Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][CH:6]=[C:5](Br)[C:3]=1[NH2:4].[C:10]([C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1)([CH3:13])([CH3:12])[CH3:11]>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>[C:10]([C:14]1[CH:19]=[CH:18][C:17]([C:2]2[CH:8]=[CH:7][CH:6]=[C:5]([C:17]3[CH:18]=[CH:19][C:14]([C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:15][CH:16]=3)[C:3]=2[NH2:4])=[CH:16][CH:15]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Reactant: Nc1c(Br)cccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)c1ccc(-c2cccc(-c3ccc(C(C)(C)C)cc3)c2N)cc1

Procedure:
The same procedure as in Example 1(1) was used except that reaction was conducted by using 2,6-dibromoaniline (9.00 g, 35.6 mmol), Pd(PPh3)4 (5.0 g), and 4-t-butylphenyl boronic acid (19.0 g, 107 mmol). Yield 3.0 g. 1H NMR (CD2Cl2): δ 7.50 (d, 4H, Harom), 7.43 (d, 4H, Harom), 7.08 (d, 2H, Harom), 6.83 (t, 1H, Harom), 3.93 (s, 2H, NH2), 1.38 (s, 18H, t-Bu).
Reaction SMILES: ClC(OCC)=O.C(Cl)(Cl)Cl.[CH2:11]([C:14]1([C:23]([C:26]([OH:28])=[O:27])([CH3:25])[CH3:24])[C:19](=[O:20])[NH:18][C:17](=[O:21])[NH:16][C:15]1=[O:22])[CH:12]=[CH2:13].[CH:29]1[C:34]([N+:35]([O-:37])=[O:36])=[CH:33][CH:32]=[C:31](O)[CH:30]=1>ClCCl.C(N(CC)CC)C>[CH2:11]([C:14]1([C:23]([C:26]([O:28][C:31]2[CH:30]=[CH:29][C:34]([N+:35]([O-:37])=[O:36])=[CH:33][CH:32]=2)=[O:27])([CH3:24])[CH3:25])[C:19](=[O:20])[NH:18][C:17](=[O:21])[NH:16][C:15]1=[O:22])[CH:12]=[CH2:13]
Reactant: C=CCC1(C(C)(C)C(=O)O)C(=O)NC(=O)NC1=O
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: C=CCC1(C(C)(C)C(=O)Oc2ccc([N+](=O)[O-])cc2)C(=O)NC(=O)NC1=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 2.19 g. of ethyl chloroformate in 90 ml. of chloroform was added to a solution of 5.08 g. of "allonalcarboxylic acid" [5-allyl-5-(1-carboxy-isopropyl)barbituric acid] and 2.02 g. of triethylamine in 100 ml. of dichloromethane, cooled to 0°-5°, and the mixture was stirred at room temperature for 5 hours. p-Nitrophenol (3.06 g.) was added and the mixture was stirred at room temperature for 14 hours. The reaction mixture was washed with saturated sodium carbonate solution (3×25 ml.), and water until the workings were neutral, dried over anhydrous sodium sulfate and filtered. Evaporation of the filtrate under reduced pressure gave 4.7 g. of an oil. Crystallization from a mixture of ether-heptane (1:1) gave 2.2 g. of the ester, m.p. 140°-141°.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.[C:32](Cl)(=O)C(Cl)=O.C(N(CC)CC)C.[NH2:45][C:46]1[S:50][C:49]([C:51]([O-:53])=[O:52])=[CH:48][CH:47]=1>CN(C1C=CN=CC=1)C>[CH3:32][O:52][C:51]([C:49]1[S:50][C:46]([NH:45][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10]2)=[O:30])=[CH:47][CH:48]=1)=[O:53]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Nc1ccc(C(=O)[O-])s1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)s1
Yield: 28.3 %

