Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][CH:12]=[CH:13][N:14]=2)=[CH:6][CH:5]=1)[CH3:2].C1C(=O)N([Br:22])C(=O)C1.C(O)(=O)C>C(Cl)Cl>[Br:22][C:12]1[S:11][C:10]([C:7]2[CH:6]=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[CH:9][CH:8]=2)=[N:14][CH:13]=1
Reactant: CCOc1ccc(-c2nccs2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOc1ccc(-c2ncc(Br)s2)cc1
Temperature: 25 °C
Yield: 94.3 %

Procedure:
To a solution of 2-(4-ethoxyphenyl)thiazole (1.03 g, 5.00 mmol) in DCM (30 mL) were added NBS (0.98 g, 5.50 mmol) and acetic acid (0.3 mL) with stirring at rt under N2. The reaction was stirred at 48° C. for 3 h, then cooled to rt and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=1:1) to give the title compound as a white solid (1.34 g, 94%).
Reaction SMILES: [CH3:1][N:2]([CH3:33])[C:3](=[O:32])[CH2:4][O:5][C:6](=[O:31])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[NH:14][C:15]([C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)=[C:16](C3C=CC(F)=CC=3)[N:17]=2)=[CH:9][CH:8]=1.[F:34][C:35]1[CH:40]=[CH:39][C:38](C2N=C(C3C=CC(C(O)=O)=CC=3)NC=2C2C=CN=CC=2)=[CH:37][CH:36]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.CN(C)C(=O)CO>CN(C=O)C.O>[CH3:1][N:2]([CH3:33])[C:3](=[O:32])[CH2:4][O:5][C:6](=[O:31])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2([C:38]3[CH:39]=[CH:40][C:35]([F:34])=[CH:36][CH:37]=3)[NH:17][CH:16]=[C:15]([C:25]3[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=3)[NH:14]2)=[CH:9][CH:8]=1
Reactant: CN(C)C(=O)COC(=O)c1ccc(-c2nc(-c3ccc(F)cc3)c(-c3ccncc3)[nH]2)cc1
Reactant: O=C(O)c1ccc(-c2nc(-c3ccc(F)cc3)c(-c3ccncc3)[nH]2)cc1
Agent: CN(C)C(=O)CO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C(=O)COC(=O)c1ccc(C2(c3ccc(F)cc3)NC=C(c3ccncc3)N2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
N,N-Dimethyl-4-[4-(4-fluorophenyl)-5-(4-pyridyl)-1H-imidazol-2-yl]-benzoyl-oxyacetamide--To a solution of 4-[4-(4-fluorophenyl)-5-(4-pyridyl)-1H-imidazol-2-yl]benzoic acid (0.15 g, 0.42 mmol) [See Ex. 9 above] in DMF(10 ml) was added carbonyldiimidazole (0.34 g, 2.1 mmol). After stirring for 18 h at rt, N,N-dimethylglycolamide (0.43 g, 4.2 mmol) was added and stirring was continued for an additional 3h at rt. The reaction mixture was poured into H2O, extracted with EtOAc and evaporated. The residue was purified by flash chromatography eluting with a solvent gradient of 2% MeOH/CHCl3 to afford the title compound: CIMS (NH3, m/z): 445 (M+ +H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1.[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[N:14]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[N:13]1[N:14]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([OH:9])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=2)[CH:15]=[C:16]2[C:21]=1[CH:20]=[CH:19][CH:18]=[CH:17]2
Reactant: O=[N+]([O-])c1cc(CCl)ccc1O
Reactant: c1ccc2[nH]ncc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(Cn2cc3ccccc3n2)ccc1O
Temperature: 23 °C
Reaction time: 18 h
Yield: 23.8 %

