Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[N:2]=[C:3]([NH:6][CH:7]2[CH2:10][CH:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8]2)[NH:4][CH:5]=1.[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH:31]([C:37](=O)[CH2:38][CH2:39][CH3:40])[C:32](OCC)=[O:33])=[C:26]([F:42])[CH:25]=1)#[N:17].C(N(CC)C1C=CC=CC=1)C.Cl>>[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31]2[C:32](=[O:33])[N:6]([CH:7]3[CH2:8][CH:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:10]3)[C:3]3[N:2]([N:1]=[CH:5][N:4]=3)[C:37]=2[CH2:38][CH2:39][CH3:40])=[C:26]([F:42])[CH:25]=1)#[N:17]
Reactant: CCOC(=O)C1CC(Nc2nnc[nH]2)C1
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1F)C(=O)OCC
Agent: Cl
Solvent: CCN(CC)c1ccccc1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n(C2CC(C(=O)OCC)C2)c2ncnn12
Temperature: 180 °C
Reaction time: 48 h
Yield: 40.9 %

Procedure:
A mixture of ethyl 3-(4H-1,2,4-triazol-3-ylamino)cyclobutanecarboxylate (4.0 g), ethyl 2-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-3-oxohexanoate (12 g) and N,N-diethylaniline (15 mL) was stirred at 180° C. for 48 hr and then at room temperature for 38 hr. The reaction mixture was added to 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (4.0 g, 41%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.[N:21]([CH2:24][CH2:25][CH2:26]/[C:27](/[C:43]1O[C:45]([CH2:48][C:49]2[CH:54]=[CH:53][C:52]([F:55])=[CH:51][CH:50]=2)=[N:46][N:47]=1)=[CH:28]\[C:29]1[CH:34]=[CH:33][C:32]([N:35]2[CH:39]=[C:38]([CH3:40])[N:37]=[CH:36]2)=[C:31]([O:41][CH3:42])[CH:30]=1)=[N+]=[N-]>C1COCC1>[F:55][C:52]1[CH:53]=[CH:54][C:49]([CH2:48][C:45]2[N:21]3[CH2:24][CH2:25][CH2:26]/[C:27](=[CH:28]\[C:29]4[CH:34]=[CH:33][C:32]([N:35]5[CH:39]=[C:38]([CH3:40])[N:37]=[CH:36]5)=[C:31]([O:41][CH3:42])[CH:30]=4)/[C:43]3=[N:47][N:46]=2)=[CH:50][CH:51]=1
Reactant: COc1cc(/C=C(\CCCN=[N+]=[N-])c2nnc(Cc3ccc(F)cc3)o2)ccc1-n1cnc(C)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(/C=C2\CCCn3c(Cc4ccc(F)cc4)nnc32)ccc1-n1cnc(C)c1
Temperature: 25 °C
Yield: 88.2 %

Procedure:
Triphenylphosphine (28 mg) and water (0.3 mL) were added to a solution of 2-{4-azido-1-{1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-(E)-methylidene}butyl}-5-(4-fluorobenzyl)[1,3,4]oxadiazole (50 mg) in THF (5 mL), and the reaction solution was heated under reflux for four hours. The reaction solution was left to cool to room temperature and then concentrated under reduced pressure. A solution of the residue in acetic acid (2 mL) was heated under reflux for three hours. The reaction solution was left to cool to room temperature and then concentrated under reduced pressure. Ethyl acetate and saturated sodium bicarbonate water were added to the residue, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: ethyl acetate->ethyl acetate:methanol=5:1) to obtain 40 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[C:13]([C:22]([NH:24][CH3:25])=[O:23])=[CH:12][C:11]2=[O:26])[CH2:4][CH2:3]1.[CH3:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH:31]=O.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[CH3:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31][NH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[C:13]([C:22]([NH:24][CH3:25])=[O:23])=[CH:12][C:11]2=[O:26])[CH2:4][CH2:3]1
Reactant: Cc1cccc(C=O)c1
Reactant: CNC(=O)c1cc(=O)n(CCN2CCC(N)CC2)c2cc(OC)ccc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CNC(=O)c1cc(=O)n(CCN2CCC(NCc3cccc(C)c3)CC2)c2cc(OC)ccc12
Temperature: 25 °C
Reaction time: 0.02 h

