Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl.[N:15]([O-])=O.[Na+].[CH2:19]([NH:22][C:23](=[O:27])[CH2:24][C:25]#[N:26])[CH2:20][CH3:21].C([O-])(=O)C.[Na+]>CC(O)=O.O.C(O)C>[C:25]([C:24](=[N:15][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:23]([NH:22][CH2:19][CH2:20][CH3:21])=[O:27])#[N:26]
Reactant: CCCNC(=O)CC#N
Reactant: O=N[O-]
Reactant: Nc1ccccc1-c1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CCCNC(=O)C(C#N)=NNc1ccccc1-c1ccccc1
Temperature: 25 °C

Procedure:
To a solution of 2-aminobiphenyl (10.16 g) in HOAc (36 ml) was added water (18 ml) and concentrated hydrochloric acid (18 ml). The solution was cooled to -15° with stirring. To this mixture was added dropwise a solution of sodium nitrite (4.36 g) in water (18 ml), maintaining the internal temperature below -5°. The resulting clear purple solution was stirred an additional 10 min at -10°, and was then added to a solution of N-propyl-2-cyanoacetamide (Prepared according to Shulka, J. S., et al., Journal of the Indian Chemical Society, (1978) 55:281-283.) (9.08 g) in water (400 ml)/ethanol (200 ml) containing sodium acetate (80 g) which had been chilled to -4°. This mixture was stirred mechanically at 0° for 6 hours before being allowed to warm to room temperature over a 15 hr. period. The mixture was then diluted with water (600 ml) and stirred. After 51/2 hours, the precipitated solid was collected by filtration and was washed with water and hexane. There was thus obtained 19.47 grams (>100% crude yield) of title product as a 5:1 ratio of Z:E isomers, m.p. 180°-184°; 1H NMR (CHCl3 -d, characteristic peaks of Z-isomer only): 0.948 (t, 3H), 1.53 (m, 2H), 3.20 (q, 2H), 6.04 (br.t, exchangeable, 1H), 7.20-7.29 (m, 2H), 7.37-7.54 (m, 6H), 7.76 (d. 1H), 13.96 (br.s, exchangeable, 1H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.ClC(Cl)(O[C:18](=[O:24])[O:19][C:20](Cl)(Cl)Cl)Cl.[N-:26]=[C:27]=[O:28]>CCOC(C)=O.CN(C=O)C>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:27]([NH:26][C:5]2[C:6]3[NH:7][C:18](=[O:24])[O:19][C:20]=3[CH:2]=[CH:3][CH:4]=2)=[O:28])=[C:4]([C:10]([F:11])([F:12])[F:13])[CH:3]=1
Reactant: [N-]=C=O
Reactant: NCc1ccc(F)cc1C(F)(F)F
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(NCc1ccc(F)cc1C(F)(F)F)Nc1cccc2oc(=O)[nH]c12
Temperature: 80 °C
Yield: 10 %

Procedure:
Commercially available 4-fluoro-2-trifluoromethylbenzylamine (0.5 ml, 3.7 mmol) was dissolved in 20 ml of AcOEt and at 0° C. triphosgene (1.12 g, 3.7 mmol) was added to the solution. The mixture was warmed at 80° C. for 4 hours then evaporated and the residue was dissolved in 5 ml of DMF. The solution of the isocyanate was added dropwise to a solution in DMF (5 ml) of compound 1b (360 mg, 2.4 mmol) and the mixture was warmed at 80° C. for 8 hours. (TLC AcOEt 4/petroleum ether 6). The solvent was evaporated and the crude was dissolved in AcOEt (30 ml) and washed with water (1×20 ml) and brine. The organic phase was dried over sodium sulfate and concentrated under vacuum. The purification of the crude residue by chromatographic column gave 90 mg of a white solid. Yield=10% 1HNMR (DMSO, 200 MHz) δ 4.36 (2H, d, J=5.6 Hz), 6.71 (1H, t, J=6 Hz), 6.98 (2H, m), 7.56 (4H, m), 8.55 (1H, bs), 11.09 (1H, bs); [M+1] 370.2 (C16H11F4N3O3 requires 369.27).
Reaction SMILES: [CH:1]1[N:6]=[C:5](Cl)[C:4]2[N:8]=[CH:9][N:10]([C@@H:11]3[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]3[OH:19])[C:3]=2[N:2]=1.Cl.[O:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]([NH2:31])[CH2:23][CH2:22]1.C([N:34](CC)CC)C>C(O)C>[O:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]([NH:31][NH:34][C:5]2[C:4]3[N:8]=[CH:9][N:10]([C:3]=3[N:2]=[CH:1][N:6]=2)[C@@H:11]2[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]2[OH:19])[CH2:23][CH2:22]1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Reactant: NC1CCOc2ccccc21
Reactant: CCN(CC)CC
Agent: Cl
Solvent: CCO
Product: OC[C@H]1O[C@@H](n2cnc3c(NNC4CCOc5ccccc54)ncnc32)[C@H](O)[C@@H]1O
Yield: 64.2 %

