Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:16]([O-])=O)[C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[H][H]>O1CCOCC1.[Ni]>[NH2:16][C:4]1[C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=2)=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Cl)cnc1Oc1ccc(O)cc1
Reactant: [H][H]
Agent: [Ni]
Solvent: C1COCCO1
Product: Nc1cc(Cl)cnc1Oc1ccc(O)cc1
Yield: 97.7 %

Procedure:
110.7 g (0.415 mole) of 4-(5-chloro-3-nitropyridin-2-yloxy)phenol are dissolved in 1200 ml of dioxan and, after addition of 22.0 g of Raney nickel catalyst, hydrogenated with hydrogen at 20°-25° C. The catalyst is then removed by filtration, the solution is concentrated and the residue is stirred in hexane and the product is filtered and dried, affording 96.0 g (98% of theory) of 4-(3-amino-5-chloropyridin-2-yloxy)phenol with a melting point of 174° C.
Reaction SMILES: [CH2:1](O)[CH:2]=[CH2:3].[CH3:5][S:6][CH3:7].[F:8][B-:9]([F:12])([F:11])[F:10].[H+]>>[F:8][B-:9]([F:12])([F:11])[F:10].[CH2:1]([S+:6]([CH3:7])[CH3:5])[CH:2]=[CH2:3]
Reactant: CSC
Reactant: C=CCO
Agent: F[B-](F)(F)F
Agent: [H+]
Product: C=CC[S+](C)C
Reaction time: 144 h

Procedure:
Into a 3-neck 5-liter flask were weighed 1161.6 g (20 moles) of allyl alcohol, 950 g (15.3 moles) of dimethyl sulfide, and 1829 g (10 moles) of 48% aqueous tetrafluoroboric acid. The flask was attached to a large (1.5 liter) capacity Dean-Stark trap (initially filled with dimethyl sulfide) which was attached to a condenser. Reflux was started and an aqueous phase began to accumulate at the bottom of the Dean-Stark trap, displacing dimethyl sulfide back into the reaction mixture. Reflux was continued for six days. At the end of this period, the rate of accumulation of aqueous phase had become very small. The aqueous phase was drained into a tared bottle and weighed; the net weight of the aqueous phase was 1136.7 g. Excess dimethyl sulfide and allyl alcohol were allowed to distill at atmospheric pressure into the Dean-Stark trap until the temperature in the flask had reached 100° C. At this point, the flask was connected to a dry ice trap and vacuum was applied. The mixture in the flask was evaporated at 70° C. under magnetic stirring for one hour, with the pressure decreasing to a final value of 200 Pa. The yield of nonvolatile product was 1952 g. The nonvolatile product (identified as VII) was a viscous liquid containing a small amount of crystals. It showed no signs of further crystallization on standing at room temperature.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:19]1[N:23]=[CH:22][CH:21]=[N:20]1)=[O:11].Cl[C:25]1[N:30]=[CH:29][C:28]([Cl:31])=[CH:27][N:26]=1>>[Cl:31][C:28]1[CH:27]=[N:26][C:25]([NH:1][CH2:2][C@H:3]2[C@@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[N:19]2[N:23]=[CH:22][CH:21]=[N:20]2)=[O:11])=[N:30][CH:29]=1
Reactant: Clc1cnc(Cl)nc1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@H](C)[C@@H]2CN)c1
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@H](C)[C@@H]2CNc2ncc(Cl)cn2)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example 16 starting with rac-cis-(2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 2,5-dichloropyrimidine. MS (ESI) 426.4 (M+H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[C:10]#[N:11].C(N)(=[S:14])C>>[CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[C:10](=[S:14])[NH2:11]
Reactant: Cn1c([N+](=O)[O-])cnc1C#N
Reactant: CC(N)=S
Product: Cn1c([N+](=O)[O-])cnc1C(N)=S
Temperature: 0 °C
Reaction time: 3 h

Procedure:
1-methyl-5-nitro-2-cyanoimidazole (0.6mole) was dissolved in this mixture at 40° C. Thioacetamide (1.2 mole) was added and stirring continued for 3 hours at 40° C. The resultant solution was poured on to 4 liters of ice/water mixture and stirred for 30 minutes. The precipitate was collected, slurried with water, filtered and dried to yield 1-methyl-2-thiocarbamyl-5-nitroimidazole, m.p. 148°-50° C.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=O.Cl.[CH2:12]([O:14][C:15](=[O:18])[CH2:16][NH2:17])[CH3:13].C([BH3-])#N.[Na+]>C(O)C>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[NH:17][CH2:16][C:15]([O:14][CH2:12][CH3:13])=[O:18]
Reactant: CCOC(=O)CN
Reactant: O=C1Cc2ccccc2C1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CNC1Cc2ccccc2C1
Reaction time: 8 h
Yield: 50.4 %

