Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C(OCC)(=O)C.C(OC([NH:15][CH:16]1[CH2:19][N:18]([C:20]2[S:21][C:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][N:24]=2)[CH2:17]1)=O)(C)(C)C.C1COCC1.CO>O1CCOCC1>[NH2:15][CH:16]1[CH2:19][N:18]([C:20]2[S:21][C:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][N:24]=2)[CH2:17]1
Reactant: CCOC(=O)c1cnc(N2CC(NC(=O)OC(C)(C)C)C2)s1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(N2CC(N)C2)s1
Temperature: 25 °C
Reaction time: 7.5 h
Yield: 77.6 %

Procedure:
A 4 N hydrochloric acid/ethyl acetate solution (1.27 mL, 5.09 mmol) was added to a solution of ethyl 2-{3-[(tert-butoxycarbonyl)amino]azetidin-1-yl)-1,3-thiazole-5-carboxylate obtained in Example (217a) (333 mg, 1.02 mmol) in 1,4-dioxane (10 mL) at 0° C., and the mixture was stirred at room temperature for 7.5 hours. Thereafter, a 4 N hydrochloric acid/ethyl acetate solution (1.27 mL, 5.09 mmol), THF (8 mL) and methanol (5 mL) were added, and the mixture was further stirred for 23 hours. The reaction solution was concentrated, and saturated aqueous sodium bicarbonate solution was added to the resulting residue. Thereafter, the mixture was extracted with ethyl acetate, and the combined organic layers were dried over anhydrous magnesium sulfate. Following filtration, the solvent was evaporated under reduced pressure to obtain 180 mg of the title compound as a pale yellow oily substance (78%).
Reaction SMILES: Br[CH:2]([CH3:13])[CH2:3][NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:6]=1[CH3:12].[CH3:14][C:15]1[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][C:16]=1[NH2:17]>>[CH3:12][C:6]1[C:7]([CH3:11])=[CH:8][CH:9]=[CH:10][C:5]=1[NH:4][CH2:3][CH:2]([NH:17][C:16]1[CH:18]=[CH:19][CH:20]=[C:21]([CH3:22])[C:15]=1[CH3:14])[CH3:13]
Reactant: Cc1cccc(NCC(C)Br)c1C
Reactant: Cc1cccc(N)c1C
Product: Cc1cccc(NCC(C)Nc2cccc(C)c2C)c1C
Yield: 84.2 %

Procedure:
N-(β-Bromopropyl)-2,3-dimethyl-aniline, prepared as indicated in point (b) above, is reacted with 2,3-dimethyl-aniline as given in Example 3, Method (c), point (b) to obtain 1,2-bis(2',3'-dimethylphenyl-amino)-propane with a yield of 84.2%. The hydrobromide of the product melts at 204°-208° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[O:17][CH:16]([CH:18]4[CH2:20][CH2:19]4)[C:15](=[O:21])[NH:14][C:13]=3[CH:22]=2)[C:5]([F:23])=[CH:4][N:3]=1.[OH:24][C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=1)[NH2:28]>>[CH2:19]1[CH2:20][CH:18]1[CH:16]1[C:15](=[O:21])[NH:14][C:13]2[CH:22]=[C:9]([NH:8][C:6]3[C:5]([F:23])=[CH:4][N:3]=[C:2]([NH:28][C:27]4[CH:29]=[CH:30][CH:31]=[C:25]([OH:24])[CH:26]=4)[N:7]=3)[CH:10]=[CH:11][C:12]=2[O:17]1
Reactant: Nc1cccc(O)c1
Reactant: O=C1Nc2cc(Nc3nc(Cl)ncc3F)ccc2OC1C1CC1
Product: O=C1Nc2cc(Nc3nc(Nc4cccc(O)c4)ncc3F)ccc2OC1C1CC1