Procedure:
A mixture of 0.97 g of 6-chloropurine riboside, 0.7 g of 4-chromanylamine hydrochloride, and 0.94 g of triethylamine is refluxed in 30 ml ethanol under nitrogen for 20 hrs. The solvent is evaporated to dryness. The residual solid is treated with cold water. Clear aqueous solution is decanted off and the residue is dissolved in ethanol. Volatiles are evaporated under vacuuo. This is repeated once more affording 0.9 g (66%) of N6 -[4-chromanylamino]adenosine having a melting point of 125°-130° (foam).
Reaction SMILES: [OH:1][N:2]=[C:3]([O:5][CH2:6][CH3:7])[CH3:4].Br[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17].[OH-].[Na+].O[N:22]1[C:26](=[O:27])[CH2:25][CH2:24][C:23]1=[O:28].C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1.CO>[O:28]=[C:23]1[CH2:24][CH2:25][C:26](=[O:27])[N:22]1[O:18][C:16](=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:1][N:2]=[C:3]([O:5][CH2:6][CH3:7])[CH3:4]
Reactant: O=C(O)CCCCCCCBr
Reactant: O=C1CCC(=O)N1O
Reactant: CCOC(C)=NO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(C)=NOCCCCCCCC(=O)ON1C(=O)CCC1=O
Temperature: 50 °C
Yield: 34 %

Procedure:
To a mixture of ethyl N-hydroxyacetimidate 1 (6.2 g, 60 mmol) and 8-bromooctanoic acid (15 g, 67 mmol) in 150 mL of solvent mixture (methanol 8: acetone 1) was added drop wise 22 mL of 10N NaOH and heated at 50° C. for 12 h. The reaction mixture was cooled, the organic solvent was removed by rotary evaporation. The dilute HCl solution was added to adjust pH down to 6. The resulting turbid mixture was extracted with CHCl3 and EtOAc. The extract was washed with brine, dried, filtered, and solvent was evaporated to crude oil (3, 12 g, 49 mmol, 82%). A mixture of 3 (12 g, 49 mmol) and N-hydroxysuccinimide (5 g, 50 mmol) in 100 mL of THF was treated with 50 mL of DCC (1.0 M solution in CH2Cl2). The solids were filtered, and the clear filtrate was evaporated. The resultant brown oil was purified on a silica gel column. Elution with 20% ethyl acetate/hexane afforded 5.8 g (17 mmol, 34%) of the product as a wet solid. 1H NMR (DMSO-d6): δ 1.21 (3H, t, J=7.0), 1.28-1.38 (6H, m), 1.57 (2H, p, J=6.8), 1.64 (2H, p, J=7.4), 1.86 (3H, s), 2.65 (2H, t, J=7.5), 2.81 (4H, s), 3.82 (2H, t, J=6.5), 3.94 (2H, q, J=7.0)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:12]O>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([O:6][CH3:12])=[O:5]
Reactant: Cc1ccc(Cl)c(C(=O)O)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(C)ccc1Cl
Temperature: 25 °C
Yield: 71 %