Procedure:
In a 100 mL round-bottomed flask was added 4-(chloromethyl)-2-nitrophenol (1.0 g, 5.33 mmol), 1H-indazole (0.630 g, 5.33 mmol), and potassium carbonate (0.884 g, 6.40 mmol) in DMF (26.7 mL). The mixture was stirred at 23° C. for 18 h. The reaction was diluted with water (100 mL) and the resulting solid was isolated by filtration, washed with water, and dried in vacuo. The crude solid was purified via ISCO flash chromatography (0-75% EtOAc in hexanes; 40 g column) to give the title compound as a yellow solid (341 mg, 24% yield): 1H NMR (DMSO-d6, 400 MHz): δ=8.50 (d, J=1.0 Hz, 1H), 7.82 (d, J=2.0 Hz, 1H), 7.68-7.72 (m, 1H), 7.56-7.61 (m, 1H), 7.48 (dd, J=8.6, 2.3 Hz, 1H), 7.10 (dd, J=8.5, 7.2 Hz, 2H), 7.00-7.06 (m, 1H), 5.62 ppm (s, 2H). ESI-MS: m/z 270.2 (M+H)+.
Reaction SMILES: Cl.[CH2:2]([O:6][NH:7][C:8]([NH:10][C:11](=N)[NH:12][C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:20])=O)[CH2:3][CH2:4][CH3:5].C[O:23][CH:24](OC)[N:25](C)C>CC#N>[CH3:19][C:18]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:20])[C:13]=1[N:12]1[CH:11]=[N:10][C:8]([NH:7][O:6][CH2:2][CH2:3][CH2:4][CH3:5])=[N:25][C:24]1=[O:23]
Reactant: CCCCONC(=O)NC(=N)Nc1c(C)cccc1C
Reactant: COC(OC)N(C)C
Agent: Cl
Solvent: CC#N
Product: CCCCONc1ncn(-c2c(C)cccc2C)c(=O)n1
Reaction time: 0.08 h

Procedure:
To a magnetically stirred suspension of 12.06 g (38 mmol) of 1-N-butoxy-3-(2,6-dimethylphenyl) amidinourea hydrochloride in 25 ml of CH3CN was added 9.11 g (76 mmol) of N,N-dimethyl-formamide dimethyl acetal and another 25 ml of CH3CN. All of the solid dissolved after the reaction was stirred for 5 minutes. The reaction solution was refluxed for two hours and allowed to come to ambient temperature, then concentrated in vacuo to yield the desired product as a white solid. This was combined with 200 ml of H2O to an insoluble, thin gummy solid which was transferred to a separatory funnel and extracted with CHCl3 (3×75 ml). The organic layers were combined, washed with H2O (2×75 ml) and saturated aqueous brine (1×75 ml). All aqueous washes were combined and back-extracted with (2×50 ml), dried (Mg2SO4), filtered and concentrated in vacuo to yield 1-(2,6-dimethylphenyl)-4-n-butoxyamino-1,2-dihydro-1,3,5-triazin-2-one, as a white solid containing some liquid. Tlc (3% NH4OH/iPA) shows four spots, one of same Rf as starting material. The product was triturated with iPA to yield a white solid: m.p. 144°-145° C.
Reaction SMILES: C(O[CH2:5][CH:6]1[CH2:35][CH2:34][N:9]2[C:10]3[C:15]([C:16]([C:17]4[C:18](=O)[O:19][C:20](=[O:32])[C:21]=4[C:22]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[N:24]([CH3:31])[CH:23]=4)=[C:8]2[CH2:7]1)=[CH:14][CH:13]=[CH:12][CH:11]=3)(=O)C.[CH3:36][S:37]([O:40]S(C)(=O)=O)(=[O:39])=[O:38].[N:45]1C=CC=CC=1>ClCCl>[CH3:36][S:37]([O:40][CH2:5][CH:6]1[CH2:35][CH2:34][N:9]2[C:10]3[C:15]([C:16]([C:17]4[C:18](=[O:19])[NH:45][C:20](=[O:32])[C:21]=4[C:22]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[N:24]([CH3:31])[CH:23]=4)=[C:8]2[CH2:7]1)=[CH:14][CH:13]=[CH:12][CH:11]=3)(=[O:39])=[O:38]
Reactant: CC(=O)OCC1CCn2c(c(C3=C(c4cn(C)c5ccccc45)C(=O)OC3=O)c3ccccc32)C1
Reactant: c1ccncc1
Reactant: CS(=O)(=O)OS(C)(=O)=O
Solvent: ClCCl
Product: Cn1cc(C2=C(c3c4n(c5ccccc35)CCC(COS(C)(=O)=O)C4)C(=O)NC2=O)c2ccccc21
Reaction time: 1 h