Procedure:
2-Indanone (25.1 g. 0.19 mol) and glycine ethyl ester hydrochloride (34.5 g, 0.247 mol) were dissolved in absolute ethanol (700 mL) and sodium cyanoborohydride (25.8 g, 0.41 mol) was added in portions to the solution. After addition the mixture was allowed to sit at room temperature overnight. The ethanol was removed under reduced pressure and the residue treated with water and extracted into ethyl acetate. The organic extract was repeatedly washed with saturated aqueous solutions of sodium bicarbonate and sodium chloride before being dried over magnesium sulfate and filtered. After the solvent was concentrated under vacuum an oil remained which was taken up in ether/ethanol (250/50 mL) and cooled by mean of an ice-water bath. Ether which had previously been saturated with anhydrous hydrogen chloride was slowly added to the solution. The precipitated product was filtered and washed with cold ether/ethanol to yield a white solid (21 g) melting at 166°-168° C.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[NH2:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[C:16]([F:24])[CH:15]=1.[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31](O)=[O:32]>N1C=CC=CC=1>[F:24][C:16]1[CH:15]=[C:14]([NH:13][C:31]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=2)=[O:32])[CH:23]=[CH:22][C:17]=1[C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)c1ccc(N)cc1F
Reactant: O=C(O)c1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(NC(=O)c2ccccn2)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride was added to a pyridine (500 ml) solution of methyl 4-amino-2-fluorobenzoate (18.9 g) and picolinic acid (16.5 g), and stirred at room temperature for 2 hours. The solvent was evaporated away under reduced pressure, ethyl acetate (600 ml) was added to it, and the organic layer was washed with aqueous 0.25 N hydrochloric acid solution, aqueous 0.25 N sodium hydroxide solution and saturated saline water. After dried, this was concentrated under reduced pressure, and solidified from a mixed solvent of hexane/ethyl acetate, and taken out through filtration. After dried under reduced pressure, the entitled compound was obtained as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C@H:12]([CH3:15])[CH2:13]Cl)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[CH3:15][C@H:12]([CH2:13][N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[CH2:11][C:8]1[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=1
Reactant: C1CCNCC1
Reactant: C[C@H](CCl)Cc1ccc(C(C)(C)C)cc1
Product: C[C@@H](Cc1ccc(C(C)(C)C)cc1)CN1CCCCC1

Procedure:
The reaction of (a) with piperidine gives the novel compound (S)-fenpropidine.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH2:8][CH2:9][CH2:10][O:11][C:6]=2[C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]2=[O:24])=[C:4]([F:25])[CH:3]=1.S(OOS([O-])(=O)=O)([O-])(=O)=[O:27].[K+].[K+]>C(#N)C.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[Cl:1][C:2]1[C:7]2[CH2:8][C:9](=[O:27])[CH2:10][O:11][C:6]=2[C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:20])[F:21])[N:14]([CH3:23])[C:13]2=[O:24])=[C:4]([F:25])[CH:3]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c3c2OCCC3)c1=O
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c3c2OCC(=O)C3)c1=O
Yield: 97.9 %