Procedure:
A mixture of 2-chloro-5-methylbenzoic acid (4.0 g, 23.4 mmol) in methanol (50 mL) and a few drops of concentrated sulfuric acid were stirred at reflux for 5 hours. After cooling to room temperature, methanol was evaporated. The residue was dissolved in ethyl acetate (50 mL). The solution was extracted with saturated NaHCO3 (3×50 mL). The organic layer was dried over MgSO4, filtered, evaporated, and dried in vacuo, affording methyl 2-chloro-5-methylbenzoate (3.07 g, 71% yield). The product was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[C:9]([Cl:15])[CH:8]=1)[OH:6])[CH3:2].[C:17](OC(=O)C)(=[O:19])[CH3:18]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:16])[CH:5]([O:6][C:17](=[O:19])[CH3:18])[C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[C:9]([Cl:15])[CH:8]=1)[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)C(O)c1ccc(SC)c(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C(OC(C)=O)c1ccc(SC)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91 %

Procedure:
A solution of (3-chloro-4-methylsulfanyl-phenyl)-hydroxy-acetic acid ethyl ester (1.43 g, 5.49 mmol) in pyridine (2 mL) was treated with acetic anhydride (2 mL) and 4-dimethylaminopyridine (50 mg, 0.41 mmol). The reaction mixture was stirred at 25° C. for 16 h. The reaction mixture was then diluted with methylene chloride (100 mL). The organic layer was washed with a 1N aqueous hydrochloric acid solution (2×30 mL), washed with a saturated aqueous sodium chloride solution (1×30 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 4/1 hexanes/ethyl acetate) afforded acetoxy-(3-chloro-4-methylsulfanyl-phenyl)-acetic acid ethyl ester (1.51 g, 91%) as a light yellow oil: EI-HRMS m/e calcd for C13H15ClO4S (M+) 302.0379, found 302.0387.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH:7]1[C:19]2[CH:18]([CH2:20][O:21][C:22]([N:24]3[CH2:28][CH2:27][CH2:26][C@H:25]3[C:29]([OH:31])=[O:30])=[O:23])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]=2[CH:10]=[CH:9][CH:8]=1.C(N(C(C)C)C(C)C)C.O[C@@H:42]([CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:43]([OH:45])=[O:44]>C(Cl)Cl.CN(C)C=O>[CH:16]1[C:17]2[CH:18]([CH2:20][O:21][C:22]([N:24]3[CH2:28][CH2:27][CH2:26][C@H:25]3[C:29]([O:31][C@@H:42]([CH2:46][C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[C:43]([OH:45])=[O:44])=[O:30])=[O:23])[C:19]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:12]=2[CH:13]=[CH:14][CH:15]=1
Reactant: O=C(O)[C@@H](O)Cc1ccccc1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCC1c2ccccc2-c2ccccc21
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(O)[C@H](Cc1ccccc1)OC(=O)[C@@H]1CCCN1C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 0 °C
Yield: 69.5 %

Procedure:
Oxalyl chloride (1.17 mL, 13.3 mmol) was added dropwise to a solution of (S)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)pyrrolidine-2-carboxylic acid (Fmoc-Pro-OH) (3.00 g, 8.89 mmol) and N,N-dimethylformamide (34 μL, 0.445 mmol) in methylene chloride (40 mL) with stirring at 0° C. under a nitrogen atmosphere, and the reaction mixture was then stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, the resulting residue was mixed with methylene chloride (36 mL), N-ethyldiisopropylamine (DIPEA) (2.33 mL, 13.3 mmol) and (S)-2-hydroxy-3-phenylpropanoic acid (HO-PhLac-OH, 2.22 g, 13.3 mmol) at 0° C., and the reaction mixture was stirred at room temperature for 2 hours. The reaction solution was washed with 1 N hydrochloric acid twice and a saturated aqueous sodium chloride solution twice, dried over sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by reverse-phase silica gel column chromatography (0.1% aqueous formic acid solution/0.1% formic acid-acetonitrile solution) to afford (S)-2-(((S)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)pyrrolidine-2-carbonyl)oxy)-3-phenylpropanoic acid (Fmoc-Pro-PhLac-OH) (Compound SP634) (3.00 g, 6.18 mmol, 70%).
Reaction SMILES: [CH2:1]([OH:13])[C@H:2]([OH:12])[C@@H:3](O)[C@H:4]([OH:10])[C:5]([C:7]([OH:9])=[O:8])=[O:6].ClC(Cl)=C(Cl)Cl.C(O)CCC.S(=O)(=O)(O)O.Cl>>[OH:10][C:4]1[C@@H:3]([C@@H:2]([OH:12])[CH2:1][OH:13])[O:8][C:7](=[O:9])[C:5]=1[OH:6]
Reactant: O=C(O)C(=O)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)=C(Cl)Cl
Solvent: CCCCO
Product: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Temperature: 85 °C
Reaction time: 2 h

