Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[F:25])[CH2:5][N:6]1[CH2:10][CH2:9][N:8]([C:11]2[CH:12]=[C:13]([CH:18]=[CH:19][N:20]=2)[C:14]([O:16]C)=O)[C:7]1=[O:21].[C-:26]#[N:27].[Na+]>N1C=CC=CC=1CN>[CH2:26]([NH:27][C:14](=[O:16])[C:13]1[CH:18]=[CH:19][N:20]=[C:11]([N:8]2[CH2:9][CH2:10][N:6]([CH2:5][C:4]3[CH:22]=[CH:23][C:24]([F:25])=[CH:2][CH:3]=3)[C:7]2=[O:21])[CH:12]=1)[C:2]1[CH:3]=[CH:4][CH:22]=[CH:23][CH:24]=1
Reactant: [C-]#N
Reactant: COC(=O)c1ccnc(N2CCN(Cc3ccc(F)c(F)c3)C2=O)c1
Agent: NCc1ccccn1
Agent: [Na+]
Product: O=C(NCc1ccccc1)c1ccnc(N2CCN(Cc3ccc(F)cc3)C2=O)c1
Yield: 116.8 %

Procedure:
A solution of methyl 2-(3-(3,4-difluorobenzyl)-2-oxoimidazolidin-1-yl)isonicotinate (0.25 g, 0.72 mmol) and sodium cyanide (0.10 g, 2.04 mmol) in pyridin-2-ylmethanamine (3.0 mL) was stirred at 95° C. for 16 hours and concentrated in vacuo. The residue was purified by column chromatography eluted with 0 to 90% of ethyl acetate in dichloromethane to give N-benzyl-2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-isonicotinamide as a colorless solid (0.17 g, yield 54%): mp 99-101° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.74 (t, J=6.0 Hz, 1H), 8.62 (s, 1H), 8.49-8.47 (m, 1H), 8.39 (d, J=5.1 Hz, 1H), 7.76-7.70 (m, 1H), 7.44-7.22 (m, 5H), 7.19-7.15 (m, 1H), 4.54 (d, J=6.0 Hz, 2H), 4.39 (s, 2H), 3.96 (t, J=8.1 Hz, 2H), 3.38 (t, J=8.1 Hz, 2H); MS (ES+) m/z 423.8 (M+1).
Reaction SMILES: [CH:1]([N:14]1[CH2:18][CH2:17][CH:16]([CH2:19][NH2:20])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]1([CH:27]([N:34]=[C:35]=[O:36])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[CH:27]([NH:34][C:35]([NH:20][CH2:19][CH:16]1[CH2:17][CH2:18][N:14]([CH:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:15]1)=[O:36])([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NCC1CCN(C(c2ccccc2)c2ccccc2)C1
Reactant: O=C=NC(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: O=C(NCC1CCN(C(c2ccccc2)c2ccccc2)C1)NC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 80 %

