Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Se](=O)=[O:2].[F:4][C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[C@H:12]1[CH2:18][N:17]2[C:19]([CH3:22])=[CH:20][N:21]=[C:16]2[C@H:15]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:14][CH2:13]1>O1CCOCC1>[F:4][C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[C@H:12]1[CH2:18][N:17]2[C:19]([CH:22]=[O:2])=[CH:20][N:21]=[C:16]2[C@H:15]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:29])[CH3:28])[CH2:14][CH2:13]1
Reactant: Cc1cnc2n1C[C@H](c1cccc(F)c1F)CC[C@H]2NC(=O)OC(C)(C)C
Reactant: O=[Se]=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(C=O)cnc21
Reaction time: 8 h
Yield: 83.6 %

Procedure:
Selenium dioxide (1.73 g, 15.63 mmol) was added to a solution of tert-butyl (6S,9R)-6-(2,3-difluorophenyl)-3-methyl-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-9-ylcarbamate (2.95 g, 7.82 mmol) in dioxane (200 mL) and the mixture heated to reflux. After 8 h, the reaction mixture was filtered and concentrated. Purification by silica gel chromatography (100% dichloromethane→40% ethyl acetate/dichloromethane) gave the title compound (2.56 g). MS 392.2 (M+1). 1H NMR (500 MHz, CDCl3) δ 9.69 (s, 1H), 7.68 (s, 1H), 7.13-7.06 (m, 2H), 6.96-6.93 (m, 1H), 6.26 (d, J=6.1 Hz, 1H), 5.56 (d, J=14.2 Hz, 1H), 4.91 (dd, J=9.8, 6.6 Hz, 1H), 4.13-4.08 (m, 1H), 3.02 (t, J=11.2 Hz, 1H), 2.43 (d, J=13.4 Hz, 1H), 2.28 (dd, J=24.5, 12.1 Hz, 1H), 2.18-1.16 (m, 1H), 1.50 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[S:7][C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.S(O)(O)(=O)=O.Cl[C:22]1[NH:23][CH2:24][CH2:25][N:26]=1>C(#N)C.ClCCl>[CH3:1][O:2][C:3]1[S:7][C:6]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:22]3[NH:26][CH2:25][CH2:24][N:23]=3)=[CH:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: ClC1=NCCN1
Reactant: COc1ccc(Cc2ccc(N)cc2)s1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CC#N
Product: COc1ccc(Cc2ccc(NC3=NCCN3)cc2)s1
Temperature: 80 °C
Yield: 69.6 %

Procedure:
To a solution of [4-(5-methoxythien-2-ylmethyl)-phenylamine (145 mg, 0.66 mmol) in acetonitrile (10 ml) was added 2-chloro-2-imidazoline sulfate (155 mg, 0.76 mmol) at 20–25° C. under nitrogen. The resulting suspension was heated at 80° C. for 1.5 hours. The mixture was diluted with dichloromethane and washed with 10% sodium hydroxide, water, dried (Na2SO4), and concentrated to dryness. Purification by preparative TLC, eluting with ethyl acetate/methyl alcohol/isopropylamine, gave 2-[4-(5-methoxythien-2-ylmethyl)phenyl]amino-imidazoline (132 mg, 70%) as a yellow oil; 1H NMR (300 MHz, CDCl3) δ 7.12 (d, J=8.4 Hz, 2H), 6.93 (d, J=8.4 Hz, 2H), 6.39 (dt, J=3.7, 1.1 Hz, 1H), 5.98 (d, J=3.7 Hz, 1H), 3.92 (bs, 2H), 3.82 (S, 3H), 3.52 (S, 4H), 3.15–3.35 (broad, 2H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH3:7])[N:4]=[N:3]1.[Li]CCCC.[CH2:13]([Sn:17](Cl)([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16].[NH4+].[Cl-]>C1COCC1.O>[CH3:1][N:2]1[C:6]([Sn:17]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:13][CH2:14][CH2:15][CH3:16])=[C:5]([CH3:7])[N:4]=[N:3]1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Cc1cn(C)nn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1c(C)nnn1C
Temperature: -70 °C
Reaction time: 1 h
Yield: 76.3 %