Procedure:
In like manner to the preparation of N4-[2-(2-cyclopropyl)-3-oxo-4H-benz[1,4]oxazin-6-yl]-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine, 2-chloro-N4-[2-(2-cyclopropyl)-3-oxo-4H-benz[1,4]oxazin-6-yl]-5-fluoro-4-pyrimidineamine and 3-hydroxyaniline were reacted to yield the desired product N4-[2-(2-cyclopropyl)-3-oxo-4H-benz[1,4]oxazin-6-yl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 8.09 (d, 1H), 7.23 (m, 2H), 7.01 (m, 3H), 6.82 (d, 1H), 6.39 (m, 1H), 1.20 (m, 4H); LCMS: retention time 9.30 min; purity 96%; MS (m/e): 394 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][N:15]3[C:19]4=[N:20][C:21]([C:24]5[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=5)=[CH:22][N:23]=[C:18]4[N:17]=[N:16]3)[CH2:9]2)=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:38]2[CH:39]=[N:40][N:41]([CH:43]3[CH2:48][CH2:47][N:46]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:45][CH2:44]3)[CH:42]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.O.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>[CH3:29][N:27]1[CH:28]=[C:24]([C:21]2[N:20]=[C:19]3[N:15]([CH2:14][CH:10]4[CH2:11][CH2:12][CH2:13][N:8]([C:5]5[N:4]=[CH:3][C:2]([C:39]6[CH:38]=[CH:42][N:41]([CH:43]7[CH2:48][CH2:47][N:46]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:45][CH2:44]7)[N:40]=6)=[CH:7][N:6]=5)[CH2:9]4)[N:16]=[N:17][C:18]3=[N:23][CH:22]=2)[CH:25]=[N:26]1
Reactant: Cn1cc(-c2cnc3nnn(CC4CCCN(c5ncc(Br)cn5)C4)c3n2)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)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: O
Solvent: C1CCOC1
Product: Cn1cc(-c2cnc3nnn(CC4CCCN(c5ncc(-c6ccn(C7CCN(C(=O)OC(C)(C)C)CC7)n6)cn5)C4)c3n2)cn1
Temperature: 80 °C
Reaction time: 2 h
Yield: 92.1 %

Procedure:
1-((1-(5-bromopyrimidin-2-yl)piperidin-3-yl)methyl)-6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazine (20 mg, 0.0434 mmol), tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (20 mg, 0.053 mmol), Pd(PPh3)4 (2.6 mg, 0.0022 mmol), and Na2CO3 (17 mg, 0.13 mmol) were dissolved in THF (1 ml)+H2O (0.6 ml), and then the mixture was degassed with N2 (gas), followed by stirring at 80° C. for 2 hours. After the completion of the reaction, the reaction mixture was extracted with H2O, EA, and brine, followed by drying (Na2SO4), filtration, and concentration under reduced pressure, and the residue was purified by column chromatography (MeOH:MC=1:20), to give tert-butyl 4-(3-(2-(3-((6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)piperidin-1-yl)pyrimidin-5-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (25 mg, 90%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@:8]1([CH2:12][N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)[C@H:10]([CH3:11])[O:9]1.[N:18]1([C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH:33]=[CH:32][NH:31][C:30]3=[O:34])=[CH:25][CH:24]=2)[CH:22]=[CH:21][N:20]=[N:19]1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@:8]([OH:9])([CH2:12][N:13]1[CH:17]=[N:16][CH:15]=[N:14]1)[C@H:10]([N:31]1[CH:32]=[CH:33][N:29]([C:26]2[CH:25]=[CH:24][C:23]([N:18]3[CH:22]=[CH:21][N:20]=[N:19]3)=[CH:28][CH:27]=2)[C:30]1=[O:34])[CH3:11]
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccccc1F
Reactant: O=c1[nH]ccn1-c1ccc(-n2ccnn2)cc1
Product: C[C@@H](n1ccn(-c2ccc(-n3ccnn3)cc2)c1=O)[C@](O)(Cn1cncn1)c1ccccc1F

Procedure:
(2R,3S)-2-(2-Fluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-yl)methyloxirane was reacted with 1-[4-(1H-1,2,3-triazol-1-yl)phenyl]-2(1H,3H)-imidazolone in the same manner as in Working Example 11 to give 1-[(1R,2R)-2-(2-fluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1H-1,2,3-triazol-1-yl)phenyl]-2(1H,3H)-imidazolone (Compound 32).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[NH:15][N:14]=[N:13][N:12]=2)[CH2:7][CH2:6]1)=[O:4].[OH-].[Li+].C1COCC1>O>[NH:15]1[C:11]([CH:8]2[CH2:7][CH2:6][CH:5]([C:3]([OH:4])=[O:2])[CH2:10][CH2:9]2)=[N:12][N:13]=[N:14]1
Reactant: COC(=O)C1CCC(c2nnn[nH]2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C1CCC(c2nnn[nH]2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.2 %

