Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([NH:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:3]=1.[CH3:26][S-:27].[Na+]>>[CH3:26][S:27][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([NH:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:3]=1
Reactant: Clc1nc(NCCc2ccccc2)c2ncn(C3CCCCO3)c2n1
Reactant: C[S-]
Agent: [Na+]
Product: CSc1nc(NCCc2ccccc2)c2ncn(C3CCCCO3)c2n1
Yield: 92.2 %

Procedure:
The title compound was prepared by a similar method to preparation 7 from 2-chloro-N-phenethyl-9-tetrahydro-2H-pyran-2-yl-9H-purin-6-amine (17.5 g, 49 mmol) (preparation 41) and sodium thiomethoxide (7.2 g, 75 mmol). This gave the title compound (16.7 g) as a white solid.
Reaction SMILES: [Br:1][C:2]1[S:6][CH:5]=[C:4]([C:7]([NH:9][C@H:10]([C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=2)[CH3:11])=[O:8])[C:3]=1[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=1>CCOC(C)=O.CCCCCC>[Br:1][C:2]1[S:6][CH:5]=[C:4]([C:7]([NH:9][C@H:10]([C:12]2[CH:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[CH:20][CH:21]=2)[CH3:11])=[O:8])[C:3]=1[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)c2csc(Br)c2Cc2cccc(Cl)c2)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C[C@H](NC(=O)c1csc(Br)c1Cc1cccc(Cl)c1)c1ccc(C(=O)O)cc1

Procedure:
Methyl 4-[(S)-1-({[5-bromo-4-(3-chlorobenzyl)-3-thienyl]carbonyl}amino)ethyl]benzoate from Example 4, Step 1 (25.0 mg, 0.0507 mmol) was reacted under conditions similar to Example 1, Step 11. After trituration of the crude product in 1:1 EtOAc/hexane, the desired product was obtained as an off-white solid. MS (−APCI): m/z 476 (M−1)−.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:30]=[CH:29][C:15]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([CH3:28])([CH3:27])[C:22]([O:24]CC)=[O:23])=[CH:14][CH:13]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[OH-].[Na+]>CO.O>[N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:30]=[CH:29][C:15]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([CH3:27])([CH3:28])[C:22]([OH:24])=[O:23])=[CH:14][CH:13]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCOC(=O)C(C)(C)CCCCOc1ccc(OCCCCCn2ccnc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(CCCCOc1ccc(OCCCCCn2ccnc2)cc1)C(=O)O
Yield: 82.2 %

Procedure:
To a solution of 3 g ethyl 6-[p-[5-(1-imidazolyl)pentyloxy]phenoxy]-2,2-dimethylhexanoate in 15 ml methanol, was added a solution of 580 mg sodium hydroxide in 6 ml water, and the mixture was heated under reflux for 5 hours. Methanol was distilled off under reduced pressure, and dilute hydrochloric acid was added to the remaining aqueous soluiton to lower its pH down to about 5. The solid which separated out was collected by filtration, washed with water, and recrystallized from methanol, affording 2.3 g of 6-[p-[5-(1-imidazolyl)pentyloxy]phenoxy]-2,2-dimethylhexanoic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:18]([CH3:20])[CH3:19])[N:10]=[C:11]3[C:17]=2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[CH:4][CH:3]=1.[CH:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:21]([N:14]1[CH2:13][CH2:12][C:11]2[C:17](=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[N:9]([CH:18]([CH3:20])[CH3:19])[N:10]=2)[CH2:16][CH2:15]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=Cc1ccccc1
Reactant: CC(C)n1nc2c(c1-c1ccc(F)cc1)CCNCC2
Product: CC(C)n1nc2c(c1-c1ccc(F)cc1)CCN(Cc1ccccc1)CC2

