Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[H-].[Na+].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22]Cl>>[CH2:7]([O:6][P:4]([O:3][CH2:1][CH3:2])([CH:9]([CH2:22][C:21]1[CH:24]=[CH:25][CH:26]=[C:19]([O:18][CH3:17])[CH:20]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:5])[CH3:8]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: COc1cccc(CCl)c1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C(Cc1cccc(OC)c1)P(=O)(OCC)OCC
Yield: 76 %

Procedure:
By working in a way similar to that described in example 11 and by using ethyl diethoxyphosphinylacetate (59 g; 0.26 moles), sodium hydride at 60% (9.33 g; 0.233 moles) and 3-methoxybenzyl chloride (20.62 g; 0.13 moles), ethyl 2-diethoxyphosphinyl-3-(3-methoxyphenyl)-propionate (34 g; 76% yield) was obtained.
Reaction SMILES: CC[N:3](C(C)C)C(C)C.[CH3:10][C:11]([C:15]1[N:19]([CH2:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:18]2[CH:27]=[CH:28][C:29]([S:31]([N:34]3[CH:38]=[C:37]([C:39]([OH:41])=O)[CH:36]=[N:35]3)(=[O:33])=[O:32])=[CH:30][C:17]=2[N:16]=1)([CH3:14])[CH2:12][CH3:13].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N>CN(C=O)C>[CH3:14][C:11]([C:15]1[N:19]([CH2:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:18]2[CH:27]=[CH:28][C:29]([S:31]([N:34]3[CH:38]=[C:37]([C:39]([NH2:3])=[O:41])[CH:36]=[N:35]3)(=[O:32])=[O:33])=[CH:30][C:17]=2[N:16]=1)([CH3:10])[CH2:12][CH3:13]
Reactant: CCC(C)(C)c1nc2cc(S(=O)(=O)n3cc(C(=O)O)cn3)ccc2n1CC1CCOCC1
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CN(C)C=O
Product: CCC(C)(C)c1nc2cc(S(=O)(=O)n3cc(C(N)=O)cn3)ccc2n1CC1CCOCC1
Yield: 18.5 %

Procedure:
Following the same procedure in Example 24, Step A, using DIPEA (105 uL, 78 mg, 0.60 mmol), 1-{[2-(1,1-dimethylpropyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]sulfonyl}-1H-pyrazole-4-carboxylic acid (0.20 mmol), HATU (114 mg, 0.30 mmol) and saturated ammonia in DMF (5 mL). The crude product was purified by MPLC using CH2Cl2/MeOH (20:1) on silica gel to give 17 mg (18%) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 0.78 (t, J=7.52 Hz, 3 H), 1.41-1.57 (m, 4 H), 1.59 (s, 6 H), 1.95 (q, J=7.42 Hz, 2 H), 2.20-2.37 (m, 1 H), 3.22-3.38 (m, 2 H), 3.90 (dd, J=11.82, 3.22 Hz, 2 H), 4.42 (d, J=7.42 Hz, 2 H), 7.94 (d, J=8.8 Hz, 1 H), 8.01 (dd, J=8.8, 1.8 Hz, 1 H), 8.05 (s, 1 H), 8.36 (d, J=1.56 Hz, 1 H), 8.79 (d, J=0.59 Hz, 1 H); MS (ESI) (M+H)+=460.3.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[N+:23]([C:26]1[CH:27]=[C:28]([S:32](Cl)(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1)([O-:25])=[O:24]>O1CCCC1>[N+:23]([C:26]1[CH:27]=[C:28]([S:32]([NH:1][C:2]2[CH:3]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH:5]=[CH:6][CH:7]=2)(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1)([O-:25])=[O:24]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: CC(C)(C)OC(=O)Nc1cccc(N)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cccc(NS(=O)(=O)c2cccc([N+](=O)[O-])c2)c1
Temperature: 0 °C
Yield: 39.7 %

