Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[Cl:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[C:21]([CH3:26])[CH:20]=1.Cl.N1C=CC=CC=1.C(OCCO)C>>[Cl:18][C:19]1[CH:25]=[CH:24][C:22]([NH:23][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:16]#[N:17])=[C:21]([CH3:26])[CH:20]=1
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Reactant: Cc1cc(Cl)ccc1N
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1cc2ncc(C#N)c(Nc3ccc(Cl)cc3C)c2cc1OC
Temperature: 139 °C
Reaction time: 24 h
Yield: 70.7 %

Procedure:
A mixture of 0.248 g (1 mmol)of 4-chloro-6,7-dimethoxy-quinoline-3-carbonitrile, 0.156 g (1.1 mmol) of 4-chloro-2-methylaniline, 0.116 g (1 mmol) pyridine hydrochloride and 12 ml of 2-ethoxyethanol was heated in a 138-140° C. oil bath for 24 hours; progress of the reaction was monitored by TLC. After 24 hours an additional 0.156 g of of 4-chloro-2-methylaniline was added and the heating continued for 24 hours. When TLC indicated the disappearance of starting material, the reaction was cooled and concentrated in vacuo to a thick oil. To this oil was added 50 ml of water followed by 5 ml of 1M NaHCO3, approximately pH 8. The gummy solid was dissolved in chloroform and passed through a pad of hydrous magnesium silicate. The liquid was concentrated in vacuo and the residue triturated 5 times with hexane. The resulting precipitate was collected, washed with hexane, and dried in vacuo at 65° C. to give 0.250 g (71%) of the desired product as brown crystals. MP 227-229° C.;: mass spectrum (electrospray, m/e,): 353.8(M+H)+.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])#[N:2].[NH2:12][C:13]1[C:18](N)=[CH:17][CH:16]=[CH:15][N:14]=1.C(N[C@H](C(O)=O)CS)(=O)C>CO>[N:2]1[C:18]2[C:13](=[N:14][CH:15]=[CH:16][CH:17]=2)[NH:12][C:1]=1[CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:10])[CH3:9]
Reactant: Nc1cccnc1N
Reactant: CC(C)(C)OC(=O)NCC#N
Agent: CC(=O)N[C@@H](CS)C(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1nc2cccnc2[nH]1
Temperature: 50 °C
Yield: 87.8 %

Procedure:
A mixture of tert-butyl cyanomethylcarbamate (1.61 g; 10 mmol), 2,3-diaminopyridine (0.56 g; 5 mmol), N-acetylcysteine (1.68 g; 10 mmol) in 10 ml of CH3OH was heated at 50° C. for 89 h. It was then concentrated, and the residue was taken up in a little CH3OH and filtered through an acidic ion exchanger (acetate on polymeric support). Renewed concentration and chromatography on silica gel (CH2Cl2/CH3OH 5%) afforded 1.09 g of the required product;
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]([C:13]2[NH:14][C:15]([CH:20]([CH3:22])[CH3:21])([CH3:19])[C:16](=[O:18])[N:17]=2)=[C:8]([CH:12]=1)[C:9]([OH:11])=[O:10])([CH3:3])=[CH2:2].[N+](=[CH2:25])=[N-]>C(Cl)Cl>[CH3:25][O:10][C:9](=[O:11])[C:8]1[CH:12]=[C:4]([C:1]([CH3:3])=[CH2:2])[CH:5]=[N:6][C:7]=1[C:13]1[NH:17][C:16](=[O:18])[C:15]([CH:20]([CH3:22])[CH3:21])([CH3:19])[N:14]=1
Reactant: C=[N+]=[N-]
Reactant: C=C(C)c1cnc(C2=NC(=O)C(C)(C(C)C)N2)c(C(=O)O)c1
Solvent: ClCCl
Product: C=C(C)c1cnc(C2=NC(C)(C(C)C)C(=O)N2)c(C(=O)OC)c1
Reaction time: 0.25 h