Procedure:
A solution of 170 mg of the pyrroledione product of Example 1 in 55 ml of dichloromethane was treated with 87 mg of methanesulfonic anhydride and 1 ml of pyridine. The resulting solution was stirred under nitrogen for 1 hour. An additional 30 mg of methanesulfonic anhydride were then added. After 1 hour, the mixture was washed with water, dried and evaporated. Crystallization of the residue from ethyl acetate/n-hexane gave 150 mg of 3-[6,7,8,9-tetrahydro-8-(methylsulphonyloxymethyl)pyrido[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione of melting point 259°-261° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Br.BrCCBr.CON(C)[C:17]([C:19]1[N:29]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[C:22]2[N:23]=[C:24]([S:27][CH3:28])[N:25]=[CH:26][C:21]=2[CH:20]=1)=[O:18].[Mg]>C1COCC1.C(OCC)C>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][C:17]([C:19]1[N:29]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[C:22]2[N:23]=[C:24]([S:27][CH3:28])[N:25]=[CH:26][C:21]=2[CH:20]=1)=[O:18]
Reactant: CON(C)C(=O)c1cc2cnc(SC)nc2n1-c1ccc(F)cc1
Reactant: Clc1ccccc1CBr
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: BrCCBr
Product: CSc1ncc2cc(C(=O)Cc3ccccc3Cl)n(-c3ccc(F)cc3)c2n1

Procedure:
To a round bottom flask equipped with a condenser is added Mg powder (0.35 g, 0.02 mmol) and diethyl ether (10 mL). 2-Chlorobenzyl bromide (0.10 mL, 0.76 mmol) and a catalytic amount of 1,2-dibromoethane (5 μL) is added to the reaction mixture. After an initial exotherm, the reaction solution develops a yellow color. 7-(4-Fluoro-phenyl)-2-methylsulfanyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid methoxy-methyl-amide, 29, (0.22 g, 0.63 mmol) is dissolved in THF (10 mL) and the Grignard reagent is then carefully transferred dropwise using a cannula using nitrogen to initiate and continue the transfer. The mixture is allowed to stir at room temperature for 2 hours after which the magnesium is removed by filtration and the filtrate concentrated in vacuo. The residue is purified by preparative HPLC to afford 64 mg of the desired product as a pale colored solid: 1H NMR (300 MHz, CDCl3) δ 9.02 (s, 1H), 7.60 (s, 1H), 7.42-7.38 (m, 1H), 7.37-7.22 (m, 5H), 7.18 (t, J=8.7 Hz, 2H), 4.40 (s, 2H), 2.44 (s, 3H); ESI+ MS: m/z (rel intensity) 411.9 (100, M++H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=O.[Cl:13][CH2:14][C:15](Cl)=[O:16].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:24]=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[NH2:23]>>[CH3:30][O:29][C:25]1[CH:24]=[C:22]([NH:23][C:5](=[O:7])[C:4]2[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:2]([NH:1][C:15](=[O:16])[CH2:14][Cl:13])[CH:3]=2)[CH:21]=[C:20]([O:19][CH3:18])[C:26]=1[O:27][CH3:28]
Reactant: O=C(Cl)CCl
Reactant: COc1ccc(C(=O)O)cc1N
Reactant: COc1cc(N)cc(OC)c1OC
Product: COc1ccc(C(=O)Nc2cc(OC)c(OC)c(OC)c2)cc1NC(=O)CCl

Procedure:
Compound 1 is synthesized following a similar method as in Example 1 and using 3-amino-4-methoxybenzoic acid, 2-chloroacetyl chloride and 3,4,5-trimethoxyaniline as materials. Total yield of the two steps: 56%.
Reaction SMILES: FC(F)(F)[C:3]([N:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=2)[CH:15]=[O:16])[CH2:7][CH2:6]1)=O.[CH2:22]1OC1C.[CH3:26][OH:27]>>[OH:27][CH:26]([CH3:22])[CH2:3][N:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=2)[CH:15]=[O:16])[CH2:7][CH2:6]1
Reactant: CC1CO1
Reactant: CO
Reactant: O=Cc1cccc(OC2CCN(C(=O)C(F)(F)F)CC2)c1
Product: CC(O)CN1CCC(Oc2cccc(C=O)c2)CC1
Temperature: 70 °C
Yield: 78 %