Procedure:
In a manner similar to the method described in Examples 144, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (0.3 g, 0.64 mmol) was reacted with oxalyl chloride (0.12 mL, 1.4 mmol), triethylamine (0.22 mL, 1.6 mmol), DMAP (5 mg), and 5-amino-2-thiophene-carboxylate (Princeton) (0.14 g, 0.96 mmol) to give rac-5-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-thiophene-2-carboxylic acid methyl ester as a yellow solid (0.11 g, 28%).
Reaction SMILES: [CH:1]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:3]([NH:4][CH2:5]3)[CH2:2]1)[CH2:9]2.[N+:12]([C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1)([O-:14])=[O:13]>C(O)C>[N+:12]([C:15]1[CH:16]=[CH:17][C:18]([C:19]([N:4]2[CH2:5][CH:6]3[CH2:11][CH:1]4[CH2:9][CH:8]([CH2:10][CH:3]2[CH2:2]4)[CH2:7]3)=[O:20])=[CH:22][CH:23]=1)([O-:14])=[O:13]
Reactant: C1NC2CC3CC1CC(C3)C2
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: CCO
Product: O=C(c1ccc([N+](=O)[O-])cc1)N1CC2CC3CC(C2)CC1C3
Yield: 83.2 %

Procedure:
A mixture of 4-azatricyclo[4.3.1.13,8 ]undecane (0.75 gram, 5 mmol) from Step B, and p-nitrobenzoyl chloride (0.93 gram, 5 mmol) in 40 ml anhydrous ethanol was refluxed for 4.5 hours. Following workup and recrystallization from isopropanol, 1.25 gram of compound 4b were obtained as white crystals (melting point 150° C.).
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:17]2[C:16]3[C@H:7]([C@H:8]4[C@@:12]([CH2:14][CH:15]=3)([CH3:13])[C:11](=[O:20])[CH2:10][CH2:9]4)[CH2:6][CH2:5][C:4]=2[CH:3]=1.C1(C)C=CC(S(O)(=O)=[O:28])=CC=1.N1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>O1CCCC1.O1C=CCCC1.C(OCC)(=O)C>[O:28]1[CH2:37][CH2:36][CH2:35][CH2:34][CH:33]1[O:1][C:2]1[CH:19]=[CH:18][C:17]2[C:16]3[C@H:7]([C@H:8]4[C@@:12]([CH2:14][CH:15]=3)([CH3:13])[C:11](=[O:20])[CH2:10][CH2:9]4)[CH2:6][CH2:5][C:4]=2[CH:3]=1
Reactant: C[C@]12CC=C3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Reactant: c1ccncc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: C1=COCCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@]12CC=C3c4ccc(OC5CCCCO5)cc4CC[C@H]3[C@@H]1CCC2=O

Procedure:
A suspension of 2.0 g of 3-hydroxy-estra-1,3,5(10),9(11)-tetraen-17-one in 20 ml of tetrahydrofuran and 3.0 ml of dihydropyran is stirred with 15 mg of para-toluenesulfonic acid for 29 hours at room temperature. Then, 0.3 ml of pyridine is added, diluted with ethyl acetate, washed with sodium bicarbonate solution as well as with saturated sodium chloride solution, dried on sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with hexane/acetone/triethylamine. 2.3 g of 3-tetrahydropyranyloxy-estra-1,3,5(10),9(11)-tetraen-17-one is obtained as a colorless oil, [α]D22 =+122.5° (c=0.515% in pyridine).
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13]([C:15]1[CH:19]=[CH:18][N:17]([C:20]2[CH:25]=[CH:24][C:23]([CH:26]([F:28])[F:27])=[CH:22][N:21]=2)[CH:16]=1)=[O:14])(C)(C)C.O>O1CCCC1>[F:28][CH:26]([F:27])[C:23]1[CH:24]=[CH:25][C:20]([N:17]2[CH:18]=[CH:19][C:15]([C:13]([OH:14])=[O:12])=[CH:16]2)=[N:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)c1ccn(-c2ccc(C(F)F)cn2)c1
Solvent: O
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccn(-c2ccc(C(F)F)cn2)c1
Yield: 96.6 %

