Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][CH:15]=1.C1C=CC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.[CH3:45][CH:46]([CH2:49][CH3:50])[CH2:47][NH2:48]>CN(C=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([NH:48][CH2:47][CH:46]([CH3:45])[CH2:49][CH3:50])=[O:22])=[CH:16][CH:15]=1
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Reactant: CCC(C)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCC(C)CNC(=O)c1ccc(-c2cc(-c3nnc(C)o3)ccc2C)cc1
Reaction time: 18 h

Procedure:
2′-Methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid (11.3 mg, 0.034 mmol), HOBT (6.0 mg, 0.044 mmol), 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (8.0 mg, 0.042 mmol) and 2-methylbutylamine (0.34 mmol) were mixed in DMF (0.7 ml) and the reaction left at room temperature for 18 h. The DMF was evaporated under vacuum and the residue partitioned between DCM (0.4 ml) and water (0.4 ml). The organic phase was washed with aqueous sodium hydroxide (0.5M, 0.2 ml) and the DCM evaporated under vacuum. The residue was purified by mass directed HPLC to give 2′-methyl-N-(2-methylbutyl)-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide.
Reaction SMILES: O1CCN([C:7]2[CH2:11][CH2:10][CH2:9][CH:8]=2)CC1.[Br:12][C:13]1[CH:14]=[C:15]([N:19]=[C:20]=[O:21])[CH:16]=[CH:17][CH:18]=1.CCCCCC.C(OCC)(=[O:30])C>C(Cl)(Cl)Cl>[Br:12][C:13]1[CH:14]=[C:15]([NH:19][C:20]([CH:7]2[CH2:8][CH2:9][CH2:10][C:11]2=[O:30])=[O:21])[CH:16]=[CH:17][CH:18]=1
Reactant: C1=C(N2CCOCC2)CCC1
Reactant: O=C=Nc1cccc(Br)c1
Reactant: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Product: O=C1CCCC1C(=O)Nc1cccc(Br)c1

Procedure:
15.2 ml (101 mmol) of 1-morpholino-1-cyclopentene is carefully added in drops to a solution of 20.0 g (101 mmol) of 3-bromophenylisocyanate in 100 ml of chloroform. The batch is refluxed for 15 minutes and concentrated by evaporation in a vacuum. Column chromatography on silica gel with hexane-ethyl acetate yielded 25.0 g (88.6 mmol) of cyclopentan-2-one-1-carboxylic acid-(3-bromophenyl)amide. The latter is mixed with 83 ml of concentrated sulfuric acid and stirred for 30 minutes at 90° C. After cooling to room temperature, the batch is poured onto 600 g of ice, the precipitated solid is suctioned off and recrystallized from ethanol: 17.0 g of product.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[S:5]1(=[O:15])(=[O:14])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH:7]=[CH:6]1>S(=O)(=O)(O)O>[N+:1]([C:11]1[CH:12]=[CH:13][C:8]2[CH:7]=[CH:6][S:5](=[O:15])(=[O:14])[C:9]=2[CH:10]=1)([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: O=S1(=O)C=Cc2ccccc21
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1ccc2c(c1)S(=O)(=O)C=C2
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 84 %

