Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]3[CH:17]=[CH:16][O:15][C:14]=3[C:18](=O)/[CH:19]=[CH:20]/N(C)C)=[CH:10][CH:11]=2)[CH2:6][CH2:5]1.C(=O)(O)O.[NH2:29][C:30]([NH2:32])=[NH:31].[OH-].[Na+]>O1CCOCC1.O>[CH3:1][O:2][N:3]=[C:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]3[CH:17]=[CH:16][O:15][C:14]=3[C:18]3[CH:19]=[CH:20][N:29]=[C:30]([NH2:32])[N:31]=3)=[CH:10][CH:11]=2)[CH2:6][CH2:5]1
Reactant: N=C(N)N
Reactant: CON=C1CCc2cc(-c3ccoc3C(=O)/C=C/N(C)C)ccc21
Agent: O=C(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CON=C1CCc2cc(-c3ccoc3-c3ccnc(N)n3)ccc21
Temperature: 100 °C
Yield: 67.1 %

Procedure:
A solution of the product of Step 2 (0.30 g, 0.93 mmol) in 1,4dioxane (6 ml) was treated with a solution of guanidine carbonate (0.33 g, 1.86 mmol) and sodium hydroxide (0.1 7 g, 4.1 mmol) in water (2 ml). The mixture was heated at 100° C. for 4 hours. After cooling to room temperature, water was added and the mixture extracted into ethyl acetate (2×). The organic layers were combined and washed with saturated brine, dried (MgSO4) and concentrated in vacuo. The residue was triturated with dichloromethane and the resulting solid filtered to afford the title compound (200 mg, 67%); MS(ES+) m/e 321 [M+H]+.
Reaction SMILES: [CH:1]([S:3]([CH:6]=[CH2:7])(=[O:5])=[O:4])=[CH2:2].[CH2:8](N(CC)CC)C.[NH2:15][CH2:16][CH2:17][CH2:18][NH:19][C@:20]12[CH2:55][CH2:54][C@@H:53]([C:56]([CH3:58])=[CH2:57])[C@@H:21]1[C@@H:22]1[C@@:35]([CH3:38])([CH2:36][CH2:37]2)[C@@:34]2([CH3:39])[C@@H:25]([C@:26]3([CH3:52])[C@@H:31]([CH2:32][CH2:33]2)[C:30]([CH3:41])([CH3:40])[C:29]([C:42]2[CH:51]=[CH:50][C:45]([C:46]([O:48]C)=[O:47])=[CH:44][CH:43]=2)=[CH:28][CH2:27]3)[CH2:24][CH2:23]1>CCO>[CH3:8][C:50]1[CH:51]=[C:42]([C:29]2[C:30]([CH3:40])([CH3:41])[C@H:31]3[C@:26]([CH3:52])([CH2:27][CH:28]=2)[C@@H:25]2[C@:34]([CH3:39])([C@@:35]4([CH3:38])[C@H:22]([CH2:23][CH2:24]2)[C@H:21]2[C@H:53]([C:56]([CH3:58])=[CH2:57])[CH2:54][CH2:55][C@:20]2([NH:19][CH2:18][CH2:17][CH2:16][N:15]2[CH2:7][CH2:6][S:3](=[O:5])(=[O:4])[CH2:1][CH2:2]2)[CH2:37][CH2:36]4)[CH2:33][CH2:32]3)[CH:43]=[CH:44][C:45]=1[C:46]([OH:48])=[O:47]
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCCN)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: C=CS(=O)(=O)C=C
Reactant: CCN(CC)CC
Solvent: CCO
Product: C=C(C)[C@@H]1CC[C@]2(NCCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)c(C)c6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 100 °C
Yield: 83.4 %

Procedure:
Vinylsulfonylethene (5.90 mg, 0.050 mmol) and triethylamine (6.96 μl, 0.050 mmol) were added to a mixture of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-aminopropylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (15 mg, 0.025 mmol) in EtOH (1 mL). The reaction mixture was heated to 100° C. for 3 hours. The reaction mixture was concentrated under reduced pressure to provide the desired product as a brown solid (15 mg, 76%). LCMS: m/e 719.46 (M+H)+, 3.68 min (method 10).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:11](=O)[CH3:12])[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(O)(=O)C.O>C1C=CC=CC=1>[OH:1][N:2]=[C:3]([C:11](=[N:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:12])[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5]
Reactant: CC(=O)C(=NO)C(=O)OC(C)(C)C
Reactant: Nc1ccccc1
Solvent: O
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: CC(=Nc1ccccc1)C(=NO)C(=O)OC(C)(C)C
Reaction time: 5 h