Procedure:
Trifluoroacetic acid (13.6 ml) was added at room temperature to a solution of 1-[5-(difluoromethyl)pyridin-2-yl]-1H-pyrrole-3-carboxylic acid tert-butyl ester (1.01 g) in tetrahydrofuran (3.4 ml) and stirred at the same temperature for an hour. After completion of the reaction, water was added to the reaction solution and the precipitated solid was collected by filtration to give the titled compound (790 mg) as a white solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][NH:13][CH:12]([CH3:16])[CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[C:22]([Cl:24])=[O:23]>C1C=CC=CC=1>[ClH:24].[C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:22]([C:18]3[O:17][CH:21]=[CH:20][CH:19]=3)=[O:23])[CH:12]([CH3:16])[CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC1CN(CCCc2ccccc2)CCN1
Reactant: O=C(Cl)c1ccco1
Solvent: c1ccccc1
Product: CC1CN(CCCc2ccccc2)CCN1C(=O)c1ccco1
Product: Cl

Procedure:
The compound was obtained by following the same process as in Example 2 from a mixture of 1-(3-phenylpropyl)-3-methylpiperazine [b.p. 120° - 125°C (3 mmHg), dipicrate, m.p. 249° - 250°C], 2-furoyl chloride and benzene.
Reaction SMILES: [CH2:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][C:12]#N)[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].[OH-:14].[K+].N.C1C=CC2C(C3C=CC(O)=CC=3)(C3C=CC(O)=CC=3)OC(=[O:24])C=2C=1>C(O)C.O>[CH2:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][C:12]([OH:24])=[O:14])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: [OH-]
Reactant: O=C1OC(c2ccc(O)cc2)(c2ccc(O)cc2)c2ccccc21
Reactant: CCCC[C@H]1CC[C@H](CC#N)CC1
Agent: N
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCCC[C@H]1CC[C@H](CC(=O)O)CC1
Temperature: 25 °C

Procedure:
A solution of 34 g (0.19 mol) of trans-4-butylcyclohexyl acetonitrile, 43 g (0.76 mol) of KOH, and 34 cm3 of water in 190 cm3 of ethanol was refluxed over a hot water bath until the generation of ammonia gas ceased (about 10 hours). Ammonia gas was detected using phenolphthalein test paper. The reaction solution was cooled to room temperature and ethanol was distilled off. The residue was dissolved in 100 cm3 of water. The resulting solution was poured into a beaker containing 100 g of water and 100 cm3 of concentrated hydrochloric acid. The crystals precipitated in the beaker were separated out by filtration and washed with water. The crystals were recrystallized from a solvent mixture of methanol and water to yield 37 g (0.19 mol) of trans-4-butylcyclohexyl acetic acid.
Reaction SMILES: [C:1]([O:5]C1C=CC=CC=1CN(CC1C=CC=CN=1)CCCN1CCC(C2C=CC=CC=2)CC1)(C)(C)C.CO[CH:38]1[CH2:43][CH:42]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:41][CH2:40][NH:39]1.[C:50]([O:54][C:55]1[CH:75]=[CH:74][CH:73]=[CH:72][C:56]=1[CH2:57][N:58]([CH2:68][CH2:69][CH2:70]Cl)[CH2:59][CH2:60][NH:61][C:62](=[O:67])[C:63]([CH3:66])([CH3:65])[CH3:64])([CH3:53])([CH3:52])[CH3:51].C([O-])([O-])=O.[K+].[K+]>>[C:50]([O:54][C:55]1[CH:75]=[CH:74][CH:73]=[CH:72][C:56]=1[CH2:57][N:58]([CH2:68][CH2:69][CH2:70][N:39]1[CH2:38][CH2:43][CH:42]([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][C:49]=2[O:5][CH3:1])[CH2:41][CH2:40]1)[CH2:59][CH2:60][NH:61][C:62](=[O:67])[C:63]([CH3:66])([CH3:65])[CH3:64])([CH3:53])([CH3:52])[CH3:51]
Reactant: CC(C)(C)Oc1ccccc1CN(CCCCl)CCNC(=O)C(C)(C)C
Reactant: CC(C)(C)Oc1ccccc1CN(CCCN1CCC(c2ccccc2)CC1)Cc1ccccn1
Reactant: COC1CC(c2ccccc2)CCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccccc1C1CCN(CCCN(CCNC(=O)C(C)(C)C)Cc2ccccc2OC(C)(C)C)CC1
Yield: 65 %