Procedure:
A mixture of 4-(1H-tetrazol-5-yl)-cyclohexanecarboxylic acid methyl ester (304 mg, 2.74 mmol), lithium hydroxide (121 mg 2.89), THF and water were stirred at RT overnight. The reaction was concentrated and diluted with water acidified with concentrated HCl to pH 1 and extracted with ethyl acetate to give 4-(1H-tetrazol-5-yl)-cyclohexanecarboxylic acid (173 mg, 61%) as an off white solid. LCMS calcd C8H12N4O2 (m/e) 196, obsd 197 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@@H:4]([C:14]([O:16]CC2C=CC=CC=2)=[O:15])[CH2:3]1.O[Li].O>O1CCOCC1.O>[C:10]([O:9][C:7]([N:5]1[CH2:6][C:2]([CH3:24])([CH3:1])[CH2:3][C@@H:4]1[C:14]([OH:16])=[O:15])=[O:8])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC1(C)C[C@H](C(=O)OCc2ccccc2)N(C(=O)OC(C)(C)C)C1
Agent: [Li]O
Solvent: C1COCCO1
Solvent: O
Product: CC1(C)C[C@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 58.5 %

Procedure:
To a mixture of (R)-2-benzyl 1-tert-butyl 4,4-dimethylpyrrolidine-1,2-dicarboxylate (D40) (198 mg, 0.59 mmol) in dioxan/water (4/4 ml), LiOH.H2O (100 mg, 2.37 mmol) was added and the mixture was left stirring at RT for 18 hrs. Organic solvent was evaporated off and the reaction mixture was diluted with water (8 ml), washed with Et2O (2×10 ml), acidified with acetic acid to pH˜4-5 and extracted with Et2O (3×10 ml). The organic phases were collected, dried over Na2SO4 and evaporated in vacuo to afford the title compound (D41) (84 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.Cl[Pd]Cl>[O:11]=[C:5]1[C:6]([C:7]([OH:9])=[O:8])=[CH:10][C:2]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:3][NH:4]1
Reactant: O=C(O)c1cc(Br)cnc1O
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(O)c1cc(-c2ccccc2)c[nH]c1=O
Temperature: 110 °C
Yield: 18.1 %

Procedure:
A mixture of 5-bromo-2-hydroxynicotinic acid (436 mg, 2.00 mmol, Syn. Comm., 19 (3&4), 553-559 (1989)), phenylboronic acid (248 mg, 2.03 mmol), Cs2CO3 (1.20 g) and PdCl2 [(t-Bu) 2P(OH)] 2 (170 mg, CombiPhos Catalysts, Inc. Princeton, N.J.) in DMF (10 mL) and water (1.0 mL) was purged with Ar gas and heated at 110° C. for 6 h. Additional phenylboronic acid (75 mg) was added and the mixture was heated at 110° C. for 5 h. To the reaction was added TFA (3 mL), and the mixture was concentrated in vacuo to a volume of ˜12 mL. The mixture was purified by preparative HPLC to afford the desired product (78 mg, 18%). 1H NMR (DMF-d7) δ 14.8 (br s, 1H), 13.8 (br s, 1H), 8.73 (s, 1H), 8.46 (s, 1H), 7.74 (d, 1H, J=7.2 Hz), 7.53-7.42 (m, 3H), 5.81 (s, 1H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9]([C:11]1[CH:19]=[C:18]2[C:14]([CH:15]=[CH:16][N:17]2[S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:22])=[O:21])=[CH:13][CH:12]=1)=O.[Cl-].[NH4+]>O1CCCC1>[C:23]1([S:20]([N:17]2[C:18]3[C:14](=[CH:13][CH:12]=[C:11]([CH2:9][OH:8])[CH:19]=3)[CH:15]=[CH:16]2)(=[O:21])=[O:22])[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COC(=O)c1ccc2ccn(S(=O)(=O)c3ccccc3)c2c1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1ccc2ccc(CO)cc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A predetermined amount of lithium aluminum hydride (167 mg, 4.42 mmol) was placed into a reaction container, and anhydrous tetrahydrofuran (THF) (15 ml) was added thereto, and this was cooled to 0° C. An anhydrous tetrahydrofuran (THF) solution (5 ml) of 1-benzenesulfonyl-1H-indole-6-carboxylic acid methyl ester (930 mg, 2.95 mmol) was added to the mixture. This was stirred at 0° C. for 30 minutes. An aqueous solution saturated with ammonium chloride (1 ml) was added to the mixture. After Celite filtration, the Celite was washed with dichloromethane. The filtrate was dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and concentration was performed. Then, by concentration under reduced pressure, (1-benzenesulfonyl-1H-indol-6-yl)-methanol was obtained as an oily brown material (859 mg, 100%).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[CH:4]=1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH2:14]Cl.C([O-])(=O)C.[Na+].II>>[CH3:1][N:2]([CH2:14][C:13]1[CH:16]=[CH:17][CH:18]=[C:11]([Cl:10])[CH:12]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[CH:4]=1
Reactant: CNc1cccc(F)c1
Reactant: ClCc1cccc(Cl)c1
Agent: CC(=O)[O-]
Agent: II
Agent: [Na+]
Product: CN(Cc1cccc(Cl)c1)c1cccc(F)c1