Procedure:
By the method of Example 3, Step A, 0.5 gram (0.0013 mole) of 3-(5-chloro-3,4-dihydro-7-fluoro-2H-1-benzopyran-8-yl)-1-methyl-6-trifluoromethyluracil was reacted with 1.1 grams (0.0040 mole) of potassium persulfate and 0.3 gram (0.0013 mole) of copper(11) sulfate pentahydrate in 30 mL of acetonitrile and 30 mL of water, yielding 0.5 gram of 3-(5-chloro-3,4-dihydro-7-fluoro-2H-1-benzopyran-3-on-8-yl)-1-methyl-6-trifluoromethyluracil. The NMR spectrum was consistent with the proposed structure. This product was combined with another run of this reaction. The combined runs were subjected to column chromatography on silica gel, with 1:4 to 1:2 ethyl acetate:hexane as eluants. The product-containing fractions were combined and concentrated under reduced pressure, yielding 0.8 gram of 3-(5-chloro-3,4-dihydro-7-fluoro-2H-1-benzopyran-4-on-8-yl)-1-methyl-6-trifluoromethyluracil. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[CH:10]=[C:11]3[C:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[O:24][CH3:25])=[CH:16][N:15](S(C4C=CC(C)=CC=4)(=O)=O)[C:12]3=[N:13][CH:14]=2)=[CH:4][C:3]=1[C:36]([N:38]1[CH2:43][CH2:42][N:41]([CH2:44][CH2:45][N:46]([CH2:49][CH3:50])[CH2:47][CH3:48])[CH2:40][CH2:39]1)=[O:37].Cl.[CH3:52][N:53]([CH2:55][C:56](Cl)=[O:57])[CH3:54].CCN(C(C)C)C(C)C>ClCCl>[CH2:49]([N:46]([CH2:47][CH3:48])[CH2:45][CH2:44][N:41]1[CH2:40][CH2:39][N:38]([C:36]([C:3]2[CH:4]=[C:5]([C:9]3[CH:10]=[C:11]4[C:17]([C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=5[O:24][CH3:25])=[CH:16][NH:15][C:12]4=[N:13][CH:14]=3)[CH:6]=[C:7]([F:8])[C:2]=2[NH:1][C:56](=[O:57])[CH2:55][N:53]([CH3:54])[CH3:52])=[O:37])[CH2:43][CH2:42]1)[CH3:50]
Reactant: CCN(CC)CCN1CCN(C(=O)c2cc(-c3cnc4c(c3)c(-c3ccccc3OC)cn4S(=O)(=O)c3ccc(C)cc3)cc(F)c2N)CC1
Reactant: CN(C)CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)CCN1CCN(C(=O)c2cc(-c3cnc4[nH]cc(-c5ccccc5OC)c4c3)cc(F)c2NC(=O)CN(C)C)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 7.5 %

Procedure:
30 mg (0.04 mmol) of {2-amino-3-fluoro-5-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-[4-(2-diethylamino-ethyl)-piperazin-1-yl]-methanone was combined with 9.0 mg (0.06 mmol) of dimethylaminoacetylchloride hydrochloride and 32 mg (0.11 mmol, 3.31 mmol/gram loading) of PS-DIEA resin (Argonaut Technologies, Inc.) in 1.0 mL dichloromethane. The reaction was shaken gently at room temperature for 48 hours. 22 mg (0.14 mmol) of dimethylaminoacetylchloride hydrochloride and 26 mg (0.09 mmol) more PS-DIEA resin (Argonaut Technologies, Inc.) was added and the reaction was continued to shake at room temperature for 24 more hours. The resin was filtered off and rinsed well with methanol and dichloromethane. The filtrate was concentrated down. The dried residue was dissolved in 0.5 mL methanol and 0.5 mL acetone. 150 μL of a 50% w/v potassium hydroxide (aqueous) solution was added and the reaction was stirred at room temperature for 1 hour. The reaction was neutralized by adding a few drops of acetic acid and concentrated. The residue was dissolved in dimethyl sulfoxide, filtered through a 0.45 μm syringe filter, and purified by reverse phase HPLC in a gradient of acetonitrile and water (containing 0.1% formic acid). The clean fractions were lyophilized to afford 1.9 mg (0.003 mmol, 7% yield) of N-{2-[4-(2-diethylamino-ethyl)-piperazine-1-carbonyl]-6-fluoro-4-[3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-2-dimethylamino-acetamide as a fluffy white powder. 1H NMR (500 MHz, CD3OD) δ 8.51 (d, 1H), 8.28 (d, 1H), 7.70 (s, 1H), 7.67 (dd, 1H), 7.60 (dd, 1H), 7.46 (s, br., 1H), 7.32 (t, 1H), 7.14 (d, 1H), 7.07 (d, 1H), 3.87 (s, 3H), 3.77 (s, br., 2H), 3.56 (d, 2H), 3.19 (s, 2H), 3.13 (s, br., 2H), 2.71 (t, 2H), 2.64 (t, 2H), 2.59 (d, 2H), 2.41 (s, 6H), 1.26 (t, 6H); MS: m/z 630.2 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:17]=[CH:16][C:12]=2[C:13](O)=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].S(Cl)([Cl:28])=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:17]=[CH:16][C:12]=2[C:13]([Cl:28])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(-c2nc(-c3ccccc3)ccc2C(=O)O)cc1OC
Product: COc1ccc(-c2nc(-c3ccccc3)ccc2C(=O)Cl)cc1OC
Yield: 100 %