Procedure:
To a solution of C-(1-benzhydryl-pyrrolidin-3-yl)-methylamine (0.26 g, 0.97 mmol) in dry CH2Cl2 (5 ml) was added diphenylmethyl isocyanate (0.18 ml, 0.97 mmol) drop wise under nitrogen. The resulting mixture was stirred at room temperature over night. Removal of solvent under reduced pressure followed by column chromatography using CH2Cl2: CH3OH (20:1) gives the desired product in 80% yield.
Reaction SMILES: CC1C(C2C=C(NC(=O)C)C(=O)NC=2)=C(C)[O:4]N=1.N1C2C(=C(CO)C=CC=2)C=C1.[C:30]1([P:36]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[P:36]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)=[O:4]
Reactant: CC(=O)Nc1cc(-c2c(C)noc2C)c[nH]c1=O
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: OCc1cccc2[nH]ccc12
Solvent: C1CCOC1
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
To a solution of 31 (700 mg, 2.83 mmol), (1H-indol-4-yl)methanol (1.25 g, 8.50 mmol), and triphenylphosphine (2.97 g, 11.3 mmol) in tetrahydrofuran (30 mL) at 60° C. under nitrogen atmosphere was added diisopropyl azodicarboxylate (1.43 g, 7.07 mmol). The mixture was cooled to room temperature, concentrated, and purified by chromatography (silica gel, 0-100% ethyl acetate/hexanes) to give crude 59 (1.94 g, contained Ph3PO).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]([C:18]3[C:19](=[O:31])[N:20]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:21]([CH3:24])[C:22]=3[CH3:23])=[O:17])=[N:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.CCN(CC)CC.[CH:39]1([C:43](Cl)=[O:44])[CH2:42][CH2:41][CH2:40]1>C1COCC1.CCOC(C)=O>[CH:39]1([C:43]([NH:1][C:2]2[CH:7]=[C:6]([O:8][C:9]3[CH:10]=[CH:11][C:12]([NH:15][C:16]([C:18]4[C:19](=[O:31])[N:20]([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=5)[N:21]([CH3:24])[C:22]=4[CH3:23])=[O:17])=[N:13][CH:14]=3)[CH:5]=[CH:4][N:3]=2)=[O:44])[CH2:42][CH2:41][CH2:40]1
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc(N)c3)cn2)c(=O)n(-c2ccccc2)n1C
Reactant: O=C(Cl)C1CCC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc(NC(=O)C4CCC4)c3)cn2)c(=O)n(-c2ccccc2)n1C
Temperature: 0 °C
Reaction time: 1.25 h
Yield: 41.8 %

Procedure:
To a suspension of N-(5-((2-aminopyridin-4-yl)oxy)pyridin-2-yl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (50 mg, 0.12 mmol) in THF (13 mL) was added Et3N (0.034 mL, 0.24 mmol). The suspension was cooled to 0° C., then a solution of cyclobutanecarbonyl chloride (28.5 mg, 0.24 mmol) in THF (3 mL) was added to the mixture slowly. The reaction was stirred at rt for 1.25 hours, then diluted with EtOAc (15 mL). The mixture was washed with water (15 mL×2), followed by washing with brine (15 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/MeOH (v/v)=60/1) to give the title compound as a white solid (25 mg, 41%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([OH:9])=O)=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=[N:3]1.S(Cl)(Cl)=O.[Cl:17][C:18]1[C:23]([NH2:24])=[CH:22][CH:21]=[CH:20][N:19]=1>CN(C)P(=O)(N(C)C)N(C)C>[Cl:17][C:18]1[C:23]([NH:24][C:7]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][C:5]=2[N+:10]([O-:12])=[O:11])=[O:9])=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: Nc1cccnc1Cl
Reactant: Cn1ncc([N+](=O)[O-])c1C(=O)O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O=S(Cl)Cl
Product: Cn1ncc([N+](=O)[O-])c1C(=O)Nc1cccnc1Cl

Procedure:
Prepared analogously to Example A(a) from 1-methyl-4-nitro-1H-pyrazole-5-carboxylic acid, thionyl chloride, and 2-chloro-3-aminopyridine in hexamethylphosphoric acid triamide.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=2)[C:6]([OH:20])=[C:5]([C:21]([NH:23][C@H:24]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@@H:25]([OH:30])[C:26]([O:28]C)=[O:27])=[O:22])[N:4]=1)#[N:2].O.CCOC(C)=O.Cl>CO.[OH-].[Na+]>[C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:11]=2)[C:6]([OH:20])=[C:5]([C:21]([NH:23][C@H:24]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@@H:25]([OH:30])[C:26]([OH:28])=[O:27])=[O:22])[N:4]=1)#[N:2]
Reactant: COC(=O)[C@H](O)[C@@H](Cc1ccccc1)NC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1nc(C(=O)N[C@H](Cc2ccccc2)[C@@H](O)C(=O)O)c(O)c2ccc(Oc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 6 h

