Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:10])[N:3]1[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.C(N(CC)CC)C.Cl.[NH2:19][OH:20]>CO>[CH3:1][N:2]([CH3:10])[N:3]1[CH2:8][CH2:7][C:6](=[N:19][OH:20])[CH2:5][CH2:4]1
Reactant: CN(C)N1CCC(=O)CC1
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CN(C)N1CCC(=NO)CC1
Temperature: 37 °C
Yield: 68.3 %

Procedure:
19.2 g 1-Dimethylamino-piperidin-4-one (prepared as described in Journal of Medicinal & Pharmaceutical Chemistry, 4, 423-36; 1961) and 30 g triethylamine are dissolved in 80 ml methanol. 18.8 g hydroxylamin hydrochloride is added in portions at ambient temperature. The internal temperature raises during the addition to 37° C. Then the mixture is heated to reflux for 3 hours, allowed to cool to room temperature, and then the solvent evaporated. The residue is partitioned between ethyl acetate and aqueous sodium bicarbonate. The organic layer is dried over sodium sulfate, and the solvent evaporated. Thus, 14.5 g 1-Dimethylamino-piperidin-4-one oxime is obtained. 1H-NMR (CDCl3): 8.10 ppm (s, broad, 1H), 2.75 ppm (m, 6H), 2.40 ppm (m, 2H), 2.40 ppm (s, 6H).
Reaction SMILES: C[O:2][C:3]1[N:8]=[C:7]2[N:9]([CH2:41][CH2:42][CH2:43][O:44][CH3:45])[C:10]([CH:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:18](=[O:40])[CH2:19][C@H:20]([NH:32]C(=O)OC(C)(C)C)[CH2:21][C:22]4[CH:31]=[CH:30][C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[CH:23]=4)[CH2:13]3)=[N:11][C:6]2=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1>O>[NH2:32][CH:20]([CH2:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=1)[CH2:19][C:18]([N:14]1[CH2:15][CH2:16][CH2:17][C@@H:12]([C:10]2[N:9]([CH2:41][CH2:42][CH2:43][O:44][CH3:45])[C:7]3[NH:8][C:3](=[O:2])[CH:4]=[CH:5][C:6]=3[N:11]=2)[CH2:13]1)=[O:40]
Reactant: COCCCn1c(C2CCCN(C(=O)C[C@@H](Cc3ccc4ccccc4c3)NC(=O)OC(C)(C)C)C2)nc2ccc(OC)nc21
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: COCCCn1c([C@@H]2CCCN(C(=O)CC(N)Cc3ccc4ccccc4c3)C2)nc2ccc(=O)[nH]c21
Temperature: 150 °C
Yield: 3.5 %

Procedure:
(R)-tert-Butyl 4-(3-(5-methoxy-3-(3-methoxypropyl)-3H-imidazo[4,5-b]pyridin-2-yl)piperidin-1-yl)-1-(naphthalen-2-yl)-4-oxobutan-2-ylcarbamate (33E) (0.114 mmol, 0.070 g) prepared according to Example 33, Steps A-E and pyridine hydrochloride (8.65 mmol, 1.00 g) were added to a 15 mL round bottomed flask equipped for stirring under nitrogen. The reaction was subsequently heated to 150° C. and stirred for 15 min. The reaction was cooled to room temperature and water (2 mL) was added. The solution was stirred for 30 minutes at room temperature to allow the solid to completely dissolve. This solution was then filtered and directly purified by preparative LC/MS (10-50% CH3CN in H2O). The resultant fractions were collected and the solvent was removed in-vacuo affording the title compound as a clear colored oil (0.004 mmol, 0.002 g, 3% yield). ESI-MS: m/z 502.2 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:20]([F:23])([F:22])[F:21])=[C:9]([S:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:24]([OH:26])=O.CN(C)C=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:44][C:45]1[CH:52]=[CH:51][C:48]([CH2:49][NH2:50])=[CH:47][CH:46]=1>O>[Cl:44][C:45]1[CH:52]=[CH:51][C:48]([CH2:49][NH:50][C:24]([C:3]2[CH:4]=[N:5][C:6]3[C:11]([C:2]=2[OH:1])=[CH:10][C:9]([S:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:8]([C:20]([F:21])([F:22])[F:23])[CH:7]=3)=[O:26])=[CH:47][CH:46]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: O=C(O)c1cnc2cc(C(F)(F)F)c(SCc3ccccc3)cc2c1O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2cc(C(F)(F)F)c(SCc3ccccc3)cc2c1O
Temperature: 37.5 °C
Reaction time: 20 h