Procedure:
A mixture of 2-(3,4-dimethoxyphenyl)-6-phenylnicotinic acid (compound no. 303; 1.8 g; 0.0054 mole) and thionyl chloride (20 ml) is heated to boiling point under reflux for 1 h. The medium is concentrated under reduced pressure. A yellow syrup (1.9 g; yield=100%) is obtained.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@@H:18]([N:28](S(C4C=CC=CC=4[N+]([O-])=O)(=O)=O)[CH2:29][CH2:30][CH2:31][NH:32][C:33](=[O:52])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][NH:39][C:40]4[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][C:41]=4[N+:49]([O-:51])=[O:50])[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].C([O-])([O-])=O.[K+].[K+].C1(S)C=CC=CC=1>CN(C)C=O>[CH3:3][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@@H:18]([NH:28][CH2:29][CH2:30][CH2:31][NH:32][C:33](=[O:52])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][NH:39][C:40]4[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][C:41]=4[N+:49]([O-:51])=[O:50])[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:1]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](N(CCCNC(=O)CCCCCNc5ccc([N+](=O)[O-])cc5[N+](=O)[O-])S(=O)(=O)c5ccccc5[N+](=O)[O-])CC[C@]4(C)[C@H]3CC[C@]12C
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](NCCCNC(=O)CCCCCNc5ccc([N+](=O)[O-])cc5[N+](=O)[O-])CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 23 °C
Reaction time: 18 h
Yield: 59.2 %

Procedure:
To a slurry of N-(3-{(3β)-cholest-5-en-3-yl[(2-nitrophenyl)sulfonyl]amino}propyl)-6-[(2,4-dinitrophenyl)amino]hexanamide (19, 164 mg, 0.180 mmol) and K2CO3 (270 mg, 1.954 mmol) in N,N-dimethylformamide (20 mL) was added thiophenol (80 μL, 0.777 mmol). After stirring at 23° C. for 18 h, the mixture was filtered and solvent was removed in vacuo. The crude product was purified by flash column chromatography (MeOH/triethylamine/CH2Cl2, 2:5:100) to afford 4 (77 mg, 59%) mp 165-166° C.; 1H NMR (500 MHz, CDCl3) δ 9.11 (d, J=2.6 Hz, 1H), 8.53 (br s, 1H), 8.25 (dd, J=2.5 Hz, J=9.5 Hz, 1H), 6.99 (t, J=4.3, 1H), 6.90 (d, J=9.5 Hz, 1H), 5.29 (d, J=4.8 Hz, 1H), 3.42-3.38 (m, 2H), 3.34 (dt, J=5.8 Hz, J=5.9 Hz, 2H), 2.74 (t, J=6.1 Hz, 2H), 2.39-2.34 (m, 1H), 2.23-2.17 (m, 3H), 2.04-1.92 (m, 4H), 1.84-0.98 (m, 32H), 0.95 (s, 3H), 0.90 (d, J=6.5Hz, 3H), 0.85 (d, J=2.1 Hz, 3H), 0.84 (d, J=2.1 Hz, 3H), 0.65 (s, 3H); 13C NMR (75.5 MHz, CDCl3) δ 172.5, 148.5, 141.5, 136.2, 130.5 (×2), 124.5, 121.2, 114.7, 58.4, 56.9, 56.3, 50.4, 45.5, 43.6, 42.5, 40.3, 39.9, 39.7, 39.3, 38.1, 37.2, 36.6, 36.4, 36.0, 32.1, 32.0, 29.7, 29.2, 28.7, 28.4, 28.2, 26.8, 25.3, 24.4, 24.0, 23.0, 22.7, 21.2, 19.6, 18.9, 12.0; IR (film) νmax 3362, 3295, 2934, 2867, 1622, 1336 cm−1; CI m/z 722.5229 (MH+, C42H68N5O5 requires 722.5220).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([C@H:11]([O:13]C1CCCCO1)[CH3:12])=[CH2:10].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[CH2:10])[C@H:11]([OH:13])[CH3:12]
Reactant: C=C(c1ccc(F)cc1F)[C@@H](C)OC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: C=C(c1ccc(F)cc1F)[C@@H](C)O
Temperature: 60 °C