Procedure:
To a solution of 4.9 g of 5-isopropenyl-2-(5-isopropyl-5-methyl-4-oxo-2-imidazolin-2-yl)nicotinic acid in 50 mL of methylene chloride, stirred at 0°, is added 60 mL of 0.25M ethereal diazomethane. After stirring for 15 minutes, the reaction is concentrated on a steam bath. The residue is chromatographed on silica gel using 2:1 ether-hexanes as eluant to afford the desired product. Recrystallization from ether-hexanes affords a solid, mp 90.5°-92.5°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:42]=[CH:43][CH:44]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[N:22][C:23]([N:26]5[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]5)=[CH:24][CH:25]=4)[CH:18]=3)[N:13]([S:32]([C:35]3[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[CH:12]=2)[CH:8]=[N:7]1.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=NC(N5CCN(C)CC5)=CC=4)C=3)NC=2)C=N1.Br[CH2:81][CH2:82][OH:83].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:42]=[CH:43][CH:44]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH2:31][CH2:30][N:29]([CH2:81][CH2:82][OH:83])[CH2:28][CH2:27]5)=[N:22][CH:21]=4)[CH:18]=3)[N:13]([S:32]([C:35]3[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[CH:12]=2)[CH:8]=[N:7]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCNCC5)nc4)cnc32)cc1
Reactant: OCCBr
Agent: CN1CCN(c2ccc(-c3cnc4[nH]cc(-c5cnn(Cc6cccc(F)c6)c5)c4c3)cn2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(CCO)CC5)nc4)cnc32)cc1
Yield: 43.9 %

Procedure:
Using similar reaction conditions as described in step-i of example-126, 3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-5-(6-(piperazin-1-yl)pyridin-3-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (step 1 compound of example 137) (150 mg, 0.297 mmol) was alkylated using 2-bromoethanol (62 mg, 0.494 mmol) and potassium carbonate (69 mg, 0.494 mmol) in DMF (1 ml) to afford 85 mg (52.7% yield) of the titled compound after purification by column (Silica gel 60/120) chromatography using 5% methanol in dichloromethane as eluent. MS: m/z=652.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[Cl:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[C:5]([F:25])=[CH:4][C:3]=1[F:26].[NH2:27][CH:28]1[CH2:32][CH2:31][N:30](CC2C=CC=CC=2)[CH2:29]1.C(N(CC)CC)C>N1C=CC=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15]([NH:27][CH:28]4[CH2:32][CH2:31][NH:30][CH2:29]4)[C:16]=3[Cl:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[C:5]([F:25])=[CH:4][C:3]=1[F:26]
Reactant: NC1CCN(Cc2ccccc2)C1
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(NC4CCNC4)c(Cl)c32)c(F)cc1F
Temperature: 25 °C
Reaction time: 26 h
Yield: 49.1 %

Procedure:
1-(6-Amino-3,5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (200 mg), 3-amino-1-benzylpyrrolidine (97 mg) and triethylamine (160 mg) were added to pyridine (600 mg), and the mixture was stirred for 26 hours at room temperature and f or 15 hours at 60° C. The reaction mixture was concentrated under reduced pressure. A process of adding ethanol (3 ml) to the residue and then concentrating the mixture under reduced pressure was conducted twice repeatedly. Acetic acid (2 ml) and 10% palladium-carbon (25 mg) were added to the resultant residue to conduct hydrogenation for 20 hours at 45° C. and for 21 hours at room temperature. After the catalyst was separated by filtration and washed with acetic acid, the filtrate and washings were concentrated under reduced pressure. A process of adding ethanol (3 ml) to the residue and then concentrating the mixture under reduced pressure was conducted twice repeatedly. Ethanol (2 ml) was added to the resultant residue, and deposits were collected by filtration and washed with ethanol and diisopropyl ether in that order to obtain the title compound (115 mg) as a pale brown powder.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]([OH:11])[O:5][CH2:6][CH:7]([CH2:9][CH3:10])[CH:8]=1)[CH3:2].[H][H]>[Ni].O>[CH2:1]([CH:3]([CH2:8][CH:7]([CH2:9][CH3:10])[CH2:6][OH:5])[CH2:4][OH:11])[CH3:2]
Reactant: [H][H]
Reactant: CCC1=CC(CC)COC1O
Agent: [Ni]
Solvent: O
Product: CCC(CO)CC(CC)CO