Procedure:
A solution of tert-butyl 2-hydroxyimino-3-oxobutyrate (130 g), aniline (76 ml) and acetic acid (14 ml) in benzene (1.2 l) was refluxed with Dean Stark water separator for 5 hours. The resulting solution was cooled and washed with 5% aqueous sodium bicarbonate solution and water. After being dried over magnesium sulfate, the organic solvent was evaporated in vacuo. The residue was triturated with a mixture of n-hexane (300 ml) and diisopropyl ether (100 ml). The precipitate was collected by filtration, washed with n-hexane to give tert-butyl 2-hydroxyimino-3-phenyliminobutyrate (71.2 g).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([CH2:19][NH:20][OH:21])=[C:9]2[CH3:22])=[O:7])=[CH:4][CH:3]=1.[CH3:25][N:26]([CH3:30])[C:27](Cl)=[O:28].C([O-])(=O)C.[Na+]>>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([CH2:19][N:20]([C:27]([N:26]([CH3:30])[CH3:25])=[O:28])[OH:21])=[C:9]2[CH3:22])=[O:7])=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1)c(CNO)c(C)n2C(=O)c1ccc(Cl)cc1
Reactant: CN(C)C(=O)Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Product: COc1ccc2c(c1)c(CN(O)C(=O)N(C)C)c(C)n2C(=O)c1ccc(Cl)cc1
Yield: 30 %

Procedure:
According to the procedure of Example 62, 1-(4-chlorobenzoyl)-N-hydroxy-5-methoxy-2-methyl-lH-indole-3-methanamine is reacted with 14 eq of dimethylcarbamoyl chloride and 3.5 eq of sodium acetate (added in portions). The crude product is purified by column chromatography (silica gel, 1:4/ethyl acetate:methylene chloride). Recrystallization from methylene chloride:hexane, followed by column chromatography (silica gel, ether) and recrystallization from methanol:water gives pure 1-(4-chlorobenzoyl)-N-[(dimethylamino)carbonyl]-N-hydroxy-5-methoxy-2-methyl-lH-indole-3-methanamine (30%); mp 173°-174° C.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([NH:11][NH2:12])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.C(O)C.[Cl:23][C:24]1[N:29]=[C:28](Cl)[C:27]([CH:31]=O)=[C:26]([Cl:33])[N:25]=1>O>[Cl:33][C:26]1[N:25]=[C:24]([Cl:23])[N:29]=[C:28]2[N:11]([CH:8]3[CH2:9][CH2:10][C:5]4([O:4][CH2:3][CH2:2][O:1]4)[CH2:6][CH2:7]3)[N:12]=[CH:31][C:27]=12
Reactant: NNC1CCC2(CC1)OCCO2
Reactant: O=Cc1c(Cl)nc(Cl)nc1Cl
Solvent: O
Solvent: CCO
Solvent: CCN(CC)CC
Product: Clc1nc(Cl)c2cnn(C3CCC4(CC3)OCCO4)c2n1
Reaction time: 0.07 h
Yield: 70.8 %

Procedure:
(1,4-Dioxa-spiro[4.5]dec-8-yl)-hydrazine (46 g, 368 mL of above solution) was cooled in an ice bath, then triethylamine (47 mL) and ethanol (368 mL) were added. When the internal temperature reached 7.6° C., 2,4,6-trichloro-pyrimidine-5-carbaldehyde (32 g, synthesized by method of WO 02/066482) was added as a solid over 1.5 min. The internal temperature jumped to 12.6° C., and continued to rise to 17° C. during 4 min. After stirring a total of 28 min, water (367 mL) was added and the slurry was filtered. The cake was washed well twice with water (300 mL), then hexane (300 mL) and air dried over house vacuum overnight. This gave a damp cake that was washed twice with hexane (400 mL). Air-drying over house vacuum over weekend gave 35.29 g (70.8%) of 4,6-dichloro-1-(1,4-dioxa-spiro[4.5]dec-8-yl)-1H-pyrazolo[3,4-d]pyrimidine, containing ˜6.5% of 2,4,6-Trichloro-pyrimidine-5-carbaldehyde. It was important to have a minimal amount of 2,4,6-trichloro-pyrimidine-5-carbaldehyde, which consumes 2 equivalents of 8-oxa-3-aza-bicyclo[3.2.1]octane in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:15]=[C:14]([NH:16][C:17]3[CH:22]=[C:21]([N+:23]([O-])=O)[CH:20]=[CH:19][C:18]=3[CH3:26])[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]>CC(O)=O.CO.[Fe]>[NH2:23][C:21]1[CH:20]=[CH:19][C:18]([CH3:26])=[C:17]([NH:16][C:14]2[CH:15]=[C:10]([NH:9][C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=3)[N:11]=[CH:12][N:13]=2)[CH:22]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1Nc1cc(Nc2ccc(F)c(Cl)c2)ncn1
Agent: [Fe]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1ccc(N)cc1Nc1cc(Nc2ccc(F)c(Cl)c2)ncn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22.3 %