Procedure:
(2R,3R)-Methyl 3-(1-cyano-4-hydroxy-7-phenoxyisoquinoline-3-carboxamido)-2-hydroxy-4-phenylbutanoate (4 mg, 0.01 mmol) was dissolved in MeOH (2 mL) and 2 N NaOH (2 mL). After stirring for 6 hours at room temperature, H2O (15 mL) and EtOAc (15 mL) were added. To the stirred mixture was added 1 N hydrochloric acid until pH was 1. The layers were separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over MgSO4, concentrated, and purified by flash chromatography (0-30% MeOH/CH2Cl2) to give the title compound in 3 mg. MS: (−) m/z 482.17 (M−1).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([OH:13])=[CH:5][CH:4]=1.C1CCN2C(=NCCC2)CC1.[Cl:25][C:26]1[CH:31]=[C:30](Cl)[N:29]=[CH:28][N:27]=1>C(#N)C>[Cl:25][C:26]1[N:27]=[CH:28][N:29]=[C:30]([O:13][C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:3]([NH2:2])=[CH:4][CH:5]=2)[CH:31]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Nc1ccc(O)c2ccccc12
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: Nc1ccc(Oc2cc(Cl)ncn2)c2ccccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-aminonaphthalen-1-ol hydrochloride (6.82 g, 31.4 mmol) in acetonitrile (80 mL) at 0° C. was added drop-wise DBU (11.0 mL, 75.0 mmol). After 10 min 4,6-dichloropyrimidine (5.00 g, 34.0 mmol) was added portion-wise over 5 min and the reaction mixture warmed to RT for 3 hr and then evaporated in vacuo. The residue was diluted with water (250 mL) and sonicated for 15 min and then stirred at RT for 16 hr. The resulting precipitate was isolated by filtration, washed with water (3×100 mL) and dried in vacuo to afford the title compound, Intermediate E3, as a grey solid (8.27 g, 97%); Rt 1.85 min (Method 2, acidic); m/z 272 (M+H)+, (ES+).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[C:8]([C:12]1C=C(O)C(=C[CH:18]=1)O)(C)(C)[CH3:9].S(CCC(OCCCCCCCCCCCC)=O)CCC(OCCCCCCCCCCCC)=O.O=O>>[CH2:9]1[CH:2]2[C:1]([O:6][C:4](=[O:5])[CH:3]2[CH2:18][CH:12]=[CH:8]1)=[O:7]
Reactant: O=C1C=CC(=O)O1
Reactant: CC(C)(C)c1ccc(O)c(O)c1
Agent: CCCCCCCCCCCCOC(=O)CCSCCC(=O)OCCCCCCCCCCCC
Agent: O=O
Product: O=C1OC(=O)C2CC=CCC12

Procedure:
3Me--THPA was produced by a combination of replacement and liquid phase aeration method. Thus, the reaction procedure of Example 8 was repeated except that the respective amounts of maleic anhydride, radical polymerization inhibitor p-tert-butylcatechol and auxiliary polymerization inhibitor dilauryl thiodipropionate were melted at 60° C. and the internal atmosphere was replaced with nitrogen gas containing 1 volume % of oxygen. Then, the same oxygen-containing nitrogen gas was introduced into the liquid phase at a rate of 5 ml/min. The procedure gave 164 g of 3Me--THPA. The investigation revealed no gels in the product.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:25])[CH2:19][CH2:20][C:21]([O:23]C)=[O:22])=[CH:14][CH:13]=1>>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([C:18](=[O:25])[CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:16][CH:17]=1)=[O:5]
Reactant: COC(=O)CCC(=O)c1ccc(N)cc1
Reactant: O=C(Cl)c1ccccc1F
Product: O=C(O)CCC(=O)c1ccc(NC(=O)c2ccccc2F)cc1
Yield: 55.6 %