Procedure:
The same procedure as described for compound 20 was applied to 2-methoxy-4-phenyl piperidin (0.5 g, 2.63 mmol), compound 23 (0.7 g, 1.75 mmol), KI (0.87 g, 5.25 mmol) and K2CO3 (1.21 g, 8.75 mmol). The residue was purified on a silica gel TLC plate that was developed in 5% methanolic NH3 (7 M NH3 in methanol/95% CH2Cl2. The product was isolated as yellow oil (65% yield). 1H NMR (CDCl3) δ 7.3965 (m, 1H, Ar), 7.2067 (dd, 1H, Ar), 7.1655 (m, 1H, Ar), 7.1315 (m, 1H, Ar), 7.0245 (dd, 1H, Ar), 7.001 (s, 1H, Ar), 6.9195 (ddd, 1H, Ar), 6.8465 (s, 1H, Ar), 3.814 (s, 3H, —OCH3), 3.599, (s, 2H, —CH2—), 3.1885 (m, 2H, —CH2—), 3.041 (m, 2H, —CH2—), 2.951 (m, 1H, —CH—), 2.525 (t, 2H, —CH2—), 2.475 (t, 2H, —CH2—), 2.367 (t, 2H, —CH2—), 2.066 (m, 2H, —CH2—), 1.7455 (m, 6H), 1.430 (s, 9H, —C(CH3)3, 1.386 (s, 9H, —C(CH3)3. Mass Spec.=554.40 (M+H)+.
Reaction SMILES: Cl.Cl.Cl.[N:4]1([CH2:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([O:17][CH2:18][CH2:19][CH2:20][NH:21][C:22](=[NH:26])[C:23](=[NH:25])[NH2:24])[CH:12]=2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[S:27](N1C(=O)C2=CC=CC=C2C1=O)N1C(=O)C2=CC=CC=C2C1=O>C(Cl)Cl.C(N(CC)CC)C>[NH2:25][C:23]1[C:22]([NH:21][CH2:20][CH2:19][CH2:18][O:17][C:13]2[CH:12]=[C:11]([CH2:10][N:4]3[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]3)[CH:16]=[CH:15][N:14]=2)=[N:26][S:27][N:24]=1
Reactant: O=C1c2ccccc2C(=O)N1SN1C(=O)c2ccccc2C1=O
Reactant: N=C(N)C(=N)NCCCOc1cc(CN2CCCCC2)ccn1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Nc1nsnc1NCCCOc1cc(CN2CCCCC2)ccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of the product prepared in Step C in 50 ml of CH2Cl2 and 5.7 ml of triethylamine was treated with N,N'-thiobisphthalimide (DMF solvate) (5.44 g; 13.7 mmoles). After stirring at ambient temperature for one hour, the mixture was washed with 40 ml of 4N NaOH, water, saturated aqueous NaCl solution, dried (Na2SO4), filtered and evaporated under reduced pressure to give the crude product. The product was purified by flash chromatography on 90 g of silica gel (230-400 mesh) using ethyl acetate-methanol (96:4) as the eluent to give 3.44 g of the title compound as a viscous oil. Treatment of the product with one equivalent of cyclohexyl sulfamic acid in acetone gave the cyclohexyl sulfamate of the title compound, mp 124.5°-126° C.
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCCl>[C:19]([C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]([C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:17][CH:18]=2)=[CH:7][CH:6]=1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: c1ccc(OCCCCOc2ccccc2)cc1
Reactant: O=C(Cl)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: O=C(c1ccccc1)c1ccc(OCCCCOc2ccc(C(=O)c3ccccc3)cc2)cc1

Procedure:
1,4-Diphenoxy-n-butane (24.2 g) and benzoyl chloride (29 g) are reacted in 250 ml of 1,2-dichloroethane in the presence of aluminum chloride (28 g) for 4 hours at 60° to yield 18.3 g (41% of theory) of colorless crystals mp 163°-164°. Calculated for C30H26O4 : C, 79.98% H, 5.82%. Found: C, 80.16%; H, 5.98%.
Reaction SMILES: [C:1]([C:3]1[N:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[N:19]=[C:18]([C:20]([O:22]C)=O)[C:17](=[O:24])[N:16]([C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=4)[C:15]=3[CH3:35])=[CH:12][CH:11]=[N:10]2)=[CH:5][CH:4]=1)#[N:2].[CH:36]1([NH2:39])[CH2:38][CH2:37]1>C(#N)C.C(O)C>[C:1]([C:3]1[N:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[N:19]=[C:18]([C:20]([NH:39][CH:36]4[CH2:38][CH2:37]4)=[O:22])[C:17](=[O:24])[N:16]([C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:33])([F:34])[F:32])[CH:26]=4)[C:15]=3[CH3:35])=[CH:12][CH:11]=[N:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: NC1CC1
Reactant: COC(=O)c1nc(-c2ccnn2-c2ccc(C#N)nc2)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Solvent: CCO
Solvent: CC#N
Product: Cc1c(-c2ccnn2-c2ccc(C#N)nc2)nc(C(=O)NC2CC2)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 60 °C
Reaction time: 10 h
Yield: 36.6 %