Procedure:
3,5-Diethyl-5,6-dihydro-2H-2-pyranol obtained in Example 3 (5 g) was put into a 100-ml autoclave together with 0.25 g of Raney nickel and 0.5 ml of water, followed by stirring at 120° C. for 5 hours at a hydrogen pressure of 30 kg/cm2. After the catalyst was filtered off from the reaction mixture, water was distilled under reduced pressure to obtain 2,4-diethyl-1,5-pentanediol quantitatively.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]2[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[C:13]([Cu])#[N:14].Cl.O>CN(C=O)C.[Fe](Cl)(Cl)Cl>[C:13]([C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]2[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1)#[N:14]
Reactant: N#C[Cu]
Reactant: O=C(c1ccc(Br)cc1)C1CC1
Agent: Cl[Fe](Cl)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(C(=O)C2CC2)cc1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
22.5 g of 4-bromophenylcyclopropylmethanone (100 mmol) and 10.3 g of CuCN (100 mmol) are dissolved in 15 ml of DMF and heated under reflux, with stirring, for 4 hours. The suspension is allowed to cool down to 70° C. and is then poured into a solution consisting of 40 g of iron(III) chloride, 10 ml of conc. HCl and 60 ml of water. The mixture is stirred at 70° C. for 20 minutes. It is then extracted three times with 90 ml of toluene on each occasion. The combined organic phases are washed with 250 ml of 2N hydrochloric acid and with 250 ml of 2N sodium hydroxide solution, and then concentrated. The solid residue is triturated with petroleum ether and filtered off with suction.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH2:15][CH2:16][CH3:17])=[N:8][C:7]([OH:18])=[CH:6]2.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[I:31]N1C(=O)CCC1=O.C([O-])(O)=O.[Na+]>CC#N.O>[I:31][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9]([CH2:15][CH2:16][CH3:17])=[N:8][C:7]=1[OH:18]
Reactant: CCCc1nc(O)cc2cc(OC)c(OC)cc12
Reactant: O=C1CCC(=O)N1I
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCCc1nc(O)c(I)c2cc(OC)c(OC)cc12
Reaction time: 2.5 h
Yield: 78 %

Procedure:
A mixture of 6,7-dimethoxy-1-propylisoquinolin-3-ol RBO 35142 (2.00 g, 8.09 mmol) and p-toluenesulfonic acid monohydrate (1.50 g, 7.89 mmol) in dry CH3CN (20 mL) in a 100 mL round-bottomed flask equipped with a magnetic stirrer was stirred for 10 min at RT before portionwise addition of N-iodosuccinimide (1.82 g, 8.09 mmol) under vigorous stirring. After 2.5 h, the mixture was slowly poured into a cold solution of NaHCO3 (2.0 g) in 50 mL of water and the solid was filtered, washed with water (50 mL) and dried overnight under vacuum to yield 4-iodo-6,7-dimethoxy-1-propylisoquinolin-3-ol CCH 42098-1 as a brown solid (2.35 g, 78% yield).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[C@@H:8]([CH2:9][O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][CH:6]=[CH:5][CH2:4]1.[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>N1C=CC=CC=1>[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24]([O:1][CH2:2][C@H:3]2[C@@H:8]([CH2:9][O:10][CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:7][CH:6]=[CH:5][CH2:4]2)(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC[C@@H]1CC=CC[C@@H]1COCc1ccccc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2CC=CC[C@@H]2COCc2ccccc2)cc1
Reaction time: 8 h
Yield: 84.2 %