Procedure:
A mixture of 4-(3-chloro-4-fluorophenyl)-6-chloropyrimidin-4-ylamine (IR-4) (1.2 g, 4.6 mmol), 2-methyl-5-nitroaniline (0.85 g, 5.5 mmol) and 1 mL of concentrated HCl in 10 mL of n-butanol was heated at 120° C. for 16 h. With stirring, 5 mL of EtOAc was added to the reaction mixture. The light yellow colored product that precipitated was filtered and dried under vacuum to give N-(3-chloro-4-fluorophenyl)-N′-(2-methyl-5-nitrophenyl)pyrimidine-4,6-diamine. MS (APCI) (m/z): 374/376 (M+1). A mixture of N-(3-chloro-4-fluorophenyl)-N′-(2-methyl-5-nitrophenyl)pyrimidine-4,6-diamine (0.55 g, 1.5 mmol) and iron powder (35 mesh, 0.5 g, 5 eq) in 5 mL of HOAc and 2 mL of MeOH was heated at reflux for 2 h. The solvent was removed in vacuo and the dark colored residue was mixed with 150 mL of CH2Cl2 and 15 mL of sat. K2CO3 solution and was stirred at room temperature for 30 min. The organic layer was dried (MgSO4), was concentrated, and was then purified by flash chromatography (silica gel, MeOH/NH4OH/CH2Cl2) to afford 0.115 g of N-(5-amino-2-methylphenyl)-N′-(3-chloro-4-fluorophenyl)pyrimidine-4,6-diamine as a light colored solid. (Int-F) MS (m/z): 344/346 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:14](=[O:15])[CH:13]=[CH:12][C:11]([C:16]([OH:18])=O)=[CH:10]1.[NH2:19][C:20]1[CH:21]=[C:22]([NH:27][C:28]([CH:30]2[CH2:32][CH2:31]2)=[O:29])[CH:23]=[CH:24][C:25]=1[CH3:26].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[CH:30]1([C:28]([NH:27][C:22]2[CH:23]=[CH:24][C:25]([CH3:26])=[C:20]([NH:19][C:16]([C:11]3[CH:12]=[CH:13][C:14](=[O:15])[N:9]([C:3]4[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])[CH:10]=3)=[O:18])[CH:21]=2)=[O:29])[CH2:31][CH2:32]1
Reactant: Cc1ccc(NC(=O)C2CC2)cc1N
Reactant: O=C(O)c1ccc(=O)n(-c2c(Cl)cccc2Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)C2CC2)cc1NC(=O)c1ccc(=O)n(-c2c(Cl)cccc2Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 51.9 %