Procedure:
A mixture of 0.15 g of 4-hydroxy-6-[(phenylmethyl)thio]-7-(trifluoromethyl)-3-quinolinecarboxylic acid and 1.2 mL of dimethylformamide is treated with 0.075 g of carbonyldiimidazole. The mixture is stirred 20 h at 35-40° C. The solution is cooled to 25° C. and it is treated with 0.075 mL of distilled water and then it is stirred for 10 min. The solution is treated with 0.053 mL of 4-chlorobenzylamine and it is stirred for 18 h. The mixture is diluted with 1.0 mL of distilled water and then it is decanted from a dark, oily precipitate. This precipitate is treated with 1 mL of glacial acetic acid and the mixture is shaken for 5 min. The solid which formed is collected by filtration and it is washed with a few mL of 50% aqueous acetic acid. The solid is dried in a stream of air to give 48 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:18]=[CH:17][C:13]([C:14](Cl)=[O:15])=[CH:12][C:11]=2[NH:19][C:20]2[C:21]3[CH:29]=[CH:28][CH:27]=[N:26][C:22]=3[N:23]=[CH:24][N:25]=2)=[CH:5][CH:4]=1.[F:30][C:31]([F:40])([F:39])[C:32]1[CH:33]=[C:34]([CH:36]=[CH:37][CH:38]=1)[NH2:35].NC1C=C(O)C(C)=CC=1.C(C1C=CC2C(NC3C=C(C=CC=3SC3C=CC(OC)=CC=3)C(Cl)=O)=NC=NC=2N=1)(C)C>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:18]=[CH:17][C:13]([C:14]([NH:35][C:34]3[CH:36]=[CH:37][CH:38]=[C:32]([C:31]([F:30])([F:39])[F:40])[CH:33]=3)=[O:15])=[CH:12][C:11]=2[NH:19][C:20]2[C:21]3[CH:29]=[CH:28][CH:27]=[N:26][C:22]=3[N:23]=[CH:24][N:25]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Sc2ccc(C(=O)Cl)cc2Nc2ncnc3ncccc23)cc1
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: COc1ccc(Sc2ccc(C(=O)Cl)cc2Nc2ncnc3nc(C(C)C)ccc23)cc1
Agent: Cc1ccc(N)cc1O
Solvent: CO
Product: COc1ccc(Sc2ccc(C(=O)Nc3cccc(C(F)(F)F)c3)cc2Nc2ncnc3ncccc23)cc1

Procedure:
The product from Example 260B was reacted with 3-(trifluoromethyl)aniline according to the procedure from Example 137C substituting 3-(trifluoromethyl)aniline for 5-amino-o-cresol and substituting the product from Example 260B for the product from Example 137B to provide the title compound as an off white solid after trituration of the reaction product from methanol (43 mg, 47%).
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([C:8]2[O:9][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:11][N:12]=2)=[O:7])[CH2:3]1.[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>>[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([O:1][CH:2]2[CH2:5][N:4]([C:6]([C:8]3[O:9][C:10]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)=[N:11][N:12]=3)=[O:7])[CH2:3]2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(c1nnc(-c2ccccc2)o1)N1CC(O)C1
Product: Cc1ccc(S(=O)(=O)OC2CN(C(=O)c3nnc(-c4ccccc4)o3)C2)cc1
Yield: 89.6 %

Procedure:
Using a similar protocol as described in Example 2C but employing 1B (250 mg, 1.02 mmol) and 4-methylbenzene-1-sulfonyl chloride (250 mg, 1.31 mmol) as starting materials afforded 365 mg (90%) of 8B as a solid. 1H NMR (500 MHz, CDCl3): δ 2.49 (s, 3H), 4.24 (dd, 1H), 4.47 (dd, 1H), 4.72 (dd, 1H), 4.98 (dd, 1H), 5.22 (m, 1H), 7.41 (d, 2H), 7.53 (t, 2H), 7.59 (t, 1H), 7.82 (d, 2H), 8.14 (d, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH2:17])[CH2:15][CH3:16])[N:5]=[C:4]([CH3:18])[C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20].[O:24]1[CH2:29][CH2:28][O:27][C:26]2[C:30]([C:34](O)=[O:35])=[CH:31][CH:32]=[CH:33][C:25]1=2>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH:17][C:34]([C:30]2[C:26]3[O:27][CH2:28][CH2:29][O:24][C:25]=3[CH:33]=[CH:32][CH:31]=2)=[O:35])[CH2:15][CH3:16])[N:5]=[C:4]([CH3:18])[C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)c1c(C)nc2cccc(OC[C@@H](N)CC)c2c1N
Reactant: O=C(O)c1cccc2c1OCCO2
Product: CCOC(=O)c1c(C)nc2cccc(OC[C@H](CC)NC(=O)c3cccc4c3OCCO4)c2c1N