Procedure:
The alcohol/benzyl ether (2) (10 g) in 20 ml of dry pyridine is added slowly at 0° C. to p-toluenesulphonyl chloride (10.4 g) in pyridine (60 ml). The mixture is kept overnight at room temperature and is then quenched by pouring over crushed ice with vigorous shaking. The product is extracted with ether, washed consecutively with water, 0.1M sodium carbonate and brine, dried (MgSO4), and concentrated in vacuo at room temperature. The crude product is purified on a silica gel column, eluting with benzene-ethyl acetate (95%: 5% v/v) to give the title compound (14 g, 90%). The i.r. spectrum shows the absence of a hydroxyl group.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].Cl[C:13]1[C:14]2[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[S:25][C:15]=2[N:16]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[N:18]=1>>[N:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:17]1[N:18]=[C:13]([NH:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:14]2[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[S:25][C:15]=2[N:16]=1
Reactant: O=[N+]([O-])c1cc2c(Cl)nc(-c3ccccn3)nc2s1
Reactant: NCc1cccc([N+](=O)[O-])c1
Product: O=[N+]([O-])c1cccc(CNc2nc(-c3ccccn3)nc3sc([N+](=O)[O-])cc23)c1

Procedure:
With the procedure of Example 1, the reaction of 3-nitrobenzylamine with 4-chloro-2-(pyridin-2-yl)-6-nitro-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-(3-nitrobenzylamino)-6-nitro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6](Br)[CH:5]=1)=[O:3].[F:11][C:12]([F:23])([F:22])[C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.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>[F:11][C:12]([F:23])([F:22])[C:13]1[CH:18]=[CH:17][C:16]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([C:2](=[O:3])[CH3:1])[CH:5]=2)=[CH:15][CH:14]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CC(=O)c1cccc(Br)c1
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: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(=O)c1cccc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 100 °C
Reaction time: 20 h
Yield: 76.4 %

Procedure:
A solution of 3-bromoacetophenone (661 μL, 5.00 mmol) and 4-(triflouromethyl)benzeneboronic acid (950 mg, 5.00 mmol) in DME (50 mL) was added Na2CO3 (1.32 g, 12.50 mmol) and Pd(PPh3)4 (283 mg, 0.24 mmol) and water (25 mL). The mixture was then stirred at 100° C. for 20 hours, diluted with water and extracted with EtOAc. The organic layer was then washed with brine, dried (Na2SO4), filtered and reduced. Purification by flash chromatography (silica) eluting with petrol:EtOAc (gradient 19:1 to 9:1) afforded the title compound (1.01 g).
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:22]=[C:21]([CH3:23])[C:20]([O:24]C(OC)=O)=[CH:19][C:4]=1[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([OH:18])=[C:13]([O:16][CH3:17])[CH:14]=2)[N:9]=[CH:8][N:7]=1.Br[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([F:37])=[C:33]([F:38])[CH:32]=1>>[ClH:1].[F:38][C:33]1[CH:32]=[C:31]([CH:36]=[CH:35][C:34]=1[F:37])[CH2:30][O:18][C:12]1[CH:11]=[C:10]2[C:15]([C:6]([NH:5][C:4]3[CH:19]=[C:20]([OH:24])[C:21]([CH3:23])=[CH:22][C:3]=3[F:2])=[N:7][CH:8]=[N:9]2)=[CH:14][C:13]=1[O:16][CH3:17]
Reactant: Fc1ccc(CBr)cc1F
Reactant: COC(=O)Oc1cc(Nc2ncnc3cc(O)c(OC)cc23)c(F)cc1C
Agent: Cl
Product: COc1cc2c(Nc3cc(O)c(C)cc3F)ncnc2cc1OCc1ccc(F)c(F)c1
Yield: 31.4 %

Procedure:
Using an analogous procedure to that described in Example 36, 4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-hydroxy-6-methoxyquinazoline hydrochloride (224 mg, 0.6 mmol), (prepared as described for the starting material in Example 22), was treated with 4-bromomethyl-1,2-difluorobenzene (149 mg, 0.72mmol) to give 7-(3,4-difluorobenzyloxy)-4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxyquinazoline hydrochloride (90 mg, 31%).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:10][CH2:9]1)C1C=CC=CC=1.C1CCCCC=1>C(O)C.[OH-].[OH-].[Pd+2]>[CH2:14]([N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCN1CCN(Cc2ccccc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1=CCCCC1
Solvent: CCO
Product: CCCCCCCCCN1CCNCC1

