Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:10]=1[CH2:23][C:24]([OH:26])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:29])=O>C1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:10]=1[CH2:23][C:24]([Cl:29])=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: O=C(Cl)Cc1ccc(OCc2ccccc2)cc1OCc1ccccc1

Procedure:
2,4-Dibenzyloxyphenylacetic acid [IX] (1.4 g) was dissolved in anhydrous benzene (30 ml) and then thereto was added thionyl chloride (5 g) and the mixture was left to stand at room temperature (20° C.) for 20 minutes. The reaction mixture was concentrated to dryness under reduced pressure to obtain crude 2,4-dibenzyloxyphenylacetyl chloride [X]. This was used for the subsequent reaction without purification.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][S:17]([CH3:16])(=[O:19])=[O:18])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O[C@H]1CCN(Cc2ccccc2)C1
Reactant: CS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CS(=O)(=O)O[C@H]1CCN(Cc2ccccc2)C1

Procedure:
(S)-1-benzyl-3-hydroxypyrrolidine in an amount of 44.18 g was dissolved in 38.34 g of toluene, and thereto was added 66.88 g of a 30% by weight aqueous sodium hydroxide solution. Next, methanesulfonyl chloride was added dropwise at a rate to allow the internal temperature to be kept at 5 to 10° C. After sodium chloride which was precipitated in the aqueous layer was dissolved by adding 90 ml of water, and liquid separation was performed, thus obtained organic layer was concentrated under reduced pressure to give the title compound as 60.14 g of a pale brown oily material.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[O:15][CH3:16].C(=O)([O-])[O-].[Na+].[Na+].Cl[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25].C(OCC)(=O)C>C1COCC1>[CH2:27]([O:26][C:24]([NH:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][C@H:3]1[O:15][CH3:16])=[O:25])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.6 %

Procedure:
tert-Butyl cis(±)-4-amino-3-methoxypiperidine-1-carboxylate obtained by the method described in Example (1e) (3.0 g, 13.0 mmol) was dissolved in THF (60 mL), followed by cooling to 0° C. Thereafter, aqueous sodium carbonate solution (30 mL) and benzyl chloroformate (2.8 mL, 19.6 mmol) were added, and the mixture was stirred for one hour. Ethyl acetate was added to the reaction solution, and the organic layer was washed with brine and dried over anhydrous sodium sulfate. Following concentration under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=90/10, 50/50) to obtain 4.29 g of the title compound as a pale yellow solid (90%).
Reaction SMILES: [ClH:1].C([N:9]1[CH2:16][CH:15]2[O:17][CH:11]([CH2:12][N:13]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]2)[CH2:10]1)C1C=CC=CC=1.CO>C(#N)C>[ClH:1].[CH:11]12[O:17][CH:15]([CH2:16][NH:9][CH2:10]1)[CH2:14][N:13]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:12]2
Reactant: CC(C)(C)OC(=O)N1CC2CN(Cc3ccccc3)CC(C1)O2
Agent: Cl
Solvent: CC#N
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC2CNCC(C1)O2
Reaction time: 1 h

Procedure:
Hydrochloride salt from step (iii) above (146 g, 0.411 mol) and 20% Pd(OH)2-C (7.5 g) were charged to a Parr hydrogenator bottle. Methanol (0.5 L) was added and the bottle was shaken vigorously under an atmosphere of hydrogen at 3.5 bar. The reaction was monitored by GC analysis and was found to be complete after one hour. The catalyst was filtered and the filtrate was concentrated to afford an off-white crystalline product. The crude product was dissolved in hot acetonitrile (1.2 L), and then filtered while hot. The filtrate was diluted with ethyl acetate (1.2 L). The clear solution was allowed to stand overnight at room temperature. The first crop of crystals was collected and dried under vacuum to afford 52 g of sub-title compound as a white solid. The filtrate was concentrated to near dryness, then dissolved in hot acetonitrile (0.4 L), and diluted with ethyl acetate (0.4 L). A second crop of crystals (38 g) was obtained after cooling the solution to 10° C. Both crops were found to be comparable by GC analysis and 1H NMR analyses. Combined yield: 90 g (83%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([CH3:8])=[N:6][CH:7]=1.[CH3:9][Si:10]([C:13]#[CH:14])([CH3:12])[CH3:11]>CCN(CC)CC.C1COCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:8][C:5]1[N:4]=[CH:3][C:2]([C:14]#[C:13][Si:10]([CH3:12])([CH3:11])[CH3:9])=[CH:7][N:6]=1
Reactant: C#C[Si](C)(C)C
Reactant: Cc1ncc(Br)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ncc(C#C[Si](C)(C)C)cn1
Yield: 72.5 %