Procedure:
Prepared as in Example 24a from (S)-ethyl 4-amino-5-(2-aminobutoxy)-2-methylquinoline-3-carboxylate (Example 97b) and 2,3-dihydrobenzo[b][1,4]dioxine-5-carboxylic acid as brown solid (40%). MS 480 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](/[C:8](=[CH:14]/[N:15](C)C)/[C:9]([O:11]CC)=O)[CH:5]=[N:6][CH:7]=1.[NH:18]([C:20]1[N:25]=[CH:24][C:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:22][CH:21]=1)N.C1(C)C=CC(S(O)(=O)=O)=CC=1.[ClH:44]>C(O)C.O1CCOCC1>[ClH:44].[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9](=[O:11])[N:18]([C:20]3[N:25]=[CH:24][C:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:22][CH:21]=3)[NH:15][CH:14]=2)[CH:5]=[N:6][CH:7]=1
Reactant: CCOC(=O)/C(=C\N(C)C)c1cncc(Br)c1
Reactant: CC(C)(C)OC(=O)c1ccc(NN)nc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)c1ccc(-n2[nH]cc(-c3cncc(Br)c3)c2=O)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
500 mg (1.7 mmol) of the compound from Example 9A and 350 mg (1.7 mmol) of the compound from Example 15A are dissolved in 2 ml of ethanol, and 58 mg (0.3 mmol) of p-toluenesulfonic acid are added. The mixture is heated under reflux for 24 h and then cooled to RT, and 0.5 ml of a 4 N solution of hydrogen chloride in dioxane is added. The mixture is stirred at RT for 30 min. The precipitate is filtered off, washed with ethanol and diethyl ether and dried under high vacuum.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([CH2:17][CH3:18])=[CH:13][CH:12]=3)=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:8][C:4]=2[N:5]=[CH:6][N:7]=1.[C:25]([O:29][C:30](=[O:39])[CH2:31][O:32][CH:33]1[CH2:37][CH:36]([OH:38])[CH:35]=[CH:34]1)([CH3:28])([CH3:27])[CH3:26].O.Cl>CN(C=O)C>[C:25]([O:29][C:30](=[O:39])[CH2:31][O:32][C@H:33]1[CH2:37][C@@H:36]([O:38][C:2]2[C:3]3[C:10]([C:11]4[CH:16]=[CH:15][C:14]([CH2:17][CH3:18])=[CH:13][CH:12]=4)=[C:9]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[O:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:35]=[CH:34]1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CCc1ccc(-c2c(-c3ccccc3)oc3ncnc(Cl)c23)cc1
Reactant: CC(C)(C)OC(=O)COC1C=CC(O)C1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CCc1ccc(-c2c(-c3ccccc3)oc3ncnc(O[C@H]4C=C[C@@H](OCC(=O)OC(C)(C)C)C4)c23)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Dissolve 390.7 mg (1.17 mmol) of 4-chloro-5-(4-ethylphenyl)-6-phenylfuro[2,3-d]pyrimidine and 250 mg (1.17 mmol) of cis-(+/−)-{[(4-hydroxycyclopent-2-en-1-yl]oxy}acetic acid tert-butyl ester in 0.95 ml of DMF, cool to 0° C. and add 0.58 ml (1.17 mmol) of phosphazene base P2-t-Bu (2 M solution in THF). After the end of the addition, warm the mixture to RT and stir for a further 1 h. Then add the reaction mixture to water, adjust to pH 7 with 1N hydrochloric acid and extract three times with dichloromethane. Combine the organic phases, wash with satd. sodium chloride solution, dry over magnesium sulphate and concentrate under reduced pressure. Isolate the crude product by chromatography on silica gel (eluent: cyclohexane/ethyl acetate 20:1→5:1). 510 mg (85.3% of theory) of the target compound are obtained.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11]([C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20]CC)=[O:19])=[CH:16][CH:15]=3)=[CH:12][N:13]=2)=[CH:5][CH:4]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[F:26][C:2]([F:1])([F:25])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[S:10][C:11]([C:14]3[CH:24]=[CH:23][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=3)=[CH:12][N:13]=2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1ccc(-c2cnc(-c3ccc(C(F)(F)F)cc3)s2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)c1ccc(-c2cnc(-c3ccc(C(F)(F)F)cc3)s2)cc1
Yield: 45 %

