyrrole-2-carboxylate (0.100 mg, 0.333 mmol; see step (ii) above) was suspended in ethanol (4 mL), THF (8 mL) and water (20 mL) to which sodium hydroxide solution (NaOH 0.190 g, 4.75 mmol in water 10 mL) was added with stirring. The reaction mixture was heated under reflux for 4 h. The reaction mixture was cooled to room temperature then HCl(conc.) was added dropwise with vigorous stirring until pH 2 was attained. The yellow, solid material was filtered off, washed with water and dried in vacuo at 60° C. to provide the title compound (50 mg, 55%), m.p.=212-215° C. (decomposition).
Reaction SMILES: [CH:1]1([NH:7][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[Mg]Br.[C:17](#[N:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Cl-].[NH4+]>C(OCC)C>[CH:8]1([N:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:17](=[NH:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: N#Cc1ccccc1
Reactant: C1CCC(NC2CCCCC2)CC1
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: N=C(c1ccccc1)N(C1CCCCC1)C1CCCCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Dicyclohexylamine (18.1 g, 0.10 mmol) was dissolved in diethylether (150 ml). The solution was heated to reflux temperature and a solution of methylmagnesiumbromide (33 ml, 3.0 M in diethylether, 0.10 mol) was added dropwise over a period of 20 minutes. After the addition, the reaction mixture was stirred for 3 hours at room temperature. Benzonitrile (10.3 g, 0.10 mol) was added and the reaction mixture was stirred for 20 hours at room temperature. A solution of ammoniumchloride (10% in water, 100 ml) was added. The water and organic layers were separated and the water layer was extracted twice with diethylether (150 ml). The combined ether layers were dried over sodium sulphate, filtered and the solvent was evaporated from the filtrate resulting in a yellow wax (23.6 g). The product was further purified by short path distillation (kugelrohr, P=0.8 mbar, T=150° C.). Yield 19.5 g (69%). The product was characterized by 1H NMR 300 MHz (CDCl3) δ (ppm): 7.3 (dd, 3H), 7.2 (dd, 2H), 5.7 (bs, 1H), 3.1 (tt, 2H), 2.0 (bq, 3H), 1.7 (m, 8H), 1.5 (d, 2H), 1.1 (m, 6H) and by 13CNMR 75 MHz (CDCl3) δ (ppm): 169.3, 131.9, 128.7, 128.3, 126.2, 58.6, 31.6, 27.0, 25.8