Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][C:9](=[O:31])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:12][CH:11]=1.[CH3:32][I:33]>>[I-:33].[CH3:32][N+:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][C:9](=[O:31])[C:10]1[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:14][CH:15]=1
Reactant: CI
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)NCc2ccccn2)cc1
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)NCc2cccc[n+]2C)cc1
Product: [I-]

Procedure:
A mixture of 1.0 g of product from Example 4 and 7.33 ml of methyl iodide is heated, in a dark sealed tube, at 100°-120° C. for 22 hours. The cooled reaction mixture is concentrated in vacuo and recrystallized 2 times from methyl alcohol to give 1.15 g of the desired product as light yellow microneedles.
Reaction SMILES: [S:1]1[C:5]([C:6]2[N:7]=[N:8][C:9](Cl)=[CH:10][CH:11]=2)=[CH:4][C:3]2[CH:13]=[CH:14][CH:15]=[CH:16][C:2]1=2.[CH3:17][N:18]1[C:23]([CH3:25])([CH3:24])[CH2:22][CH:21]([NH2:26])[CH2:20][C:19]1([CH3:28])[CH3:27].CCN(C(C)C)C(C)C>C(O)CCC.CCOC(C)=O>[S:1]1[C:5]([C:6]2[N:7]=[N:8][C:9]([NH:26][CH:21]3[CH2:20][C:19]([CH3:27])([CH3:28])[N:18]([CH3:17])[C:23]([CH3:25])([CH3:24])[CH2:22]3)=[CH:10][CH:11]=2)=[CH:4][C:3]2[CH:13]=[CH:14][CH:15]=[CH:16][C:2]1=2
Reactant: CN1C(C)(C)CC(N)CC1(C)C
Reactant: Clc1ccc(-c2cc3ccccc3s2)nn1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CN1C(C)(C)CC(Nc2ccc(-c3cc4ccccc4s3)nn2)CC1(C)C
Temperature: 180 °C
Yield: 16 %

Procedure:
To a suspension of 3-(benzo[b]thiophen-2-yl)-6-chloropyridazine (100 mg, 0.41 mmol) in n-butanol (2 mL) in a 2 mL microwave vial was added 1,2,2,6,6-pentamethylpiperidin-4-amine (276 mg, 1.62 mmol) and DIPEA (0.14 mL, 0.81 mmol). The reaction vessel was sealed and heated via microwave radiation for 180 min at 180° C. The crude reaction mixture was diluted in EtOAc. The organic layer was washed with water (5×), brine, dried over MgSO4, filtered and concentrated. The crude product was purified via HPLC to give 25 mg of 6-(benzo[b]thiophen-2-yl)-N-(1,2,2,6,6-pentamethylpiperidin-4-yl)pyridazin-3-amine. LCMS Rt=0.54 min (LCMS method Q); (M+1)=381.1. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.73-7.82 (m, 1H), 7.64-7.73 (m, 1H), 7.54 (d, J=9.1 Hz, 1H), 7.53 (s, 1H), 7.21-7.34 (m, 2H), 6.56 (d, J=9.3 Hz, 1H), 4.55 (d, J=7.8 Hz, 1H), 4.14-4.32 (m, 1H), 2.20 (s, 3H), 1.93 (dd, J=12.4, 3.8 Hz, 2H), 1.30 (apparent t, J=12.1 Hz, 2H), 1.07 (s, 6H), 1.10 (s, 6H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH:8](Br)[CH:9]([Br:13])[N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1.N1C=CC=CC=1>C1CCCCC1>[N+:10]([C:9]([Br:13])=[CH:8][C:5]1[CH:4]=[CH:3][CH:2]=[CH:7][CH:6]=1)([O-:12])=[O:11]
Reactant: O=[N+]([O-])C(Br)C(Br)c1ccc(Cl)cc1
Solvent: C1CCCCC1
Solvent: c1ccncc1
Product: O=[N+]([O-])C(Br)=Cc1ccccc1