Procedure:
Nitric acid (10 mL) was slowly added to sulfuric acid (10 mL) at 0° C., and the mixture was stirred at the same temperature for 10 min. To this solution was slowly added 1-benzothiophene 1,1-dioxide (3.99 g) at 0° C., and the mixture was further stirred at the same temperature for 30 min. The reaction mixture was poured into ice water, and the mixture was extracted with ethyl acetate. The extract was washed twice with water, saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound as a pale-yellow solid (yield 4.26 g, 84%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[S:11]([NH:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[N:21]([CH3:25])[C:20](=[O:26])[C:19]([CH2:27][C:28]2[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=2)=[N:18]3)(=[O:13])=[O:12])[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:39][C:40]([O:42][CH2:43]C)=[O:41]>O1CCCC1>[CH3:43][O:42][C:40]([CH2:39][N:14]([S:11]([C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:1]=[CH:2][CH:3]=[CH:4]2)(=[O:12])=[O:13])[C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]([CH3:25])[C:20](=[O:26])[C:19]([CH2:27][C:28]1[CH:29]=[CH:30][C:31]([C:32]#[N:33])=[CH:34][CH:35]=1)=[N:18]2)=[O:41]
Reactant: Cn1c(=O)c(Cc2ccc(C#N)cc2)nc2cc(NS(=O)(=O)c3cccc4cccnc34)ccc21
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)CN(c1ccc2c(c1)nc(Cc1ccc(C#N)cc1)c(=O)n2C)S(=O)(=O)c1cccc2cccnc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.0 g (4.15 mmol) of 4-{[6-(quinolin-8-yl-sulphonylamino)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}-benzonitrile are dissolved in 150 ml tetrahydrofuran and after the addition of 0.2 g (4.15 mmol) of sodium hydride (50% in oil) stirred for 2 hours at ambient temperature. After the addition of 0.47 ml (4.15 mmol) of ethyl bromoacetate the reaction mixture was stirred for 5 hours. The precipitate is suction filtered, the mother liquor is evaporated down and chromatographed on silica gel, eluting initially with petroleum ether and then with petroleum ether/ethyl acetate (55:45). The desired fractions are combined and evaporated down.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([OH:11])[CH3:10])=[CH:5][CH:4]=1.CC(C1C=CC(OC)=CC=1)=O.COC1C=CC([C@@H](O)C)=CC=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]([OH:11])[CH3:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(C)O)cc1
Agent: COc1ccc(C(C)=O)cc1
Agent: COc1ccc([C@H](C)O)cc1
Product: COc1ccc([C@@H](C)O)cc1
Reaction time: 120 h
Yield: 48 %

Procedure:
As shown here, the biochemical conversion reaction of immobilized soy bean protein for the substrate (±)-1-(4-methoxyphenyl)ethanol (200 mg) requires 5 days by going through bioconversion to 4-methoxyacetophenone accompanying sterically selective oxidation of (S)-1-(4-methoxyphenyl)ethanol to obtain 96 mg of (R)-1-(4-methoxyphenyl)ethanol at a yield of 48%. Optical purity was obtained at 97% e.e.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#[N:11])[CH:5]=[C:6]([F:8])[CH:7]=1>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][NH2:11])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: N#CCc1cc(F)cc(F)c1
Solvent: C1CCOC1
Product: NCCc1cc(F)cc(F)c1

Procedure:
3,5 difluorophenylacetonitrile (5 g) was dissolved in THF (100 mL) and a solution of BH3 in THF (200 mL of 1 M) was added dropwise. The mixture was refluxed overnight, cooled in an ice bath, and the reaction quenched with methanol (20 mL). The solvent was removed by rotary evaporation and the residue partitioned between ethyl acetate and water. The organic layer was washed with sat NaCl and the solvent again removed to give product, which was used in the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]23[CH2:13][CH:12]2[CH2:11][NH:10][CH2:9]3)=[CH:4][CH:3]=1.[C:14](Cl)(=[O:16])[CH3:15]>>[C:14]([N:10]1[CH2:11][CH:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)([CH2:13]2)[CH2:9]1)(=[O:16])[CH3:15]
Reactant: Clc1ccc(C23CNCC2C3)cc1
Reactant: CC(=O)Cl
Product: CC(=O)N1CC2CC2(c2ccc(Cl)cc2)C1

Procedure:
Using the method of Example 15, 1-(p-chlorophenyl)-3-azabicyclo[3.1.0]hexane (Example 1) is reacted with acetyl chloride to give 3-acetyl-1-(p-chlorophenyl)-3-azabicyclo[3.1.0]hexane and then is converted to 1-(p-chlorophenyl)-3-ethyl-3-azabicyclo[3.1.0]hexane which is obtained as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([C:18]3[C:19]4[CH:31]=[CH:30][C:29](=[O:32])[N:28]([C:33]5[C:38]([F:39])=[CH:37][CH:36]=[CH:35][C:34]=5[F:40])[C:20]=4[N:21]=[C:22](S(C)(=O)=O)[N:23]=3)[CH:12]=2)=[O:9])=[CH:4][CH:3]=1.Cl.Cl.[NH:43]1[CH:47]=[CH:46][N:45]=[C:44]1[CH2:48][NH2:49]>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([C:18]3[C:19]4[CH:31]=[CH:30][C:29](=[O:32])[N:28]([C:33]5[C:38]([F:39])=[CH:37][CH:36]=[CH:35][C:34]=5[F:40])[C:20]=4[N:21]=[C:22]([NH:49][CH2:48][C:44]4[NH:43][CH:47]=[CH:46][N:45]=4)[N:23]=3)[CH:12]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(NC(=O)c2ccc(Cl)nc2)cc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: NCc1ncc[nH]1
Agent: Cl
Product: Cc1ccc(NC(=O)c2ccc(Cl)nc2)cc1-c1nc(NCc2ncc[nH]2)nc2c1ccc(=O)n2-c1c(F)cccc1F