Procedure:
N-methyl-N-m-chlorobenzyl-m-fluoroaniline was prepared from 17.5 grams (0.14 mole) of N-methyl-m-fluoroaniline, 23. grams (0.14 mole) m-chlorobenzyl chloride (Aldrich), 11.9 grams anhydrous sodium acetate and 0.12 grams iodine according to the procedure described in Example III. Yield 28.6 grams (83.7 percent), boiling point 172° C. at 0.07 mmHg.
Reaction SMILES: [Cl:1][C:2]1[NH:11][C:10]2[C:9](=[O:12])[N:7]([CH3:8])[C:6](=[O:13])[N:5]([CH3:14])[C:4]=2[N:3]=1.[CH3:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18]Br>>[Cl:1][C:2]1[N:11]([CH2:15][C:16]2[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=2[CH3:18])[C:10]2[C:9](=[O:12])[N:7]([CH3:8])[C:6](=[O:13])[N:5]([CH3:14])[C:4]=2[N:3]=1
Reactant: Cc1ccccc1CBr
Reactant: Cn1c(=O)c2[nH]c(Cl)nc2n(C)c1=O
Product: Cc1ccccc1Cn1c(Cl)nc2c1c(=O)n(C)c(=O)n2C

Procedure:
8-Chlorotheophylline and 2-methylbenzyl bromide were reacted and purified as described in the General procedure C, step A, to afford 85A as white crystals in 86%.
Reaction SMILES: [O:1]1[C:9]2[CH:8]=[CH:7][N:6]=[C:5]([NH:10][C:11](=[O:18])[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[CH:3]=[CH:2]1.C([Li])CCC.CN(C)[CH:26]=[O:27].[Cl-].[NH4+]>C1COCC1>[CH:26]([C:2]1[O:1][C:9]2[CH:8]=[CH:7][N:6]=[C:5]([NH:10][C:11](=[O:18])[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[CH:3]=1)=[O:27]
Reactant: O=C(Nc1nccc2occc12)c1ccccc1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=Cc1cc2c(NC(=O)c3ccccc3)nccc2o1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
7.13 g (30 mmol) N-(Furo[3,2-c]pyridin-4-yl)benzamide (Example 2A) were dissolved in 150 ml dry THF under inert gas atmosphere. At −78° C., 26.4 ml (66 mmol) n-butyllithium solution (2.5 M in hexane) were added dropwise, and the mixture was stirred for 30 min at this temperature. Then, 5.1 ml (66 mmol) dry N,N-dimethylformamide were added dropwise. After addition was completed, the mixture was slowly warmed up to rt, and 300 ml saturated aq. ammonium chloride solution were added. After extraction with 300 ml diethyl ether, the organic phase was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford a brown solid. This material was purified by chromatography on silica gel (eluent dichloromethane/methanol 99:1 v/v) to afford 5.2 g (65% of th.) of the title compound as a pale yellow solid [cf. J. B. M. Rewinkel et al., Bioorg. Med. Chem. Lett. 9, 2837-2842 (1999)].
Reaction SMILES: Br[C:2]1[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=[C:6]([Br:8])[N:7]=1.[O:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=2)[CH2:13][CH2:12]1>>[Br:8][C:6]1[N:7]=[C:2]([NH:21][C:20]2[CH:19]=[CH:18][C:17]([N:14]3[CH2:15][CH2:16][O:11][CH2:12][CH2:13]3)=[CH:23][CH:22]=2)[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=1
Reactant: Cn1cc(Br)nc(Br)c1=O
Reactant: Nc1ccc(N2CCOCC2)cc1
Product: Cn1cc(Br)nc(Nc2ccc(N3CCOCC3)cc2)c1=O