Procedure:
To a refluxing solution of 1-(4-chlorophenyl)-1,2-dibromo-2-nitroethane (from example 1) in cyclohexane (200 mL) is added a solution of pyridine (6 mL, 74 mmoles) in cyclohexane (200 mL) over a 1 hour period. The mixture is refluxed for an additional hour. The refluxing mixture is then extracted with approximately 200 mL of dilute HCl and 2×200 mL H2O. The organic layer is dried over magnesium sulfate (anhydrous) filtered, and the solvent removed from the filtrate by evaporation to yield a yellow solid. The solid is recrystallized from cyclohexane to give beta-nitrobromostyrene.
Reaction SMILES: [C:1]([Si:5]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]#[CH:17])[C:11]=1[F:18])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.CCCCCC.Cl[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32].[Cl-].[NH4+]>C1COCC1>[Si:5]([O:8][CH2:9][C:10]1[C:11]([F:18])=[C:12]([C:16]#[C:17][C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:32])[CH:13]=[CH:14][CH:15]=1)([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:7])[CH3:6]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C#Cc1cccc(CO[Si](C)(C)C(C)(C)C)c1F
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCc1cccc(C#CC(=O)OCc2ccccc2)c1F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 93.5 %

Procedure:
tert-Butyl [(3-ethynyl-2-fluorobenzyl)oxy]dimethylsilane (1 g) was mixed with THF (20 ml), and a 1.65 M n-butyl lithium/hexane solution (2.5 ml) was added dropwise thereto at −78° C., followed by stirring at −78° C. for 30 minutes. Benzyl chloroformate (774 mg) was added dropwise thereto at the same temperature, followed by stirring overnight while raising the temperature to room temperature. A saturated aqueous ammonium chloride solution was added thereto at 0° C., followed by extraction with CHCl3. The organic layer was washed with water and saturated brine, and dried over Na2SO4, and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (EtOAc/hexane) to obtain benzyl 3-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]prop-2-ynoate (1.41 g).
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[N:10](CC=C)[C:9]=2[C:8](=[O:18])[NH:7][C:6]1=[O:19])[CH2:2][CH2:3][CH3:4].Br[CH2:21][CH2:22][CH2:23][N:24]1[N:28]=[N:27][C:26]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[N:25]1.C([O-])([O-])=O.[Cs+].[Cs+].N1CCOCC1>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.CO.CN(C=O)C>[CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[NH:10][C:9]=2[C:8](=[O:18])[N:7]([CH2:21][CH2:22][CH2:23][N:24]2[N:28]=[N:27][C:26]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[N:25]2)[C:6]1=[O:19])[CH2:2][CH2:3][CH3:4]
Reactant: BrCCCn1nnc(Cc2ccccc2)n1
Reactant: C=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: C1COCCN1
Product: CCCCn1c(=O)n(CCCn2nnc(Cc3ccccc3)n2)c(=O)c2[nH]c(Cl)nc21
Temperature: 45 °C
Reaction time: 24 h

Procedure:
A mixture of 3-butyl-8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (1.74 g, 6.1 mmol), crude 2-(3-bromopropyl)-5-(phenylmethyl)-2H-tetrazole) (1.9 g, 6.8 mmol), Cs2CO3 (2.2 g, 6.8 mmol) and DMF (60 ml) was stirred at 45° C. under nitrogen for 24 h. The mixture was degassed by applying a vacuum and then nitrogen was introduced. Pd(PPh3)4 (705 mg, 0.61 mmol) was added and the mixture degassed once more. Morpholine (5.4 ml, 61.4 mmol) was added and the mixture was stirred under nitrogen for 4 h, and then partitioned between 2M HCl (aq) and EtOAc. The organic layer was separated, washed with brine, dried (MgSO4) and concentrated, giving a yellow residue. MeOH was added and then passed down an aminopropyl column with the product eluting with 2% AcOH/MeOH. The product was further purified by the Companion™ system using EtOAc/cyclohexane mixtures. The resulting solid was stirred with boiling Et2O and filtered after cooling to rt. The title compound was collected as a white solid (1.01 g, 37%) and dried at 50° C. under vacuum.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14](=[O:30])[CH2:15][NH:16][CH:17]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:3].[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.COC1C=CC=CC=1C(Cl)=O>>[CH3:3][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:11])[CH3:12])[C:5]=1[NH:13][C:14](=[O:30])[CH2:15][N:16]([CH:17]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=2[C:19]2[C:18]1=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:31](=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH3:1]
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)CNC(c1ccccc1)c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Agent: COc1ccccc1C(=O)Cl
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CN(C(=O)c1ccccc1)C1c2ccccc2-c2ccccc21