Procedure:
In a manner similar to that described in Example 3, 2-fluorobenzoyl chloride (0.053 g, 0.00033 mol) was allowed to react with 4-(4-amino-phenyl)-4-oxo-butyric acid, methyl ester (0.052 g, 0.00025 mol) (Example 1, Step (c)), and the resulting intermediate was hydrolyzed to give 0.0438 g of 4-[4-(2-fluoro-benzoylamino)-phenyl]-4-oxo-butyric acid as an off-white solid; mp 191-193° C.
Reaction SMILES: [NH2:1][CH:2]1[C:29](=[O:30])[N:4]2[C:5]([C:26]([OH:28])=[O:27])=[C:6]([CH2:9][S:10][C:11]3[CH:12]=[CH:13][C:14]4[N:15]([C:17](=[O:25])[N:18]([CH2:20][CH2:21][C:22]([OH:24])=[O:23])[N:19]=4)[N:16]=3)[CH2:7][S:8][C@H:3]12.[C:31]([O:35][C:36]([N:38]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[CH2:47][C:48]([O:50]C1C=CC([N+]([O-])=O)=CC=1[N+]([O-])=O)=O)[CH3:39])=[O:37])([CH3:34])(C)C.[C:63](OC(N(CC1C=CC=CC=1CC(O)=O)C)=O)(C)(C)[CH3:64].[N+](C1C=C([N+]([O-])=O)C=CC=1O)([O-])=O.C1CCC(N=C=NC2CCCCC2)CC1>C(#N)C.C1COCC1.C(N(CC)CC)C>[CH2:31]([O:35][C:36]([N:38]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[CH2:47][C:48]([NH:1][CH:2]1[C:29](=[O:30])[N:4]2[C:5]([C:26]([OH:28])=[O:27])=[C:6]([CH2:9][S:10][C:11]3[CH:12]=[CH:13][C:14]4[N:15]([C:17](=[O:25])[N:18]([CH2:20][CH2:21][C:22]([OH:24])=[O:23])[N:19]=4)[N:16]=3)[CH2:7][S:8][C@H:3]12)=[O:50])[CH3:39])=[O:37])[CH2:34][CH2:63][CH3:64]
Reactant: CN(Cc1ccccc1CC(=O)O)C(=O)OC(C)(C)C
Reactant: CN(Cc1ccccc1CC(=O)Oc1ccc([N+](=O)[O-])cc1[N+](=O)[O-])C(=O)OC(C)(C)C
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3ccc4nn(CCC(=O)O)c(=O)n4n3)CS[C@H]12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=[N+]([O-])c1ccc(O)c([N+](=O)[O-])c1
Solvent: CC#N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCOC(=O)N(C)Cc1ccccc1CC(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3ccc4nn(CCC(=O)O)c(=O)n4n3)CS[C@H]12
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
To a mixture of 7-amino-3-[2-(2-carboxyethyl)-2,3-dihydro-s-triazolo[4,3-b]pyridazin-3-on-6-ylthiomethyl]-3-cephem-4-carboxylic acid (452 mg., 1 m.mole) and triethylamine (0.46 ml., 3.3 m.mole) in 50% aqueous acetonitrile (4 ml.) was added a THF solution (3ml.) of 2,4-dinitrophenyl o-(N-t-butoxycarbonyl-N-methylaminomethyl)phenylacetate prepared from o-(N-t-butoxycarbonyl-N-methylaminomethyl)phenylacetic acid (283 mg., 1.1 m.mole), 2,4-dinitrophenol (202 mg., 1.1 m.mole) and DCC (227 mg., 1.1 m.mole). The mixture was stirred at room temperature overnight and concentrated under reduced pressure to remove the organic solvents. The aqueous concentrate was washed with ether (3 × 20 ml.), acidified with c.HCl to pH 1 - 2 and extracted with ethyl acetate (5 × 20 ml.). The combined extracts were dried with anhydrous Na2SO4 and evaporated to dryness. The residue was chromatographed on a column of silica gel (Wako gel, C-200, 10 g.) by eluting with a mixture of MeOH-- CHCl3 (MeOH: 0 to 3%). The combined eluates which contained the desired product were evaporated to give 359 mg. (50%) of the title compound. M.P. > 150° C. (dec.).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:2]1.[Br:15][C:16]1[C:17](F)=[C:18]2[C:24]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])=[CH:23][NH:22][C:19]2=[N:20][CH:21]=1>CCCCO>[Br:15][C:16]1[C:17]([N:1]2[CH2:6][CH2:5][CH2:4][C@@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:2]2)=[C:18]2[C:24]([NH:25][C:26](=[O:30])[CH:27]([CH3:28])[CH3:29])=[CH:23][NH:22][C:19]2=[N:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: CC(C)C(=O)Nc1c[nH]c2ncc(Br)c(F)c12
Solvent: CCCCO
Product: CC(C)C(=O)Nc1c[nH]c2ncc(Br)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)c12
Temperature: 160 °C
Reaction time: 24 h
Yield: 46.9 %