Procedure:
The title compound was prepared as described in Example 1d from 6-chloro-N-{3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylphenyl}-3-pyridinecarboxamide and (1H-imidazol-2-ylmethyl)amine dihydrochloride: LC-MS m/z 599 (M+H)+, 1.92 min (ret time).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[NH2:19][C@@H:20]([CH2:25][C:26]1[N:27]=[CH:28][S:29][CH:30]=1)[C:21]([O:23][CH3:24])=[O:22]>CO.C(Cl)Cl>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:19][C@@H:20]([CH2:25][C:26]2[N:27]=[CH:28][S:29][CH:30]=2)[C:21]([O:23][CH3:24])=[O:22])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1cscn1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1cscn1)NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1

Procedure:
Following General Procedure A and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and methyl (S)-2-amino-3-(thiazol-4-yl)propionate hydrochloride (General Procedure H with methanol and HCl on methyl (S)-2-amino-3-(thiazol-4-yl)propyl acid (Synthetech)), the title compound was prepared as a solid (mp=136-139° C.). The reaction was monitored by tlc (Rf=0.4 in 10% MeOH/DCM) and the product was purified by recrystallization from DCM.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][C:8]1=[CH:17][C:18]([CH:20]=[C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]1[CH3:31])=O.[Cl:32]([O-:36])(=[O:35])(=[O:34])=[O:33].C([NH+]1C2=NC3C(N=C2N(CC)C1C#CC=C1N(CC)C2=NC4C(N=C2N1CC)=CC=CC=4)=CC=CC=3)C.C(#N)C>N1C=CC=CC=1>[Cl:32]([O-:36])(=[O:35])(=[O:34])=[O:33].[CH3:6][N+:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][C:8]=1[C:17]#[C:18][CH:20]=[C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]1[CH3:31]
Reactant: CN1C(=CC(=O)C=C2C=Cc3ccccc3N2C)C=Cc2ccccc21
Agent: CCN1C(=CC#CC2N(CC)c3nc4ccccc4nc3[NH+]2CC)N(CC)c2nc3ccccc3nc21
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: CC#N
Product: CN1C(=CC#Cc2ccc3ccccc3[n+]2C)C=Cc2ccccc21
Reaction time: 0.08 h
Yield: 35 %

Procedure:
Phosphoryl chloride (1.0 ml) is added to a stirred suspension of 1,3-Bis(1-methyl-2-(1H)-quinolylidene)acetone (0.68 g, 0.002 mol) in pyridine (10 ml). The mixture is stirred for 5 min., then the solid is collected and washed with a little pyridine, then with ether. The dye is converted to its perchlorate salt by solution in methanol, followed by addition of aqueous sodium perchlorate solution. After recrystallization from acetonitrile, the yield of purified dye is 0.30 g (36%) with the melting point indistinct. The following two dyes were prepared by procedures similar to that described above: 1,3-Diethyl-2-[(1,3-diethyl-1H-imidazo[4,5-b]quinoxalin-2-(3H)-ylidene)-1-propynyl]-1H-imidazo[4,5-b]quinoxalinium perchlorate. ##STR20##Recrystallized from acetonitrile. Purified yield 35%. mp > 300°. 1,3,3-Trimethyl-2-[(1,3,3-trimethyl-2-indolinylidene)-1-propynyl]-3H-indolium perchlorate. ##STR21##Recrystallized from methanol. Purified yield 43% mp 194°-7° dec.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C:13]2([C:26]([F:29])([F:28])[F:27])[O:17][N:16]=[C:15]([C:18]3[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=3)[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C[Si]([C:36]#[N:37])(C)C.[NH3:38].CO>[I-].[Zn+2].[I-]>[NH2:38][CH:22]([C:21]1[CH:24]=[CH:25][C:18]([C:15]2[CH2:14][C:13]([C:5]3[CH:6]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:8]=[C:3]([C:2]([F:30])([F:1])[F:31])[CH:4]=3)([C:26]([F:28])([F:27])[F:29])[O:17][N:16]=2)=[CH:19][CH:20]=1)[C:36]#[N:37]
Reactant: C[Si](C)(C)C#N
Reactant: O=Cc1ccc(C2=NOC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1
Reactant: N
Agent: [I-]
Agent: [Zn+2]
Solvent: CO
Product: N#CC(N)c1ccc(C2=NOC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1
Temperature: 0 °C