Procedure:
To a solution of 1-(2,6-dichlorophenyl)-6-oxo-1,6-dihydro-3-pyridinecarboxylic acid (30 mg) in DMF (0.6 mL) were added N-(3-amino-4-methylphenyl)cyclopropanecarboxamide (30 mg), HATU (60 mg) and iPr2NEt (62 mg) successively, and the mixture was stirred under a nitrogen atmosphere at room temperature for 16 hr. The reaction mixture was diluted with EtOAc (3 mL), and the resulting mixture was washed with 1 M HCl (3 mL×2), saturated aqueous NaHCO3 (3 mL×2) and brine successively, dried over MgSO4 and evaporated in vacuo. The residue was triturated with 10% MeOH in CH2Cl2, and the precipitates produced were collected by filtration to give N-{5-[(cyclopropylcarbonyl)amino]-2-methylphenyl}-1-(2,6-dichlorophenyl)-6-oxo-1,6-dihydro-3-pyridinecarboxamide (25 mg).
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].CO[C:7](=[O:15])[C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=1.[Cl-].[NH4+].O1CC[CH2:20][CH2:19]1>>[Br:14][C:11]1[CH:10]=[CH:9][C:8]([C:7]([OH:15])([CH2:1][CH3:2])[CH2:19][CH3:20])=[CH:13][CH:12]=1
Reactant: COC(=O)c1ccc(Br)cc1
Reactant: C1CCOC1
Reactant: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Product: CCC(O)(CC)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
Ethylmagnesium bromide (3 M solution in diethyl ether, 77.5 mL, 233 mmol) was added to a solution of 4-bromo-benzoic acid methyl ester (20 g, 93 mmol) in tetrahydrofuran (220 mL) in a nitrogen atmosphere at 0° C., and the mixture was stirred at 0° C. for 30 minutes. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give the target compound as a colorless oil (22.1 g, 98%).
Reaction SMILES: [Mg].Br[CH2:3][CH:4]1[CH2:6][CH2:5]1.C1(C[Mg]Br)CC1.[CH3:13][C:14]1[C:18]([C:19]2[CH:20]=[C:21]([C:31]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=3)=[O:32])[C:22]3[N:26]=[C:25]([O:27]CC)[NH:24][C:23]=3[CH:30]=2)=[C:17]([CH3:39])[O:16][N:15]=1>C1COCC1>[CH3:13][C:14]1[C:18]([C:19]2[CH:20]=[C:21]([C:31]([OH:32])([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=3)[CH2:6][CH2:5][CH:4]=[CH2:3])[C:22]3[NH:26][C:25](=[O:27])[NH:24][C:23]=3[CH:30]=2)=[C:17]([CH3:39])[O:16][N:15]=1
Reactant: BrCC1CC1
Reactant: CCOc1nc2c(C(=O)c3ccccn3)cc(-c3c(C)noc3C)cc2[nH]1
Agent: Br[Mg]CC1CC1
Agent: [Mg]
Solvent: C1CCOC1
Product: C=CCCC(O)(c1ccccn1)c1cc(-c2c(C)noc2C)cc2[nH]c(=O)[nH]c12
Temperature: 65 °C
Reaction time: 0.17 h

Procedure:
Magnesium metal (20 mg, 0.82 mmol) was taken up in THF (1.5 mL) and (bromomethyl)cyclopropane (100 mg, 0.71 mmol) was added dropwise and the reaction was heated to 65° C. for 1 hr. (Cyclopropylmethyl)magnesium bromide (0.5 M, 0.83 mL, 0.41 mmol) was then added dropwise to a solution of (6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazol-4-yl)(pyridin-2-yl)methanone (50 mg, 0.14 mmol) in dry THF (1.4 mL) which was cooled to 0° C. Reaction mixture was allowed to stir for 10 mins, quenched with water and extracted three times with EtOAc. Combined organic layers were washed once with water and concentrated. Residue was dissolved in a mixture of EtOH (1.5 mL) and 4.0M HCl/dioxane (0.75 mL) and heated for 2 hours at 65° C. Reaction was then concentrated and purified by reverse-phase HPLC to afford the desired product as a white powder.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[N:8]([CH2:17]O)[N:7]=1)[CH3:2].P(Br)(Br)[Br:21]>CCOCC>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[N:8]([CH2:17][Br:21])[N:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1nn(CO)c(=O)c2ccccc12
Reactant: BrP(Br)Br
Solvent: CCOCC
Product: CCOC(=O)Cc1nn(CBr)c(=O)c2ccccc12
Yield: 60.4 %

Procedure:
A solution of ethyl-3-hydroxymethyl-4-oxo-3-H-phthalazin-1-ylacetate (13.1 g), phosphorous tribromide (13.5 g) and anhydrous ether (250 ml) was stirred overnight at room temperature. It was then poured onto water (200 ml). The organic layer was collected, washed again with water (3×100 ml) and then dried over anhydrous sodium sulfate. The dried organic extract was evaporated to dryness and the resulting crude solid was purified by chromatography on silica gel, eluting with 95% CH2Cl2- 5% ethyl acetate (percents by volume) to obtain the title compound (yield: 9.8 g; m.p. 96° C.).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:10])[CH:9]=1)[CH:5]=O.[OH:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([OH:21])=[O:20])=[CH:14][CH:13]=1.C([O-])(=O)C.[K+].C(OC(=O)C)(=O)C>O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:18]([C:15]2[CH:16]=[CH:17][C:12]([OH:11])=[CH:13][CH:14]=2)[C:19]([OH:21])=[O:20])[CH:7]=[C:8]([CH3:10])[CH:9]=1
Reactant: Cc1cc(C)cc(C=O)c1
Reactant: O=C(O)Cc1ccc(O)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: Cc1cc(C)cc(C=C(C(=O)O)c2ccc(O)cc2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 41.2 %