Procedure:
370 μL of a methanol solution containing 14 mg of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxy-N-methyl-2-oxo-1,2-dihydroquinolin-4-carboxamide and 10 μL of acetic acid were added to 3.6 mg of 3-methylbenzaldehyde, and stirred at room temperature for 1 min. To the reaction mixture, 120 μL of a methanol solution containing 3.8 mg of sodium cyanoborohydride was added, and stirred at the same temperature overnight. After the solvent was removed under reduced pressure, ethyl acetate and aqueous saturated sodium hydrogen carbonate solution were added, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and extracts were combined, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Fuji Silysia Chemical Ltd., Chromatorex-NH, eluent; ethyl acetate:methanol=20:1], to give 7.6 mg of (1-(2-(4-(3-methylbenzylamino)piperidin-1-yl)ethyl)-7-methoxy-N-methyl-2-oxo-1,2-dihydroquinolin-4-carboxamide as a pale yellow foam.
Reaction SMILES: [CH:1]([CH:3]([Br:6])[CH:4]=O)=O.[CH3:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[CH:10]=1.C(O)(=O)C>C(O)C>[Br:6][C:3]1[CH:1]=[N:15][C:11]2[C:12]([CH:4]=1)=[CH:13][CH:14]=[C:9]([O:8][CH3:7])[CH:10]=2
Reactant: O=CC(Br)C=O
Reactant: COc1cccc(N)c1
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccc2cc(Br)cnc2c1
Temperature: 25 °C
Reaction time: 240 h
Yield: 20 %

Procedure:
For the synthesis of this starting compound, 1.80 g (12.3 mmol, 1.1 eq) of bromomalondialdehyde was first dissolved in 30 ml of ethanol, and 1.25 ml of m-anisidine was added. This reaction mixture is stirred over night at RT and, after the addition of acetic acid (20 ml), at 100° C. for 10 days. The solvent is subsequently removed in vacuum on a rotary evaporator, and the residual solid is partitioned between a water and an ethyl acetate phase. The aqueous phase is made alkaline with an ammonia solution, and insoluble particles were filtered off. The filtrate is extracted with ethyl acetate, and the organic phase is dried over MgSO4, filtered, and the solvent is removed in vacuum on a rotary evaporator. The product was purified by column chromatography with a mixture of hexane/ethyl acetate 8/2 as the eluent in a yield of 20% (700 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1.C(O)(=O)C>O.[Fe]>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[N:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1)[NH2:8]
Reactant: O=[N+]([O-])c1ccc(-n2cccc2)c(Cl)c1
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: Nc1ccc(-n2cccc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
A stirred mixture of 15.0 g (0.07 mole) of 1-(2-chloro-4-nitrophenyl)pyrrole and 30.0 g (0.53 mole) of iron powder in 100 ml of water was heated at reflux. During a three hour period 59.0 g (0.98 mole) of glacial acetic acid was added dropwise to the refluxing reaction mixture. Reflux was continued for one hour after complete addition. The mixture was cooled to room temperature, filtered and the filter cake rinsed with toluene. The filtrate was extracted with toluene (three 150 ml portions) and the extracts combined with the toluene rinse. The toluene solution was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure to leave an oil which solidified. The solid was purified by column chromatography using silica gel and eluting with methylene chloride, to yield 8.5 g of 3-chloro-4-(pyrrol-1-yl)aniline.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:46])[C@H:10]([CH3:45])[NH:11][C:12](=[O:44])[C@H:13]([CH2:40][CH:41]([CH3:43])[CH3:42])[N:14]([C:16](=[O:39])[C@H:17]([CH:35]([CH2:37][F:38])[CH3:36])[NH:18][C:19](=[O:34])[C@H:20]([CH2:30][CH:31]([CH3:33])[CH3:32])[N:21](C(OC(C)(C)C)=O)[CH3:22])[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:46])[C@H:10]([CH3:45])[NH:11][C:12](=[O:44])[C@H:13]([CH2:40][CH:41]([CH3:43])[CH3:42])[N:14]([C:16](=[O:39])[C@H:17]([CH:35]([CH2:37][F:38])[CH3:36])[NH:18][C:19](=[O:34])[C@H:20]([CH2:30][CH:31]([CH3:33])[CH3:32])[NH:21][CH3:22])[CH3:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C[C@@H](C(=O)N[C@H](C(=O)N(C)[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)OCc1ccccc1)C(C)CF)N(C)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN[C@@H](CC(C)C)C(=O)N[C@H](C(=O)N(C)[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)OCc1ccccc1)C(C)CF
Temperature: -15 °C
Reaction time: 16 h
Yield: 989 %