Procedure:
A mixture of crude 5b, and pyridinium-p-toluenesulfonate (17.5 g, 0.07 mole) in ethanol (500 ml) is heated at 60° C. for 9 hours. The reaction mixture is concentrated in vacuo and co-evaporated with toluene. The residue is diluted with toluene and the resulting solid is removed by filtration. The filtrate is evaporated under reduced pressure to give the crude 6b as light brown oil.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6].C(Cl)(Cl)Cl.Cl[C:20]([O:22][C:23]1([CH3:27])[CH2:26][CH2:25][CH2:24]1)=[O:21]>C(N(CC)CC)C>[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH:6][C:20]([O:22][C:23]1([CH3:27])[CH2:26][CH2:25][CH2:24]1)=[O:21]
Reactant: CC1(OC(=O)Cl)CCC1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)OC1(C)CCC1
Reaction time: 8 h

Procedure:
A suspension of 171 mg. (0.74 mM) of phenylalanine methyl ester hydrochloride in 10 ml. of chloroform is cooled to 0°C. and the pH adjusted to 8 by addition of triethylamine. 1-Methylcyclobutyl chloroformate 1.5 mM is added portion-wise at 0°C. and the pH of the reaction is maintained at 8 by addition of triethylamine. Upon completion of the addition, the reaction is stirred overnight at 20°-25°C. The reaction solution is washed successively with 10 ml. portions of a saturated sodium bicarbonate solution, 50% saturated solution of sodium chloride, 0.2 N sulfuric acid saturated with sodium sulfate, 50% saturated solution of sodium chloride (twice), and the chloroform solution is dried over sodium acetate. Removal of the chloroform affords N-(1-methylcyclobutyloxycarbonyl)-phenylalanine methyl ester. Saponification of the above ester is carried out by dissolving the residue in 10 ml. of methanol, water (10 ml.) is added and the pH is adjusted to 12 by addition of 2 N sodium hydroxide. After stirring overnight at 25°C., the pH is adjusted to 7 with 2 N sulfuric acid. The methanol is removed in vacuo and saturated sodium bicarbonate solution is added to the water solution. The aqueous bicarbonate solution is washed two times with ether and then the pH is adjusted to 3 by addition of concentrated hydrochloric acid. The acidified solution is extracted three times with ethyl acetate and the organic extracts combined, washed twice with sodium chloride solution and dried over sodium sulfate. The solvent is removed in vacuo and trituration with pet ether affords N-(1-methylcyclobutyl-oxycarbonyl)-phenylalanine, which is isolated by filtration.
Reaction SMILES: Cl.O[CH2:3][C:4]1[N:5]=[CH:6][NH:7][C:8]=1[CH3:9].Cl.[NH2:11][CH2:12][CH2:13][SH:14].[BrH:15]>C(O)(=O)C>[BrH:15].[BrH:15].[CH3:9][C:8]1[N:7]=[CH:6][NH:5][C:4]=1[CH2:3][S:14][CH2:13][CH2:12][NH2:11]
Reactant: NCCS
Reactant: Cc1[nH]cnc1CO
Agent: Br
Agent: Cl
Solvent: CC(=O)O
Product: Cc1nc[nH]c1CSCCN

Procedure:
A mixture of 4-hydroxymethyl-5-methylimidazole hydrochloride (15.0 g.), cysteamine hydrochloride (11.5 g.) and a solution of hydrogen bromide in acetic acid (48%, 225 ml.) was heated under reflux for 7 hours. Cooling afforded 4-methyl-5-[(2-aminoethyl)thiomethyl]imidazole dihydrobromide (21.6 g.), m.p. 208°-211°.
Reaction SMILES: Br[C:2](=[N:12][OH:13])[CH:3]([C:8](=[O:11])[NH:9][CH3:10])[C:4]([CH3:7])([CH3:6])[CH3:5].[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1>CCOCC>[CH3:5][C:4]([CH3:7])([CH3:6])[CH:3]([C:8](=[O:11])[NH:9][CH3:10])[C:2](=[N:12][OH:13])[N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: C1CCNC1
Reactant: CNC(=O)C(C(Br)=NO)C(C)(C)C
Solvent: CCOCC
Product: CNC(=O)C(C(=NO)N1CCCC1)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 12.6 g of 1-bromo-3,3-dimethyl-2-methylcarbamyloximinobutane in 100 ml of anhydrous ether is added, dropwise, 7.8 (0.11 m) of pyrrolidine. The mixture is stirred at room temperature for 1 hour and at reflux for 0.5 hour, then cooled and washed with water. The ether solution is separated, dried, and stripped of solvent to give 11.8 g of amber oil which solidifies on standing to an amber solid, m. 43°-46° C. Properties of this and analogous compounds prepared by substantially the same procedure are shown in Tables 5 and 6.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8](F)[C:5]([C:6]#[N:7])=[C:4]([F:11])[CH:3]=1.[NH3:12]>C(O)C>[NH2:12][C:8]1[CH:9]=[C:2]([Br:1])[CH:3]=[C:4]([F:11])[C:5]=1[C:6]#[N:7]
Reactant: N#Cc1c(F)cc(Br)cc1F
Reactant: N
Solvent: CCO
Product: N#Cc1c(N)cc(Br)cc1F
Temperature: 25 °C