Procedure:
The title compound (115 mg) was prepared from 3-(4-fluoro-phenyl)-2-isopropyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene (Example 190) and benzaldehyde as in Example 35. MS (ESI): exact mass calculated for C23H26FN3, 363.21; found, m/z 364.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.58-7.55 (m, 2H), 7.53-7.51 (m, 3H), 7.37-7.33 (m, 2H), 7.31-7.27 (m, 2H), 4.52 (s, 2H), 4.34 (m, 1H), 3.80-3.75 (m, 1H), 3.68-3.64 (m, 1H), 3.35-3.16 (m, 4H), 2.83-2.80 (m, 2H), 1.38 (t, J=6.7 Hz, 6H).
Reaction SMILES: [C:1]1([C:7]2([CH2:13]/[CH:14]=[CH:15]/[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.[Pd]>[C:1]1([C:7]2([CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)/C=C/CC1(c2ccccc2)CCCCC1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CCCC1(c2ccccc2)CCCCC1
Reaction time: 1 h

Procedure:
To a solution of (E)-ethyl 4-(1-phenylcyclohexyl)but-2-enoate (140 mg, 0.514 mmol) in MeOH (15 mL) was added about 50 mg of 10% Pd/C and the mixture was stirred under H2 (30 psi) for 1 hr. The catalyst was filtered off and the filtrate was evaporated to give ethyl 4-(1-phenylcyclohexyl)butanoate as an oil. 1H NMR (400 MHz, CDCl3) δ ppm 7.31 (2 H, s), 7.30 (2 H, s), 7.13-7.20 (1 H, m), 4.06 (2 H, q, J=7.03 Hz), 2.04-2.13 (4 H, m), 1.33-1.63 (10 H, m), 1.24-1.32 (2 H, m), 1.20 (3 H, t, J=7.14 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][CH2:10][CH2:11][CH2:12][OH:13].O[CH:15](S([O-])(=O)=O)[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Na+]>C(O)C>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]2[N:9]([CH2:10][CH2:11][CH2:12][OH:13])[C:15]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:1][C:2]=2[CH:7]=1
Reactant: O=S(=O)([O-])C(O)Cc1ccccc1
Reactant: Nc1cc(Cl)ccc1NCCCO
Agent: [Na+]
Solvent: CCO
Product: OCCCn1c(Cc2ccccc2)nc2cc(Cl)ccc21

Procedure:
A mixture of 30 parts of 3-[(2-amino-4-chlorophenyl)amino]-1-propanol, 44.8 parts of sodium α-hydroxybenzeneethanesulfonate and 120 parts of ethanol is stirred and refluxed for 30 minutes. The reaction mixture is evaporated and the residue is taken up in water. The oily product is extracted with trichloromaethane. The extract is dried, filtered and evaporated, yielding 5-chloro-2-(phenylmethyl)-1H-benzimidazole-1-propanol as a residue.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[NH:26]1[CH2:30][CH2:29][C@H:28]([OH:31])[CH2:27]1>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([N:26]3[CH2:30][CH2:29][C@H:28]([OH:31])[CH2:27]3)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: O[C@H]1CCNC1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(N3CC[C@H](O)C3)c2c1