Procedure:
3-(1-(2,2,2-trifluoroacetyl)piperidin-4-yloxy)benzaldehyde (62) (1 eq) was taken in MeOH to which propylene oxide (4 eq) was added and the reaction mixture was heated in a sealed tube at 70° C. for 8 h when LCMS showed completion of reaction. The reaction mixture was concentrated and purified by column chromatography using silica gel (100-200 mesh) to afford the pure product as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH:17]2[CH:24]3[CH2:25][CH:20]4[CH2:21][CH:22]([CH2:26][CH:18]2[CH2:19]4)[CH2:23]3)=[O:15])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27]I.[H-].[Na+].Cl>C1COCC1>[C:1]([O:5][C:6]([N:8]([CH3:27])[CH:9]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH:17]2[CH:18]3[CH2:19][CH:20]4[CH2:21][CH:22]([CH2:23][CH:24]2[CH2:25]4)[CH2:26]3)=[O:15])[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3].[CH2:2]([O:5][C:6]([NH:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH:17]2[CH:24]3[CH2:23][CH:22]4[CH2:21][CH:20]([CH2:19][CH:18]2[CH2:26]4)[CH2:25]3)=[O:15])[CH2:10]1)=[O:7])[CH:1]([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(C(=O)OC2C3CC4CC(C3)CC2C4)C1
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)COC(=O)N[C@@H]1CCN(C(=O)OC2C3CC4CC(C3)CC2C4)C1
Product: CN(C(=O)OC(C)(C)C)C1CCN(C(=O)OC2C3CC4CC(C3)CC2C4)C1
Temperature: 50 °C
Reaction time: 8 h
Yield: 60.5 %

Procedure:
2-adamantyl 3-(tert-butoxycarbonyl(methyl)amino)pyrrolidine-1-carboxylate was prepared as follows. A vial equipped with a flea stirbar was charged with (3R)-(2-adamantyl) 3-(tert-butoxycarbonylamino)pyrrolidine-1-carboxylate (105 mg, 0.29 mmol), methyl iodide (36 μL, 0.58 mmol) and dry THF (1 mL). 60% NaH in oil (14 mg, 0.58 mmol) was added and the mixture was stirred overnight under N2. The mixture was heated at 50° C. for 1 h, cooled and applied to a 10-mL ChemElut cartridge, prewetted with 5% aq HCl (6 mL), and eluted with ether (20 mL). The eluate was concentrated and the residue was purified by preparative HPLC to afford (R) 2-adamantyl 3-(tert-butoxycarbonyl(methyl)amino)pyrrolidine-1-carboxylate (32 mg, 29%).
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].[Cl:9][C:10]1[C:29](I)=[CH:28][C:13]([C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([Cl:27])([F:26])[F:25])=[CH:19][CH:18]=2)=[O:15])=[CH:12][N:11]=1.[CH3:31][C:32]1[CH:33]=[N:34][N:35]([CH:46]2[CH2:51][CH2:50][CH2:49][CH2:48][O:47]2)[C:36]=1B1OC(C)(C)C(C)(C)O1.O>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:9][C:10]1[C:29]([C:36]2[N:35]([CH:46]3[CH2:51][CH2:50][CH2:49][CH2:48][O:47]3)[N:34]=[CH:33][C:32]=2[CH3:31])=[CH:28][C:13]([C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([Cl:27])([F:26])[F:25])=[CH:19][CH:18]=2)=[O:15])=[CH:12][N:11]=1
Reactant: Cc1cnn(C2CCCCO2)c1B1OC(C)(C)C(C)(C)O1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(I)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cnn(C2CCCCO2)c1-c1cc(C(=O)Nc2ccc(OC(F)(F)Cl)cc2)cnc1Cl
Temperature: 110 °C