Procedure:
A solution of 1,4-dimethyl-1,2,3-triazole (0.56 g, 5.77 mmol) in THF (5 mL) was added dropwise to a solution of BuLi (2.77 ml, 6.92 mmol, 2.5 M in hexane) in 30 mL of THF at −78° C. under N2. The resulting cloudy mixture was stirred at −70° C. for 1 h. Then tributyltinchloride (1.711 ml, 6.34 mmol) was added. The reaction mixture became clear and was stirred at this temperature for 30 min, and gradually warmed to rt. To the reaction mixture was added 10 ml of NH4Cl and 10 ml of water. The reaction mixture was extracted with ether. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated. The residue was purified on FCC (20% EA/Hexane) to give 1.7 g of a clear liquid (73%). LC-MS (ES) m/z=388 (M+H)+, 1H NMR (CDCl3, 400 MHz) δ 4.05 (s, 3H), 2.38 (s, 3H), 1.5-0.9 (m, 27H)
Reaction SMILES: [CH3:1][N:2]1[C:6](=[N:7][CH:8]([Cl:15])[CH:9]([Cl:14])[C:10]([Cl:13])([Cl:12])[Cl:11])[C:5](=[O:16])[N:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2F)[C:3]1=[O:24].[F:25][C:26]1C=[CH:30][CH:29]=[CH:28][C:27]=1N1C(=NC(Cl)C(Cl)C(Cl)(Cl)Cl)CN(C)C1>>[F:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:1]=1[N:2]1[C:6](=[N:7][CH:8]([Cl:15])[CH:9]([Cl:14])[C:10]([Cl:12])([Cl:11])[Cl:13])[C:5](=[O:16])[N:4]([CH:17]2[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]2)[C:3]1=[O:24]
Reactant: CN1CC(=NC(Cl)C(Cl)C(Cl)(Cl)Cl)N(c2ccccc2F)C1
Reactant: CN1C(=O)N(c2ccccc2F)C(=O)C1=NC(Cl)C(Cl)C(Cl)(Cl)Cl
Product: O=C1C(=NC(Cl)C(Cl)C(Cl)(Cl)Cl)N(c2ccccc2F)C(=O)N1C1CCCCC1

Procedure:
Similarly the reverse 1-position-3-position isomers of each of the above prepared compounds are prepared by using the corresponding position isomer of formula A as the starting material. For example by using 1-methyl-3-(2-fluorophenyl)-5-(1,2,3,3,3-pentachloropropyl)imino-1,3-diazolidine-2,4-dione in place of 1-(2-fluorophenyl-3-methyl-5-(1,2,3,3,3-pentachloropropyl)imino-1,3-diazolidine the following compounds (as well as the other position isomers of the above products) are prepared:
Reaction SMILES: C([O:8][N:9]1[CH2:13][CH2:12][NH:11][C:10]1=[N:14][C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:22])C1C=CC=CC=1.[BrH:23]>>[BrH:23].[Cl:21][C:20]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:22])[C:15]=1[N:14]=[C:10]1[NH:11][CH2:12][CH2:13][N:9]1[OH:8]
Reactant: Clc1cccc(Cl)c1N=C1NCCN1OCc1ccccc1
Agent: Br
Product: ON1CCNC1=Nc1c(Cl)cccc1Cl

Procedure:
A suspension of 45.3 g. of 1-benzyloxy-2-[(2,6-dichlorophenyl)imino]-imidazolidine in 450 ml. of 48% strength hydrobromic acid is warmed to 80° for 4 hours. The resulting solution is poured onto ice and extracted with ether. The aqueous phase is evaporated in vacuo. The residue is distilled azeotropically five times with a mixture of ethanol/ethyl acetate. 2-[(2,6-dichlorophenyl)imino]-1-hydroxyimidazolidine hydrobromide is obtained by crystallization from a mixture of ethanol/ethyl acetate/ether. An analytically pure sample, m.p. 233°-234°, is obtained by recrystallization from methanol/acetonitrile.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]3[CH:17]=[CH:16][O:15][C:14]=3[C:18](=[O:20])[CH3:19])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1.CO[CH:23](OC)[N:24]([CH3:26])[CH3:25]>>[CH3:1][O:2][N:3]=[C:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]3[CH:17]=[CH:16][O:15][C:14]=3[C:18](=[O:20])/[CH:19]=[CH:23]/[N:24]([CH3:26])[CH3:25])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1
Reactant: COC(OC)N(C)C
Reactant: CON=C1CCc2cc(-c3ccoc3C(C)=O)ccc21
Product: CON=C1CCc2cc(-c3ccoc3C(=O)/C=C/N(C)C)ccc21
Temperature: 25 °C
Yield: 98 %