Procedure:
The title compound was prepared in analogy to Example 15-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and (3S)-pyrrolidin-3-ol. MS obsd. (ESI+) [(M+H)+] 424, 1H NMR (400 MHz, CD3OD) δ ppm 7.90 (dd, J=7.83, 1.26 Hz, 1 H), 7.80-7.72 (m, 2 H), 7.54 (td, J=7.52, 1.39 Hz, 1 H), 7.43 (d, J=8.59 Hz, 1 H), 7.34 (td, J=7.71, 1.01 Hz, 1 H), 7.23 (dd, J=8.59, 1.77 Hz, 1 H), 6.05 (s, 1 H), 5.06 (s, 2 H), 4.55-4.43 (m, 1 H), 3.84 (dd, J=10.48, 4.42 Hz, 2 H), 3.58-3.43 (m, 4 H), 3.35 (s, 2 H), 2.35 (s, 3 H), 2.11 (dd, J=8.84, 4.55 Hz, 1 H), 2.06-1.97 (m, 1 H).
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.[Na+].[Cl-].[CH3:11][NH:12][CH3:13]>>[CH3:11][N:12]([CH3:13])[CH2:2][CH:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1
Reactant: BrCC1CCOCC1
Reactant: CNC
Agent: [Cl-]
Agent: [Na+]
Product: CN(C)CC1CCOCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-(Bromomethyl)tetrahydro-2H-pyran (0.50 g, 2.8 mmol) was dissolved in dimethylamine (40% in water, 5 mL) and the reaction mixture was stirred at RT for 18 hours. The mixture was saturated with NaCl and extracted into Et2O (2×). The combined organic extract was dried (K2CO3), filtered and concentrated in vacuo to give the title compound as a colourless oil (0.40 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N+:4]([O-])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]>[Pd].CO>[CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1cc[n+]([O-])cc1C
Agent: [Pd]
Solvent: CO
Product: COc1ccncc1C
Yield: 90.2 %

Procedure:
A mixture of 4 g (28.8 mmol) 3-methyl-4-methoxy pyridine N-oxide (prepared according to the method described in Kohl, Bernhard et al; J. Med. Chem.; 1992; 1049–1057) and 1.1 mg of 5% palladium on charcoal in 50 ml of methanol is hydrogenated at 20 atms at room temperature for 12 hours (2*6 hours). Filtration through celite, and evaporation gave 3,2 g (90%) of a light green oil.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=S)[CH3:2].[C:11]([NH:19][NH2:20])(=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(O)CCC>O>[CH3:2][C:1]1[N:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:19][N:20]=1
Reactant: NNC(=O)c1ccccc1
Reactant: CC(=S)Nc1ccccc1
Solvent: CCCCO
Solvent: O
Product: Cc1nnc(-c2ccccc2)n1-c1ccccc1
Yield: 18 %