Procedure:
Methyl 6-[1-(6-cyanopyridin-3-yl)-1H-pyrazol-5-yl]-5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxylate (0.026 g, 0.054 mmol) in acetonitrile (0.33 ml) and ethanol (0.074 ml) were placed in a vial. Cyclopropylamine (0.14 ml, 2.0 mmol) was added, the vial sealed and stirred at 60° C. for 10 h. After evaporation, the residue was purified by preparative HPLC to give 0.010 g (37%) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].Cl.Cl[CH2:14][C:15]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]2[C:16]=1[CH:17]=[CH:18][CH:19]=[N:20]2.C(N(C(C)C)CC)(C)C>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([CH2:14][C:15]2[CH:24]=[CH:23][C:22]([OH:25])=[C:21]3[C:16]=2[CH:17]=[CH:18][CH:19]=[N:20]3)[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCNCC1
Reactant: Oc1ccc(CCl)c2cccnc12
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)N1CCN(Cc2ccc(O)c3ncccc23)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 42.9 %

Procedure:
N-Ethoxycarbonylpiperazine (1.5 ml, 10.2 mmol) was added to a mixture of 5-chloromethyl-8-hydroxyquinoline hydrochloride (2.36 g, 10.2 mmol) and diisopropylethylamine (3.6 ml, 20.6 mmol) in CHCl3 (50 ml) at 5° C. The mixture was stirred for 24 h at room temperature. CHCl3 (100 ml) was then added and the solution was washed with 5% NaHCO3 (3×50 ml) and brine (2×50 ml) and then dried over Na2SO4. The solution was filtered and evaporated to dryness. The residue was crystallized from a mixture of benzene hexane and gave 1.38 g (42%) of the title product. M.p. −96° C. TLC (CHCl3-MeOH-NH3 9:1:0.1) Rf=0.6; TLC (CHCl3-MeOH-Me3 9:0.5:0.05) Rf−0.4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH3:16])([CH3:15])[C:10](OCC)=O)=[CH:4][CH:3]=1.[OH-:17].[Na+].C1[CH2:23][O:22]CC1>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([CH3:15])([CH3:16])[CH2:10][C:23]([OH:22])=[O:17])=[CH:6][CH:7]=1
Reactant: [OH-]
Reactant: C1CCOC1
Reactant: CCOC(=O)C(C)(C)Nc1ccc(Cl)cc1
Agent: [Na+]
Solvent: CO
Product: CC(C)(CC(=O)O)Nc1ccc(Cl)cc1
Temperature: 50 °C
Yield: 91 %