Procedure:
A solution of the product of Step 1 (0.15 g, 0.56 mmol) in N,N-dimethylformamide dimethyl acetal (5 ml) was heated at 100° C. for 18 hours. After cooling to room temperature, the solvent was removed in vacuo to afford the title compound (0.18 g, 98%); MS (ES+) m/e 325 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:43])[CH2:4][C:5]1[C:6]([CH2:11][CH2:12][C:13]2[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([CH:30]4[CH2:35][CH2:34][CH2:33][N:32]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:31]4)=[CH:26][CH:25]=3)[N:14]=2)=[N:7][CH:8]=[CH:9][CH:10]=1.O.[OH-].[Li+]>C1COCC1.O.CO>[C:39]([O:38][C:36]([N:32]1[CH2:33][CH2:34][CH2:35][CH:30]([C:27]2[CH:28]=[CH:29][C:24]([NH:23][C:15]3[N:14]=[C:13]([CH2:12][CH2:11][C:6]4[C:5]([CH2:4][C:3]([OH:43])=[O:2])=[CH:10][CH:9]=[CH:8][N:7]=4)[C:18]([C:19]([F:20])([F:21])[F:22])=[CH:17][N:16]=3)=[CH:25][CH:26]=2)[CH2:31]1)=[O:37])([CH3:42])([CH3:40])[CH3:41]
Reactant: COC(=O)Cc1cccnc1CCc1nc(Nc2ccc(C3CCCN(C(=O)OC(C)(C)C)C3)cc2)ncc1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ncccc4CC(=O)O)n3)cc2)C1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of tert-butyl 3-(4-((4-(2-(3-(2-methoxy-2-oxoethyl)pyridin-2-yl)ethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (I148) (0.030 g, 0.050 mmol) in THF (7 mL), water (1.5 mL) and MeOH (1 mL) was added lithium hydroxide monohydrate (0.020 g, 0.48 mmol). The reaction mixture was stirred at room temperature for 17 hours then the volatiles were removed in vacuo and the residue was partitioned between ethyl acetate (10 mL) and saturated aqueous sodium hydrogen carbonate (10 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×10 mL). The combined organic layers were washed with brine (10 mL), dried (MgSO4) then the solvent removed in vacuo to give the title compound (I149) (0.029 g, 99%) as a white solid. LCMS Method C: rt 5.50 min, m/z=586.1 [M+H]+, 584.2 [M−H]+.
Reaction SMILES: [C:1]([C:4]1[CH:13]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:23]=2[O:22][C:21]([CH3:24])=[CH:20][C:19]3=[O:25])[C:12]2[C:11](=[O:26])[NH:10][CH:9]=[CH:8][C:7]=2[NH:6][C:5]=1[CH3:27])(=[O:3])[CH3:2].[CH:28]1([S:31](Cl)(=[O:33])=[O:32])[CH2:30][CH2:29]1>>[CH:28]1([S:31]([O:26][C:11]2[N:10]=[CH:9][CH:8]=[C:7]3[C:12]=2[CH:13]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]4[C:23]=2[O:22][C:21]([CH3:24])=[CH:20][C:19]4=[O:25])[C:4]([C:1](=[O:3])[CH3:2])=[C:5]([CH3:27])[NH:6]3)(=[O:33])=[O:32])[CH2:30][CH2:29]1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: CC(=O)C1=C(C)Nc2cc[nH]c(=O)c2C1c1cccc2c(=O)cc(C)oc12
Product: CC(=O)C1=C(C)Nc2ccnc(OS(=O)(=O)C3CC3)c2C1c1cccc2c(=O)cc(C)oc12

Procedure:
The title compound is prepared in analogy to example 10 from 50 mg (0.13 mmol) of 3-acetyl-2-methyl-4-(2-methyl-4-oxo-4H-chromen-8-yl)-4,6-dihydro-1,6-naphthyridin-5(1H)-one and 22 mg (0.15 mmol) of cyclopropanesulfonyl chloride. 54 mg (84% of theory) of the product are obtained as a pale yellow solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4](Cl)([CH3:6])[CH3:5].[Cl:8][C:9]([Cl:11])=[CH2:10].[Cl-].[Al+3].[Cl-].[Cl-]>>[CH3:5][C:4]([CH3:6])([CH2:3][CH2:2][Cl:1])[CH:10]=[C:9]([Cl:11])[Cl:8]
Reactant: C=C(Cl)Cl
Reactant: CC(C)(Cl)CCCl
Agent: [Al+3]
Agent: [Cl-]
Product: CC(C)(C=C(Cl)Cl)CCCl