Procedure:
(R)-tert-Butyl piperidin-3-ylcarbamate (327 mg, 1.63 mmol) was added to N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)isobutyramide (140 mg) in n-BuOH (3 mL), and the reaction was stirred at 160° C. for 24 hours in a sealed tube. The reaction was concentrated to dryness. Then the residue was purified by C-18 reverse phase flash chromatography (Biotage SP4 unit, C-18 25M column, 10-90% gradient CH3CN/water gradient; CV) to yield (R)-tert-butyl 1-(5-bromo-3-isobutyramido-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3ylcarbamate (105 mg, 47% yield) as a solid.
Reaction SMILES: [CH2:1]([N:4]([CH2:19][CH2:20][CH3:21])[CH2:5][CH2:6][CH2:7][CH2:8][NH:9][CH2:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1)[CH2:2][CH3:3].C[O-].[Na+].CO.[H][H]>[Ni].CO>[CH2:19]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6][CH2:7][CH2:8][NH:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:15][NH2:16])=[CH:17][CH:18]=1)[CH2:20][CH3:21]
Reactant: CCCN(CCC)CCCCNCc1ccc(C#N)cc1
Reactant: [H][H]
Agent: [Ni]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCN(CCC)CCCCNCc1ccc(CN)cc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 98.7 %

Procedure:
4.0 g (13.91 mmol, 1.0 equivalent) of 4-[(4-dipropylaminobutyl)amino]methylbenzonitrile (2a) and 24 ml of methanol were charged in a 100 ml three-necked flask. 400 mg (10 wt %) of the Raney nickel prepared in Example 1 was then slowly added to the mixture. After the addition of 2.58 g (13.35 mmol, 0.96 equivalents) of a 28% sodium methoxide/methanol solution, the atmosphere in the flask was replaced with nitrogen and then with hydrogen. The mixture was then stirred at room temperature for five days using a hydrogen balloon. After completion of the reaction, the reaction solution was filtered through celite. After concentration, the resulting residue was added to 50 ml of water. The product was extracted with 100 ml of chloroform three times. The chloroform layer was washed twice with 100 ml of water, dried over anhydrous sodium sulfate, and concentrated, thereby obtaining 4.0 g of 4-[(4-dipropylaminobutyl)amino]methylbenzylamine (5a) as a colorless oily substance (yield: 99%, GC: 96.0%).
Reaction SMILES: [C:1]([OH:7])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH2:8]=[S:9]1[CH:15]2[N:12]([C:13](=[O:17])[C:14]2=O)[CH:11]([C:18]([OH:20])=[O:19])[C:10]1([CH3:22])[CH3:21].[CH2:23]([O:25][P:26]([CH2:31][C:32]([CH:34]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:33])([O:28][CH2:29][CH3:30])=[O:27])[CH3:24]>C1C=CC=CC=1>[C:1]([OH:7])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH2:8]=[S:9]1[C@H:15]2[N:12]([C:13](=[O:17])[C:14]2=[CH:34][C:32](=[O:33])[CH2:31][P:26]([O:28][CH2:29][CH3:30])([O:25][CH2:23][CH3:24])=[O:27])[C@@H:11]([C:18]([OH:20])=[O:19])[C:10]1([CH3:22])[CH3:21].[C:1]([OH:7])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH2:8]=[S:9]1[C@H:15]2[N:12]([C:13](=[O:17])/[C:14]/2=[CH:31]/[C:32]([CH3:34])=[O:33])[C@@H:11]([C:18]([OH:20])=[O:19])[C:10]1([CH3:22])[CH3:21]
Reactant: CCOP(=O)(CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1)OCC
Reactant: C=S1C2C(=O)C(=O)N2C(C(=O)O)C1(C)C
Agent: CC(C)(C)C(=O)O
Solvent: c1ccccc1
Product: C=S1[C@@H]2/C(=C\C(C)=O)C(=O)N2[C@@H](C(=O)O)C1(C)C
Product: C=S1[C@@H]2C(=CC(=O)CP(=O)(OCC)OCC)C(=O)N2[C@@H](C(=O)O)C1(C)C
Reaction time: 0.17 h