Procedure:
When in the procedure of Example 94 an appropriate amount of product of Example 77 was substituted for the product of Example 4 and an appropriate amount of benzoyl chloride was substituted for 2-methoxybenzoyl chloride and the general procedure of Example 94 was followed the title compound was obtained. Total yield, 0.56 g (76%).
Reaction SMILES: [CH3:1][I:2].[O:3]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:4]1>CC(C)=O>[I-:2].[O:3]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[N+:10]([CH3:1])[CH:11]=[CH:12][CH:13]=2)=[N:4]1
Reactant: CI
Reactant: c1cncc(-c2cnon2)c1
Solvent: CC(C)=O
Product: C[n+]1cccc(-c2cnon2)c1
Product: [I-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methyl iodide (1 ml, 15 mmol) was added to a solution of 3-(1,2,5-oxadiazol-3-yl)pyridine (430 mg, 2.9 mmol) in acetone (20 ml). The reaction mixture was stirred at room temperature for 18 h. The product precipitated from the solution and the title compound was collected by filtration in 82% (700 mg) yield.
Reaction SMILES: [ClH:1].F[C:3]1[CH:8]=[C:7]([C@@H:9]2[O:14][CH2:13][CH2:12][NH:11][CH2:10]2)[CH:6]=[CH:5][C:4]=1[NH:15][C:16]([C:18]1[CH:19]=[N:20][N:21]([C:23]2[CH:28]=[N:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]=2)[CH:22]=1)=[O:17].C(OC(N1CCO[C@@H](C2C=CC(N)=CC=2[F:53])C1)=O)(C)(C)C>>[ClH:1].[F:53][C:6]1[CH:5]=[C:4]([NH:15][C:16]([C:18]2[CH:19]=[N:20][N:21]([C:23]3[CH:28]=[N:27][CH:26]=[C:25]([C:29]([F:31])([F:32])[F:30])[N:24]=3)[CH:22]=2)=[O:17])[CH:3]=[CH:8][C:7]=1[C@@H:9]1[O:14][CH2:13][CH2:12][NH:11][CH2:10]1
Reactant: O=C(Nc1ccc([C@H]2CNCCO2)cc1F)c1cnn(-c2cncc(C(F)(F)F)n2)c1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(N)cc2F)C1
Agent: Cl
Product: O=C(Nc1ccc([C@H]2CNCCO2)c(F)c1)c1cnn(-c2cncc(C(F)(F)F)n2)c1