Procedure:
To a stirred solution of 650 mg (0.001 mole) of Boc-N-methyl-L-leucyl-4-fluoro-L-valyl-N-methyl-L-leucyl-L-alanine benzyl ester in 10 ml of dry methylene chloride and cooled at 10° C. was added 6.5 ml of trifluoroacetic acid, which was previously cooled at -15° C. The reaction was stirred for 16 hours, then carefully poured into a mixture of 7.7 g. of sodium bicarbonate, ice, and 75 ml of methylene chloride with stirring. The organic layer was extracted with 3×20 ml of saturated sodium bicarbonate solution, then dried over magnesium sulfate. The solvent was removed in vacuo leaving the product as a stiff oil, which weighed 540 mg. The yield is 989% of theory and the FAB m.s. showed a molecular ion peak at 551.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[CH3:19][N:20]([CH3:26])[CH:21]1[CH2:25][CH2:24][NH:23][CH2:22]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][N:23]3[CH2:24][CH2:25][CH:21]([N:20]([CH3:26])[CH3:19])[CH2:22]3)=[CH:8][C:6]=2[N:7]=1
Reactant: CN(C)C1CCNC1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Product: CN(C)C1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)C1
Yield: 61 %

Procedure:
2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carboxaldehyde 10 was reacted with 3-(dimethylamino)pyrrolidine using standard reductive amination conditions. The resulting crude oil was triturated with diethyl ether and methanol to give [1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-pyrrolidin-3-yl]dimethyl-amine as a solid (61% yield), which was reacted with 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine according to General Procedure A. The resulting solid was triturated with diethyl ether and methanol to give 341 as an off white solid (86% yield). NMR (CDCl3, 400 MHz), 1.76-1.82 (1H, m), 2.20-2.10 (1H, m), 2.23 (6H, s), 2.48 (2H, dd, J=7.4 and 8.5), 2.66-2.17 (2H, m), 2.81-2.95 (3H, m), 3.88-3.90 (4H, m), 3.90-3.99 (2H, m), 4.03-4.06 (4H, m), 5.23 (2H, br s), 7.28 (1H, s), 9.30 (2H, s). MS: (ESI+): MH+=441
Reaction SMILES: [N:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4](=[O:11])[NH:3][N:2]=1.C(=O)([O-])[O-].[K+].[K+].[Br:18][CH:19](Br)[CH3:20]>CN(C)C=O.O>[Br:18][CH2:19][CH2:20][N:3]1[C:4](=[O:11])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:1]=[N:2]1
Reactant: O=c1[nH]nnc2ccccc12
Reactant: CC(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2ccccc2nnn1CCBr
Reaction time: 0.33 h
Yield: 68.3 %

Procedure:
To a solution of the compound 1,2,3-benzotriazin-4(3H)-one (500 mg) (commercially available) in dimethylformamide (13 ml) was added anhydrous potassium carbonate (2.8 g) and stirred for 20 minutes. To it was added dibromoethane (2 g) and stirred the reaction mixture first at room temperature for few minutes and then at 60° C. for 2 hours. The solid thus obtained was filtered and the filterate was concentrated under reduced pressure. The residue thus obtained was diluted with water and extracted with ethylacetate. The organic layer was separated, washed with water and brine and dried over anhydrous sodium sulphate. The solvent was evaporated under reduced pressure and the residue thus obtained was purified by column chromatography using 20% ethyl acetate in hexane as eluant to furnish the title compound (590 mg).
Reaction SMILES: [NH2:1][C:2]1[C:18]([Br:19])=[CH:17][C:5]2[C:6]([C:12]([O:14]CC)=[O:13])=[C:7]([CH:9]3[CH2:11][CH2:10]3)[O:8][C:4]=2[CH:3]=1.O[Li].O.Cl>O1CCOCC1.O>[NH2:1][C:2]1[C:18]([Br:19])=[CH:17][C:5]2[C:6]([C:12]([OH:14])=[O:13])=[C:7]([CH:9]3[CH2:11][CH2:10]3)[O:8][C:4]=2[CH:3]=1
Reactant: CCOC(=O)c1c(C2CC2)oc2cc(N)c(Br)cc12
Agent: Cl
Agent: [Li]O
Solvent: C1COCCO1
Solvent: O
Product: Nc1cc2oc(C3CC3)c(C(=O)O)c2cc1Br
Yield: 97.6 %