Procedure:
First, 5.04 g of thioacetanilide, 5.44 g of benzoylhydrazine, and 50 mL of 1-butanol were put in a round-bottom flask provided with a reflux pipe, and the air in the flask was replaced with argon. This reaction container was subjected to irradiation with a microwave (2.45 GHz, 100 W) for 2 hours and 45 minutes to perform heating. Then, water was added to this solution and an organic layer was extracted with dichloromethane. The obtained organic layer was washed with water and dried over magnesium sulfate. After the drying, the solution was filtered. The solvent of this solution was distilled off, and the resulting residue was purified by silica gel column chromatography which uses ethyl acetate as a developing solvent, so that 3-methyl-4,5-diphenyl-4H-1,2,4-triazole (abbreviation: HMptz) was obtained (pale yellow powder, 18% yield). The synthesis scheme of Step 1 is shown below.
Reaction SMILES: [CH2:1]([C:8]1([N:26]([CH3:28])[CH3:27])[CH2:13][CH2:12][C:11]([C:14]2[NH:15][C:16]3[C:21]([C:22]=2[CH3:23])=[CH:20][C:19]([O:24][CH3:25])=[CH:18][CH:17]=3)=[CH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>Br.CCO.C(OCC)(=O)C>[CH2:1]([C:8]1([N:26]([CH3:28])[CH3:27])[CH2:9][CH2:10][CH:11]([C:14]2[NH:15][C:16]3[C:21]([C:22]=2[CH3:23])=[CH:20][C:19]([O:24][CH3:25])=[CH:18][CH:17]=3)[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc2[nH]c(C3=CCC(Cc4ccccc4)(N(C)C)CC3)c(C)c2c1
Agent: Br
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc2[nH]c(C3CCC(Cc4ccccc4)(N(C)C)CC3)c(C)c2c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
(±)-N-[1-Benzyl-4-(5-methoxy-3-methyl-1H-indol-2-yl)cyclohex-3-enyl]-N,N-dimethylamine (1.97 g, 5.26 mmol) was suspended in HBr/glacial acetic acid (33% HBr, 30 ml). Sn powder (3.12 g, 26.3 mmol) was then added to the mixture in portions in the course of 30 min. When the addition had ended, the reaction mixture was stirred at RT for a further 48 h.—For working up, the mixture was diluted with EtOH (20 ml) and concentrated to dryness on a rotary evaporator. The residue which remained was rendered basic by addition of 5 N NaOH (100 ml). The aqueous mixture obtained was extracted with methylene chloride (4×20 ml). The combined organic phases were washed with water (50 ml), dried over Na2SO4 and then concentrated. The residue obtained (1.7 g) was dissolved in ethyl acetate (10 ml). The mixture was placed in a refrigerator for 2 h for crystallization. 1-Benzyl-4-(5-methoxy-3-methyl-1H-indol-2-yl)-N,N-dimethylcyclohexanamine (less polar diastereoisomer) was separated off by filtration in a yield of 500 mg (25%) as a beige solid. The mother liquor was concentrated and the residue was purified by column chromatography [silica gel 60 G (150 g); EtOAc (1,000 ml)]. The polar product was obtained in a yield of 134 mg (7%) as a brown oil.
Reaction SMILES: [CH3:1][C:2]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])[CH3:3].C(N(CC)CC)C.[S:16]1[C:20]([CH2:21][CH:22]([OH:25])[C:23]#[CH:24])=[CH:19][C:18]2[CH:26]=[CH:27][CH:28]=[CH:29][C:17]1=2.[NH4+].[Cl-]>CN(C1C=CN=CC=1)C.ClCCl>[S:16]1[C:20]([CH2:21][CH:22]([O:25][Si:5]([C:2]([CH3:4])([CH3:3])[CH3:1])([CH3:7])[CH3:6])[C:23]#[CH:24])=[CH:19][C:18]2[CH:26]=[CH:27][CH:28]=[CH:29][C:17]1=2
Reactant: C#CC(O)Cc1cc2ccccc2s1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CC(Cc1cc2ccccc2s1)O[Si](C)(C)C(C)(C)C
Reaction time: 17 h
Yield: 69.9 %

Procedure:
DMAP (2.306 g, 18.9 mmol), TBSCl (11.502 g, 76.3 mmol) and triethylamine (5.25 mL, 37.7 mmol) were added to a solution of 9-4 (7.67 g, 37.9 mmol) in dichloromethane (120 mL). After 17 h, 150 mL of saturated NH4Cl solution was added and the layers were separated. The aqueous layer was extracted with dichloromethane (3×100 mL) and the combined organic solution was dried (Na2SO4), filtered and evaporated. Purification by flash chromatography on silica gel (4% ethyl acetate/hexanes) gave 9-5 (8.38 g, 26.5 mmol, 70%).
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[C@H:12]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:22]=[C:23]([NH:27][C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])[CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:16]1.NN>C(O)C>[NH2:3][C@H:12]([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:22]=[C:23]([NH:27][C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])[CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:16]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@@H](c3ccccc3)N3C(=O)c4ccccc4C3=O)CC2)c1
Agent: NN
Solvent: CCO
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](N)c3ccccc3)CC2)c1
Yield: 84.3 %