Procedure:
5-Bromo-2-methyl-pyrimidine (prepared according to UK patent application GB 2 157 288) (0.2 g, 1.16 mmol), (trimethylsilyl)acetylene (164 μL, 1.3 mmol), CuI (0.022 g, 0.116 mmol) and PdCl2(PPh3)2 (0.082 g, 0.116 mmol) in Et3N (2 mL) and THF (2 mL) were stirred at 80° C. for 4 h. After cooling, the solvents were removed under vacuum and the residue chromatographed to give the subtitle compound (0.16 g, 50%).
Reaction SMILES: [N:1]1[NH:2][C:3](=[O:8])[NH:4][C:5](=[O:7])[CH:6]=1.[Br:9]Br.N>O>[Br:9][C:6]1[C:5](=[O:7])[NH:4][C:3](=[O:8])[NH:2][N:1]=1
Reactant: O=c1cn[nH]c(=O)[nH]1
Reactant: BrBr
Agent: N
Solvent: O
Product: O=c1[nH]nc(Br)c(=O)[nH]1

Procedure:
2H-[1,2,4]triazin-3,5-dione (50 g, 442 mmol) is placed in the presence of 60 ml of bromine in 800 ml of water at 60° C. for 10 h. The reaction medium is then slowly added to an ammonia solution until pH=5. It is then extracted in ethyl acetate and the organic phases are dried on MgSO4. After filtration and dry concentration, 1a is isolated in the form of a white solid (79.2 g, yield=93%). TLC silica gel 60 F 254 Merck, CH2Cl2:MeOH 90:10, Rf=0.32.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.[Cu][C:13]#[N:14].[C-]#N.[Na+]>CN(C=O)C.O>[O:9]=[C:7]1[NH:6][C:5]2[CH:10]=[CH:11][C:2]([C:13]#[N:14])=[CH:3][C:4]=2[O:8]1
Reactant: N#C[Cu]
Reactant: O=c1[nH]c2ccc(Br)cc2o1
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc2[nH]c(=O)oc2c1
Temperature: 150 °C
Reaction time: 1 h
Yield: 100.3 %

Procedure:
A mixture of 6-bromo-1,3-benzoxazol-2(3H)-one (2 g; 9.34 mmol) and copper (I) cyanide (1.42 g; 15.86 mmol) in 6 ml DMF is heated at 150° C. under nitrogen atmosphere for 22 hr. After cooling to room temperature, a solution of 1.55 g (31.6 mmol) of sodium cyanide in 32 ml water is added followed by 1 hr stirring. The system is extracted thoroughly with ethyl acetate, washed with brine, dried and concentrated in vacuo to provide 1.5 g (93% yield) of the title compound enough pure as to prosecute the synthesis.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5](I)=[CH:4][N:3]=1.[CH3:12][Si:13]([C:16]#[CH:17])([CH3:15])[CH3:14].C(N(CC)CC)C>C(#N)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5]([C:17]#[C:16][Si:13]([CH3:15])([CH3:14])[CH3:12])=[CH:4][N:3]=1
Reactant: Cc1c(I)cnc(N)c1C#N
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1c(C#C[Si](C)(C)C)cnc(N)c1C#N
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 5.1 grams (0.020 mole) of 2-amino-3-cyano-5-iodo-4-methylpyridine (prepared as in Step E of Example 9) and 4.2 mL (0.030 mole) of trimethylsilylacetylene in 40 mL of acetonitrile is stirred, and 10.5 mL (0.078 mole) of triethylamine, 0.1 gram of copper(I) iodide, and 0.3 gram of bis(triphenyl-phosphine)palladium(II) chloride are added in order. Upon completion of addition, the reaction mixture is stirred at ambient temperature for about 20 hours and then is warmed to 70 ° C., where it stirred for about 7.5 hours. The reaction is monitored by thin layer chromatography. Upon completion of the reaction, the reaction mixture is concentrated under reduced pressure to a residue. The residue is dissolved in ethyl acetate, and the solution is washed with 50 mL of aqueous dilute hydrochloric acid. The organic layer is dried with magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure, yielding 2-amino-3-cyano-4-methyl-5-(trimethylsilylethynyl) pyridine.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH3:9])[CH:3]=1.C([Li])CCC.CN([CH:18]=[O:19])C>C1COCC1.C(OCC)C>[CH2:8]([C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[CH:18]=[O:19])[CH3:9]
Reactant: CCc1cccc(Br)c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCc1cccc(C=O)c1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 109.6 %