Procedure:
To a solution of ethyl 6-amino-5-bromo-2-cyclopropylbenzofuran-3-carboxylate (7 g, 22.5 mmol) in 1,4-dioxane and H2O (50 mL and 50 mL) was added LiOH.H2O (4.6 g, 112 mmol). The reaction mixture was refluxed for 2 hours, and then 400 mL H2O was added to the reaction mixture. After acidifying to pH 4˜5 with HCl, the resulting solid were filtered to give the product of 6-amino-5-bromo-2-cyclopropylbenzofuran-3-carboxylic acid (6.5 g, yield: 97%). 1H-NMR (400 MHz, MeOD) δ 7.86 (s, 1H), 6.85 (s, 1H), 4.31 (s, 2H), 2.93˜3.00 (m, 1H), 1.19˜1.22 (m, 2H), 1.13˜1.16 (m, 2H). MS (M+H)+: 296/298.
Reaction SMILES: [F:1][C:2]1([F:10])[CH2:7][CH2:6][CH:5]([CH2:8][NH2:9])[CH2:4][CH2:3]1.Cl[C:12]1[CH:13]=[CH:14][C:15]2[N:16]([C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]([F:31])([F:30])[F:29])[CH:22]=3)=[CH:19][N:20]=2)[N:17]=1.CCN(C(C)C)C(C)C.[F-].[Cs+]>CS(C)=O>[F:1][C:2]1([F:10])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]([F:29])([F:31])[F:30])[CH:22]=4)=[CH:19][N:20]=3)[N:17]=2)[CH2:4][CH2:3]1
Reactant: FC(F)(F)Oc1cccc(-c2cnc3ccc(Cl)nn23)c1
Reactant: NCC1CCC(F)(F)CC1
Agent: [Cs+]
Agent: [F-]
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: FC1(F)CCC(CNc2ccc3ncc(-c4cccc(OC(F)(F)F)c4)n3n2)CC1
Temperature: 120 °C
Reaction time: 5 h
Yield: 0.8 %

Procedure:
To the solution of compound (4,4-difluorocyclohexyl)methanamine (100 mg, 6 mmol) and compound 6-chloro-3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazine (190 mg, 6 mmol) in 3 mL DMSO was added DIEA (0.21 mL, 12 mmol) and 10 mg CsF, the solvent was stirred for 5 h at 120° C., Then the mixture was purified by HPLC to afford the compound N-((4,4-difluorocyclohexyl)methyl)-3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazin-6-amine (21 mg, 10%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.[C:14]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([O:8][CH3:14])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: COc1cc(Cl)c(Cl)cc1C(=O)O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Cl)c(Cl)cc1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 4,5-dichloro-2-methoxybenzoic acid (8.2 g, 37 mmol) and K2CO3 (11.8 g, 111 mmol) in DMF (100 mL), CH3I (6.3 g, 44 mmol) was added dropwise and the resulting mixture was stirred at room temperature for 16 h. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate=10:1) to afford the desired product.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](=[O:22])[C:8]2[CH2:16][C:15](=[N:17]C(OC)=O)[S:14][C:9]=2[N:10]([CH2:12][CH3:13])[CH:11]=1)=[O:5])C.[OH-:23].[Na+].Cl>O>[CH2:12]([N:10]1[CH:11]=[C:6]([C:4]([OH:3])=[O:5])[C:7](=[O:22])[C:8]2[CH2:16][C:15](=[N:17][O:23][CH2:6][C:4]([OH:5])=[O:3])[S:14][C:9]1=2)[CH3:13]
Reactant: CCOC(=O)c1cn(CC)c2c(c1=O)CC(=NC(=O)OC)S2
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCn1cc(C(=O)O)c(=O)c2c1SC(=NOCC(=O)O)C2
Reaction time: 3 h
Yield: 40 %