Procedure:
Into a 1-neck round-bottom flask were added tert-butyl (3-aminophenyl)carbamate (2.0 g, 9.6 mmol) and tetrahydrofuran (30 mL) and triethylamine (2.0 mL, 14 mmol). The mixture was stirred at 0° C. and m-nitrobenzenesulfonyl chloride (2.1 g, 9.6 mmol) was slowly added. The reaction was warmed to rt and stirred for 1 h. The solvent was removed under vacuum and EtOAc and water were added. The aqueous phase was extracted again with EtOAc. The organics were combined, dried over Na2SO4 and the solvents were removed under vacuum. The crude was purified by combi-flash column chromatography to give the desired product (1.5 g, 39%). LCMS for C17H19N3O6S (M-tBu+H)+: m/z=338.0. 1H NMR (400 MHz, DMSO-d6): δ 10.47 (s, 1H), 9.35 (s, 1H), 8.51 (t, J=2.0 Hz, 1H), 8.43 (ddd, J=8.2, 2.2, 1.0 Hz, 1H), 8.12 (ddd, J=7.8, 1.8, 1.0 Hz, 1H), 7.84 (t, J=8.0 Hz, 1H), 7.35 (br, 1H), 7.07 (m, 1H), 7.06 (s, 1H), 6.68 (dt, J=7.0, 2.0 Hz, 1H), 1.42 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:13][C@H:14]2[CH2:19][CH2:18][C@@H:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][OH:25])[CH2:16][CH2:15]2)[CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:13][C@@H:14]2[CH2:19][CH2:18][C@H:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][S:27]([CH3:26])(=[O:29])=[O:28])[CH2:16][CH2:15]2)[CH3:12])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: CN(C[C@H]1CC[C@@H](OCCCCO)CC1)S(=O)(=O)c1ccc(Cl)cc1
Product: CN(C[C@H]1CC[C@@H](OCCCCOS(C)(=O)=O)CC1)S(=O)(=O)c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described in example 3.4, cis-4-chloro-N-[4-(4-hydroxy-butoxy)-cyclohexylmethyl]-N-methyl-benzenesulfonamide was treated with methane-sulfonyl chloride to yield cis-methanesulfonic acid 4-(4-{[(4-chloro-benzenesulfonyl)-methyl-amino]-methyl}-cyclohexyloxy)-butyl ester as colorless viscous oil, MS: 468 (MH+, 1 Cl).
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:18])[CH3:17])=[CH:11][CH:10]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[C:16]([NH:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][CH2:7][CH2:6][CH2:5][OH:4])=[CH:10][CH:11]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)Nc1ccc(CCCCOC(C)=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(=O)Nc1ccc(CCCCO)cc1
Temperature: 55 °C

Procedure:
To a solution of 19.3 g (0.077 mole) of acetic acid, 4-[4-(acetylamino)phenyl]butyl ester in 300 ml of ethanol, add a solution of 21 g potassium carbonate in 300 ml of water. Heat the resulting solution at 55° C. for 4 hrs, following the progress of the reaction by thin-layer chromatography on silica gel (acetonitrile:ammonium hydroxide, 90:10). At the completion of the reaction, filter off any insolubles and remove the ethanol in vacuo. Extract the aqueous residue with 3×300 ml methylene chloride. Wash the combined organic layers with 100 ml water, dry over potassium carbonate, filter and remove the solvent in vacuo. Recrystallize the resulting solid from 140 ml acetonitrile to obtain the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[O:6][C:7]([CH3:12])([CH3:11])[C:8]([OH:10])=O.[NH2:16][CH2:17][CH2:18][C:19]1[CH:33]=[CH:32][C:22]([O:23][C:24]([CH3:31])([CH3:30])[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:21][CH:20]=1.ClC(OCC)=O>C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[O:6][C:7]([CH3:12])([CH3:11])[C:8]([NH:16][CH2:17][CH2:18][C:19]1[CH:20]=[CH:21][C:22]([O:23][C:24]([CH3:30])([CH3:31])[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:32][CH:33]=1)=[O:10]
Reactant: COc1cccc(OC(C)(C)C(=O)O)c1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCN)cc1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C)(C)Oc1ccc(CCNC(=O)C(C)(C)Oc2cccc(OC)c2)cc1
Yield: 84 %