Procedure:
To a solution of ethyl 2-(4-chlorophenylamino)-2-methylpropanoate (1.2 g, 4.96 mmol) in THF (5 mL) and MeOH (2 mL), was added aqueous sodium hydroxide (3.97 g, 9.93 mmol). The mixture was heated at 50° C. for 3 h, cooled to rt, concentrated, and then neutralized to pH=3. The mixture was extracted with EtOAc, and the combined organic extracts were washed with brine, dried over Na2SO4, and concentrated to give 3-(4-chlorophenylamino)-3-methylbutanoic acid (0.96 g, 91% yield) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]3=[O:20])[CH:11]=[C:10]([C:21](O)=[O:22])[CH:9]=2)=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[CH3:47][C:48]1[N:53]=[CH:52][C:51]([C@H:54]([NH2:56])[CH3:55])=[CH:50][N:49]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[C:12]([N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]3=[O:20])[CH:11]=[C:10]([C:21]([NH:56][C@@H:54]([C:51]3[CH:50]=[N:49][C:48]([CH3:47])=[N:53][CH:52]=3)[CH3:55])=[O:22])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(N3CCCCC3=O)c2)cc1
Reactant: Cc1ncc([C@@H](C)N)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(-c2cc(C(=O)N[C@H](C)c3cnc(C)nc3)cc(N3CCCCC3=O)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4′-methyl-5-(2-oxopiperidin-1-yl)biphenyl-3-carboxylic acid (45 mg, 0.14 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (56 mg, 0.29 mmol), 1-hydroxybenzotriazole hydrate (22 mg, 0.15 mmol), and CH2Cl2 (3 mL) were added (R)-1-(2-methylpyrimidin-5-yl)ethanamine (30 mg, 0.22 mmol) and N,N-diisopropylethylamine (51 μL, 0.29 mmol). The mixture was stirred at room temperature overnight and then concentrated. The residue was purified by preparative HPLC (100×20.2 mm, C18 column; 30-80% CH3CN-water [10 mM Et2NH]) to afford a white foam.
Reaction SMILES: [CH3:1][C:2]1[NH:14][CH2:13][CH2:12][C:4]2=[C:5]3[C:10](=[N:11][C:3]=12)[CH:9]=[CH:8][CH:7]=[CH:6]3.[C:15](OC(=O)C)(=[O:17])[CH3:16].C(OCC)(=O)C>N1C=CC=CC=1>[CH2:1]=[C:2]1[C:3]2[NH:11][C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]=2[CH2:12][CH2:13][N:14]1[C:15](=[O:17])[CH3:16]
Reactant: CC1=C2N=c3ccccc3=C2CCN1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: C=C1c2[nH]c3ccccc3c2CCN1C(C)=O

Procedure:
To a solution of harmalan (1 mmol) in pyridine (2 ml) is added acetic anhydride (1.1 eq). After acid hydrolysis and extraction with ethyl acetate, the crude product is flash-chromatographed (eluent: EtOAc/pet. ether; 50/50). The 1-methylene-2-acetyl-1,2,3,4-tetrahydro-β-carboline elutes off first.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:20][CH3:21])[C:13](=[O:14])[N:12]([CH3:15])[C:11]3[CH:16]=[CH:17][CH:18]=[CH:19][C:10]=3[S:9]2)=[CH:4][CH:3]=1.C1C=CC=CC=1.Cl.[C:29](OC(=O)C)(=[O:31])[CH3:30]>N1C=CC=CC=1>[C:29]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([O:20][CH3:21])[C:13](=[O:14])[N:12]([CH3:15])[C:11]3[CH:16]=[CH:17][CH:18]=[CH:19][C:10]=3[S:9]2)=[CH:6][CH:7]=1)(=[O:31])[CH3:30]
Reactant: CC(=O)OC(C)=O
Reactant: COC1(c2ccc(O)cc2)Sc2ccccc2N(C)C1=O
Agent: Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: COC1(c2ccc(OC(C)=O)cc2)Sc2ccccc2N(C)C1=O
Reaction time: 3 h
Yield: 52.7 %

Procedure:
3,4-Dihydro-2-(4-hydroxyphenyl)-2-methoxy-4-methyl-3-oxo-2H-1,4-benzothiazine (0.2 g, compound No. 5) is dissolved in a mixture of acetic anhydride (2 ml) and pyridine (5 ml). The mixture is standed for 3 hours at room temperature, and then poured into a mixture of benzene and dilute hydrochloric acid. The organic layer is washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo. The separated crystals are collected by filtration to give 0.1 g (52.7%) of the titled compound.
Reaction SMILES: [Cl:1][C:2]1[S:6][N:5]=[C:4]([CH2:7]Cl)[N:3]=1.[NH2:9][CH2:10][CH2:11][SH:12]>>[NH2:9][CH2:10][CH2:11][S:12][CH2:7][C:4]1[N:3]=[C:2]([Cl:1])[S:6][N:5]=1
Reactant: NCCS
Reactant: ClCc1nsc(Cl)n1
Product: NCCSCc1nsc(Cl)n1