Procedure:
5.0 g (22.9 mmol) 4-bromo-2,6-difluorobenzonitrile in 200 ml of a solution of NH3 in ethanol and heated in a pressure vessel to 90° C. for 20 h. After cooling to RT the solvent is evaporated and the residue taken up in water/DCM. The organic phase is separated, dried and evaporated.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[N:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=2[CH:27]=[O:28])=[CH:21][CH:20]=1.[F:33][C:34]([Si](C)(C)C)([F:36])[F:35].Cl>C1COCC1>[F:33][C:34]([F:36])([F:35])[CH:27]([C:26]1[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=1[C:22]1[CH:23]=[CH:24][N:19]=[CH:20][CH:21]=1)[OH:28]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=Cc1ccccc1-c1ccncc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: OC(c1ccccc1-c1ccncc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 43.4 %

Procedure:
Tetrabutylammonium fluoride (0.027 ml; 1.0 M solution in tetrahydrofuran) was added to a solution of 2-pyridin-4-yl-benzaldehyde (500 mg, 2.73 mmol) and trifluoromethyltrimethylsilane (TMSCF3) (485 μl, 3.28 mmol) in 5 ml of THF at 0° C. The formed mixture was warmed up to room temperature and stirred at room temperature for 4 hours. The reaction mixture was then treated with 5 ml of 1N HCl and stirred at room temperature overnight. The solvent was evaporated to dryness, 9 ml of 1M sodium carbonate aqueous solution was added, the aqueous phase was extracted with chloroform (3×10 ml), and the combined organic layer was washed with water, dried over MgSO4. The organic solvent was evaporated to give 300 mg of 2,2,2-trifluoro-1-(2-pyridin-4-yl-phenyl)ethanol, yield: 43%.
Reaction SMILES: [NH2:1][CH:2]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH2:14])[C:3](O)=[O:4].C[Si](C)(C)N[Si](C)(C)C.Cl[Si](C)(C)C.C(O)C>C1(C)C(C)=CC=CC=1>[NH2:1][CH:2]1[CH2:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:14][C:3]1=[O:4]
Reactant: Nc1ccccc1CCC(N)C(=O)O
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: Cc1ccccc1C
Solvent: CCO
Product: NC1CCc2ccccc2NC1=O

Procedure:
Alternatively, a solution of 2-amino-4-(2-nitrophenyl)butyric acid hydrochloride (2.5 g) in water (200 ml) was hydrogenated at room temperature and atmospheric pressure, using 10% Pd-C (0.5 g) as catalyst. After uptake of hydrogen ceased, the catalyst was filtered off, and the filtrate evaporated to dryness. The residue was dissolved in water (50 ml) and the pH adjusted to 7 by the addition of 10% sodium hydroxide. The solid was filtered off, washed with water, and dried to give 2-amino-4-(2-aminophenyl)butyric acid. A solution of the 2-amino-4-(2-aminophenyl)butyric acid (1.0 g), hexamethyldisilazane (5.4 g), and chlorotrimethylsilane (0.1 g) in xylene (125 ml) was refluxed for 65 hours. The reaction mixture was cooled, poured into ethanol (200 ml) and evaporated under reduced pressure. Water (100 ml) was added, and the solution extracted with dichloromethane (2×125 ml). The combined dichloromethane solutions were washed with water (50 ml), dried over magnesium sulfate, and evaporated under reduced pressure to give 3-amino-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one as above.