Procedure:
A mixture of N-(3-{1-[(3S)-3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (4.60 g, 9.06 mmol) and hydrazine (3.62 g, 72.4 mmol) in ethanol (150 mL) was refluxed for 12 h. The resulting white precipitate was filtered out and the filtrate was concentrated under vacuum. The residue was washed with CH2Cl2/EtOAc (1:1, 3×50 mL) and the combined organic fractions were concentrated in vacuo to give the desired product (2.90 g, 95%). 1H NMR (400 MHz, CDCl3) δ 7.45 (s, 1H), 7.39-7.30 (m, 6H), 7.29-7.19 (m, 2H), 6.95 (d, 1H, J=7.2), 4.01 (t, 1H, J=6.8 Hz), 3.04 (t, 2H, J=10.6 Hz), 2.62-2.30 (m, 6H), 2.05-1.70 (m, 8H), 1.24 (d, 6H, J=6.8 Hz); ESMS m/e: 380.4 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([CH3:19])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]2[N:15]=[N:16][N:17]=[C:7]2[C:6]=1[NH2:18].[C:20](OC(OCC)OCC)(=O)C.[Na]>O>[CH3:1][CH:2]([CH3:19])[CH2:3][N:4]1[C:5]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]3[N:15]=[N:16][N:17]=[C:7]3[C:6]=2[N:18]=[CH:20]1
Reactant: CC(C)CNc1c(N)c2nnnn2c2ccccc12
Reactant: CCOC(OCC)OC(C)=O
Agent: [Na]
Solvent: O
Product: CC(C)Cn1cnc2c1c1ccccc1n1nnnc21

Procedure:
N5-(2-Methylpropyl)tetrazolo[1,5-a]quinoline-4,5-diamine (0.2 g, 0.78 mmole, Example 16) was combined with diethoxymethyl acetate (2 mL) and heated on a steam bath for 3 hours. Water (10 mL) and 10% sodium hdyroxide (2 mL) were added and the reaction mixture was heated on a steam bath for 1 hour. A solid was isolated by filtration then recrystallized from methanol/ethyl acetate to provide 0.16 g of 6-(2-methylpropyl)-6H-imidazo[4,5-c]tetrazolo[1,5-a]quinoline as a white crystalline solid, m.p. 210-212° C. Analysis: Calculated for C14H14N6; %C, 63.14; %H, 5.30; %N, 31.56; Found: %C, 63.12; %H, 5.32; %N, 31.61.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[C:7]([CH2:9][N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:8]=1)#[CH:2].[N:15]1([C:20]2[CH:21]=[C:22]([NH:30][C:31](=[O:40])[C:32]3[CH:37]=[CH:36][C:35]([CH3:38])=[C:34](I)[CH:33]=3)[CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=2)[CH:19]=[CH:18][N:17]=[CH:16]1.C(N(C(C)C)CC)(C)C>CN(C=O)C.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.[Cu]I>[N:15]1([C:20]2[CH:21]=[C:22]([NH:30][C:31](=[O:40])[C:32]3[CH:37]=[CH:36][C:35]([CH3:38])=[C:34]([C:2]#[C:1][C:3]4[CH:4]=[N:5][CH:6]=[C:7]([CH2:9][N:10]5[CH2:14][CH2:13][CH2:12][CH2:11]5)[CH:8]=4)[CH:33]=3)[CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=2)[CH:19]=[CH:18][N:17]=[CH:16]1
Reactant: C#Cc1cncc(CN2CCCC2)c1
Reactant: Cc1ccc(C(=O)Nc2cc(-n3ccnc3)cc(C(F)(F)F)c2)cc1I
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)Nc2cc(-n3ccnc3)cc(C(F)(F)F)c2)cc1C#Cc1cncc(CN2CCCC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-Ethynyl-5-(pyrrolidin-1-ylmethyl)pyridine (0.52 mmol), 0.245 g (0.52 mmol) of N-(3-(1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-iodo-4-methylbenzamide (as prepared above), 0.030 g (0.026 mmol) of Pd(PPh3)4, 0.007 g (0.039 mmol) of CuI, and 0.14 mL (0.78 mmol) of diisopropylethylamine in 3.0 mL of DMF is stirred at ambient temperature overnight under an atmosphere of N2. The reaction mixture is concentrated and the crude product is purified by silica gel flash chromatography (eluted with 10% EtOAc/hexanes, then 100% EtOAc, then 10% MeOH/EtOAc) to provide the title product.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:9]2[O:10][C:11]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20]Br)=[CH:16][CH:15]=3)=[N:12][N:13]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.C([O-])([O-])=O.[Na+].[Na+].[CH3:28][NH2:29]>O>[Br:1][C:2]1[N:3]=[C:4]([C:9]2[O:10][C:11]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][NH:29][CH3:28])=[CH:16][CH:15]=3)=[N:12][N:13]=2)[C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: CN
Reactant: Nc1ncc(Br)nc1-c1nnc(-c2ccc(CBr)cc2)o1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CNCc1ccc(-c2nnc(-c3nc(Br)cnc3N)o2)cc1
Temperature: 60 °C
Yield: 85 %