Procedure:
Reacting 5-chloro-3-chloromethyl-1,2,4-thiadiazole with cysteamine by the procedure of Example 1(i)(c) gives 3-[(2-aminoethyl)thiomethyl]-5-chloro-1,2,4-thiadiazole.
Reaction SMILES: [CH3:1][CH:2]1[C:7](=O)[CH:6]2[CH2:9][CH2:10][N:3]1[CH2:4][CH2:5]2.[C:11]1([C:17]2[N:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][CH:2]1[N:3]2[CH2:10][CH2:9][CH:6](/[C:7]/1=[N:23]/[C:20]1[CH:21]=[N:22][C:17]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:18][CH:19]=1)[CH2:5][CH2:4]2
Reactant: CC1C(=O)C2CCN1CC2
Reactant: Nc1ccc(-c2ccccc2)nc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC1/C(=N\c2ccc(-c3ccccc3)nc2)C2CCN1CC2

Procedure:
A solution of 2-methyl-1-aza-bicyclo[2.2.2]octan-3-one (1.33 g, 9.5 mmol), 6-phenyl-pyridin-3-ylamine (1.25 g, 7.3 mmol) and p-toluene sulfonic acid monohydrate (139 mg, 0.73 mmol) in toluene (40 ml) is heated under reflux for 18 hours using a Dean-Stark apparatus. The toluene is evaporated and the residue is dissolved in ethyl acetate and washed with brine. The organic layer is dried over anhydrous magnesium sulfate, filtered and evaporated to dryness, and the residual oil purified by silica gel column chromatography (eluent: EtOAc: CH3OH:NH4OH; 9:1:0.1) to afford [2-Methyl-1-aza-bicyclo[2.2.2]oct-(3Z)-ylidene]-(6-phenyl-pyridin-3-yl)-amine. A solution of LiAlH4 (1.03 ml, 1 M) in THF is added to a solution of [2-Methyl-1-aza-bicyclo[2.2.2]oct-(3Z)-ylidene]-(6-phenyl-pyridin-3-yl)-amine (300 mg, 1.02 mmol) in THF (10 ml). The resulting mixture is stirred at room temperature for 18 hours and then quenched with a saturated aqueous solution of sodium sulfate (1 ml). The solvents are removed by evaporation and the residue is redissolved in ethyl acetate and filtered. The filtrate is evaporated and purified by silica gel column chromatography (eluent: EtOAc: CH3OH: NH4OH; 8.5:1.5:0.1) to afford Rac.-trans-2-Methyl-1-aza-bicyclo[2.2.2]oct-3-yl)-(6-phenyl-pyridin-3-yl)-amine. MS (ES+): m/e=294.4 (MH+); preparative enantiomer separation (column: Chiralpak AD-H 10 um; (4.6×250 mm), eluent: n-hexane : EtOH 50:50, flow: 1.0 ml/min, detector: UV 210 nm): peak 1: 6.29 min; peak 2: 20.16 min.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[C:10]([C:18](=[O:20])[CH3:19])=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].[C:22]([O-])([O-])=O.[K+].[K+].IC>CC#N>[C:1]([O:5][C:6](=[O:21])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:22])=[CH:14][CH:15]=2)[C:10]([C:18](=[O:20])[CH3:19])=[CH:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)c1cn(CC(=O)OC(C)(C)C)c2ccc(O)cc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: COc1ccc2c(c1)c(C(C)=O)cn2CC(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of (3-acetyl-5-hydroxy-indol-1-yl)-acetic acid tert-butyl ester (500 mg, 1.73 mmol) in CH3CN (15 mL) was added K2CO3 (358 mg, 2.59 mmol) and iodomethane (0.162 mL, 2.59 mmol). The reaction mixture was stirred at 50° C. overnight. Additional K2CO3 (716 mg, 5.18 mmol) and iodomethane (0.324 mL, 5.18 mmol) were added and heating was continued for an additional 2 days. Volatiles were evaporated, the reaction mixture was taken up in water and extracted twice with AcOEt. The combined organic phases were dried (Phase separator) and evaporated to give the title compound. MS (LC/MS): 304.0 [M+H]+, 629.0 [2M+Na]+; tR (HPLC conditions c): 4.92 min.