Procedure:
1,3-Dichloro-3-methyl-butane was reacted with 1,1-dichloroethene in the presence of aluminum chloride in the temperature range between -10° and +5° C. 3,3-Dimethyl-1,1,5-trichloro-1-pentene was thereby obtained and was purified by distillation. 1,1-Dichloro-3,3-dimethyl-1,4-pentadiene was obtained by splitting off hydrogen chloride with quinoline in the temperature range between 200° and 240° C. (See Application Ser. No. 281,614 filed July 9, 1981 now pending, corresponding to German Patent Application No. P 30 29 270.7 of 1.8.1980). ##STR6##
Reaction SMILES: [CH:1]([C:4]1[N:8]2[N:9]=[C:10]([CH:13]=C)[CH:11]=[CH:12][C:7]2=[N:6][N:5]=1)([CH3:3])[CH3:2].I([O-])(=O)(=O)=[O:16].[Na+]>O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[CH:1]([C:4]1[N:8]2[N:9]=[C:10]([CH:13]=[O:16])[CH:11]=[CH:12][C:7]2=[N:6][N:5]=1)([CH3:3])[CH3:2]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1ccc2nnc(C(C)C)n2n1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)c1nnc2ccc(C=O)nn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.5 %

Procedure:
The 3-isopropyl-6-vinyl-[1,2,4]triazolo[4,3-b]pyridazine (3.28 g, 17.4 mmol, Preparation #1) in 1,4-dioxane (75 mL) and water (15 mL) was treated with osmium tetroxide (3.5 mL, 0.28 mmol, 2.5 wt % in 2-methyl 1-propanol) and then sodium periodate (7.45 g, 34.9 mmol) was added. The mixture was stirred at ambient temperature for about 1 h and then diluted with 1,4-dioxane (50 mL) and filtered through Celite®. The filter cake was washed with 1,4-dioxane then EtOAc. The filtrate was concentrated under reduced pressure and then the residue was purified by flash chromatography on silica gel with DCM/MeOH (9:1) as an eluent to give the title compound (2.30 g, 69.4%) as a beige solid: 1H NMR (CDCl3) δ 1.61 (d, 6H), 3.76 (m, 1H), 7.65 (d, 1H), 8.21 (m, 1H), 10.06 (d, 1H).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]([CH3:21])[CH2:16][NH:17][CH2:18][C:19]#[N:20])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1>N.CO.[Ni]>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]([CH3:21])[CH2:16][NH:17][CH2:18][CH2:19][NH2:20])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(C(C)CNCC#N)cc1OC1CCCC1
Agent: [Ni]
Agent: N
Solvent: CO
Product: COc1ccc(C(C)CNCCN)cc1OC1CCCC1
Yield: 79.2 %

Procedure:
A mixture of intermediate 21 (0.0117 mol) in NH3 /CH3OH (60 ml) was hydrogenated at RT with Raney Nickel (2 g) as a catalyst. After uptake of H2, the catalyst was filtered off and the filtrate was evaporated. The residue was treated with a 10% aqueous HCl solution, and this mixture was extracted with ethylacetate. The layers were separated. The aqueous phase was basified, then extracted with ethylacetate. The separated organic layer was dried, filtered, and the solvent was evaporated, yielding 2.71 g (75%) of (±)-N-[2-[3-(cyclopentyloxy)-4-methoxyphenyl]propyl]-1,2-ethanediamine (intermediate 22).
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]([NH:11][C:12](=[O:40])[CH2:13][NH:14][C:15]([C:17]1[CH:18]=[C:19]([N:26]2[CH2:31][C@@H:30]3[CH2:32][C@H:27]2[CH2:28][N:29]3C(OC(C)(C)C)=O)[CH:20]=[CH:21][C:22]=1[N+:23]([O-:25])=[O:24])=[O:16])([CH3:10])[CH3:9]>ClCCl>[C@H:27]12[CH2:32][C@H:30]([NH:29][CH2:28]1)[CH2:31][N:26]2[C:19]1[CH:20]=[CH:21][C:22]([N+:23]([O-:25])=[O:24])=[C:17]([CH:18]=1)[C:15]([NH:14][CH2:13][C:12]([NH:11][CH:8]([CH3:10])[CH3:9])=[O:40])=[O:16]
Reactant: CC(C)NC(=O)CNC(=O)c1cc(N2C[C@@H]3C[C@H]2CN3C(=O)OC(C)(C)C)ccc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)NC(=O)CNC(=O)c1cc(N2C[C@@H]3C[C@H]2CN3)ccc1[N+](=O)[O-]
Reaction time: 8 h
Yield: 83.7 %