Procedure:
To a solution of 1-bromo-3-ethylbenzene (5 g, 27.2 mmol) in THF (135 mL) at −78° C. was added butyl lithium (1.6 M in hexanes, 18 mL, 28.8 mmol) dropwise. The mixture was stirred at −78° C. for 5 min. DMF (2.1 mL, 27.2 mmol) was added and the mixture was warmed to ambient temperature over 2 h. The mixture was diluted with diethyl ether (500 mL), washed with sat. NaHCO3 and brine, dried (Na2SO4) and concentrated to yield 4 g of Intermediate 370.1 as a clear oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.27 (t, J=7.58 Hz, 3H) 2.73 (q, J=7.58 Hz, 2H) 7.39-7.51 (m, 2H) 7.64-7.76 (m, 2H) 9.99 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[C:9]([C:11]1[CH:12]=[CH:13][C:14]([F:24])=[C:15]([NH:17][C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH:16]=1)#[CH:10]>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[N:7]=[C:6]([C:10]#[C:9][C:11]2[CH:12]=[CH:13][C:14]([F:24])=[C:15]([NH:17][C:18](=[O:23])[C:19]([F:20])([F:21])[F:22])[CH:16]=2)[CH:5]=[CH:4][N:3]=1
Reactant: C#Cc1ccc(F)c(NC(=O)C(F)(F)F)c1
Reactant: Clc1ccnc(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Product: O=C(Nc1cc(C#Cc2ccnc(Cl)n2)ccc1F)C(F)(F)F
Temperature: 60 °C
Reaction time: 8 h
Yield: 78.7 %

Procedure:
To an oven-dried flask under N2 was added 2,4-dichloropyrimidine (5.1 g, 34 mmol), anhydrous degassed THF (250 mL), dichlorobis(triphenylphosphine)-palladium(II) (595 mg, 0.85 mmol), copper(I) iodide (97 mg, 0.5 mmol), and TEA (9.5 mL, 68 mmol), and the resulting suspension was heated to 60° C. A solution of N-(5-ethynyl-2-fluorophenyl)-2,2,2-trifluoroacetamide (3.9 g, 17 mmol) in THF (100 mL) was added dropwise, and the resulting mixture stirred overnight at 60° C. After 16 h, the crude reaction mixture was filtered through celite, adsorbed to silica gel, and purified by column chromatography to afford the desired product (4.6 g, 78%) as an off white solid. 1H NMR (400 MHz, CDCl3): δ 8.65 (d, J=5.1 Hz, 1H), 8.58 (d, J=7.3 Hz, 1H), 7.49 (m, 1H), 7.41 (d, J=5.0 Hz, 1H), 7.24 (m, 1H). ES-LC/MS m/z=344 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[C:4]([NH2:9])=[N:5][CH:6]=[CH:7][CH:8]=1.C1C(=O)N([Br:19])C(=O)C1.C([O-])(O)=O.[Na+]>C(#N)C>[Br:19][C:7]1[CH:8]=[C:3]([C:2]([F:1])([F:10])[F:11])[C:4]([NH2:9])=[N:5][CH:6]=1
Reactant: Nc1ncccc1C(F)(F)F
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: Nc1ncc(Br)cc1C(F)(F)F
Temperature: 23 °C
Reaction time: 1 h
Yield: 98.4 %