Procedure:
To a mixture of 43 (3.23 g, 24 mmol), 4-hydroxyphenylacetic acid (3.66 g, 24 mmol) and potassium acetate (2.83 g, 28 mmol) was added acetic anhydride (100 mL). The mixture was heated to reflux for 4 h, cooled to room temperature, and then poured over water (400 mL). After stirring for 1.5 h, a solid gum settled to the bottom and the supernatant was decanted. To the residue was added THF (100 mL) and 1N NaOH (150 mL) and the mixture was stirred for 30 min. The mixture was acidified with 1N HCl (200 mL) and the product was extracted into ethyl acetate (300 mL), washed with water (300 mL), brine (300 mL), dried (MgSO4), filtered and concentrated in vacuo. The crude solid was crystallized in toluene to yield 2.65 g (42%) of a pale yellow solid 44.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[C:15]1(=[O:21])[O:20][C:18](=[O:19])[CH2:17][CH2:16]1.[N+](C1C=CC=CC=1)([O-])=O.[Cl-].[Al+3].[Cl-].[Cl-]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([C:15](=[O:21])[CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: O=C1CCC(=O)O1
Reactant: COc1ccc(-c2ccccc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: COc1ccc(-c2ccc(C(=O)CCC(=O)O)cc2)cc1
Reaction time: 15 h

Procedure:
A 50 g. portion of p-methoxybiphenyl and 30 g. of succinic anhydride are mixed in 600 ml. of nitrobenzene and cooled to about 5° C. A 73 g. portion of aluminum chloride is added in portions keeping the temperature at about 5° C. The mixture is then stirred for 15 hours and allowed to stand at room temperature. The mixture is poured into ice and then steam distilled until no more nitrobenzene comes over. The residue solidifies and is dissolved in 1,250 ml. of water containing 63 g. sodium carbonate. The solution is boiled with charcoal, filtered and the filtrate is chilled. The precipitate is filtered at room temperature and the gummy mixture is acidified with HCl and cooled. The precipitate is triturated with 50% acetic acid and the insoluble portion is recovered by filtration giving 4'-methoxy-γ-oxo-4-biphenyl-butyric acid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16](=[O:30])[C:17]3[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[C:19]([O:25][CH2:26][CH:27]4[CH2:29][CH2:28]4)[CH:18]=3)[CH2:10][CH2:9]2)[CH:5]=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:39]2[CH:40]=[C:41]([C:45]3[N:46]([CH2:50][O:51][CH2:52][CH2:53][Si:54]([CH3:57])([CH3:56])[CH3:55])[CH:47]=[CH:48][N:49]=3)[CH:42]=C[CH:44]=2)O1.C([O-])([O-])=O.[Na+].[Na+].CC#[N:67].O>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:27]1([CH2:26][O:25][C:19]2[CH:18]=[C:17]([CH:22]=[C:21]([O:23][CH3:24])[CH:20]=2)[C:16]([NH:15][CH2:14][CH:11]2[CH2:10][CH2:9][N:8]([C:6]3[N:67]=[C:4]([C:5]4[CH:44]=[CH:39][CH:40]=[C:41]([C:45]5[N:46]([CH2:50][O:51][CH2:52][CH2:53][Si:54]([CH3:57])([CH3:56])[CH3:55])[CH:47]=[CH:48][N:49]=5)[CH:42]=4)[N:3]=[CH:2][N:7]=3)[CH2:13][CH2:12]2)=[O:30])[CH2:29][CH2:28]1
Reactant: COc1cc(OCC2CC2)cc(C(=O)NCC2CCN(c3ccnc(Cl)n3)CC2)c1
Reactant: CC1(C)OB(c2cccc(-c3nccn3COCC[Si](C)(C)C)c2)OC1(C)C
Reactant: CC#N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: COc1cc(OCC2CC2)cc(C(=O)NCC2CCN(c3ncnc(-c4cccc(-c5nccn5COCC[Si](C)(C)C)c4)n3)CC2)c1
Temperature: 150 °C
Reaction time: 0.17 h