Procedure:
A mixture of ethyl 4-[2-(4-trifluoromethylphenyl)-5-thiazolyl]benzoate (360 mg), a 1N aqueous solution of sodium hydroxide (3 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at 60 to 70° C. for 1 hour. The reaction mixture was poured into 1N hydrochloric acid, and precipitated 4-[2-(4-trifluoromethylphenyl)-5-thiazolyl]benzoic acid (150 mg, yield: 45%) was collected by filtration. The product was recrystallized from acetone-isopropyl ether to obtain pale yellow prisms. Melting point: 294 to 295° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[C:16]([C:34]([NH2:36])=[O:35])=[N:17][C:18]([C:31]([CH3:33])=[CH2:32])=[C:19]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-])=O)[CH:23]=4)[N:20]=3)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.C(O)C>[Pd].O1CCCC1>[NH2:28][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[O:21][C:19]1[N:20]=[C:15]([NH:14][C:11]2[CH:10]=[CH:9][C:8]([N:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]3)=[CH:13][CH:12]=2)[C:16]([C:34]([NH2:36])=[O:35])=[N:17][C:18]=1[CH:31]([CH3:32])[CH3:33]
Reactant: C=C(C)c1nc(C(N)=O)c(Nc2ccc(N3CCN(C)CC3)cc2)nc1Oc1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)c1nc(C(N)=O)c(Nc2ccc(N3CCN(C)CC3)cc2)nc1Oc1cccc(N)c1
Reaction time: 6 h
Yield: 65.9 %

Procedure:
To a mixture of 3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-5-(3-nitrophenoxy)-6-(prop-1-en-2-yl)pyrazine-2-carboxamide (1.13 g), ethanol (60 mL), and tetrahydrofuran (30 mL) was added 10% palladium-supported carbon (53% wet product) (1.23 g), followed by stirring for 6 hours under a hydrogen gas atmosphere (4 atm). The reaction mixture was filtered through celite and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; chloroform:methanol:28% aqueous ammonia=100:1:0.1-30:1:0.1) to obtain 5-(3-aminophenoxy)-6-isopropyl-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide (702 mg) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][CH:12]3[CH2:14][CH2:13]3)[C:6]=2[CH:5]=[CH:4][C:3]=1[C:15]1[CH:34]=[CH:33][C:18]([CH2:19][N:20]2[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]2)=[CH:17][CH:16]=1.Cl.C(=O)(O)[O-].[Na+]>ClCCl.CO.O>[Cl:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][CH:12]3[CH2:14][CH2:13]3)[C:6]=2[CH:5]=[CH:4][C:3]=1[C:15]1[CH:16]=[CH:17][C:18]([CH2:19][N:20]2[CH2:21][CH2:22][NH:23][CH2:24][CH2:25]2)=[CH:33][CH:34]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(-c3ccc4c(nnn4CC4CC4)c3Cl)cc2)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: Clc1c(-c2ccc(CN3CCNCC3)cc2)ccc2c1nnn2CC1CC1
Temperature: 0 °C