Procedure:
To the solution obtained in Example V containing 4,7-dihydro-7-ethyl-2-carbomethoxyimino-4-oxo-thieno[2,3-b]pyridine-5-carboxylic acid ethyl ester was added 0.15 g (3.7 mmols) of sodium hydroxide in 5 ml of water. The medium was maintained under stirring for 3 hours at room-temperature. The precipitate formed was filtered out, washed with ethanol and then with ethyl ether. The product so obtained was then taken up in 20 ml of water and the solution was acidified with concentrated hydrochloric acid. The precipitate so formed was filtered out, washed with water and then with ethanol. After drying, 4,7-dihydro-7-ethyl-2-carboxymethoxyimino-4-oxo-thieno[2,3-b]pyridine-5-carboxylic acid was obtained in a yield of 40%.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[O:55]1[CH:59]=[CH:58][N:57]=[C:56]1[C:60](O)=[O:61]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([C:60]([C:56]2[O:55][CH:59]=[CH:58][N:57]=2)=[O:61])[CH2:49][CH2:48]1
Reactant: O=C(O)c1ncco1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC1CCN(C(=O)c2ncco2)CC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 31 %

Procedure:
The desired compound was prepared according to the procedure of Example A27 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 1,3-oxazole-2-carboxylic acid as starting materials in 31% yield. LCMS for C28H28ClN8O3 (M+H)+: m/z=559.2.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl.C(N(CC)CC)C.[C:13]([C:15]1[CH:16]=[C:17]([CH:22]=[C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=1)[C:18]([O:20][CH3:21])=[O:19])#[N:14].Cl>CN(C=O)C>[CH2:26]([O:25][C:23]1[CH:22]=[C:17]([CH:16]=[C:15]([C:13]2[NH:14][N:3]=[N:2][N:1]=2)[CH:24]=1)[C:18]([O:20][CH3:21])=[O:19])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: COC(=O)c1cc(C#N)cc(OCc2ccccc2)c1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OCc2ccccc2)cc(-c2nnn[nH]2)c1
Temperature: 100 °C
Reaction time: 6 h

Procedure:
Sodium azide (1.5 g) and triethylamine hydrochloride (3.2 g) were added to a DMF (70 mL) solution of methyl 3-cyano-5-benzyloxybenzoate (2.07 g), and stirred at 100° C. for 6 hours and then overnight at room temperature. With cooling with ice, diluted hydrochloric acid was added to it, the precipitate was taken out through filtration, washed with water, and dried to obtain the title compound as a white powder.
Reaction SMILES: [C:1]1([NH:7][C:8](=[NH:10])[SH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:11](Br)[CH3:12].C(OC(=O)C)C>C(O)C>[CH2:11]([S:9][C:8](=[NH:10])[NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:12]
Reactant: N=C(S)Nc1ccccc1
Reactant: CCBr
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCSC(=N)Nc1ccccc1

Procedure:
4 gram N-phenylisothiourea (33 mmol) and 5 ml ethyl bromide were refluxed for 10 hours in ethanol. Again 5 ml ethyl bromide was added. The reaction course was followed by thin layer chromatography (ethylacetate/petroleumether 3:7). Subsequently the solvent was evaporated and the residue crystallised from ethanol/ethylacetate.
Reaction SMILES: B(O)(O)[C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[CH:6][CH:7]=1.Br[C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH:22]=[CH:21][CH:20]=[N:19]2)=[CH:14][CH:13]=1.CC#N.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH:22]=[CH:21][CH:20]=[N:19]3)=[CH:14][CH:13]=2)=[CH:3][CH:4]=1
Reactant: Brc1ccc(-n2cccn2)cc1
Reactant: Cc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC#N
Product: Cc1ccc(-c2ccc(-n3cccn3)cc2)cc1
Temperature: 130 °C
Yield: 56 %