Procedure:
3,5-Dibromo-1-methylpyrazin-2(1H)-one (2.21 g) was reacted with 4-morpholinoaniline (1.48 g) using the same general procedure as Example 107a, whereby 108a was obtained as a grey solid in 115% crude yield (3.46 g): 1H NMR (500 MHz, DMSO-d6) δ 9.49 (s, 1H), 7.87 (d, 2H, J=8.0 Hz), 7.31 (s, 1H), 7.21 (m, 2H), 3.83 (m, 4H), 3.43 (s, 3H), 3.27 (m, 4H); MS (ESI+) m/z 365 (M+H). This material contained 18 wt % of DL-10-camphorsulfonic acid. Corrected yield 2.83 g (94%).
Reaction SMILES: [Li+].[CH3:2][CH:3]([N-]C(C)C)C.[F:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1.C(I)C>C1COCC1>[CH2:2]([C:15]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[F:9])[CH3:3]
Reactant: CC(C)[N-]C(C)C
Reactant: Fc1cccnc1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCI
Product: CCc1ccncc1F
Reaction time: 0.5 h
Yield: 51.9 %

Procedure:
To a stirred solution of LDA (200 mmol) in dry THF (400 ml) (prepared by a similar method to that used in Example 1) at -70° C. and under a nitrogen atmosphere was added dropwise 3-fluoro-pyridine (20 g, 200 mmol). After 30 minutes at this temperature ethyl iodide (60 g, 370 mmol) was added dropwise to the reaction and the mixture was allowed to warm slowly to between -10° and -5° C. whereupon an exotherm occurred and the temperature rose to 15° to 20° C. The mixture was stirred for a further 30 minutes after which time the reaction was quenched by the addition of water (50 ml) and the organic phase separated. The aqueous phase was extracted with ether (3×50 ml) and the combined organic layers were dried over magnesium sulphate and concentrated under reduced pressure. The resulting liquid was distilled at atmospheric pressure to yield the title compound (13 g), b.p. 154°-158° C., which was characterised by 1H-NMR spectroscopy.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH3:19])[CH:17]=2)[N:12]=[C:11]([C:20]([NH:22][CH2:23][CH2:24][O:25][CH3:26])=[O:21])[N:10]=1.Cl.C(O[C:31](=[NH:33])[CH3:32])C.C(N(CC)CC)C>C(O)C>[C:31]([NH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH3:19])[CH:17]=2)[N:12]=[C:11]([C:20]([NH:22][CH2:23][CH2:24][O:25][CH3:26])=[O:21])[N:10]=1)(=[NH:33])[CH3:32]
Reactant: CCOC(C)=N
Reactant: COCCNC(=O)c1nc(N[C@H]2CCCC[C@H]2N)c2cc(C)ccc2n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COCCNC(=O)c1nc(N[C@H]2CCCC[C@H]2NC(C)=N)c2cc(C)ccc2n1
Temperature: 80 °C
Reaction time: 8 h
Yield: 77.9 %

Procedure:
To a solution of 450 mg of 4-{[(1S,2R)-2-aminocyclohexyl]amino}-N-(2-methoxyethyl)-6-methylquinazolin-2-carboxamide and 467 mg of ethylacetoimidate hydrochloride in 10 ml of ethanol, 764 mg of triethylamine was added, and the mixture was stirred at 80° C. for 8 hours. After the reaction solution was concentrated, the residue was purified by silica gel column chromatography (chloroform:methanol=20:1), whereby 391 mg of a desired compound was obtained as a pale yellow powder.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[O:6][CH2:7][C:8]([OH:10])=[O:9])=[O:2].[C:14](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C.O>[CH3:14][O:9][C:8](=[O:10])[CH2:7][O:6][C:5]1[CH:11]=[CH:12][CH:13]=[C:3]([CH:1]=[O:2])[CH:4]=1
Reactant: O=C([O-])[O-]
Reactant: O=Cc1cccc(OCC(=O)O)c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COC(=O)COc1cccc(C=O)c1
Temperature: 110 °C
Reaction time: 16 h
Yield: 87.5 %