Procedure:
To a mixture of 0.83 g of 4-[5-[3,5-bis(trifluoromethyl)phenyl]-5-trifluoromethyl-4,5-dihydroisoxazole-3-yl]benzaldehyde and 0.36 g of trimethylsilylcyanide, 0.01 g of zinc iodide was added while stirring the mixture at 0° C. The resultant mixture was stirred at 60° C. for 10 minutes, and then left to be cooled down to room temperature. 2 mL of a 2M ammonia-methanol solution was added to the resultant reaction mixture, followed by continuing the stirring of the resultant reaction mixture at 50° C. further for 3.5 hours. After the completion of the reaction, the solvent was distilled off under reduced pressure and the resultant residue was purified by silica gel column chromatography eluting with ethyl acetate-hexane (1:2) to obtain 0.60 g of the objective substance as a brown resinoid.
Reaction SMILES: [Br:1]Br.[C:3]([C:6]1[CH:14]=[CH:13][C:9]2[N:10]=[CH:11][NH:12][C:8]=2[CH:7]=1)(=[O:5])[CH3:4].[BrH:15]>C(O)(=O)C>[BrH:1].[Br:15][CH2:4][C:3]([C:6]1[CH:14]=[CH:13][C:9]2[N:10]=[CH:11][NH:12][C:8]=2[CH:7]=1)=[O:5]
Reactant: CC(=O)c1ccc2nc[nH]c2c1
Reactant: BrBr
Agent: Br
Solvent: CC(=O)O
Product: O=C(CBr)c1ccc2nc[nH]c2c1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
1.21 g (7.6 mmol) of bromine in 5 ml of glacial acetic acid are added to a solution of 1.2 g (7.5 mmol) of 5-acetylbenzimidazole and 1.35 g of 48% strength aqueous HBr (=8 mmol of HB) in 15 ml of glacial acetic acid at room temperature. The mixture is stirred at 40° C. for 30 minutes and cooled and the product which has precipitated out is filtered off.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][CH2:9][CH2:10][CH2:11][NH:12][CH:13]2[CH2:16][CH2:15][CH2:14]2)=[C:6]([CH3:17])[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:25](Cl)(Cl)=[S:26].O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:7]([N:8]2[CH2:9][CH2:10][CH2:11][N:12]([CH:13]3[CH2:16][CH2:15][CH2:14]3)[C:25]2=[S:26])=[C:6]([CH3:17])[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(Cl)c1NCCCNC1CCC1
Reactant: S=C(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1cccc(Cl)c1N1CCCN(C2CCC2)C1=S
Reaction time: 0.25 h
Yield: 81 %

Procedure:
To a solution of the diamine of Step A (3.28 g) in dry chloroform (48 mL) was added dropwise under nitrogen at 0° C. triethylamine (3.62 mL). Thiophosgene (1.49 mL) was then added dropwise via syringe and the mixture was stirred in the cold for another 15 minutes. Stirring was continued at room temperature for 1.5 hours, water was added and the the pH was adjusted to 8 with triethylamine. The aqueous layer was further extracted with dichloromethane and the combined extracts were washed with 20% aqueous sodium chloride, dried over anhydrous potasium carbonate and evaporated to dryness. The residue was dissolved in dichloromethane and absorbed onto a column of Merck-60 flash silica gel. Elution with hexane-ethyl acetate 9:1 provided the title compound (3.1 g, 81%) which was further triturated and sonicated with hexane and hexane-ether. The off-white solid was collected, washed with hexane and dried (2.69 g, 75.3%), m.p. 89-91° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:8]=1[C:9]#[N:10])=[O:5])[CH3:2].Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:19]>>[NH2:10][C:9]1[C:8]2[C:7](=[CH:14][C:13]([F:15])=[CH:12][CH:11]=2)[N:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:17]=1[C:18](=[O:19])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)Nc1cc(F)ccc1C#N
Reactant: O=C(CBr)c1ccccc1
Product: CCOC(=O)n1c(C(=O)c2ccccc2)c(N)c2ccc(F)cc21