Procedure:
Prepared using General Procedure 16. A stirring mixture of p-tolylboronic acid (391 mg, 2.88 mmol) and 1-(4-bromophenyl)-1H-pyrazole (535 mg, 2.40 mmol) INT-84 in THF (4 mL), MeCN (4 mL) and sodium carbonate (1 M aqueous) (4.8 mL, 4.80 mmol) was de-gassed by bubbling through N2 gas. PdCl2dppf (88 mg, 0.120 mmol) was added and the reaction mixture further de-gassed. The reaction was heated at 130° C. for 30 min in a microwave. The mixture was cooled to room temperature, poured onto water (100 mL) and extracted with EA/THF (2×50/10 mL). The combined organic extracts were washed with brine (50 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by chromatography (EA/hexanes) to afford 315 mg (56%) of 1-(4′-methyl-[1,1′-biphenyl]-4-yl)-1H-pyrazole INT-85. LCMS-ESI (m/z) calculated for C16H14N2: 234; found 235 [M+H]+, tR=2.60 min (Method 10).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([F:19])=[C:6]([CH:13]([O:17][CH3:18])[C:14]([OH:16])=O)[CH:7]=[C:8]([O:10][CH2:11][CH3:12])[CH:9]=1)[CH3:2].[NH2:20][CH2:21][C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=1>>[C:21]([C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH:27][C:14](=[O:16])[CH:13]([C:6]2[CH:7]=[C:8]([O:10][CH2:11][CH3:12])[CH:9]=[C:4]([O:3][CH2:1][CH3:2])[C:5]=2[F:19])[O:17][CH3:18])=[CH:24][CH:23]=1)#[N:20]
Reactant: N#Cc1ccc(CN)cc1
Reactant: CCOc1cc(OCC)c(F)c(C(OC)C(=O)O)c1
Product: CCOc1cc(OCC)c(F)c(C(OC)C(=O)NCc2ccc(C#N)cc2)c1

Procedure:
(RS)-(3,5-Diethoxy-2-fluoro-phenyl)-methoxy-acetic acid was coupled with 4-aminomethyl benzonitrile according to general procedure B to give (RS)-N-(4-cyano-benzyl)-2-(3,5-diethoxy-2-fluoro-phenyl)-2-methoxy-acetamide. Light yellow oil. MS 387.3 ([M+H]+)
Reaction SMILES: [CH3:1][C:2]([CH3:19])([C:11]#[C:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:3]#[C:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[NH3:20]>CCCCCC>[CH:12](=[C:11]1[C:2]([CH3:19])([CH3:1])[CH2:3][C:4]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)=[N:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N
Reactant: CC(C)(C#Cc1ccccc1)C#Cc1ccccc1
Solvent: CCCCCC
Product: CC1(C)CC(c2ccccc2)=NC1=Cc1ccccc1
Yield: 88 %

Procedure:
2-benzylidene-3,3-dimethyl-5-phenyl-3,4-dihydro-2H-pyrrole was prepared by reacting (3,3-dimethylpenta-1,4-diyne-1,5-diyl)dibenzene with ammonia in the presence of 10 mol % of catalyst E (165° C., 18 h). Compound 6f was the major product of the reaction (60%) which had a yield of 88%. Single crystals suitable for an X-ray diffraction study were obtained by slow evaporation of a hexane solution. mp: 101-103° C. (n-hexane) an Ortep diagram is shown in FIG. 6; 1H NMR (300 MHz, CDCl3) δ=1.37 (6H, s, CH3), 2.99 (2H, s, CH2), 5.98 (1H, s, CH), 7.24 (1H, t, J=7.4 Hz, CH), 7.41 (2H, t, J=7.7 Hz, CH), 7.49 (1H, d, J=1.3 Hz, CH), 7.51 (2H, d, J=2.3 Hz, CH), 8.05-8.10 (4H, m, CH); 13C NMR (75 MHz, CDCl3) δ=29.6 (CH3), 41.9 (Cq), 49.3 (CH2), 115.6 (CH), 126.5 (CH), 128.4 (CH), 128.4 (CH), 129.6 (CH), 131.3 (CH), 134.8 (Cq), 137.6 (Cq), 165.9 (NCqCH), 174.4 (N═CqCH2); HRMS (ESI): 262.1594 [(M+H)+, 262.1596 (C19H20N)].