Procedure:
A solution of 1.0 g of methylene-6,7-dioxo-3,3-dimethyl-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate pivalate in 30 ml of benzene is treated at room temperature with 1.8 g of diethoxyphosphinylacetylmethylenetriphenylphosphorane. After 10 minutes, the reaction mixture is evaporated. The residue is chromatographed on silica gel while eluting with ethyl acetate. There is obtained methylene-(2S,5R)-6-[3-(diethoxyphosphinyl)-2-oxopropylidene]-3,3-dimethyl-7-oxo-4-thia-1-aza-bicyclo[3.2.0]heptane-2-carboxylate pivalate as a yellow oil [Rf: 0.35; ethyl acetate; NMR (CDCl3), δ (ppm): 1.23 (9H); 1.36 (3H); 1.51 (3H); 1.59 (3H); 3.12 and 3.42 (2H, P-CH2); 4.21 (4H); 4.63 (1H); 5.90 (2H): 6.08 (1H); 6.82 (1H)].
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH2:9].N1C=CC=CC=1.[F:16][C:17]([F:29])([F:28])[C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.Cl>ClCCl.C(OCC)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:24]([C:21]1[CH:20]=[CH:19][C:18]([C:17]([F:16])([F:28])[F:29])=[CH:23][CH:22]=1)(=[O:26])=[O:25]
Reactant: Nc1ccc(F)cc1F
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccc(F)cc1F)c1ccc(C(F)(F)F)cc1
Reaction time: 0.33 h
Yield: 34.6 %

Procedure:
To 2,4-difluoro-phenylamine (1, 2.09 mL, 20.7 mmol) in 13.04 mL of dichloromethane, pyridine (0.522 mL, 6.45 mmol) was added and the mixture was stirred under nitrogen for 20 minutes. 4-Trifluoromethyl-benzenesulfonyl chloride (2, 5.00 g, 20.4 mmol) was added slowly and the reaction was stirred overnight. The reaction mixture was treated with 2 mL of 1 M hydrochloric acid in diethyl ether and allowed to sit for 1 hour. The solid precipitate was filtered off, and the filtrate was extracted with 1 N aqueous hydrochloric acid followed by brine. The organic portion was dried over magnesium sulfate, filtered and the filtrate was concentrated under vacuum. The resulting solid was treated with dichloromethane, and the solid was collected and dried to provide the desired compound as a white solid (3, 2.383 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1.[Mg].[CH3:10][N:11]1[C:15](=[O:16])[CH2:14][CH2:13][C:12]1=[O:17].S(=O)(=O)(O)O>C1C=CC=CC=1.C(OCC)C>[OH:16][C:15]1([C:2]2[CH:3]=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=2)[N:11]([CH3:10])[C:12](=[O:17])[CH2:13][CH2:14]1
Reactant: Cc1cccc(Br)c1
Reactant: CN1C(=O)CCC1=O
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CCOCC
Solvent: c1ccccc1
Product: Cc1cccc(C2(O)CCC(=O)N2C)c1
Reaction time: 8 h