Procedure:
tert-Butyl 4-{4-[4-chloro-1-(cyclopropylmethyl)-1H-benzotriazol-5-yl]benzyl}piperazine-1-carboxylate (Example 52, 430 mg, 0.89 mmol) was dissolved in a dichloromethane (8.9 mL) and methanol (8.9 mL), cooled to 0° C. and treated with a hydrochloric acid (2.2 mL, 4 M in dioxane, 8.9 mmol). The mixture was warmed to ambient temperature and treated with hydrochloric acid (200 μL, 12 N aqueous). The mixture was stirred at ambient temperatures until complete, at which time the mixture was treated with aqueous saturated sodium bicarbonate, diluted with water and extracted with ethyl acetate (3×40 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (100:0 to 90:5; dichloromethane:methanol) to afford the product as a clear oil: 1H-NMR (400 MHz, CDCl3) δ 7.51 (1H, d, J=1.9 Hz); 7.48-7.42 (5H, m); 4.56 (2H, d, J=7.0 Hz); 3.57 (2H, s); 2.93 (5H, t, J=4.8 Hz); 2.81 (3H, t, J=4.8 Hz); 1.49-1.38 (1H, m); 0.73-0.65 (2H, m); 0.57-0.48 (2H, m) ppm; high resolution mass spectrometry (ES+) m/z 382.1796 [(M+H)+; calculated for C21H25ClN5: 382.1793].
Reaction SMILES: COC1C=CC(C[N:8]2[C:16]3[CH:15]=[C:14]([NH:17][C:18]4[N:19]=[CH:20][C:21]([C:24]#[N:25])=[N:22][CH:23]=4)[N:13]=[CH:12][C:11]=3[N:10]=[CH:9]2)=CC=1.FC(F)(F)C(O)=[O:31]>>[NH:8]1[C:16]2[CH:15]=[C:14]([NH:17][C:18]3[N:19]=[CH:20][C:21]([C:24]([NH2:25])=[O:31])=[N:22][CH:23]=3)[N:13]=[CH:12][C:11]=2[N:10]=[CH:9]1
Reactant: COc1ccc(Cn2cnc3cnc(Nc4cnc(C#N)cn4)cc32)cc1
Reactant: O=C(O)C(F)(F)F
Product: NC(=O)c1cnc(Nc2cc3[nH]cnc3cn2)cn1
Yield: 8 %

Procedure:
5-(1-(4-Methoxybenzyl)-1H-imidazo[4,5-c]pyridin-6-ylamino)pyrazine-2-carbo-nitrile (0.16 mmol) was treated overnight with trifluoroacetic acid at 80° C. The solution was evaporated to dryness and the residue was purified using preparative HPLC to give the title compound (3.23 mg, 8%). 1H NMR (d6-DMSO, 400 MHz) δ 12.68 (br s, 1H), 10.46 (br s, 1H), 8.76 (d, 1H, J=1.2 Hz), 8.72 (d, 2H, =1.2 Hz), 8.28 (br s, 2H), 7.90 (s, 1H), 7.51 (s, 1H). LCMS (2) Rt=1.02 min; m/z (ESI+) 256 (MH+), (ESI−) 254 (M−H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[NH2:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[C:22]#[N:23].C(OC(O)C)C>N1C=CC=CC=1>[C:22]([C:21]1[CH:20]=[C:19]([NH:18][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:16]#[N:17])[CH:26]=[CH:25][CH:24]=1)#[N:23]
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Reactant: N#Cc1cccc(N)c1
Agent: CCOC(C)O
Solvent: c1ccncc1
Product: COc1cc2ncc(C#N)c(Nc3cccc(C#N)c3)c2cc1OC
Yield: 88.8 %

Procedure:
A mixture of 0.5 g of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile, 0.47 g of 3-aminobenzonitrile, 0.16 ml of pyridine, and 12 ml of ethoxyethanol was stirred, under nitrogen, at reflux temperature for 22 h. The mixture was cooled and partitioned with dichloromethane and aqueous sodium bicarbonate. The organic layer was washed with water, dried and evaporated. The residue was recrystallized from ethyl acetate-hexanes to give 0.59 g of 4-[(3-cyanophenyl)amino]-6,7-dimethoxy-3-quinolinecarbonitrile as a solid, mp 285-288° C.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[NH:9][CH:8]=[C:7](C[C@@H](N)C(O)=O)[C:5]=2[CH:6]=1.O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.C[N:29](C1C=CC2N=C3C(=CC(C=C3)=[N+](C)C)SC=2C=1)C>P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[NH:9]1[C:4]2[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=2)[CH:7]=[C:8]1[NH2:29]
Reactant: CN(C)c1ccc2nc3ccc(=[N+](C)C)cc-3sc2c1
Reactant: N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: Nc1cc2ccccc2[nH]1