Procedure:
To a solution of 3-trifluoromethyl-pyridin-2-ylamine (16.21 g, 100 mmol) in acetonitrile (300 mL) at 5° C. was added NBS (17.8 g, 100 mmol) and the mixture was stirred at 23° C. for 1 h. Poured onto ice and sat. NaHCO3 soln., extracted with EtOAc, washed with brine, dried over Na2SO4. Removal of the solvent in vacuum left a yellow solid. Silica gel & cotton wool column filtration with DCM gave the product as a yellow solid (23.71 g, 98%). MS (ISP) 240.1 [(M+H)+].
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=1)([O-])=O>O1CCCC1.NN.[Ni]>[CH2:9]([N:6]1[CH:7]=[CH:8][C:4]([NH2:1])=[N:5]1)[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=[N+]([O-])c1ccn(CCc2ccccc2)n1
Agent: [Ni]
Agent: NN
Solvent: C1CCOC1
Product: Nc1ccn(CCc2ccccc2)n1
Reaction time: 0.08 h

Procedure:
To a solution containing 3-nitro-1-phenethyl-1H-pyrazole (92 mg, 0.42 mmol) in tetrahydrofuran (2 mL), anhydrous hydrazine (100 μL) was added to the clear solution. Raney nickel (˜100 mg washed 3 times with 5 mL of anhydrous tetrahydrofuran) was then added in tetrahydrofuran (300 μL). Gas evolved from the mixture and the reaction was allowed to proceed for 5 min, after which time the raney nickel was removed by filtration through a celite plug. The solvent was removed in vacuo to afford 1-phenethyl-1H-pyrazol-3-ylamine as a yellow oil which was used in the following step with no further purification.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[N:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19](OB(O)O)=[CH:18][CH:17]=1>O1CCOCC1.CO.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:15][C:16]1[CH:21]=[CH:20][C:19]([C:8]2[N:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=2)=[CH:18][CH:17]=1
Reactant: Nc1cnc(Br)cn1
Reactant: OB(O)Oc1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: Nc1cnc(-c2ccc(Cl)cc2)cn1
Temperature: 110 °C

Procedure:
50 mL of 2N sodium carbonate solution and 1.16 g (1.00 mmol) of Pd(PPh3)4 were added to a solution of 8.70 g (174 mmol) of 5-bromopyrazin-2-ylamine and 7.98 g (156 mmol) of 4-chlorophenylboric acid in 150 mL of 1,4-dioxane and 50 mL of MeOH and the mixture was heated to 110° C. for 2.5 hours. The reaction mixture was evaporated down in vacuo and diluted with EtOAc. The organic phase was washed with water, dried over sodium sulfate, and evaporated down in vacuo. The residue was purified by column chromatography (silica gel, DCM→DCM/MeOH 20:1). Yield: 8.30 g (81% of theoretical); C10H8ClN3 (M=205.643); calc.: molpeak (M+H)+:206/208 (Cl); found: molpeak (M+H)+:206/208 (Cl); HPLC-MS: 7.15 minutes (method G).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].ClS([N:17]=[C:18]=O)(=O)=O.C([O-])(O)=O.[Na+]>CN(C=O)C.CC#N>[N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:18]#[N:17])=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2cc[nH]c2c1
Reactant: O=C=NS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: N#Cc1c[nH]c2cc([N+](=O)[O-])ccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.9 %

Procedure:
To a solution of 6-nitroindole (4.86 g 30 mmol) in DMF (24.3 mL) and CH3CN (243 mL) was added dropwise a solution of ClSO2NCO (5 mL, 57 mmol) in CH3CN (39 mL) at 0° C. After addition, the reaction was allowed to warm to room temperature and stirred for 2 h. The mixture was poured into ice-water, basified with sat. NaHCO3 solution to pH 7-8 and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and concentrated to give 6-nitro-1H-indole-3-carbonitrile (4.6 g, 82%).
Reaction SMILES: Cl.[NH:2]1[CH:6]=[C:5]([CH2:7][C:8]([OH:10])=[O:9])[N:4]=[CH:3]1.S(=O)(=O)(O)O.[CH3:16]O>>[CH3:16][O:9][C:8](=[O:10])[CH2:7][C:5]1[N:4]=[CH:3][NH:2][CH:6]=1
Reactant: O=C(O)Cc1c[nH]cn1
Reactant: CO
Agent: Cl
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1c[nH]cn1
Temperature: 80 °C
Yield: 66 %