Procedure:
2,2,2-Trifluoroacetic acid (4.6 g, 39.5 mmol) was added to a solution of (1S,4S)-tert-butyl 5-(3-(2-(isopropylamino)-2-oxoethylcarbamoyl)-4-nitrophenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (Intermediate 5A) (1.5 g, 3.25 mmol) in dichloromethane (15 mL). The resulting solution was stirred overnight. The resultant crude material was purified using a 20 g SCX cartridge to afford 5-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-(2-(isopropylamino)-2-oxoethyl)-2-nitrobenzamide (984 mg, 2.72 mmol).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:26])[C:8]([CH2:24][CH3:25])=[C:9]([C:22]#[N:23])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[NH:21][N:20]=[N:19][N:18]=2)=[CH:13][CH:12]=1)=[O:5])[CH3:2].[H-].[Na+].Br[CH2:30][CH:31]([CH3:33])[CH3:32]>CN(C=O)C.[Cl-].[Na+].O>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:26])[C:8]([CH2:24][CH3:25])=[C:9]([C:22]#[N:23])[C:10]=1[C:11]1[CH:12]=[CH:13][C:14]([C:17]2[N:18]([CH2:30][CH:31]([CH3:33])[CH3:32])[N:19]=[N:20][N:21]=2)=[CH:15][CH:16]=1)=[O:5])[CH3:2]
Reactant: CC(C)CBr
Reactant: CCOC(=O)c1c(-c2ccc(-c3nnn[nH]3)cc2)c(C#N)c(CC)n1C
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(-c2ccc(-c3nnnn3CC(C)C)cc2)c(C#N)c(CC)n1C
Temperature: 0 °C

Procedure:
Into a round bottom flask containing a solution of 4-cyano-5-ethyl-1-methyl-3-[4-(1H-tetrazol-5-yl)-phenyl]-1H-pyrrole-2-carboxylic acid ethyl ester (0.150 g, 0.428 mmol, prepared in example E-242) in DMF (2 mL) cooled to 0° C. while stirring add NaH (0.019 g, 0.479 mmol, 60% in mineral oil). Let stir for 1 h, then add 1-bromo-2-methylpropane (0.052 mL, 0.479 mmol) and let stir overnight. Dilute the mixture with brine (20 mL) and extract the mixture with EtOAc (3×15 mL). Combine the organic layers and wash with brine (2×20 mL), aqueous NH4Cl (1×20 mL), aqueous NaHCO3 (1×20 mL) and water (1×20 mL). Dry the organic layer over anhydrous Na2SO4, filter, and concentrate under reduced pressure. Purify the residue via silica gel chromatography (eluent: 20 to 98% EtOAc in hexanes). Concentrate under reduced pressure the purified fractions and azeotroped with methylene chloride/hexanes. Place the residue under vacuum to provide the title compound as a colorless tar (0.011 g); mass spectrum (m/e): 407.3 (M+H)
Reaction SMILES: [CH3:1][C:2]([C:4]([CH3:7])([CH3:6])[CH3:5])=[O:3].[CH3:8][O:9][C:10](=[O:15])[C:11](OC)=[O:12]>>[CH3:8][O:9][C:10](=[O:15])[C:11]([CH2:1][C:2](=[O:3])[C:4]([CH3:7])([CH3:6])[CH3:5])=[O:12]
Reactant: CC(=O)C(C)(C)C
Reactant: COC(=O)C(=O)OC
Product: COC(=O)C(=O)CC(=O)C(C)(C)C