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 1 from 2-[(ethoxycarbonyl)amino]-4fluorobenzonitrile (step 1) and 2-bromoacetophenone.
Reaction SMILES: FC(F)(F)C([N:5]([CH2:15][CH2:16][CH2:17][CH:18]=[CH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1)=O.C(N(CC)CC)C.C([O:40][C:41](=[O:45])[C@H:42]([CH3:44])[NH2:43])C>CCOCC>[CH2:15]([NH:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([NH:43][C@H:42]([C:41]([OH:45])=[O:40])[CH3:44])=[O:11])=[CH:13][CH:14]=1)[CH2:16][CH2:17][CH:18]=[CH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCOC(=O)[C@H](C)N
Reactant: CCCCCCCCCC=CCCCN(C(=O)C(F)(F)F)c1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCCCCCCCCC=CCCCNc1ccc(C(=O)N[C@@H](C)C(=O)O)cc1

Procedure:
A solution of 4.75 g. of N-trifluoroacetyl-4-(4-tetradecenylamino)benzoyl chloride and 1.2 g. of triethylamine in 200 ml. of warm ether is treated with 1.55 g. alanine ethyl ester and refluxed for 24 hours. The hot solution is filtered, the residue is washed with hot ether, and the combined filtrate and washings are evaporated. After treatment of the residue with aqueous methanolic potassium carbonate, the product is precipitated by acidification, filtered, and dried. Crystallization from acetone yields the product a white, crystalline solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.O.[NH2:12][NH2:13]>C(O)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:12][NH2:13])=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: NN
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Solvent: CCO
Solvent: O
Product: NNc1ccc([N+](=O)[O-])cn1

Procedure:
To a solution of 2-chloro-5-nitropyridine (30 mmol, 5.0 g) in absolute ethanol was added a solution of hydrazine hydrate (320 mmol, 15.8 g) in ethanol using syringe pump. At the end of the addition, the reaction was refrigerated. The named product precipitated from the reaction medium, was collected by filtration, and recrystallized from ethanol.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N:11]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)[CH:4]=[CH:3][CH:2]=1.O=S(Cl)[Cl:26]>CO>[ClH:26].[N:11]1([C:9]2[CH:8]=[CH:7][CH:6]=[C:5]3[C:10]=2[N:1]=[CH:2][CH:3]=[CH:4]3)[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3cccnc23)CC1
Solvent: CO
Product: Cl
Product: c1cnc2c(N3CCNCC3)cccc2c1
Reaction time: 2 h

Procedure:
tert-Butyl 4-(quinolin-8-yl)piperazine-1-carboxylate (2.4 g, 7.66 mmol) was dissolved in methanol (50 ml) and SOCl2 was added to the solution dropwise at 0° C. The resulting solution was refluxed for 1 day and evaporated under reduced pressure. EtOAc (50 ml) was added to the residue and stirred for 2 hours to produce light yellow solid. The title compound was collected by filtration (1.7 g, 89%) as light yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:11]2[S:15][C:14]([C:16]([OH:18])=O)=[CH:13][CH:12]=2)=[N:4][O:5][C:6]=1[C:7]([F:10])([F:9])[F:8].C([N:26]1[CH2:31][CH2:30][NH:29][C@H:28]([CH3:32])[CH2:27]1)(OC(C)(C)C)=O.[ClH:33]>O1CCOCC1>[ClH:33].[CH3:32][C@@H:28]1[CH2:27][NH:26][CH2:31][CH2:30][N:29]1[C:16]([C:14]1[S:15][C:11]([C:3]2[C:2]([CH3:1])=[C:6]([C:7]([F:8])([F:9])[F:10])[O:5][N:4]=2)=[CH:12][CH:13]=1)=[O:18]
Reactant: Cc1c(-c2ccc(C(=O)O)s2)noc1C(F)(F)F
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1c(-c2ccc(C(=O)N3CCNC[C@H]3C)s2)noc1C(F)(F)F
Reaction time: 2 h
Yield: 86 %