Procedure:
594 g (3 mol) of anhydrous 2-keto-L-gulonic acid were suspended in a solvent mixture consisting of 72 ml (0.7 mol) of perchloroethylene and 1 l (11 mol) of n-butanol. After addition of 7 g (69 mmol) of conc. sulfuric acid, the mixture was evacuated to 300 mbar and heated to an internal temperature of 85° C. The distillate was removed. After 2 hours, 24 ml of water were removed. After addition of 725 ml (7 mol) of fresh perchloroethylene, the viscous reaction mixture was rapidly treated with 79 g (0.8 mol) of conc. hydrochloric acid and stirred at 75° C. for 17 hours. The precipitated L-ascorbic acid was filtered off with suction, washed with n-butanol and dried in vacuo. Yield: 460 g (86%) of a gray crystallizate having a vitamin C purity of 99%. Vitamin C of high purity can be obtained by processes known from the literature, e.g. recrystallization.
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]([C:17]4[N:18]=[N:19][NH:20][CH:21]=4)=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1.IC.[C:24](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]4[CH:21]=[N:20][N:19]([CH3:24])[N:18]=4)=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Fc1ccc(-n2ccc3cc(-c4c[nH]nn4)ccc32)cc1
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: Cn1ncc(-c2ccc3c(ccn3-c3ccc(F)cc3)c2)n1

Procedure:
A mixture of 1-(4-fluorophenyl)-5-triazol-4-yl-1H-indole (6.0 g), iodomethane (6.7 mL), potassium carbonate (6.0 g) and acetone (100 mL) was boiled under weak reflux for 18 hours. The reaction mixture was filtered and the volatile solvents evaporated in vacuo. The mixture of 1-methyl- and 2-methyl-substituted triazoles was separated by column chromatography on silica gel (ethyl acetate/heptane 1:1). Evaporation of the fastest eluting fractions in vacuo afforded pure 1-(4-fluorophenyl)-5-(2-methyltriazol-4-yl)-1H-indole (20a) as an oil: (2.1 g): 1H NMR (CDCl3) δ 4.25 (s, 3H), 6.70 (d, 1H), 7.20 (t, 2H), 7.30 (d, 1H), 7.40-7.55 (m, 3H), 7.65 (broad d, 1H), 7.85 (s, 1H), 8.10 (broad s, 1H). Evaporation of the slowest eluting fractions in vacuo afforded pure 1-(4-fluorophenyl)-5-(1-methyltriazol-4-yl)-1H-indole (20b) as an oil (0.8 g): 1H NMR (CDCl3) δ 4.15 (s, 3H), 6.70 (d, 1H), 7.20 (t, 2H), 7.30 (d, 1H), 7.50 (dd, 2H), 7.55 (d, 1H), 7.70 (broad d, 1H), 7.75 (s, 1H), 8.10 (broad s, 1H).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[C:14]2[N:22]3[C:17]([CH:18]=[N:19][C:20](O)=[N:21]3)=[CH:16][CH:15]=2)[CH2:6]1)(=[O:4])=[O:3].C1C=CC(N(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O)=CC=1.C(N(CC)C(C)C)(C)C.CN(C)C=O.[NH2:59][C:60]1[CH:65]=[CH:64][C:63]([CH:66]2[CH2:69][N:68]([CH2:70][C:71]([NH2:73])=[O:72])[CH2:67]2)=[CH:62][CH:61]=1>>[CH3:1][S:2]([N:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[C:14]2[N:22]3[C:17]([CH:18]=[N:19][C:20]([NH:59][C:60]4[CH:65]=[CH:64][C:63]([CH:66]5[CH2:67][N:68]([CH2:70][C:71]([NH2:73])=[O:72])[CH2:69]5)=[CH:62][CH:61]=4)=[N:21]3)=[CH:16][CH:15]=2)[CH2:6]1)(=[O:3])=[O:4]
Reactant: NC(=O)CN1CC(c2ccc(N)cc2)C1
Reactant: CS(=O)(=O)N1Cc2cccc(-c3ccc4cnc(O)nn34)c2C1
Agent: O=S(=O)(N(c1ccccc1)S(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)N1Cc2cccc(-c3ccc4cnc(Nc5ccc(C6CN(CC(N)=O)C6)cc5)nn34)c2C1
Yield: 7.7 %