Procedure:
In a manner analogous to that described in Example 4, from 2-(3-methoxyphenoxy)-2-methylpropionic acid and ethyl 2-[4-(2-aminoethyl)-phenoxy]-2-methylpropionate, in the presence of triethylamine and ethyl chloroformate, there is obtained, in a yield of 84% of theory, ethyl 2-{{4-{2-[2-(3-methoxyphenoxy)-2-methylpropionylamino]-ethyl}-phenoxy}}-2-methylpropionate which, after recrystallization from cyclohexane and ethyl acetate, melts at 68°-69° C. and from this 2-{{4-{2-[2-(3-methoxyphenoxy)-2-methylpropionylamino]-ethyl}-phenoxy}}-2-methylpropionic acid in a yield of 64% of theory which, after recrystallization from cyclohexane and ethyl acetate, melts at 80°-81° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH2:11][C@@H:12]([NH:16][C:17]([N:19]2[CH2:24][CH2:23][CH:22]([N:25]3[CH2:31][CH2:30][C:29]4[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=4[NH:27][C:26]3=[O:36])[CH2:21][CH2:20]2)=[O:18])[C:13](O)=[O:14])[CH:6]=[CH:7][C:8]=1[CH2:9][CH3:10])[CH3:2].[NH:37]1[CH2:40][CH:39]([N:41]2[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]2)[CH2:38]1>>[N:41]1([CH:39]2[CH2:38][N:37]([C:13](=[O:14])[C@H:12]([NH:16][C:17]([N:19]3[CH2:24][CH2:23][CH:22]([N:25]4[CH2:31][CH2:30][C:29]5[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=5[NH:27][C:26]4=[O:36])[CH2:21][CH2:20]3)=[O:18])[CH2:11][C:5]3[CH:6]=[CH:7][C:8]([CH2:9][CH3:10])=[C:3]([CH2:1][CH3:2])[CH:4]=3)[CH2:40]2)[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1
Reactant: CCc1ccc(C[C@@H](NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1CC
Reactant: C1CCCN(C2CNC2)CC1
Product: CCc1ccc(C[C@@H](NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CC(N3CCCCCC3)C2)cc1CC

Procedure:
Prepared analogously to Example 34 from (R)-3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid and 1-azetidin-3-yl-perhydro-azepine.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[N:13]=[N:14][C:15]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:16]([CH3:19])[C:17]=2[CH3:18])[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+]>CCO.O>[CH2:20]([C:15]1[N:14]=[N:13][C:12]([N:9]2[CH2:10][CH2:11][CH:6]([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]2)=[C:17]([CH3:18])[C:16]=1[CH3:19])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)C1CCN(c2nnc(Cc3ccccc3)c(C)c2C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1c(Cc2ccccc2)nnc(N2CCC(C(=O)O)CC2)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.6 %