Procedure:
To a solution of 4-imidazoleacetic acid hydrochloride (499 mg, 3.07 mmol) in MeOH (10 mL) was added concentrated sulfuric acid (1 mL) and the mixture was heated to 80° C. overnight. Then the mixture was cooled and concentrated. The residue was dissolved in CH2Cl2 (30 mL) and washed with saturated NaHCO3 (30 mL). The aqueous layer was saturated with NaCl (s) and extracted with EtOAc (3×30 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated to afford (1H-imidazol-4-yl)-acetic acid methyl ester as a yellow oil (330 mg, 66%). 1H NMR (CDCl3) δ 3.70 (s, 2H), 3.72 (s, 3H), 6.97 (s, 1H), 7.59 (s, 1H).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:14]=[CH:13][C:9]2[N:10]=[CH:11][NH:12][C:8]=2[CH:7]=1)=O)C.CC(C[AlH]CC(C)C)C>C(Cl)Cl>[OH:3][CH2:4][C:6]1[CH:14]=[CH:13][C:9]2[N:10]=[CH:11][NH:12][C:8]=2[CH:7]=1
Reactant: CCOC(=O)c1ccc2nc[nH]c2c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: OCc1ccc2nc[nH]c2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a cooled (0° C.) suspension of ethyl-benzimidazole-5-carboxylate (4.76 g, 25 mmol) in CH2Cl2 (100 mL) was added a 1 M solution of DIBAL in CH2Cl2 (100 mL) and the mixture was stirred for 4 h. The reaction was quenched by the sequential addition of MeOH (8 mL), 1M NaOH (16 mL), and 30% sodium potassium tartrate (40 mL). The mixture was warmed to RT and filtered, and the solid residue was washed with CH2Cl2. The filtrate was concentrated in vacuo to afford the title compound as a brown solid: 1H NMR (400 MHz, DMSO-d6): δ4.58 (s, 1H), 7.14 (m, 1H), 7.46 (s, 1H), 7.51 (m, 1H), 8.15 (s, 1H); HRMS (FAB) C8H9N2O calcd. 149.1723 (M+1). Found 149.1045.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:23])[CH2:9][CH2:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([CH2:17]OS(C)(=O)=O)[CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C-:24]#[N:25].[Na+]>CN(C)C=O.CCOCC>[C:1]([O:5][C:6](=[O:7])[N:8]([CH2:9][CH2:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([CH2:17][C:24]#[N:25])[CH2:13][CH2:12]1)[CH3:23])([CH3:4])([CH3:3])[CH3:2]
Reactant: [C-]#N
Reactant: CN(CC[C@H]1CC[C@H](COS(C)(=O)=O)CC1)C(=O)OC(C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CN(CC[C@H]1CC[C@H](CC#N)CC1)C(=O)OC(C)(C)C

Procedure:
A solution of 12.64 g (36.17 mmol) of trans-methanesulfonic acid 4-[2-(tert-butoxycarbonyl-methyl-amino)-ethyl]-cyclohexylmethyl ester (example 13.1) and 4.51 g (92 mmol) of sodium cyanide in 100 ml of dimethylformamide was stirred for 6 hours at 110° C. The reaction mixture was then taken up in ether and washed four times with water. The ether layer was dried over sodium sulfate and concentrated under reduced pressure, giving 10.14 g of crude trans-[2-(4-cyanomethyl-cyclohexyl)-ethyl]-methyl-carbamic acid tert-butyl ester as a colorless oil, which was used without further purification.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:13])[CH2:11][NH2:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].[Cl:20][CH2:21][C:22](Cl)=[O:23]>C(Cl)Cl.O>[CH2:2]([O:9][C:10](=[O:13])[CH2:11][NH:12][C:22](=[O:23])[CH2:21][Cl:20])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: NCC(=O)OCc1ccccc1
Reactant: O=C(Cl)CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: O=C(CCl)NCC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 993.1 %