Procedure:
When a mixture, heated to 50° C., of pinacolin and oxalic acid dimethyl ester was added and the procedure was otherwise the same as in Example 6, a amount of 166.7 g of pivaloylpyruvic acid methyl ester (89% of the theoretical yield) were obtained. Purity: 99.3%.
Reaction SMILES: [N+:1]([C:4]1[CH:27]=[CH:26][C:7]([CH2:8][C:9]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)([C:13](O)=[O:14])[C:10](O)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]>C1COCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][C:9]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)([CH2:10][OH:11])[CH2:13][OH:14])=[CH:26][CH:27]=1)([O-:3])=[O:2]
Reactant: O=C(O)C(Cc1ccc([N+](=O)[O-])cc1)(Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(CC(CO)(CO)Cc2ccc([N+](=O)[O-])cc2)cc1
Reaction time: 19 h
Yield: 102.5 %

Procedure:
4.0 g (10.7 mmol) 2,2-bis(4-nitrobenzyl)malonic acid are dissolved in 40 ml THF and added dropwise at the course of 2 hours to 64.1 ml (64.1 mmol) of a borane-tetrahydrofuran complex 1.0 M solution in THF, which is used without further purification. After 19 hours at 25° C., 50 ml of water are carefully added. The reaction mixture is then partitioned between ethyl acetate and water. The organic phase is washed repeatedly with water, dried over sodium sulfate, filtered and concentrated by rotary evaporation to give 3.8 g of 2,2-bis(4-nitrobenzyl)-1,3-propandiol as a white powder.
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][C:2]1=[CH2:3].[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][OH:16])=[CH:13][CH:12]=1>CCCCCC>[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][O:16][C:5]([CH2:4][C:2]([C:1]([OH:8])=[O:7])=[CH2:3])=[O:6])=[CH:13][CH:12]=1
Reactant: COc1ccc(CO)cc1
Reactant: C=C1CC(=O)OC1=O
Solvent: CCCCCC
Product: C=C(CC(=O)OCc1ccc(OC)cc1)C(=O)O
Temperature: 25 °C
Yield: 60.5 %

Procedure:
A 250 ml one-necked round bottomed flask equipped with reflux condenser, nitrogen inlet, and magnetic stir bar was charged with itaconic anhydride (33.6 g, 0.3 mol) toluene (100 ml) and 4-methoxybenzyl alcohol (41.5 g, 0.3 mol). The solution was then warmed to reflux for 60 minutes and then cooled to room temperature. The solution was poured into a 500 ml Erlenmeyer flask, diluted with 100 ml of hexane and allowed to stand whereupon crystals of pure monoester formed. The product was isolated by filtration on a Buchner funnel and air dried to give 45.4 g, 61% of material with mp 83°-85° C., a second crop, 12.9 g, 17% was isolated after cooling of the filtrate in an ice bath.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]2[CH:13]=[CH:12][N-:11][C:10]2=S)=[CH:4][N:3]=1.[N:15]#[C:16][NH2:17]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]2[CH2:13][CH2:12][NH:11][C:10]2=[N:17][C:16]#[N:15])=[CH:4][N:3]=1
Reactant: N#CN
Reactant: S=C1[N-]C=CC1Cc1ccc(Cl)nc1
Solvent: CCO
Product: N#CN=C1NCCC1Cc1ccc(Cl)nc1

Procedure:
A mixture of 3.6 g of 3-(2-chloropyrid-5-yl-methyl)pyrrolide-2-thione, 2.42 g of cyanamide and 30 ml of ethanol is boiled at reflux temperature for 90 minutes. The mixture is concentrated by evaporation in vacuo and the residue is chromatographed on silica gel using ethyl acetate/methanol (9:1) as eluant. The title compound having a melting point of 137-140° C. (compound 6.3) is obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH:13]=O)[CH2:11][O:10][C:9]1([CH3:16])[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17]C(C)([O-])C.[K+].C(OP(C=[N+]=[N-])(=O)OCC)C>CCOCC>[C:6]([N:8]1[C@@H:12]([C:13]#[CH:17])[CH2:11][O:10][C:9]1([CH3:16])[CH3:15])([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C)OC(=O)N1[C@@H](C=O)COC1(C)C
Agent: CCOP(=O)(C=[N+]=[N-])OCC
Agent: [K+]
Solvent: CCOCC
Product: C#C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
(S)-N-Boc-2,2-dimethyl-4-ethynyl-oxazolidine was prepared according to Method X above by the treatment of tert-butyl-(R)-4-formyl-2,2-dimethyl-3-oxazolidine-carboxylate (1.00 g, 4.36 mmol) (Aldrich) with potassium tert-butoxide (730 mg, 6.54 mmol) and diazomethyl-phosphonic-acid-diethylester (1.20 g, 6.54 mmol) (Method X above). The reaction was allowed slowly to warm up to room temperature and stirred for a total of 12 hrs. (S)-N-Boc-2,2-dimethyl-4-ethynyl-oxazolidine was obtained after silica gel column chromatography with 20% Et2O in hexanes. (Yield 420 mg, 43%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:29](=[O:30])[N:28]([CH3:31])[C:12]2[N:13]([CH:25]([F:27])[F:26])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[CH:24]=[CH:23][NH:22][N:21]=1)=[CH:16][CH:15]=3.I[CH2:33][CH3:34]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:29](=[O:30])[N:28]([CH3:31])[C:12]2[N:13]([CH:25]([F:26])[F:27])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[CH:24]=[CH:23][N:22]([CH2:33][CH3:34])[N:21]=1)=[CH:16][CH:15]=3
Reactant: CCI
Reactant: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4cc[nH]n4)ccc3n(C(F)F)c21
Product: CCn1ccc(-c2ccc3c(c2)c2cc(-c4ccc(Cl)cc4Cl)c(=O)n(C)c2n3C(F)F)n1