Procedure:
Human indoleamine 2,3-dioxygenasae (IDO) with an N-terminal His tag was expressed in E. coli and purified to homogeneity. IDO catalyzes the oxidative cleavage of the pyrrole ring of the indole nucleus of tryptophan to yield N′-formylkynurenine. The assays were performed at room temperature as described in the literature using 95 nM IDO and 2 mM D-Trp in the presence of 20 mM ascorbate, 5 μM methylene blue and 0.2 mg/mL catalase in 50 mM potassium phosphate buffer (pH 6.5). The initial reaction rates were recorded by continuously following the absorbance increase at 321 nm due to the formation of N′-formlylkynurenine (See: Sono, M., et al., 1980, J. Biol. Chem. 255, 1339-1345).
Reaction SMILES: [Na].[C:2]([C:4]1[CH:5]=[N:6][N:7]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[C:29]=2[Cl:36])[C:8]=1[N:9](C(OC1C=CC=CC=1)=O)[C:10]([O:12][C:13]1[CH:18]=CC=C[CH:14]=1)=[O:11])#[N:3].[C:37](=O)=O>C(O)(C)(C)C>[C:13]([O:12][C:10]([NH:9][C:8]1[N:7]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[C:29]=2[Cl:36])[N:6]=[CH:5][C:4]=1[C:2]#[N:3])=[O:11])([CH3:37])([CH3:18])[CH3:14]
Reactant: N#Cc1cnn(-c2ccc(Cl)c(Cl)c2Cl)c1N(C(=O)Oc1ccccc1)C(=O)Oc1ccccc1
Reactant: O=C=O
Agent: [Na]
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)Nc1c(C#N)cnn1-c1ccc(Cl)c(Cl)c1Cl

Procedure:
Sodium (0.5 g) was added to a stirred mixture of 4-cyano-5-di(phenoxycarbonyl)amino-1-(2,3,4-trichlorophenyl)pyrazole (prepared as described in Example 27; 25 g) in t-butanol (400 ml) and the mixture was heated at reflux for 15 minutes. Solid carbon dioxide pellets were then added to the cooled reaction mixture to adjust the pH to 7. The neutralized reaction mixture was filtered and the filtrate evaporated under reduced pressure to give an oil which was crystallised from ethyl acetate-n-hexane to give 5-t-butoxycarbonylamino-4-cyano-1-(2,3,4-trichlorophenyl)pyrazole (11.0 g), m.p. 140°-141° C., in the form of colourless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]23[CH2:13][CH:12]2[CH2:11][NH:10][CH2:9]3)=[CH:4][CH:3]=1.[C:14](Cl)(=[O:16])[CH3:15]>>[C:14]([N:10]1[CH2:11][CH:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)([CH2:13]2)[CH2:9]1)(=[O:16])[CH3:15]
Reactant: CC(=O)Cl
Reactant: Clc1ccc(C23CNCC2C3)cc1
Product: CC(=O)N1CC2CC2(c2ccc(Cl)cc2)C1

Procedure:
Using the method of Example 15, 1-(p-chlorophenyl)-3-azabicyclo[3.1.0]hexane (Example 1) is reacted with acetyl chloride to give 3-acetyl-1-(p-chlorophenyl)-3-azabicyclo[3.1.0]hexane and then is converted to 1-(p-chlorophenyl)-3-ethyl-3-azabicyclo[3.1.0]hexane which is obtained as a brown oil.
Reaction SMILES: C(N(CC)CC)C.CN(C)C=O.[O:13]1[CH2:18][CH2:17][N:16]([C:19]2[NH:20][N:21]3[CH2:26][C:25]4[CH2:27][NH:28][CH2:29][C:30](=[O:31])[C:24]=4[N:23]=[C:22]3[N:32]=2)[CH2:15][CH2:14]1.[C:33](Cl)(=[O:36])[CH2:34][CH3:35]>O.CN(C)P(=O)(N(C)C)N(C)C>[O:13]1[CH2:14][CH2:15][N:16]([C:19]2[NH:20][N:21]3[CH2:26][C:25]4[CH2:27][N:28]([C:33](=[O:36])[CH2:34][CH3:35])[CH2:29][C:30](=[O:31])[C:24]=4[N:23]=[C:22]3[N:32]=2)[CH2:17][CH2:18]1
Reactant: CCC(=O)Cl
Reactant: O=C1CNCC2=C1N=C1N=C(N3CCOCC3)NN1C2
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCC(=O)N1CC(=O)C2=C(C1)CN1NC(N3CCOCC3)=NC1=N2
Reaction time: 16 h
Yield: 63.2 %