Procedure:
To a solution of 1-(6-benzyl-4,5-dimethyl-pyridazin-3-yl)-piperidine-4-carboxylic acid ethyl ester (0.88 g, 2.5 mmol) in EtOH (8 mL) is added a solution of sodium hydroxide (0.8 g, 20.1 mmol) in H2O (8 mL). After being stirred at 25° C. for 2 h, the mixture is concentrated, and extracted with CH2Cl2 (2×10 mL) to remove impurities. The aqueous layer is acidified by 1N HCl to pH ˜5, and extracted with CH2Cl2 (6×20 mL). The combined organic solution is dried over Na2SO4, filtered and concentrated to give 1-(6-benzyl-4,5-dimethyl-pyridazin-3-yl)-piperidine-4-carboxylic acid (0.68 g, 83%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13]([F:16])([F:15])[F:14])=[C:10]([C:17](Cl)=[O:18])[CH:9]=2)=[CH:4][CH:3]=1.[F:20][C:21]1[CH:22]=[C:23]([NH2:31])[CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1.C(N(CC)C(C)C)(C)C.Cl.C([O-])(O)=O.[Na+]>ClCCl>[F:20][C:21]1[CH:22]=[C:23]([NH:31][C:17]([C:10]2[CH:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[O:12][C:11]=2[C:13]([F:16])([F:15])[F:14])=[O:18])[CH:24]=[C:25]([C:27]([F:29])([F:30])[F:28])[CH:26]=1
Reactant: Nc1cc(F)cc(C(F)(F)F)c1
Reactant: O=C(Cl)c1cc(-c2ccc(Cl)cc2)oc1C(F)(F)F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cc(F)cc(C(F)(F)F)c1)c1cc(-c2ccc(Cl)cc2)oc1C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 26.1 %

Procedure:
5-(4-Chloro-phenyl)-2-trifluoromethyl-furan-3-carbonyl chloride (0.200 g) was added to a solution of 3-fluoro-5-trifluoromethyl-phenylamine (0.105 g) and N,N-diisopropylethylamine (0.102 mL) in dichloromethane (5 mL). After stirring at room temperature for 1 day, the reaction underwent an aqueous acidic (dilute HCl, 2×15 mL) and basic (dilute NaHCO3, 2×15 mL) workup followed by washing with brine (saturated NaCl, 2×15 mL), drying over MgSO4, and concentration. The crude compound was triturated with hexanes/ethyl ether (1:1) to afford the title compound (0.069 g, 24% yield). 1H NMR (CDCl3) δ 7.69 (d, 1H, J=0.02 Hz), 7.68 (s, 1H), 7.67 (d, 2H, J=0.017 Hz), 7.53 (s, 1H), 7.47 (d, 2H, J=0.017 Hz), 7.16 (d, 1H, J=0.02 Hz), 7.02 (s, 1H). ES-MS negative Q1 (m/z) 451.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[C:12]([N:19]1[CH2:24][CH2:23][CH:22]([CH2:25][CH2:26]I)[CH2:21][CH2:20]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>CN(C=O)C.CCOC(C)=O>[C:12]([N:19]1[CH2:20][CH2:21][CH:22]([CH2:25][CH2:26][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=2)[CH2:23][CH2:24]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(CCI)CC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OCCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of methyl 4-hydroxybenzoate (Aldrich) (0.4 g, 2.6 mmoles) 9-1 in DMF (10 ml) was treated with 2-(N-Boc-4-piperidinyl)ethyl iodide 1-4 (0.6 g, 1.77 mmoles) and CS2CO3 (1.15 g, 3.5 mmoles) with stirring at room temperature for 48 hours. The reaction mixture was diluted with EtOAc, washed with H2O, saturated NaHCO3, 10% KHSO4, brine dried (MgSO4) and concentrated. The residue was purified by flash chromatography on silica gel eluting with 20% EtOAc/hexanes to give pure 9-2. Rf 0.3.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[OH:14])[C:7]([O:9][CH3:10])=[O:8])[CH:2]=[CH2:3]>CO.[Pd]>[OH:14][C:13]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[CH2:1][CH2:2][CH3:3]
Reactant: C=CCc1cc(C(=O)OC)ccc1O
Agent: [Pd]
Solvent: CO
Product: CCCc1cc(C(=O)OC)ccc1O
Temperature: 0 °C
Yield: 48.1 %