Procedure:
In analogy to example 83, step a) using 1-(6-Trifluoromethyl-pyrazin-2-yl)-1H-pyrazole-4-carboxylic acid (prepared as described in example 125) instead of 2-(trifluoromethyl)-4-pyridinecarboxylic acid (CAS 131747-41-6) and (−)-(S)-2-(4-Amino-2-fluoro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester (described in example 83) instead of (+)—(R)-2-(4-Amino-2-fluoro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:39]=[CH:38][C:5]2[N:6]([CH:23]3[CH2:27][N:26](CC4C=CC(OC)=CC=4)[C:25](=[O:37])[CH2:24]3)[C:7]([CH2:9][N:10]3[C:14]4=[CH:15][N:16]=[CH:17][CH:18]=[C:13]4[C:12]([S:19]([CH3:22])(=[O:21])=[O:20])=[N:11]3)=[N:8][C:4]=2[CH:3]=1>CC#N.O.CCOC(C)=O>[Cl:1][C:2]1[CH:39]=[CH:38][C:5]2[N:6]([CH:23]3[CH2:27][NH:26][C:25](=[O:37])[CH2:24]3)[C:7]([CH2:9][N:10]3[C:14]4=[CH:15][N:16]=[CH:17][CH:18]=[C:13]4[C:12]([S:19]([CH3:22])(=[O:21])=[O:20])=[N:11]3)=[N:8][C:4]=2[CH:3]=1
Reactant: COc1ccc(CN2CC(n3c(Cn4nc(S(C)(=O)=O)c5ccncc54)nc4cc(Cl)ccc43)CC2=O)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CS(=O)(=O)c1nn(Cc2nc3cc(Cl)ccc3n2C2CNC(=O)C2)c2cnccc12
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 4-(5-chloro-2-{[3-(methylsulfonyl)-1H-pyrazolo[3,4-c]pyridin-1-yl]methyl}-1H-benzimidazol-1-yl)-1-(4-methoxybenzyl)pyrrolidin-2-one (208 mg, 0.37 mmol) in 60 mL of CH3CN and 12 mL of H2O was added (NH4)2Ce(NO3)6 (1.01 g, 1.84 mmol). The resulting mixture was stirred at RT for 6 hours. The solution was diluted with 40 mL of water and 15 mL of EtOAc. The separated aqueous phase was extracted with EtOAc (15 mL×3) and THF (5 mL×3). The combined organic phases were washed with 30 mL of brine, and then dried over Na2SO4, then filtered and concentrated. The residue was purified by column chromatography (DCM: MeOH=20:1) to afford 4-(5-chloro-2-{[3-(methylsulfonyl)-1H-pyrazolo[3,4-c]pyridin-1-yl]methyl}-1H-benzimidazol-1-yl)pyrrolidin-2-one.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1)=[O:3].[CH2:11]([C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1)[CH2:12][CH3:13].C(N(CC)CC)C>C1COCC1>[C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:18](=[O:19])[C:17]2[CH:21]=[CH:22][C:14]([CH2:11][CH2:12][CH3:13])=[CH:15][CH:16]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:1]
Reactant: CC(=O)c1ccc(N)cc1
Reactant: CCCc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCc1ccc(C(=O)Nc2ccc(C(C)=O)cc2)cc1
Yield: 78.6 %

Procedure:
Reaction of 4-aminoacetophenone (76 mg, 0.56 mmol) in THF (6 mL) with 4-propylbenzoyl chloride (100 μL, 0.65 mmol) in presence of triethylamine (90 μL, 0.65 mmol) according to method A gave N-(4-acetyl-phenyl)-4-propyl-benzamide (125 mg, 0.44 mmol, 78% yield) as a white powder after washing by dichloromethane and hexane.
Reaction SMILES: [CH2:1]([N:5]([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].C(O)(=O)[C@@H]([C@H](C(O)=O)O)O.[Cl-].[Cl:25]CC(O)C[N+](C)(C)C>O>[ClH:25].[CH2:10]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:11][CH2:12][CH3:13]
Reactant: C[N+](C)(C)CC(O)CCl
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: [Cl-]
Solvent: O
Solvent: CCCCN(CCCC)CCCC
Product: Cl
Temperature: 30 °C