Procedure:
K3PO4 (191 mg, 0.9 mmol) and Pd(PPh3)4 (17.33 mg, 0.015 mmol) were added to a solution of 6-Chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-iodonicotinamide (Stage 25.2, 138 mg, 0.3 mmol) and 4-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (131 mg, 0.45 mmol) in toluene (1.5 mL) under an argon atmosphere in a vial, which was sealed and heated at 110° C. for 18 h. The RM was poured into 20 mL water and extracted with EtOAc. The combined extracts were dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a residue which was purified by flash chromatography (RediSep® Silica gel column, n-heptane/EtOAc, from 5 to 50% EtOAc) and crystallized from n-heptane to afford the title compound as an off-white powder. HPLC (Condition 4) tR=6.8 min, UPLC-MS (Condition 3) tR=1.26 min, m/z=495 [M−H]−.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[C:8]([CH2:12][CH3:13])[C:9]([OH:11])=[O:10])[CH:2]=1.[C:14]1([CH:20]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][CH2:30][NH2:31])[CH2:23][CH2:22]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl.C(N=C=NCCCN(C)C)C.ClCCl.[C:53]([OH:60])(=[O:59])/[CH:54]=[CH:55]/[C:56]([OH:58])=[O:57]>C(O)C.C(OCC)C>[C:53]([OH:60])(=[O:59])/[CH:54]=[CH:55]/[C:56]([OH:58])=[O:57].[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[C:8]([CH2:12][CH3:13])[C:9]([NH:31][CH2:30][CH2:29][CH2:28][CH2:27][N:24]2[CH2:25][CH2:26][N:21]([CH:20]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:22][CH2:23]2)=[O:11])[CH:2]=1.[C:53]([OH:60])(=[O:59])/[CH:54]=[CH:55]/[C:56]([OH:58])=[O:57].[C:53]([OH:60])(=[O:59])/[CH:54]=[CH:55]/[C:56]([OH:58])=[O:57].[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[C:8]([CH2:12][CH3:13])[C:9]([NH:31][CH2:30][CH2:29][CH2:28][CH2:27][N:24]2[CH2:23][CH2:22][N:21]([CH:20]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:26][CH2:25]2)=[O:10])[CH:2]=1
Reactant: NCCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: CCC(=Cc1cccnc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCO
Solvent: CCOCC
Solvent: ClCCl
Product: CCC(=Cc1cccnc1)C(=O)NCCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 0.8 g of 3-(3-pyridyl)-2-ethylacrylic acid, 2.2 g of 4-(4-diphenylmethyl-1-piperazinyl)butylamine, 0.87 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, and 30 ml of dichloromethane is stirred at room temperature overnight. The reaction mixture is washed with water and dried over magnesium sulfate, and the solvent is distilled off. The residue is chromatographed on silica gel with chloroform-methanol (30:1) to give a brown oil, which is dissolved in 5 ml of ethanol containing 1.0 g of fumaric acid. To the resulting solution is added 15 ml of diethyl ether, and the solid separated is collected to give 1.4 g of the title compound. m.p. 137°-141° C. (recrystallized from ethanol-diethyl ether)
Reaction SMILES: C([NH:8][C:9]([C@H:11]1[CH2:14][C@@H:13]([C:15]([NH2:17])=[O:16])[NH:12]1)=[O:10])C1C=CC=CC=1>C(O)(=O)C.CO.[Pd]>[NH:12]1[C@H:13]([C:15]([NH2:17])=[O:16])[CH2:14][C@@H:11]1[C:9]([NH2:8])=[O:10]
Reactant: NC(=O)[C@@H]1C[C@H](C(=O)NCc2ccccc2)N1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: NC(=O)[C@@H]1C[C@H](C(N)=O)N1
Reaction time: 8 h