Procedure:
A solution of 363 g of methyl 3-allyl-4-hydroxybenzoate in 1.5 L of methanol was hydrogenated for 1 hr in a Parr® type shaker at 40 psi and ambient temperature using 1.5 g of 10% palladium on Carbon as the catalyst. The reaction was filtered through Solka-Floc® and the cake washed with 1 L of methanol. The combined filtrate, was concentrated and the oil flushed with ether. Hexanes (1.5 L) were added and the resulting suspension cooled to 0° C. The product was collected by filtration, washed with hexanes and dried affording 176.6 g of methyl 4-hydoxy-3-n-propylbenzoate. A second crop of 166.4 g was obtained by concentrating the filtrate, diluting with hexanes and filtering, bringing the total to 343 g (94.3% yield).
Reaction SMILES: OC1C=CC([CH:8]2[CH:13]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]4[O:24][CH2:23][C:22](=[O:25])[N:21]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:20]=4[CH:31]=3)[CH2:12][CH2:11][CH2:10][N:9]2[C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])=CC=1.C1(C)C=CC(S([O:51][CH2:52][CH2:53][O:54][S:55]([C:58]2[CH:63]=[CH:62][C:61]([CH3:64])=[CH:60][CH:59]=2)(=[O:57])=[O:56])(=O)=O)=CC=1>>[CH3:30][O:29][CH2:28][CH2:27][CH2:26][N:21]1[C:20]2[CH:31]=[C:16]([CH2:15][O:14][CH:13]3[CH:12]([C:16]4[CH:17]=[CH:18][C:19]([O:51][CH2:52][CH2:53][O:54][S:55]([C:58]5[CH:59]=[CH:60][C:61]([CH3:64])=[CH:62][CH:63]=5)(=[O:56])=[O:57])=[CH:20][CH:31]=4)[CH2:11][CH2:10][N:9]([C:32]([O:34][CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[O:33])[CH2:8]3)[CH:17]=[CH:18][C:19]=2[O:24][CH2:23][C:22]1=[O:25]
Reactant: COCCCN1C(=O)COc2ccc(COC3CCCN(C(=O)OCc4ccccc4)C3c3ccc(O)cc3)cc21
Reactant: Cc1ccc(S(=O)(=O)OCCOS(=O)(=O)c2ccc(C)cc2)cc1
Product: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OCCOS(=O)(=O)c4ccc(C)cc4)cc3)cc21

Procedure:
Analogously to Method I, 0.417 g of benzyl 4-hydroxyphenyl-3-[4-(3-methoxypropyl)-3-oxo-3,4-dihydro-2H-benz[1,4]oxazin-6-ylmethoxy]piperidinecarboxylate and 0.984 g of ethylene di(p-toluenesulphonate) are reacted. The title compound is obtained as a colourless oil. Rf=0.31 (2:1 EtOAc-heptane); Rt=5.35.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH2:31][CH:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[C:14](=O)[CH2:15][CH2:16][C:17]([C:19]3[S:20][C:21]([CH2:24][O:25][CH2:26][CH2:27][O:28][CH3:29])=[CH:22][N:23]=3)=O)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.C([O-])(=O)C.[NH4+:42].[OH-].[Na+]>C(O)(=O)C>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:14]3[NH:42][C:17]([C:19]4[S:20][C:21]([CH2:24][O:25][CH2:26][CH2:27][O:28][CH3:29])=[CH:22][N:23]=4)=[CH:16][CH:15]=3)[CH2:31][CH:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[CH:9][CH:8]=2)(=[O:5])=[O:6])[CH2:2][CH2:3]1
Reactant: [NH4+]
Reactant: COCCOCc1cnc(C(=O)CCC(=O)C(CC2CCOCC2)c2ccc(S(=O)(=O)C3CC3)cc2)s1
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COCCOCc1cnc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)s1
Temperature: 100 °C
Reaction time: 2 h
Yield: 93.6 %