Procedure:
7-(2-Methanesulfonyl-2,3-dihydro-1H-isoindol-4-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-ol (80 mg, 0.2 mmol), N-Phenylbis(trifluoromethanesulphonimide) (95.1 mg, 0.266 mmol), N,N-Diisopropylethylamine (0.126 mL, 0.726 mmol), and N,N-Dimethylformamide (2 mL, 30 mmol) and stir at room temperature for half an hour. Add 2-[3-(4-Amino-phenyl)-azetidin-1-yl]-acetamide (71 mg, 0.34 mmol) and stir at 60° C. overnight. The reaction was concentrated, DMSO added, filtered and placed onto the Gilson for purification. The most pure fractions were collected, basified with sat sodium bicarbonate extracted with EtOAc, dried, filtered and concentrated to give a yellow solid (8 mg, 6%). MP 216-218° C. LCMS (E/I+) 518 (M+H). NMR 1H (DMSO-d6)-9.48 (s, 1H), 9.02 (s, 1H), 7.97 (d, 1H, J=7.81 Hz), 7.64 (d, 2H, J=8.55 Hz), 7.56 (t, 1H, J=7.80 Hz), 7.44 (d, 1H, J=7.74 Hz), 7.21 (d, 2H, J=8.34 Hz), 7.12 (bs, 1H), 7.05-7.08 (m, 2H), 6.99 (d, 1H, J=4.69 Hz), 4.74 (s, 4H), 3.69 (t, 2H, J=7.40 Hz), 3.53-3.61 (m, 1H), 3.15 (t, 2H, J=6.86 Hz), 3.02 (s, 2H), 2.92 (s, 3H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10]N.C[N:13]1[CH:17]2[CH2:18][C:19]([CH2:21][CH:14]1[CH2:15][CH2:16]2)=O.Cl.O1CCOC[CH2:24]1>C(O)C>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:5]=1[NH:10][C:15]1[CH2:24][CH:14]3[NH:13][CH:17]([C:16]2=1)[CH2:18][CH2:19][CH2:21]3
Reactant: COc1ccccc1NN
Reactant: C1COCCO1
Reactant: CN1C2CCC1CC(=O)C2
Agent: Cl
Solvent: CCO
Product: COc1cccc2c3c([nH]c12)CC1CCCC3N1
Temperature: 80 °C