Procedure:
To a suspension of glycine benzylester hydrochloride (25.2 g, 12.5 mmol, Aldrich) in CH2Cl2 (200 ml) was added a solution of K2CO3 (77 g, 55.8 mmol) in H2O (200 ml). The mixture was cooled to 0° C. and chloroacetylchloride (21.0 g, 18.6 mol, Aldrich) was added dropwise in 15 min. The mixture was warmed to room temperature and stirred for 2 h. The two layers were separated and the aqueous layer was extracted with CH2Cl2 (100 ml). The organic layers were combined and washed with H2O (100 ml), brine (100 ml), dried (MgSO4). Evaporation of solvent afforded a light yellowish glassy solid. This was triturated with 250 ml of hexane. The colorless solid was collected and dried to give 30.0 g of the material 1.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9]O)=[CH:4][CH:3]=1.S(Cl)([Cl:13])=O>C(Cl)(Cl)Cl>[I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][Cl:13])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: OCCc1ccc(I)cc1
Solvent: ClC(Cl)Cl
Product: ClCCc1ccc(I)cc1
Yield: 98.6 %

Procedure:
To a 500 mL round-bottomed flask equipped with dropping funnel, condenser and N2 inlet were added 307 g (124 mmol) 2-(4-iodophenyl)ethanol, 200 mL chloroform, and 10.0 mL (124 mmol) pyrdine. A solution of 13.5 mL (186 mmol) thionyl chloride in 50 mL chloroform was added dropwise over 15 min, and the reaction then heated at reflux for 2 hr. The reaction was cooled, the solvent evaporated, and the residue taken up in ethyl acetate, washed with 1 N hydrochloric acid, water, saturated aqueous sodium bicarbonate solution and brine, dried, and evaporated. The resulting oil was chromatographed on silica gel using 20% ethyl acetate in hexane as eluant to afford 32.6 g (99%) of the product as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH2:12]([NH2:15])[CH2:13][NH2:14]>Cl>[ClH:1].[NH2:14][CH2:13][CH2:12][NH:15][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: NCCN
Reactant: O=[N+]([O-])c1ccc(O)cc1Cl
Agent: Cl
Product: NCCNc1cc(O)ccc1[N+](=O)[O-]
Temperature: -10 °C

Procedure:
0.432 mol (75 g) of 3-chloro-4-nitrophenol is introduced into 282 ml of ethylenediamine and the reaction mixture is heated on a boiling waterbath for 13 hours. The cooled solution is then poured into 2.6 liters of ice-water to which 1.09 liters of hydrochloric acid (d=1.18) have been added. After the mixture has been cooled to -10° C. for a few hours, 3-β-aminoethylamino-4-nitrophenol hydrochloride crystallises. It is filtered off with suction and washed with an ice-cold 2N hydrochloric acid solution and then with ethanol. After recrystallisation from water, the dried product melts, with decomposition, at a temperature above 260° C.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][CH2:10][O:11][C:12]([CH2:14][C:15]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=O)=[O:13]>C1(C)C=CC=CC=1>[CH2:10]([O:11][C:12](=[O:13])[CH:14]=[C:15]([NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH3:9]
Reactant: NCc1ccccc1
Reactant: CCOC(=O)CC(=O)CC(=O)OCC
Solvent: Cc1ccccc1
Product: CCOC(=O)C=C(CC(=O)OCC)NCc1ccccc1
Temperature: 25 °C
Reaction time: 15.5 h

Procedure:
Benzylamine (89.1 g, 0.83 moles) is added over 10 minutes to a suspension of 5A powdered molecular sieves (270 g) and diethyl 1,3-acetonedicarboxylate (160 g) (0.79 moles) in 350 ml toluene (external cooling applied to control exotherm). The suspension is stirred at room temperature for 14-17 hours and then filtered to provide 2. The filter cake is washed with three portions of toluene. The combined filtrates may be used as in the subsequent ketene reaction.