Procedure:
A mixture of 5-[4-(cyclopropylsulfonyl)phenyl]-1-[5-[(2-methoxyethoxy)methyl]-1,3-thiazol-2-yl]-6-(tetrahydro-2H-pyran-4-yl)hexane-1,4-dione (0.52 g), ammonium acetate (0.55 g) and acetic acid (6 mL) was stirred at 100° C. for 2 hr. The reaction mixture was neutralized with 8M aqueous sodium hydroxide solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (0.47 g, yield 94%) was obtained as a yellow resin from a fraction eluted with tetrahydrofuran-hexane (1:4, volume ratio). MS: 531 (MH+).
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3]1([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:8][CH2:7][N:6](CC2C=CC=CC=2)[CH2:5][CH2:4]1.C(O)=O.C([O-])=O.[NH4+]>[Pd].CO>[CH3:23][N:2]([CH3:1])[C:3]1([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:4][CH2:5][NH:6][CH2:7][CH2:8]1
Reactant: CN(C)C1(Cc2ccccc2)CCN(Cc2ccccc2)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: O=CO
Product: CN(C)C1(Cc2ccccc2)CCNCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 67.2 %

Procedure:
A suspension of palladium on carbon (10%, 2 g) was added to a solution of 4-(dimethylamino)-1,4-bis(phenylmethyl)piperidine (Description 13, 4.62 g, 15 mmol) and formic acid (90%, 1.4 mL) in methanol (100 mL). Ammonium formate (4.73 g, 75 mmol) was added and the mixture was stirred at room temperature for 20 hours. The mixture was filtered, washing with methanol, and the solvent was evaporated under reduced pressure. Ether (40 mL) was added and the mixture was extracted with hydrochloric acid (1M, 3×40 mL). The combined aqueous layers were washed with ether (40 mL), adjusted to pH 12.0 with aqueous sodium hydroxide (4M) and extracted with dichloromethane (3×40 mL). The combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was triturated with hexane (20 mL) and the solid was collected and dried in vacuo to give the the title compound as a colorless solid (2.20 g, 67%). m/z (ES+) 219 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:28])[N:4]([CH2:17][C:18]2[CH:27]=[CH:26][CH:25]=[CH:24][C:19]=2[C:20](OC)=[O:21])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1.[Li+].[BH4-]>C1COCC1>[Br:1][C:2]1[C:3](=[O:28])[N:4]([CH2:17][C:18]2[CH:27]=[CH:26][CH:25]=[CH:24][C:19]=2[CH2:20][OH:21])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=1
Reactant: COC(=O)c1ccccc1Cn1ccc(OCc2ccc(F)cc2)c(Br)c1=O
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1c(Br)c(OCc2ccc(F)cc2)ccn1Cc1ccccc1CO
Temperature: 40 °C
Reaction time: 6 h

Procedure:
To an ice-cold solution of 3-bromo-4-(4-fluorobenzyloxy)-1-(2-hydroxymethylbenzyl)-1H-pyridin-2-one (Example 72) (0.25 g, 0.56 mmol) in THF (1 mL) was added LiBH4 (2.0 M solution in THF, 0.56 mmol), and the reaction mixture was stirred at 40° C. for 6 hours. The reaction mixture was cooled to room temperature, the solvent was removed under reduced pressure, and the residue was dissolved in EtOAc. The organic solution was washed with brine, dried (MgSO4), filtered, and concemtrated under reduced pressure. 1H NMR (300 MHz, DMSO-d6) δ 7.82 (d, J=8 Hz, 1H), 7.54-7.49 (m, 2H), 7.41 (d, J=7 Hz, 1H), 7.29-7.21 (m, 4H), 6.81 (d, J=7 Hz, 1H), 6.53 (d, J=8 Hz, 1H), 5.30-5.25 (m, 3H), 5.18 (s, 2H), 4.60 (d, J=7 Hz, 2H). ES HRMS m/z 418.0437 (M+H C20H18BrFNO3 requires 418.0449).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[Br:11]N1C(=O)CCC1=O>C(#N)C>[Br:11][C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][C:2](=[O:10])[CH2:3]2
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C1Cc2ccccc2N1
Solvent: CC#N
Product: O=C1Cc2cc(Br)ccc2N1
Yield: 91.8 %