Procedure:
A mixture of (3-formyl-phenoxy)-acetic acid (3.6 g, 20.0 mmol), potassium carbonate (3.30 g, 23.9 mmol) and methyl iodide (1.86 g, 30.0 mmol) in 25 mL DMF was heated to 110° C. for 2 hours and was stirred at room temperature for 16 h. The mixture was diluted with water and the aqueous solution was extracted with EtOAc. The organic solution was washed with water, dried over MgSO4, filtered and concentrated in vacuo. The product was purified via silica gel chromatography (4:1 hexanes:EtOAc) to afford the title compound as a pale yellow oil (3.4 g). 1H NMR (400 MHz, CDCl3) δ 9.94 (s, 1H), 7.48 (m, 2H), 7.33 (s, 1H), 7.23 (m, 1H), 4.68 (s, 2H), 3.79 (s, 3).
Reaction SMILES: [CH:1]12[CH2:15][CH2:14]O[CH:12]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2.C1(=O)CCCCCCCCCCC1.C(CC(O)=O)#[N:30]>>[C:1]1([CH2:15][C:14]#[N:30])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: N#CCC(=O)O
Reactant: C1CCCCCC2OCCC2CCCC1
Agent: O=C1CCCCCCCCCCC1
Product: N#CCC1=CCCCCCCCCCC1

Procedure:
13-oxabicyclo[10.3.0]pentadecane, a valuable ambergris fragrance, is prepared by reacting cyclododecanone with cyanoacetic acid in the presence of a Knoevenagel catalyst to form cyclododecenylacetonitrile, the nitrile is hydrolyzed to cyclododecenylacetic acid, and the acid is cyclized to the lactone, and the lactone is reduced to the corresponding diol which is cyclized to 13-oxabicyclo[10.3.0]pentadecane.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][N:4]([C@@H:7]2[CH2:12][CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8]2)[C:3]1=[O:20].Cl>O1CCOCC1>[CH3:1][N:2]1[CH2:6][CH2:5][N:4]([C@@H:7]2[CH2:12][CH2:11][CH2:10][NH:9][CH2:8]2)[C:3]1=[O:20]
Reactant: CN1CCN([C@@H]2CCCN(C(=O)OC(C)(C)C)C2)C1=O
Agent: Cl
Solvent: C1COCCO1
Product: CN1CCN([C@@H]2CCCNC2)C1=O
Yield: 52.9 %