Procedure:
5-bromo-3-(5-(4-(bromomethyl)phenyl)-1,3,4-oxadiazol-2-yl)pyrazin-2-amine (100 mg, 0.2433 mmol) and Na2CO3 (77.36 mg, 0.7299 mmol) were suspended in and treated with methylamine (182.4 μL of 2 M, 0.36 mmol). The reaction was heated at 60° C. for 10 min and then additional methylamine (426.0 μL of 2 M, 0.86 mmol) was then added and the reaction heated at 60° C. or another 10 min. The reaction was cooled, diluted with water (5 mL extracted into dichloromethane (3×5 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to yield 5-bromo-3-[5-[4-(methylaminomethyl)phenyl]-1,3,4-oxadiazol-2-yl]pyrazin-2-amine (74.7 mg, 85.34% yield) as a yellow solid; MS (ES+) 362.3
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[ClH:13].[NH:14]([C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH2:25])(=[O:24])=[O:23])=[CH:18][CH:17]=1)[NH2:15]>>[ClH:13].[NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:15][NH:14][C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH2:25])(=[O:23])=[O:24])=[CH:18][CH:17]=1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Reactant: Nc1ccc2c(c1)C(=O)C(=O)N2
Agent: Cl
Product: Nc1ccc2c(c1)C(=NNc1ccc(S(N)(=O)=O)cc1)C(=O)N2

Procedure:
The title compound was prepared from 5-amino-1H-indole-2,3-dione and 4-hydrazinobenzenesulfonamide hydrochloride according to Procedure G: 1H NMR (DMSO-d6): δ 6.95 (d, J=8 Hz, 1H), 7.2 (d, J=8 Hz, 1H), 7.26 (s, 2H), 7.46 (s, 1H), 7.5 (d, J=8 Hz, 2H), 7.8 (d, J=8 Hz, 2H), 9.7 (br s, 3H), 11.2 (s, 1H), 12.8 (s, 1H); APCI-MS m/z 330.2 (M−H)−.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:17]1[S:18][C:19]([C:23]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[C:29]([F:34])[CH:28]=2)=[O:24])=[C:20]([CH3:22])[N:21]=1>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:17]2[S:18][C:19]([C:23]([NH:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[C:29]([F:34])[CH:28]=3)=[O:24])=[C:20]([CH3:22])[N:21]=2)[C:11](=[O:15])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc(Br)sc1C(=O)NCc1ccc(F)c(F)c1
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Product: Cc1nc(-n2ccc(OCc3ccccc3)cc2=O)sc1C(=O)NCc1ccc(F)c(F)c1
Yield: 85 %