Procedure:
2-Oxindole (1.3 g) in 20 mL of acetonitrile was cooled to −10° C. and 2.0 g of N-bromosuccinimide was slowly added with stirring. The reaction was stirred for 1 hour at −10° C. and 2 hours at 0° C. The precipitate was collected, washed with water and dried to give 1.9 g (90% yield) of 5-bromo-2-oxindole.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:30])[N:19]([CH2:23][CH:24]5[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:33]([F:36])([F:35])[F:34])[CH:3]=1.[CH2:37]=O>>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:30])[N:19]([CH2:23][CH:24]5[CH2:25][CH2:26][N:27]([CH3:37])[CH2:28][CH2:29]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:33]([F:36])([F:34])[F:35])[CH:3]=1
Reactant: C=O
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1CC1CCNCC1
Product: CN1CCC(CN2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)CC1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(1-methylpiperidin-4-yl)methyl]-1,3-thiazolidine-2,4-dione was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-(piperidin-4-ylmethyl)-1,3-thiazolidine-2,4-dione (Example 130) and formaldehyde following General Procedure R.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:13][C:14]#[N:15])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[H-].[Na+].Br[CH:19]([CH3:21])[CH3:20].C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH3:20][CH:19]([CH3:21])[CH:13]([C:5]1[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:14]#[N:15]
Reactant: CC(C)Br
Reactant: COc1cc(CC#N)cc(OC)c1OC
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(C(C#N)C(C)C)cc(OC)c1OC
Yield: 54.2 %

Procedure:
With stirring under ice cooling, 20.25 g (97.7 mmols) of 3,4,5-trimethoxyphenylacetonitrile was added by small portions to 50 ml of a solution of 2.45 g (102.1 mmols) of sodium hydride in dimethylformamide. The solution was dropwise added to 100 ml of a solution of 12.45 g (101.2 mmols) of 2-bromopropane in dimethylformamide with stirring under ice cooling. The mixture was stirred under ice cooling for further 3 hours. After the reaction, an aqueous saturated sodium bicarbonate solution was added to the mixture followed by extraction of the solution with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate =4/1) to afford 13.2 g (yield: 54%) of 3-methyl-2-(3,4,5-trimethoxyphenyl)butyronitrile.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][NH:10][CH2:11][CH2:12][C:13]([OH:22])([P:18]([OH:21])(=[O:20])[OH:19])[P:14]([OH:17])(=[O:16])[OH:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:23](O)=O.C=O>O>[C:1]1([CH2:7][CH2:8][CH2:9][N:10]([CH2:11][CH2:12][C:13]([OH:22])([P:18]([OH:21])(=[O:19])[OH:20])[P:14]([OH:15])(=[O:17])[OH:16])[CH3:23])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=CO
Reactant: O=P(O)(O)C(O)(CCNCCCc1ccccc1)P(=O)(O)O
Agent: C=O
Solvent: O
Product: CN(CCCc1ccccc1)CCC(O)(P(=O)(O)O)P(=O)(O)O

Procedure:
9.3 g (26.3 mmol) of 3-(3-phenylpropylamino)-1-hydroxypropane-1,1-diphosphonic acid are refluxed for 36 hours with 6.1 ml of formic acid and 4.2 ml of a 38% formaldehyde solution in water. The reaction solution is concentrated by evaporation under reduced pressure and the residue is diluted with acetone, yielding 3-[N-(3-phenylpropyl)-N-methyl-amino]-1-hydroxy-propane-1,1-diphosphonic acid in the form of colourless crystals of m.p. 219° (decomp.).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([F:11])[CH:3]=1.Cl.[CH3:13][NH2:14]>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:14][CH3:13])=[O:7])=[C:4]([F:11])[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1F
Reactant: CN
Agent: Cl
Product: CNC(=O)c1ccc(Br)cc1F

Procedure:
The sub-title compound was prepared by the method of example 18 step a) using 4-bromo-2-fluorobenzoic acid and methylamine hydrochloride.