Procedure:
While stirring, 18.54 g (100 mmole) of tri-n-butylamine was added drop by drop to 7.50 g (50 mmole) of L-(+)-tartaric acid, which was dissolved in 50 ml of water, whereby the solution was heated to 30° C. Subsequently, 18.81 g (100 mmole) of 3-chloro-2-hydroxy-propyltrimethylammonium chloride, which was dissolved in 100 ml of water, was added to the solution. The resultant clear solution was extracted with 8 separate portions of 150 ml of methylene chloride. The extractions were evaporated under vacuum. 21.65 g (97.6 percent yield) of tributylamine hydrochloride was obtained. (Together, the two last extractions only still contained 0.14 g of material.) The aqueous layer was evaporated in a rotary evaporator until dry. 23.22 g of a very viscous oil (102.5 percent) resulted. This was dissolved hot in 30 ml of methanol. It was mixed slowly with 93 ml of acetone until it became cloudy. The latter was again made to disappear by the addition of a few drops of methanol. After 72 hours, the mother liquor was decanted. The crystal crust was washed with acetone/methanol (3:1) and was dried under vacuum. The yield was 7.20 g of crystals (31.8 percent or 63.6 percent of the theory). The crystals had a melting point of 147° to 170° C. The crude tartrate was dissolved in 10 g of hot methanol and gradually 45 ml of acetone were added, whereupon the crystallization immediately started. The crystallization vessel was kept overnight in the refrigerator. The mother liquor was decanted off; the crystal cake was washed with acetone and dried. 5.78 g of crystals, corresponding to 51 percent of the theory, were obtained. The crystals had a melting point of 150° to 152° C. and a [α]D24 of -7.5° (c=1.04 in water). The tributylamine was recovered from the methylene chloride residue (raw tributylamine hydrochloride) with a yield of 96 percent by placing the residue in a solution of methylene chloride, shaking the solution with 1N of caustic soda solution and removing the solvent under vacuum.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[C:11]([C:12]#[N:13])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2.Br[CH2:17][C:18]1[O:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=1>>[F:15][C:2]([F:14])([F:1])[C:3]1[C:11]([C:12]#[N:13])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][N:7]2[CH2:17][C:18]1[O:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=1
Reactant: N#Cc1ccc2[nH]ccc2c1C(F)(F)F
Reactant: FC(F)(F)c1ccc(CBr)o1
Product: N#Cc1ccc2c(ccn2Cc2ccc(C(F)(F)F)o2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 23 using 4-(trifluoromethyl)-1H-indole-5-carbonitrile and 2-(bromomethyl)-5-(trifluoromethyl)furan: MS (ES) m/z 359 (M+1).
Reaction SMILES: Cl.O1CCOCC1.[C:8]([C:11]1[C:12]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[CH:31]=2)=[N:13][C:14]([NH:17][C:18]2[CH:28]=[CH:27][C:21]([CH2:22][NH:23]C(=O)O)=[CH:20][CH:19]=2)=[N:15][CH:16]=1)(=[O:10])[NH2:9].O>C(OCC)(=O)C>[NH2:23][CH2:22][C:21]1[CH:20]=[CH:19][C:18]([NH:17][C:14]2[N:13]=[C:12]([NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[CH:31]=3)[C:11]([C:8]([NH2:9])=[O:10])=[CH:16][N:15]=2)=[CH:28][CH:27]=1
Reactant: Cc1cccc(Nc2nc(Nc3ccc(CNC(=O)O)cc3)ncc2C(N)=O)c1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cccc(Nc2nc(Nc3ccc(CN)cc3)ncc2C(N)=O)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A 4 ml portion of 4 M hydrochloric acid-dioxane solution was added to 183 mg of tert-butyl ester of {4-[5-carbamoyl-4-(3-methylanilino)pyrimidin-2-ylamino]benzyl}carbamic acid, followed by stirring at room temperature for 16 hours. Water and ethyl acetate were added to the reaction mixture, the thus formed insoluble matter was removed by filtration and the filtrate was alkalified by adding 1 M sodium hydroxide aqueous solution. After extraction with ethyl acetate, the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue concentrated under a reduced pressure was recrystallized from a mixed solvent of ethyl acetate and n-hexane, thereby obtaining 44 mg of 2-(4-aminomethylanilino)-4-(3-methylanilino)pyrimidine-5-carboxamide (light yellow crystals).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([OH:15])=O)[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[CH:16]([C:19]1[N:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=1)([CH3:18])[CH3:17].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:25][C:22]4[CH:23]=[N:24][C:19]([CH:16]([CH3:18])[CH3:17])=[CH:20][CH:21]=4)=[O:15])[CH2:11][CH2:12]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)c1ccc(N)cn1
Reactant: O=C(O)C1(c2ccc3c(c2)OCO3)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cn1
Reaction time: 3 h