Procedure:
To a solution of N-((1-(4-chloro-1,3,5-triazin-2-yl)piperidin-4-yl)methyl)-3-(cyclopropylmethoxy)-5-methoxybenzamide (Example 31, step v, 150 mg, 0.35 mmol) in CH3CN H2O (4 ml, 3/1) were added 2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (Example 9, 140 mg, 0.35 mmol), Na2CO3 (73 mg, 0.70 mmol) and Pd(PPh3)2Cl2 (12 mg, 0.018 mmol) under a nitrogen atmosphere. The reaction mixture was stirred at 150° C. for 10 minutes in a microwave reactor. After cooling to room temperature the mixture was filtered, the filtrate dried over Na2SO4 and the solvents were removed under reduced pressure. The residue was purified by using prep HPLC to give 3-(cyclopropylmethoxy)-5-methoxy-N-((1-(4-(3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)phenyl)-1,3,5-triazin-2-yl)piperidin-4-yl)methyl)benzamide (35 mg) as a solid.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:4][N:5]1[C:9](=[O:10])[C:8]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]2[C:6]1=[O:15].N12CCCN=C1CCCCC2>CS(C)=O>[Br:1][CH:2]=[C:3]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:4][N:5]1[C:9](=[O:10])[C:8]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]2[C:6]1=[O:15]
Reactant: O=C1c2ccccc2C(=O)N1CC(Br)(CBr)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CS(C)=O
Product: O=C1c2ccccc2C(=O)N1CC(=CBr)c1ccccc1
Temperature: 0 °C
Yield: 64.3 %

Procedure:
A solution of 1,2-dibromo-2-phenyl-3-phthalimidopropane (1.27 g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.51 g) in dimethyl sulfoxide (DMSO, 50 ml) is heated at 90° for 16 hours. The solution is cooled, diluted with ice-water, and exhaustively extracted with ether. The orange oil (0.98 g) is chromatographed on silica gel (75 g) with 20% ethyl acetate in light petroleum as eluent to give a colorless mass which is crystallized from n-hexane/dichloromethane to give 1-bromo-2-phenyl-3-phthalimidopropene (0.66 g): colorless plates; m.p. 128°-129°;
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:5]=1[C:6]([NH2:8])=[NH:7].C1O[C:17]2([CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)OC1.CCOCC>C(O)C.Cl>[ClH:1].[ClH:1].[F:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:4]2[C:5]=1[C:6]([NH2:8])=[N:7][C:17]1([CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)[NH:3]2
Reactant: N=C(N)c1c(N)cccc1F
Reactant: C1CC2(CCN1)OCCO2
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: NC1=NC2(CCNCC2)Nc2cccc(F)c21
Yield: 169.3 %

Procedure:
To a solution of 2-amino-6-fluorobenzamidine dihydrochloride (Example C, 226 mg, 1 mmol) and 4-piperidone ethylene ketal (143 mg, 1 mmol) in dry ethanol (10 ml) was added IN HCl in ether (1 ml, 1 mmol) and the resulting mixture was heated at reflux for 36 h. The solid which separated on cooling was collected by filtration and recrystallised from ethanol to give the title compound (260 mg) as yellow crystals, m.p. 305°-307° C. (dec.).
Reaction SMILES: [C:1](O)(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH3:6].[OH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]#[C:17][C:18]2[S:22][C:21]([C:23]#[N:24])=[CH:20][CH:19]=2)=[CH:12][CH:11]=1>ClCCl.CN(C)C1C=CN=CC=1>[CH2:1]([O:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]#[C:17][C:18]2[S:22][C:21]([C:23]#[N:24])=[CH:20][CH:19]=2)=[CH:14][CH:15]=1)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH3:6]
Reactant: CCC/C=C/C(=O)O
Reactant: N#Cc1ccc(C#Cc2ccc(O)cc2)s1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCC/C=C/COc1ccc(C#Cc2ccc(C#N)s2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 96.5 %

Procedure:
A solution of N,N-dicyclohexylcarbodiimide (0.22 g) in dichloromethane (10 cm3) is added to a solution of (E)-hex-2-enoic acid (0.10 g), 1-(4-hydroxyphenyl)-2-(2-cyanothiophen-5-yl)acetylene (0.32 g), 4-(dimethylamino)pyridine (0.04 g) in dichloromethane (20 cm3), cooled in an ice bath (0° C.) under an atmosphere of nitrogen. The reaction mixture is stirred overnight, filtered to remove precipitated material and the filtrate is evaporated down under reduced pressure. The crude product is purified by column chromatography on silica gel using a 9:1 petroleum ether (40-60° C.)/ethyl acetate mixture as eluent, followed by recrystallisation from ethanol to yield 1-(4-[(E)-hex-2-enyloxy]phenyl)-2-(2-cyanothiophen-5-yl)acetylene (0.26 g).