Procedure:
To a Grignard prepared from 27.3g (0.16 mole) of 3-bromotoluene and 3.7 g. (0.16 mole) of magnesium turnings in 100 ml. of dry diethylether, there is added dropwise over a period of about 10 minutes 12.2 g. (0.11 mole) of N-methylsuccinimide in 100 ml. of dry benzene. The resulting mixture is stirred and refluxed for about 4 hours and then allowed to stand overnight at room temperature. Stirring is resumed and 40 ml. of 50% sulfuric acid is added dropwise at such a rate to maintain a gentle reflux. After an additional 0.5 hours, the water layer is separated and washed twice with 50 ml. of benzene. The organic layers are combined and washed with 50 ml. of sodium carbonate and then twice more with 50 ml. of water. The resulting layer is dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The resulting residue is crystallized from methylene chloride/hexane to give 5-hydroxy-1-methyl-5-(m-tolyl) pyrrolidone; m.p. 128°-130°C.
Reaction SMILES: [N+]([O-])(O)=O.[N+]([O-])(O)=O.[F:9][C:10]1[CH:11]=[C:12]([NH:22][C:23]([NH2:25])=[NH:24])[CH:13]=[CH:14][C:15]=1[N:16]1[CH:20]=[C:19]([CH3:21])[N:18]=[CH:17]1.CN(C)[CH:28]=[CH:29][C:30](=O)[C:31]([CH3:42])([C:33]1[CH:38]=[C:37]([F:39])[C:36]([F:40])=[C:35]([F:41])[CH:34]=1)[CH3:32]>>[F:9][C:10]1[CH:11]=[C:12]([NH:22][C:23]2[N:25]=[C:30]([C:31]([CH3:42])([C:33]3[CH:34]=[C:35]([F:41])[C:36]([F:40])=[C:37]([F:39])[CH:38]=3)[CH3:32])[CH:29]=[CH:28][N:24]=2)[CH:13]=[CH:14][C:15]=1[N:16]1[CH:20]=[C:19]([CH3:21])[N:18]=[CH:17]1
Reactant: CN(C)C=CC(=O)C(C)(C)c1cc(F)c(F)c(F)c1
Reactant: Cc1cn(-c2ccc(NC(=N)N)cc2F)cn1
Solvent: O=[N+]([O-])O
Product: Cc1cn(-c2ccc(Nc3nccc(C(C)(C)c4cc(F)c(F)c(F)c4)n3)cc2F)cn1
Yield: 56 %

Procedure:
The title compound was prepared in analogous manner as described in example 5b) from N-[3-fluoro-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate (81 mg, 0.30 mmol) and 1-dimethylamino-4-methyl-4-(3,4,5-trifluoro-phenyl)-pent-1-en-3-one (98 mg, 0.36 mmol) as a light yellow solid (74 mg) in 56% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17](O)[C:18]4[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=4)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH2:28]([O:35]/[C:36](/[O:39][Si](C)(C)C)=[CH:37]/[CH3:38])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[CH2:28]([O:35][C:36](=[O:39])[CH:37]([CH3:38])[CH:17]([C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1)[C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[N:9]=[CH:10]2)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(O)c1ccc(C(O)c2ccc3c(cnn3-c3ccc(F)cc3)c2)cc1
Reactant: C/C=C(/OCc1ccccc1)O[Si](C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(C(=O)OCc1ccccc1)C(c1ccc(C(=O)O)cc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Reaction time: 3 h
Yield: 55.1 %

Procedure:
To a solution of 4-((1-(4-fluorophenyl)-1H-indazol-5-yl)(hydroxy)methyl)benzoic acid (180 mg, 0.5 mmol) and (Z)-(1-(benzyloxy)prop-1-enyloxy)trimethylsilane (10.0 mmol, prepared using General Silyl Ketene Acetal Method A) in 10 mL of dry DCM was added TiCl4 (1.0 mL of 1.0 M DCM solution, 1.0 mmol) and then stirred 3 h. The reaction was quenched with MeOH, poured into aqueous sodium bicarbonate and extracted 2×EtOAc. The organic layers were dried over MgSO4, filtered, and concentrated. MPLC purification on SiO2 using a 0-100% EtOAc/hexane gradient gave 140 mg (55% yield) of 4-(3-(benzyloxy)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-methyl-3-oxopropyl)benzoic acid. MS found: (M+H)+=509.