Procedure:
Following the procedure as described in Example 3, making variations only as required to use 4-(benzyloxy)pyridin-2(1H)-one in place of 4-aminopyridin-2(1H)-one to react with 2-bromo-N-(3,4-difluorobenzyl)-4-methylthiazole-5-carboxamide, the title compound was obtained as a colorless solid in 85% yield: mp 225-227° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.67 (d, J=7.9 Hz, 1H), 7.43-7.35 (m, 5H), 7.17-7.05 (m, 3H), 6.35-6.19 (m, 2H), 6.05 (s, 1H), 5.03 (s, 2H), 4.52 (s, 2H), 2.67 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 167.4, 162.3, 162.0, 153.5, 152.6, 152.1, 151.5, 148.8, 135.0, 134.5, 131.5, 128.8, 127.7, 123.7, 121.8, 117.6, 116.9, 104.1, 97.3, 70.8, 42.9, 17.3; MS (ES+) m/z 468.3 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:4]=1[C:5](Cl)=[O:6].[CH3:14][C:15]1[C:24]2[C:19](=[C:20]([O:29][CH3:30])[C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=2)[CH2:18][CH2:17][N:16]=1.C(N(CC)CC)C>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:4]=1[C:5]([N:16]1[CH2:17][CH2:18][C:19]2[C:24](=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[C:20]=2[O:29][CH3:30])[C:15]1=[CH2:14])=[O:6]
Reactant: COc1cc2c(c(OC)c1OC)CCN=C2C
Reactant: COc1ccc(OC)c(C(=O)Cl)c1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: C=C1c2cc(OC)c(OC)c(OC)c2CCN1C(=O)c1cc(OC)ccc1OC
Reaction time: 2 h
Yield: 88 %

Procedure:
A solution of compound 45 (746 mg, 3.7 mmol) in anhydrous benzene (2 mL) was slowly added at room temperature to a solution of compound 44 (880 mg, 3.7 mmol) in anhydrous benzene (10 mL) containing triethylamine (568 mg, 5.6 mmol, 0.78 mL). The resulting solution was heated at reflux with stirring under Ar for 2 h. White NH4Cl precipitated and was removed by filtration. The filtrate was evaporated to dryness and the residue was subjected to flash chromatography (ether:triethylamine, 99:1 by volume, silica gel 230-300 mesh) to give compound 46 as an oil (1.3 g, 87.8%): 1H NMR (CDCl3, 200 MHz) δ6.87 (s, 1H), 6.85 (d, 1H, J=10 Hz), 6.80 (d, 1H, J=3 Hz), 6.70 (d, 1H, J=10 Hz), 5.21 (s, br 1H), 4.55 (s, br, 1H), 3.90 (s, 6H), 3.88 (s, 3H), 3.84 (s, 3H), 3.75 (s, 3H), 3.41 (s, br, 2H), 2.88 (t, 2H, J=6 Hz). CIMS (isobutane) m/e 400 (MH+, 100).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([C:13]3[N:18]=[C:17]([N:19]([CH3:26])[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:16]=[C:15]([NH2:27])[N:14]=3)[N:9]=2)=[CH:4][CH:3]=1.[CH:28]([NH2:31])([CH3:30])[CH3:29].CCN(C(C)C)C(C)C>CCO>[CH3:26][N:19]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:17]1[N:16]=[C:15]([NH2:27])[N:14]=[C:13]([C:10]2[N:9]=[C:8]([C:5]3[CH:6]=[N:7][C:2]([NH:31][CH:28]([CH3:30])[CH3:29])=[CH:3][CH:4]=3)[O:12][N:11]=2)[N:18]=1
Reactant: CN(c1ccccc1)c1nc(N)nc(-c2noc(-c3ccc(Cl)nc3)n2)n1
Reactant: CC(C)N
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(C)Nc1ccc(-c2nc(-c3nc(N)nc(N(C)c4ccccc4)n3)no2)cn1
Yield: 27.3 %

Procedure:
A mixture of 6-[5-(6-chloropyridin-3-yl)-1,2,4-oxadiazol-3-yl]-2-N-methyl-2-N-phenyl-1,3,5-triazine-2,4-diamine (Intermediate 135, 0.100 g, 0.263 mmol), isopropylamine (0.087 mL, 1.052 mmol), DIPEA (0.091 mL, 0.525 mmol) in EtOH (1 mL) was heated 3 times under microwave conditions (first treatment: 100 W, 130 C, 40 min; second treatment: 100 W, 130 C, 45 min; third treatment: 100W, 130 C, 45 min). The reaction mixture was cooled down and concentrated under vacuum. The resulting dark oil was purified by preparative HPLC, to afford the title compound (29 mg, 27%).