Procedure:
45.8 mg (196 μmol) of cis-N-benzylazetidine-2,4-dicarboxamide in 10 ml of glacial acetic acid (no reaction occurs in methanol) are hydrogenated in a Parr shaker over 11 mg of 10% Pd/C under a hydrogen pressure of 4 atm for 7 hours. The mixture is filtered through a fluted filter and the catalyst washed with several portions of methanol. Evaporation and drying in vacuo yields a colorless film which crystallizes slowly on addition of a few drops of methanol. After standing in a freezer overnight, the crystals are isolated, washed with a small volume of ethyl acetate/methanol (5:1), and dried in vacuo; yield 16.7 mg (60%). Mp. 215°-218° C. (dec.) after strong shrinking and darkening from approx. 200° C. on (measured with oil bath preheated to 190° C). 1H NMR (D2O): δ4.29 (t, 2H, J=8.5), 2.98 (dt, 1H, J=9 (t), 11 (d)), 2.23 (dt, 1H, J=8 (t), 11.5 (d)). IR (nujol): 3391, 3335, 3208, 3073, 1683, 1669, 1281, 1211, 1109, 1030, 843, 749, 722, 677 cm-1. Mass Spectrum: CI(isobutane): m/z 144 (M+H, 100%), 99 (56).
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]([F:17])([F:16])[CH:13]([F:15])[F:14])[CH:6]=1)[C:3]#[N:4].CO.[ClH:20].[O:21]1CCOC[CH2:22]1>C(OCC)C>[ClH:20].[OH:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]([F:16])([F:17])[CH:13]([F:14])[F:15])[CH:6]=1)[C:3](=[NH:4])[O:21][CH3:22]
Reactant: C1COCCO1
Reactant: N#CC(O)c1cccc(OC(F)(F)C(F)F)c1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: COC(=N)C(O)c1cccc(OC(F)(F)C(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 130A (249 mg, 1.0 mmol) in anhydrous diethyl ether (4 mL) at 0° C. was added MeOH (0.4 mL, 10 mmol) and 4.0 N HCl in dioxane (2.0 mL, 8 mmol). The mixture was stirred at 0° C. for 30 min and then at rt for 4.0 h. The solvent was removed to give methyl 2-hydroxy-2-(3-(1,1,2,2-tetrafluoroethoxy)phenyl)acetimidate HCl salt. To this salt in CH2Cl2 (4.0 mL) was added H2O (8.0 mL). The mixture was stirred at rt for 30 min, then extracted with CH2Cl2 (2×50 mL). The combined organic extracts were dried and concentrated. The crude product was purified by silica gel chromatography to give 130B (170 mg, 60% yield) as a viscous oil. 1H NMR (400 MHz, CDCl3) δ ppm 3.73 (s, 3H) 5.14 (s, 1H) 5.71-6.08 (m, 1H) 7.17 (d, J=7.03 Hz, 1H) 7.28 (s, 1H) 7.31-7.43 (m, 2H).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)[C:4]([O:6][CH3:7])=[O:5].[CH:13]([O:15][CH2:16][CH3:17])=[CH2:14]>C(OCC)(=O)C.P(Cl)(Cl)(Cl)=O>[CH2:13]([O:15][CH2:16][CH2:17][O:1][N:2]=[C:3]([C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)[C:4]([O:6][CH3:7])=[O:5])[CH3:14]
Reactant: COC(=O)C(=NO)c1cccs1
Reactant: C=COCC
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: CCOCCON=C(C(=O)OC)c1cccs1
Reaction time: 0.33 h
Yield: 100 %

Procedure:
To a stirred mixture of methyl 2-hydroxyimino-2-(thien-2-yl)acetate syn-isomer (3.98 g.) and ethyl vinyl ether (2.5 mls) in ethyl acetate (25 mls) was added phosphorous oxychloride (2 drops). After 20 mins. at 50° the ethyl acetate was washed with saturated sodium bicarbonate solution, dried over sodium sulphate and evaporated to an oil, giving methyl 2-(1 -ethoxy)ethoxyimino-2-(thien-2-yl)acetate (syn-isomer) (5.7 g; 100 percent) λmax. (EtOH) 289 nm (ε 11,700), τ (CDCl3 ; 60 MHz) 2.61 (multiplet; thienyl H5), 2.82 to 2.97 (multiplet; thienyl H3 and H4), 4.64 (quartet, J5 Hz; ##EQU20## 6.06 (singlet, -COOCH3), 6.24 (quartet, J 7 Hz, OCH2), 8.56 (doublet J 5 Hz; CH-CH3), 8.79 (triplet, J 7 Hz; O.CH 2 CH3).
Reaction SMILES: C[O:2][C:3](=[O:19])[CH:4]([O:17][CH3:18])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][CH2:14][CH2:15]Br)[CH:7]=1.[C:20]1([OH:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[CH3:18][O:17][CH:4]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][CH2:14][CH2:15][O:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:7]=1)[C:3]([OH:2])=[O:19]
Reactant: Oc1ccccc1
Reactant: COC(=O)C(Cc1cccc(OCCCBr)c1)OC
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: COC(Cc1cccc(OCCCOc2ccccc2)c1)C(=O)O