Procedure:
A suspension of (2-methoxyphenyl)hydrazine hydrochloride (875 mg, 5.0 mmol; TCI-US), tropinone (696 mg, 5.0 mmol; Aldrich), and 4 M HCl-dioxane (2.5 mL, 10.0 mmol; Aldrich) in ethanol (10 mL) was heated to 80° C. for 16 hours. After cooling to room temperature, the reaction mixture was concentrated, basified with 5 N NaOH (aqueous), and then extracted with ethyl acetate (3×50 mL). The combined organic phase was concentrated and the residue was purified by reverse-phase HPLC [Waters XBridge™ RP18 column, 5 μm, 30×100 mm, flow rate 40 mL/minute, 20-95% gradient of methanol in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to afford the title compound: 1H NMR (300 MHz, methanol-d4) δ ppm 1.62-1.80 (m, 1H), 1.97 (t, J=9 Hz, 1H), 2.24-2.38 (m, 2H), 2.47 (s, 3H), 2.57 (d, J=17 Hz, 1H), 3.25-3.36 (m, 1H), 3.65-3.73 (m, 1H), 3.92 (s, 3H), 4.34 (d, J=4Hz, 1H), 6.59 (d, J=8 Hz, 1H), 6.87-6.95 (m, 1H), 6.97-7.04 (m, 1H); MS (DCI/NH3) m/z 243 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:21]([NH:22][C:23]([NH:25][C:26]2[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[CH:27]=2)=[O:24])=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14](C)(C)C)=[O:12])[CH2:7][CH2:6]1.Cl.CCN(CC)CC.ClC(OC)=O>CO.C(Cl)Cl>[F:1][C:2]1[C:21]([NH:22][C:23]([NH:25][C:26]2[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[CH:27]=2)=[O:24])=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH3:14])=[O:12])[CH2:7][CH2:6]1
Reactant: Cc1cc(NC(=O)Nc2cccc(CN3CCN(C(=O)OC(C)(C)C)CC3)c2F)ccn1
Agent: COC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: COC(=O)N1CCN(Cc2cccc(NC(=O)Nc3ccnc(C)c3)c2F)CC1
Reaction time: 1 h
Yield: 37.1 %

Procedure:
To a solution of tert-butyl 4-(2-fluoro-3-(3-(2-methylpyridin-4-yl)ureido)benzyl)piperazine-1-carboxylate (600 mg, 1.35 mmol, 1.0 equiv) in MeOH (3 mL) was added HCl (4N in dioxane, 3 mL, 12 mmol, 8.9 equiv). After 1 h, the solvent was removed in vacuo. To this residue was added DCM (10 mL) and Et3N (875 μL, 6.28 mmol, 4.65 equiv), and the resulting solution was divided into two equal parts. To the resulting solution was added methyl chloroformate (75 μL, 0.95 mmol, equiv) dropwise by syringe. After 30 min, the reaction was quenched by the addition of aq. satd. NaHCO3. The reaction was diluted with EtOAc, and washed twice with aq. satd. NaHCO3 and once with brine. The solution was then dried over sodium sulfate, filtered and concentrated in vacuo. Purification by reverse phase preparative HPLC provided methyl 4-(2-fluoro-3-(3-(2-methylpyridin-4-yl)ureido)benzyl)piperazine-1-carboxylate (201.3 mg, 77%). LCMS m/z (APCI)=402.2 (M+H). LCMS m/z (APCI)=402.2 (M+H).
Reaction SMILES: [O:1]([C:6]([N:8]1[CH2:13][CH:12]2[CH:10]([CH:11]2[N:14]=[C:15]=[S:16])[CH2:9]1)=[O:7])[C:2]([CH3:5])([CH3:4])[CH3:3].C[O:18][C:19](=O)[C:20]([NH2:31])([CH2:28][CH:29]=[CH2:30])[CH2:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1>>[C:2]([O:1][C:6]([N:8]1[CH2:13][CH:12]2[CH:10]([CH:11]2[N:14]2[C:19](=[O:18])[C:20]([CH2:28][CH:29]=[CH2:30])([CH2:21][C:22]3[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=3)[NH:31][C:15]2=[S:16])[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CC2C(C1)C2N=C=S
Reactant: C=CCC(N)(Cc1ccncc1)C(=O)OC
Product: C=CCC1(Cc2ccncc2)NC(=S)N(C2C3CN(C(=O)OC(C)(C)C)CC32)C1=O
Yield: 87.9 %