Procedure:
Prepared from 5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carboxylic acid and 4-N-Boc-2-(R)-methyl-piperazine by the method described in Example 2 Method B. The reaction mixture was evaporated to a solid, triturated and filtered with the aid of water, then washed with a 1 N aqueous hydrochloric acid solution followed by water. The solid was air dried to afford intermediate N-Boc protected product as a colorless solid (106 mg, 92%). The Boc-protected intermediate was dissolved in a 4 N solution of hydrogen chloride in 1,4,-dioxane (2 mL) and stirred for 2 hr, after which time the reaction mixture was evaporated to approximately ¼ volume and diluted with ethyl ether (4 mL). The resulting solids were filtered and air dried to afford product as a colorless solid (85 mg, 86% overall). 1H NMR (D2O) 1.27 (d, J=7.5, 3H), 2.02 (s, 3H), 3.04 (dt, J=12.7, 3.1, 1H), 3.12-3.18 (m, 2H), 3.30-3.50m (m, 2H), 4.21 (d, J=14.5, 1H), 7.23 (s, 2H). 19F NMR −64.1. LC/MS 4.50 min, [M+1]+ 360.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5](C=O)=[CH:4][CH:3]=1.[CH:10](OC)([O:13][CH3:14])[O:11][CH3:12].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>CO>[CH3:12][O:11][CH:10]([O:13][CH3:14])[C:5]1[CH:8]=[CH:9][C:2]([Br:1])=[CH:3][CH:4]=1
Reactant: COC(OC)OC
Reactant: O=Cc1ccc(Br)cc1
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(OC)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
21.1 g (114 mmol) of 4-bromobenzaldehyde and 20 ml (182 mmol) of trimethyl orthoformate (both Fluka, Buchs, Switzerland) are dissolved in 35 ml of methanol, and 0.65 g (3.4 mmol) of p-toluenesulfonic acid monohydrate is added at room temperature (exothermic reaction). The reaction mixture is stirred at room temperature under nitrogen for 20 hours. The acid is then neutralised with 0.62 ml of 30% sodium methanolate solution in methanol (3.4 mmol); the reaction mixture is concentrated using a rotary evaporator and the residue is distilled. The title compound is obtained in the form of a colourless liquid. TLC: Rt =0.58 (hexane/ethyl acetate 2:1). B.p.: 90°-92° C. (4 mbar). 1H-NMR (CDCl3 ; 200 MHz): 7.50 and 7.32/each d, J=9 (2×2H); 5.36/s (1H); 3.31/s (6H).
Reaction SMILES: [Cl-].[NH4+].[N+:3]([C:6]1[CH:7]=[C:8]2[CH:14]=[N:13][N:12]([CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[C:9]2=[N:10][CH:11]=1)([O-])=O>C(O)C.C1COCC1.O.[Fe]>[O:18]1[CH2:17][CH2:16][CH:15]([N:12]2[C:9]3=[N:10][CH:11]=[C:6]([NH2:3])[CH:7]=[C:8]3[CH:14]=[N:13]2)[CH2:20][CH2:19]1
Reactant: O=[N+]([O-])c1cnc2c(cnn2C2CCOCC2)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1cnc2c(cnn2C2CCOCC2)c1
Temperature: 100 °C
Yield: 108.8 %

Procedure:
Iron (2.41 g, 42.3 mmol) and ammonium chloride (2.58 g, 48.4 mmol) are added to a solution of 5-nitro-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine (3 g, 12 mmol) in ethanol/THF/H2O (4:2:1, 35 mL). The mixture is heated at 100° C. for 2 h. The iron is removed by filtration through pad of Celite® and the filtrate was evaporated under reduced pressure. The residue is purified by flash column chromatography using a gradient of 70% ethyl acetate/petroleum ether to afford the title compound as an off-white solid (2.85 g, 93%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[C:18]2[C:17](=[O:19])[N:16]([CH3:20])[C:15](=[O:21])[N:14]([CH3:22])[C:13]=2[N:12]=[C:11](Cl)[C:10]=1[C:24]#[N:25].[C:26]1([CH:32]([NH2:40])[CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.NCC1C(N2CCOCC2)=NC2N(C)C(=O)N(C)C(=O)C=2C=1C1C=C(F)C=CC=1Br>>[NH2:25][CH2:24][C:10]1[C:11]([NH:40][CH:32]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[N:12][C:13]2[N:14]([CH3:22])[C:15](=[O:21])[N:16]([CH3:20])[C:17](=[O:19])[C:18]=2[C:9]=1[C:3]1[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[Br:1]
Reactant: Cn1c(=O)c2c(-c3cc(F)ccc3Br)c(C#N)c(Cl)nc2n(C)c1=O
Reactant: NC(Cc1ccccc1)c1ccccc1
Agent: Cn1c(=O)c2c(-c3cc(F)ccc3Br)c(CN)c(N3CCOCC3)nc2n(C)c1=O
Product: Cn1c(=O)c2c(-c3cc(F)ccc3Br)c(CN)c(NC(Cc3ccccc3)c3ccccc3)nc2n(C)c1=O

Procedure:
The title compound was prepared from Compound 47a (Example and 1,2-diphenylethanamine, according to procedure described in the synthesis of Compound 47. MS [m+H] calc'd C30H28BrFN5O2 588; found 588.