Procedure:
The process is carried out as indicated in Example 110 above, with compound A, 3-(2,4-dichlorophenyl)-9-difluoromethyl-1-methyl-6-(1H-pyrazol-3-yl)-1,9-dihydropyrido[2,3-b]indol-2-one, and iodoethane.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[C:12]([N:16]2[CH2:21][CH2:20][N:19]([C:22]([CH:24]3[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]3)=O)[CH2:18][CH2:17]2)[CH:13]=[CH:14][CH:15]=1>C1COCC1>[CH3:30][N:27]1[CH2:26][CH2:25][CH:24]([CH2:22][N:19]2[CH2:20][CH2:21][N:16]([C:12]3[CH:11]=[C:10]([C:2]4[NH:1][C:5]5[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=5[N:3]=4)[CH:15]=[CH:14][CH:13]=3)[CH2:17][CH2:18]2)[CH2:29][CH2:28]1
Reactant: CN1CCC(C(=O)N2CCN(c3cccc(-c4nc5ccccc5[nH]4)c3)CC2)CC1
Solvent: C1CCOC1
Product: CN1CCC(CN2CCN(c3cccc(-c4nc5ccccc5[nH]4)c3)CC2)CC1
Temperature: 60 °C
Yield: 58.7 %

Procedure:
To a solution of {4-[3-(1H-benzoimidazol-2-yl)-phenyl]-piperazin-1-yl}-(1-methyl-piperidin-4-yl)-methanone (0.12 g, 0.35 mmol) in dry THF (4 mL) boran-methyl sulfide complex in THF ((CH3)2S.BH3) (0.07 mL, 0.74 mmol) was added and the resulting suspension was heated at 60° C. overnight. The reaction was then cooled to room temperature, the solvent removed under reduced pressure and 1N HCl (3 mL) was added to the residue before heating at 100° C. for 5 h. The reaction was then cooled to room temperature, neutralized with 10% NaOH and extracted with dichloromethane (3×10 mL) The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford a residue that was purified by Preparative HPLC, to obtain 0.08 g (69%) of the title compound.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[C@@H:3]([CH3:5])[OH:4].[CH2:9](O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[NH2:1][C@H:2]([C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])[C@@H:3]([CH3:5])[OH:4]
Reactant: OCc1ccccc1
Reactant: C[C@@H](O)[C@H](N)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: C[C@@H](O)[C@H](N)C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 28.5 %

Procedure:
L-threonine 21.2 g (178 mmol) was dissolved in toluene (100 mL), and benzyl alcohol (100 mL, 966 mmol) and p-toluenesulfonic acid monohydrate (35.0 g, 194 mmol) were added, followed by heating to reflux for 17 hours under nitrogen atmosphere. After cooling to room temperature, water (200 mL) was added, followed by washing three times with ethyl acetate (100 mL). To the aqueous layer, a saturated aqueous sodium hydrogencarbonate solution was added, and extraction was carried out three times with ethyl acetate (100 mL). After the organic layer was washed with saturated brine, drying was carried out over anhydrous magnesium sulfate, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=0%-15%) to afford the desired product (10.6 g, yield 28%) as a white solid.