Procedure:
To a mixture of 0.50 g (0.005 mole, 0.69 ml) of triethyl amine, 4 ml of dimethyl formamide, 1 ml of hexamethyl phosphoric triamide and 0.828 g (0.003 mole) of 2-morpholino-6,7,8,9-tetrahydro-pyrido[4,3-d]-1,2,4-triazolo[1,5-a]-pyrimidine-5(10H)-one are added. To the mixture 0.46 g (0.005 mole, 0.43 ml) of propionyl chloride are added under stirring and the reaction mixture is first stirred at 25° C. for six hours and a half and then allowed to stand at room temperature for 16 hours. After addition of 25 ml of water the precipitated crystals are filtered and washed with acetone. The solid is dissolved in 6 ml of hot dimethyl formamide and precipitated by adding 15 ml of acetonitrile. Thus 0.63 g of the desired compound is obtained, yield 63%, m.p.: 278°-280° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH:11][C:12]3[N:17]=[C:16]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[N:15]=[C:14]([NH:24][C:25]4[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=4)[N:13]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.Cl.[NH2:57][C@@H:58]([CH2:63][NH:64][C:65]([O:67][C:68]([CH3:71])([CH3:70])[CH3:69])=[O:66])[C:59]([O:61][CH3:62])=[O:60].CCN(C(C)C)C(C)C>CN(C=O)C>[C:68]([O:67][C:65]([NH:64][CH2:63][C@H:58]([NH:57][C:29](=[O:30])[C:28]1[CH:27]=[CH:26][C:25]([NH:24][C:14]2[N:13]=[C:12]([NH:11][C:8]3([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[CH2:9][CH2:10]3)[N:17]=[C:16]([O:18][CH2:19][C:20]([F:23])([F:21])[F:22])[N:15]=2)=[CH:33][CH:32]=1)[C:59]([O:61][CH3:62])=[O:60])=[O:66])([CH3:71])([CH3:70])[CH3:69]
Reactant: O=C(O)c1ccc(Nc2nc(NC3(c4ccc(Cl)cc4)CC3)nc(OCC(F)(F)F)n2)cc1
Reactant: COC(=O)[C@@H](N)CNC(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](CNC(=O)OC(C)(C)C)NC(=O)c1ccc(Nc2nc(NC3(c4ccc(Cl)cc4)CC3)nc(OCC(F)(F)F)n2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoic acid (50 mg) in DMF (2 mL) was added O-(benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (23.82 mg) and (S)-methyl 2-amino-3-(tert-butoxycarbonylamino)propanoate hydrochloride (18.90 mg) and iPr2NEt (0.052 ml). After stirring at rt for 4 h, the mixture was purified by preparative HPLC to give (S)-methyl 3-(tert-butoxycarbonylamino)-2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)propanoate.
Reaction SMILES: [CH2:1]([C:4]1[CH:18]=[CH:17][CH:16]=[CH:15][C:5]=1[O:6][C@@H:7]1[CH2:11][N:10]([CH2:12][CH3:13])[CH2:9][C@H:8]1[OH:14])[CH:2]=[CH2:3].[CH2:19]([N:21]=[C:22]=[O:23])[CH3:20]>C1C=CC=CC=1>[CH2:19]([NH:21][C:22]([O:14][C@H:8]1[C@H:7]([O:6][C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[CH2:1][CH:2]=[CH2:3])[CH2:11][N:10]([CH2:12][CH3:13])[CH2:9]1)=[O:23])[CH3:20]
Reactant: CCN=C=O
Reactant: C=CCc1ccccc1O[C@@H]1CN(CC)C[C@H]1O
Solvent: c1ccccc1
Product: C=CCc1ccccc1O[C@@H]1CN(CC)C[C@H]1OC(=O)NCC

Procedure:
A mixture of 7.3 g. of trans 4-(2-allylphenoxy)-1-ethyl-3-pyrrolidinol and 2.5 g. of ethylisocyanate in 30 ml. of benzene was stirred for 48 hr. The benzene was replaced by petroleum ether and the solution chilled. The yield of precipitate melting at 53-6° C. was 78%.