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (20.6 mg, 0.100 mmol) and 6-isopropylpyridin-3-amine (13.6 g, 0.100 mmol) were dissolved in N,N-dimethylformamide (DMF, 1 mL) containing triethylamine (0.042 mL, 0.300 mmol). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 39.9 mg, 0.105 mmol) was added and the solution was allowed to stir for 3 hours. The mixture was then purified by reverse phase preparative liquid chromatography utilizing a gradient of 0-99% acetonitrile in water containing 0.05% trifluoroacetic acid to yield the pure product. ESI-MS m/z calc. 324.2, found 325.3 (M+1)+. Retention time 2.14 minutes.
Reaction SMILES: [CH:1]1([C:4](=O)[CH:5]=[CH:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[N+:14]([CH2:17][CH3:18])([O-:16])=[O:15].C[O-:20].[Na+].[Na]>CO>[CH:1]1([CH2:4][C:5](=[O:20])[CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:17]([N+:14]([O-:16])=[O:15])[CH3:18])[CH2:3][CH2:2]1
Reactant: C[O-]
Reactant: O=C(C=Cc1ccccc1)C1CC1
Reactant: CC[N+](=O)[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: CC(C(C(=O)CC1CC1)c1ccccc1)[N+](=O)[O-]

Procedure:
22.5 G of 1-cyclopropyl-3-phenylprop-2-en-1-one and 12 ml of nitroethane in 130 ml of methanol containing sodium methylate prepared from 1.6 g of sodium is refluxed for 12 hours. After cooling, the reagents are destroyed with water-ice, neutralised with dilute hydrochloric acid and extracted with ether; the ether extract is washed with water and dried over sodium sulphate. The ether is evaporated in vacuo to give 19 g of 1-cyclopropyl-3-phenyl-4-nitropentanone which is used in the crude form for the remainder of the operations.
Reaction SMILES: [C:1]([C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[C:12]([CH2:13][OH:14])=[CH:11][N:10]=[CH:9]2)=[CH:5][CH:4]=1)#[N:2].C(N(CC)CC)C.CCOC(C)=O>CS(C)=O>[C:1]([C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[C:12]([CH:13]=[O:14])=[CH:11][N:10]=[CH:9]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(Cn2cncc2CO)cc1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: N#Cc1ccc(Cn2cncc2C=O)cc1
Reaction time: 0.75 h
Yield: 87.7 %