Procedure:
To a solution of (R)-tert-butyl 3-aminopiperidine-1-carboxylate (50 g, 250 mmol) and Et3N (50.5 g, 500 mmol) in DCM (500 mL) was added 2-chloroethyl isocyanate (31.65 g, 300 mmol) dropwise. The resulting mixture was stirred at RT for 4 hours before being quenched with water (100 mL). The layers were separated and the organic layer was washed with brine, dried, concentrated, and subjected to silica flash column using 0 to 50% EA in to isolate (R)-tert-butyl 3-(3-(2-chloroethyl)ureido)piperidine-1-carboxylate (364) (63.6 g, 81.5%) as a colorless oil. At 0° C., to a solution of (R)-tert-butyl 3-(3-(2-chloroethyl)ureido)piperidine-1-carboxylate (364, 31.0 g, 102 mmol) in anhydrous THF (350 mL) was added NaH (60% in mineral oil, 4.82 g, 122 mmol) in small portions slowly. The resulting mixture was stirred at RT for 6 hours before being quenched with water (50 mL). The layers were separated and the aqueous was extracted with DCM (20 mL×3). The combined organic layers were washed with brine, dried, concentrated and subjected to silica flash column using 0 to 5% MeOH in DCM to isolate (R)-tert-butyl 3-(2-oxoimidazolidin-1-yl)piperidine-1-carboxylate (365) (25.4 g, 93%) as a white solid. At 0° C., to a solution of (R)-tert-butyl 3-(2-oxoimidazolidin-1-yl)piperidine-1-carboxylate (365) (16.2 g, 60.2 mmol) in anhydrous THF (160 mL) was added NaH (60%, 3.6 g, 90.3 mmol) in small portions. The resulting mixture was stirred at RT for 30 min, cooled back to 0° C., and then iodomethane (12.9 g, 90.3 mmol) was added dropwise. After the addition, the mixture was stirred at RT for 3 hours. The reaction was quenched with water and extracted with DCM (50 mL×2). The combined organic layers were washed with brined, dried, concentrated, and purified by silica flash column using 0 to 3% MeOH in DCM to get (R)-tert-butyl 3-(3-methyl-2-oxoimidazolidin-1-yl)piperidine-1-carboxylate (366) (13.0 g, 74%) as a light yellow oil. (R)-tert-butyl 3-(3-methyl-2-oxoimidazolidin-1-yl)piperidine-1-carboxylate (366) (3.5 g, 12.37 mmol) was treated with 40 mL commercial 4N HCl in dioxane at RT for 2 hours. The solvent was removed in vacuo, and the residue was basified to pH 9 with ammonium hydroxide. The solvent was then removed in vacuo, and the residue was subjected to silica flash column using 0 to 10% MeOH in DCM to isolate (R)-1-methyl-3-(piperidin-3-yl)imidazolidin-2-one (367) (1.2 g, 53%) as an oil. LC-MS (ESI): m/z (M+1) 184.2. Proton NMR (CDCl3): δ 3.95-3.83 (2H, m), 3.75 (1H, s), 3.39-3.26 (5H, m), 3.08-2.97 (1H, m), 2.93-2.79 (1H, m), 2.78 (3H, s), 1.94-1.86 (2H, m), 1.82-1.56 (2H, m), 1.48-1.21 (1H, m) ppm.
Reaction SMILES: [Cl:1][C:2]1[C:11]([Cl:12])=[CH:10][C:5]2[NH:6][C:7](=S)[NH:8][C:4]=2[CH:3]=1.[BrH:13].BrBr.[O-]S([O-])(=O)=O.[Na+].[Na+]>CO>[Br:13][C:7]1[NH:6][C:5]2[CH:10]=[C:11]([Cl:12])[C:2]([Cl:1])=[CH:3][C:4]=2[N:8]=1
Reactant: S=c1[nH]c2cc(Cl)c(Cl)cc2[nH]1
Reactant: Br
Agent: BrBr
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: Clc1cc2nc(Br)[nH]c2cc1Cl
Temperature: 0 °C
Reaction time: 8 h

Procedure:
5,6-dichloro-2,3-dihydro-1H-1,3-benzodiazole-2-thione (2 mmol, 438 mg) was dissolved in MeOH (20 ml). The reaction mixture was cooled to 0° C. and hydrobromic acid (0.4 ml) was added, then bromine (8 mmol, 1.3 g) was added. The resulting mixture was stirred at RT overnight, then Na2SO4 was added. Next MeOH was evaporated. The aqueous layer was extracted with DCM. The product was purified on silica gel using EA/hex (1:1) to afford yellow solid (1 mmol, 260 mg), m/z 266.7; rt 2.8 min.
Reaction SMILES: [CH:1]1[C:6]2=[N:7][S:8][N:9]=[C:5]2[C:4]([NH:10][C:11]2[NH:15][CH2:14][CH2:13][N:12]=2)=[C:3]([Cl:16])[CH:2]=1.[C:17]([OH:21])(=[O:20])[CH2:18][CH3:19]>C(O)(C)C>[CH:1]1[C:6]2=[N:7][S:8][N:9]=[C:5]2[C:4]([NH:10][C:11]2[NH:15][CH2:14][CH2:13][N:12]=2)=[C:3]([Cl:16])[CH:2]=1.[C:17]([O-:21])(=[O:20])[CH2:18][CH3:19]
Reactant: CCC(=O)O
Agent: Clc1ccc2nsnc2c1NC1=NCCN1
Solvent: CC(C)O
Product: CCC(=O)[O-]
Temperature: 2.5 °C

Procedure:
To 7 ml of isopropyl alcohol, 3.0 g of the tizanidine base (99.15% HPLC) and 2.5 g of propionic acid are added. After brief heating to boil a yellowish solution results, from which a precipitated product starts to separate. After cooling to 0 to 5° C. and aspiration 3.53 g of tizanidine propionate are obtained.