Procedure:
The title compound was prepared from 3-[3-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid methyl ester (Example 323, Step 1) and phenol via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1). The enantiomers were separated by chiral HPLC.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=3[Cl:23])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Br:24]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(#N)N(C)C>[Br:24][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=3[Cl:23])=[O:15])=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccc(C(=O)c3ccc(Cl)cc3Cl)cc2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Solvent: CN(C)C#N
Product: O=C(c1ccc(-c2ccc(CBr)cc2)cc1)c1ccc(Cl)cc1Cl
Yield: 89.3 %

Procedure:
A mixture of 5.0 g of 2,4-dichlorophenyl 4'-methyl-4-biphenylyl ketone, 2.7 g of N-bromosuccinimide and 20 mg of azaisobutyronitrile in 70 mL of carbon tetrachloride was heated to boiling under reflux for 4 hours. The precipitated material was filtered off and the filtrate was evaporated. The residue was recrystallized from toluene/cyclohexane. There were obtained 5.5 g (89%) of 2,4-dichlorophenyl 4'-bromomethyl-4-biphenylyl ketone as a colorless solid with a m.p. of 92° C.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[O:9][CH3:10].[CH:11](=O)/[CH:12]=[CH:13]/[CH3:14].[OH-].[NH4+]>Cl>[F:1][C:2]1[CH:8]=[C:7]2[C:5](=[CH:4][C:3]=1[O:9][CH3:10])[N:6]=[C:13]([CH3:14])[CH:12]=[CH:11]2
Reactant: COc1cc(N)ccc1F
Reactant: C/C=C/C=O
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Product: COc1cc2nc(C)ccc2cc1F

Procedure:
To 4-fluoro-3-methoxyaniline (1.0 g, 7.1 mmol) in refluxing 6N HCl (20 mL) was added dropwise (E)-but-2-enal (0.99 g, 14 mmol) and the reaction was heated to reflux for 2 hours. After cooling, the reaction was neutralized with ammonium hydroxide and extracted with DCM. The combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressure to yield 6-fluoro-7-methoxy-2-methylquinoline as a brown solid.
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH:9]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)O[C:7]2=[O:32].[CH:33](=O)[C:34]1[O:38][CH:37]=[CH:36][CH:35]=1.C(N(CC)CC)C.O.[NH2:48][NH2:49]>C(Cl)Cl>[O:38]1[CH:37]=[CH:36][CH:35]=[C:34]1[CH2:33][C:9]1[C:10]2[C:6](=[CH:5][C:4]([O:3][CH3:2])=[CH:12][CH:11]=2)[C:7](=[O:32])[NH:49][N:48]=1
Reactant: COc1ccc2c(c1)C(=O)OC2[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: NN
Reactant: O=Cc1ccco1
Agent: [Br-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc2c(Cc3ccco3)n[nH]c(=O)c2c1
Reaction time: 1.5 h
Yield: 44.9 %

Procedure:
A mixture of (5-methoxy-3-oxo-1,3-dihydro-isobenzofuran-1-yl)-triphenyl-phosphonium bromide (8 g, 15.83 mmoles), prepared as described in example 36, CH2Cl2 (100 ml) and furfural (1.31 ml, 15.83 mmoles), cooled in ice and under N2, was dropwise added with triethylamine (2.2 ml, 15.83 mmoles). The cooling was removed and the mixture was stirred for 1.5 hours, then washed with water, anhydrified over Na2SO4 and dried. The residue was dissolved in CH3OH (50 ml) and added with hydrazine monohydrate (2.3 ml, 47.49 mmoles). The mixture was refluxed for 1 hour, then concentrated to half volume. A precipitate crystallised and dried under vacuum at 40° C. gave 1.82 g of the title compound (yield: 45%).