Procedure:
To a solution of the alcohol from Step D (21.5 g, 101 mmol) in 500 mL of DMSO at room temperature was added triethylamine (56 mL, 402 mmol), then SO3 -pyridine complex (40.5 g, 254 mmol). After 45 minutes, the reaction was poured into 2.5 L of EtOAc, washed with water (4×1 L) and brine, dried (Na2SO4), filtered, and concentrated in vacuo to provide the aldehyde (18.7 g, 88% yield) as a white powder which was sufficiently pure for use in the next step without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH:8]([OH:10])[CH3:9])[CH:5]=[CH:4][N:3]=1.O.[NH2:12][NH2:13]>CO.CCOCC>[NH:12]([C:2]1[CH:7]=[C:6]([CH:8]([OH:10])[CH3:9])[CH:5]=[CH:4][N:3]=1)[NH2:13]
Reactant: NN
Reactant: CC(O)c1ccnc(Cl)c1
Solvent: CO
Solvent: O
Solvent: CCOCC
Product: CC(O)c1ccnc(NN)c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
1-(2-chloropyridin-4-yl)ethanol (5d) (14.3 g) was dissolved in hydrazine hydrate (275 mL). The resulting mixture was heated at 100° C. with stirring overnight. The mixture was concentrated under vacuum to give a yellow oil that was dissolved in a small volume of methanol and ether was added, which resulted in precipitation of a white solid. The obtained suspension was stirred for 30 minutes and filtered, and the residue (hydrazine hydrochloride) was discarded. The filtrate was concentrated under vacuum to give the title compound (13.7 g) as a light-brown oil.
Reaction SMILES: [CH2:1]([CH:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[CH2:25])[C:12]([OH:14])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10].[C:26]([O-])([O-])=O.[K+].[K+].CI.Cl>C(OCC)(=O)C.CC(C)=O>[CH2:1]([CH:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[CH2:25])[C:12]([O:14][CH3:26])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10]
Reactant: C=CCCCCCCCCCC(CCCCCCCCC=C)C(=O)O
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Solvent: CCOC(C)=O
Product: C=CCCCCCCCCCC(CCCCCCCCC=C)C(=O)OC
Yield: 97.5 %

Procedure:
2-(Dec-9-enyl)-tridec-12-enoic acid (63 mg, 0.18 mmol, Example 67) was added to a 100 mL three-neck round-bottom flask fitted with a reflux condenser (cooled with ice cold water) followed by 15 mL of reagent-grade acetone. The resulting solution was vigorously stirred and 0.062 g K2CO3 (0.45 mmol, 2.5 eq.) was added in one portion and the mixture was stirred for 5 minutes at room temperature. An excess of methyl iodide (˜2.0 mL) was then added and the mixture was refluxed under argon for 24 hours, after which TLC analysis (5:95 ethyl acetate:hexanes) indicated complete reaction. The mixture was acidified to pH 5 with 3N aqueous HCl and extracted with CH2Cl2. This solution was dried over MgSO4 and a small amount of Na2S2O3 (to destroy iodine). The solvent was then evaporated to afford methyl 2-(dec-9-enyl)-tridec-12-enoate (64 mg, quantitative yield) as a clear oil. 1H NMR (300 MHz, CDCl3): δ 5.80 (m, 2H), 4.93 (m, 4H), 3.65 (s, 1H), 2.35 (m, 1H), 2.03 (q, 4H), 1.58 (m, 2H) 1.42, 1.35, and 1.27 (m, 28H) ppm. 13C NMR (75 MHz, CDCl3): δ 177.04, 139.17, 139.15, 114.08, 114.06, 51.23, 45.68, 33.78 (2 C, unresolved), 32.48, 29.51, 29.50, 29.48 (2 C, unresolved), 29.42 (2 C, unresolved), 29.37 (2 C, unresolved), 29.09, 29.06, 28.90, 28.88, 27.44 (2 C, unresolved) ppm. Analysis calculated for C24H44O2: C, 79.06; H, 12.16. Found: C, 78.83; H, 12.16. HRMS-FAB: Theoretical: 365.3420; Found: 365.3399 [M]+. A copolymer of methyl 2-(dec-9-enyl)-tridec-12-enoate and 1,9-decadiene, prepared similarly to polymer 21, would have the following features: The end groups R2 and R3 would be H. For this polymer, e and f would be derived from methyl 2-(dec-9-enyl)-tridec-12-enoate and would equal 9 and 10, respectively; d would derive from 1,9-decadiene and would equal 8. The run length distribution would therefore be: rHH=(9+0)+8z; rHT=(9+10)+8z; and rTT=(10+10)+8z; therefore rtotal=(18+8z),(19+8z),(20+8z).