Procedure:
A mixture of 1-benzyl-4-nonylpiperazine (0.54 g, 1.80 mmol) (prepared by reacting 1-benzylpiperazine, Aldrich, with 1-bromononane, Aldrich, and NaH in DMF), palladium hydroxide on carbon (0.14 g) and cyclohexene (7 mL) in ethanol (15 mL) was heated at reflux overnight. After filtration, the filtrate was concentrated in vacuo to dryness to give 1-nonylpiperazine as an oil, 0.38 g, 100%.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([CH3:7])[NH:4][N:3]=1.[F:8][C:9]1[CH:10]=[C:11]([CH:15]([C:21](OCC)=[O:22])[C:16](OCC)=[O:17])[CH:12]=[CH:13][CH:14]=1.C(N(CCCC)CCCC)CCC>[OH-].[Na+].O>[F:8][C:9]1[CH:10]=[C:11]([C:15]2[C:21]([OH:22])=[N:1][C:2]3[N:3]([N:4]=[C:5]([CH3:7])[N:6]=3)[C:16]=2[OH:17])[CH:12]=[CH:13][CH:14]=1
Reactant: Cc1nc(N)n[nH]1
Reactant: CCOC(=O)C(C(=O)OCC)c1cccc(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCN(CCCC)CCCC
Solvent: O
Product: Cc1nc2nc(O)c(-c3cccc(F)c3)c(O)n2n1
Yield: 88.7 %

Procedure:
5 g (51.87 mmol) 3-Amino-5-methyl-1,2,4-triazole, 16.2 g (67.4 mmol) diethyl (3-fluorophenyl)malonate and 20.4 mL tributylamine are stirred at 180° C. over night. The mixture is diluted with 2N NaOH solution and water and extracted three times with methyl-tert. butylether. These organic extracts are discarded. The aqueous phase is acidified at 0° C. with concentrated HCl until pH 3. The white precipitate is collected by filtration, washed with water (4 L) and dried in vacuo at 50° C. 11.97 g (88.7%) of the product are obtained and are used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])/[C:4](/C)=[CH:5]/[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12].[CH2:15](OC(=O)C=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.C(=O)C1C(=CC=CC=1)O>>[CH2:1]([O:2][C:3](=[O:14])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12])[CH3:15]
Reactant: COC(=O)/C(C)=C/c1ccccc1O
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O=Cc1ccccc1O
Product: CCOC(=O)/C=C/c1ccccc1O