Procedure:
Using the same procedure as described in Example 2B, 3-(tert-butoxylcarbonyl)-6-isothiocyanato-3-aza-bicyclo[3.1.0]hexane (23.4 mmol, prepared in 1A) and 2-amino-2-allyl-3-pyridin-4-yl-propionic acid methyl ester (11.6 mmol) were reacted to afford the title compound of 30A (4.37 g, 10.2 mmol, 88% yield).
Reaction SMILES: C([C:5]([CH3:10])([CH3:9])[C:6]([NH2:8])=[O:7])CCC.[CH2:11]([Li])[CH2:12][CH2:13][CH3:14].[CH3:16][C:17]1[N:18]=[C:19](S(C)=O)[O:20][CH:21]=1.O>C1COCC1>[CH2:11]([N:8]([C:19]1[O:20][CH:21]=[C:17]([CH3:16])[N:18]=1)[C:6](=[O:7])[CH:5]([CH3:9])[CH3:10])[CH2:12][CH2:13][CH3:14]
Reactant: Cc1coc(S(C)=O)n1
Reactant: [Li]CCCC
Reactant: CCCCC(C)(C)C(N)=O
Solvent: C1CCOC1
Solvent: O
Product: CCCCN(C(=O)C(C)C)c1nc(C)co1
Temperature: -20 °C
Reaction time: 0.33 h
Yield: 78 %

Procedure:
n-Butyl-isobutyramide (0.99 g, 0.0069 m) in dry THF (10 ml) was cooled to -20° C. under nitrogen during the dropwise addition of a 1.445 M solution of n-butyl lithium (4.8 ml, 0.0069 m). The mixture was stirred for 20 minutes at -20° C. and then 4-methyl-2-methylsulphinyloxazole (1.0 g, 0.0068 m) in dry THF (10 ml) was added rapidly and the mixture allowed to warm to 0° C. It was stirred at this temperature for 11/2 hours then allowed to warm to room temperature and stirred for a further 1/2 hour. The mixture was hydrolysed with water and the solvent was evaporated under reduced pressure. The residue was extracted with diethyl ether and the extract was evaporated. The resulting oil was chromatographed on silica using ether/hexane. The compound was distilled in vacuo to give the title compound as a colourless oil 1.21 g, (78%), b.p. (airbath) 70° C. at 0.01 mm.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([NH2:11])[S:9][CH:10]=1)=[O:5])[CH3:2].[CH3:12][O:13][CH2:14][CH2:15][Br:16]>>[BrH:16].[NH:11]=[C:8]1[N:7]([CH2:15][CH2:14][O:13][CH3:12])[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:10][S:9]1
Reactant: CCOC(=O)c1csc(N)n1
Reactant: COCCBr
Product: Br
Product: CCOC(=O)c1csc(=N)n1CCOC
Yield: 54.9 %

Procedure:
2-Aminothiazole-4-carboxylic acid ethyl ester (17.2 g, 100 mmol) and 2-bromoethyl methyl ether (15.3 g, 110 mmol) were processed as described as described in Example 2A to afford 17.1 g (83%) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.30 (t, J=7 Hz, 3H) 3.22 (s, 3H) 3.60 (t, J=5 Hz, 2H) 4.32 (t, J=7 Hz, 2H) 4.35-4.61 (m, 2H) 7.84 (s, 1H) 9.76 (s, 1H); MS (DCI/NH3) m/z 231 (M+H)+.
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][N:4]([CH2:9][C:10]([O:12]C)=O)[CH2:3]1.O.[NH2:15][NH2:16]>CO>[CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][N:4]([CH2:9][C:10]([NH:15][NH2:16])=[O:12])[CH2:3]1
Reactant: NN
Reactant: COC(=O)CN1C[C@@H](C)O[C@@H](C)C1
Solvent: CO
Solvent: O
Product: C[C@@H]1CN(CC(=O)NN)C[C@H](C)O1
Temperature: 70 °C
Yield: 66.3 %

Procedure:
Methyl [(2R,6S)-2,6-dimethyl-4-morpholinyl]acetate (5.05 g, 27.0 mmol, see Journal of Fluorine Chemistry (1998) 193-201 for literature preparation) was dissolved in methanol (20 ml) and hydrazine hydrate (2.013 ml, 27.0 mmol) added. The reaction mixture was heated to 70° C. for 18 h. The solvent was partially concentrated in vacuo to remove the methanol and extracted with ethyl acetate (3×20 ml). The combined organic layers were dried and concentrated to afford the title compound as a yellow solid (3.35 g).