Procedure:
According to the procedure of Example 1, (E)-3-(2-hydroxy-phenyl)-2-methyl-acrylic acid methyl ester was prepared from ethyl(triphenyl-phosphoranylidene)acetate and salicylaldehyde.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[NH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[C:8]=1[CH2:14][OH:15].CCN(C(C)C)C(C)C>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[Br:13][C:9]1[C:8]([CH2:14][OH:15])=[C:7]([NH:6][C:3](=[O:4])[CH2:2][Cl:1])[CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Cl)CCl
Reactant: Nc1cccc(Br)c1CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CCl)Nc1cccc(Br)c1CO
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 2-chloroacetyl chloride (380 mg, 3.37 mmol) in DCM (10 mL) was added (2-amino-6-bromophenyl)methanol (630 mg, 3.12 mmol) followed by DIPEA (1.253 mL, 7.17 mmol). The reaction was stirred at room temperature for 3 d. The mixture was diluted with a solution of saturated sodium bicarbonate (15 mL) and extracted with ethyl acetate (20 mL). The organic layer was dried over sodium sulfate and concentrated to give N-(3-bromo-2-(hydroxymethyl)phenyl)-2-chloroacetamide. The above product was dissolved in IPA (10 mL), and added 50% w/w aqueous NaOH (374 mg, 4.68 mmol). The mixture was stirred at room temperature for 3 h and concentrated. The residue was diluted with a solution of saturated sodium bicarbonate (15 mL) and extracted with DCM (80 mL). The organic layer was dried over sodium sulfate and concentrated to give 6-bromo-3,5-dihydrobenzo[e][1,4]oxazepin-2(1H)-one. The above intermediate was dissolved in THF (60 mL) and added 2.0 M borane dimethyl sulfide methyl sulfide complex in THF (6.24 mL, 12.47 mmol). The reaction was refluxed for 60 min, cooled to room temperature, and added MeOH (5.0 mL) dropwise. The mixture was refluxed for 30 min concentrated. The residue was diluted with a solution of saturated sodium bicarbonate (60 mL) and extracted with ethyl acetate (60 mL). The organic layer was dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography (0-100% ethyl acetate:hexanes) to afford the title compound (237 mg, 32% yield) as clear gum. LCMS, [M+H]+=229.9. 1H NMR (400 MHz, CDCl3) δ 7.13 (dd, J=7.9, 1.1 Hz, 1H), 6.94 (t, J=7.9 Hz, 1H), 6.74 (dd, J=7.9, 0.9 Hz, 1H), 4.92 (s, 2H), 4.06 (br. s., 1H), 3.89-3.81 (m, 2H), 3.24-3.17 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([O:16][CH3:17])[C:13]=1[O:14][CH3:15])[CH:6]=[CH:7][C:8](Cl)=[O:9].C(N(CC)CC)C.[CH2:25]([NH:27][C:28]([CH:30]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)[CH3:31])=[O:29])[CH3:26]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([O:16][CH3:17])[C:13]=1[O:14][CH3:15])[CH:6]=[CH:7][C:8]([N:35]1[CH2:34][CH2:33][N:32]([CH:30]([C:28]([NH:27][CH2:25][CH3:26])=[O:29])[CH3:31])[CH2:37][CH2:36]1)=[O:9]
Reactant: COc1cc(C=CC(=O)Cl)cc(OC)c1OC
Reactant: CCNC(=O)C(C)N1CCNCC1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCNC(=O)C(C)N1CCN(C(=O)C=Cc2cc(OC)c(OC)c(OC)c2)CC1
Reaction time: 1 h

Procedure:
17.19 g of 3,4,5-trimethoxycinnamoyl chloride and 6.78 g of triethylamine are added with ice cooling to a solution of 9.54 g of 1-[1-(ethylaminocarbonyl)ethyl]piperazine in 200 ml of chloroform, and the resulting solution is kept standing at room temperature for 1 hour.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([O:16][CH3:17])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].N1C=CN=C1.O>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH2:10][C@H:9]1[C:14]([O:16][CH3:17])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 95.3 %

Procedure:
To a solution of (2S,4R)-1-t-butoxycarbonyl-4-hydroxy-2-methoxycarbonylpyrrolidine (20.0 g) and t-butyldimethylsilyl chloride (18.44 g) in dimethylformamide (60 ml) was added imidazole (11.1 g) under ice-cooling, and the mixture was stirred at 0°-10° C. for 1 hour and then at ambient temperature for 18 hours. The reaction mixture was poured into water (300 ml) and extracted with ethyl acetate (100 ml×3). The combined organic layer was washed with water (200 ml×2) and brine (150 ml) successively, dried over magnesium sulfate, and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (250 g) to give (2S,4R)-1-t-butoxycarbonyl-4-t-butyldimethylsilyloxy-2-methoxycarbonylpyrrolidine (27.95 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C@@H:22]([OH:24])[CH3:23])=[CH:17][CH:16]=1>>[OH:24][C@@H:22]([CH3:23])[CH2:21][C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:2]2[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=2[N+:11]([O-:13])=[O:12])=[CH:16][CH:17]=1
Reactant: C[C@H](O)Cc1ccc(N)cc1
Reactant: CC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Product: CC(=O)c1ccc(Nc2ccc(C[C@H](C)O)cc2)c([N+](=O)[O-])c1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 162 from 1-(4-chloro-3-nitrophenyl)ethanone and (2S)-1-(4-aminophenyl)-2-propanol (step 2).