Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:14]2[CH:13]=[C:12](B(O)O)[CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.Br[C:20]1[CH:21]=[C:22]([C:27]2[N:32]=[C:31]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:30]=[C:29]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[N:28]=2)[CH:23]=[C:24](Br)[CH:25]=1.C([O-])([O-])=O.[K+].[K+].[N:51]1[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=1[C:57]1[CH:62]=[CH:61][C:60](B(O)O)=[CH:59][CH:58]=1>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.C(O)C.C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:18])[C:14]2[CH:13]=[C:12]([C:20]3[CH:21]=[C:22]([C:27]4[N:32]=[C:31]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[N:30]=[C:29]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)[N:28]=4)[CH:23]=[C:24]([C:60]4[CH:59]=[CH:58][C:57]([C:52]5[CH:53]=[CH:54][CH:55]=[CH:56][N:51]=5)=[CH:62][CH:61]=4)[CH:25]=3)[CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2
Reactant: Brc1cc(Br)cc(-c2nc(-c3ccccc3)nc(-c3ccccc3)n2)c1
Reactant: OB(O)c1ccc(-c2ccccn2)cc1
Reactant: CC1(C)c2ccccc2-c2ccc(B(O)O)cc21
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: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC1(C)c2ccccc2-c2ccc(-c3cc(-c4ccc(-c5ccccn5)cc4)cc(-c4nc(-c5ccccc5)nc(-c5ccccc5)n4)c3)cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 61.5 %

Procedure:
In a stream of argon, 0.95 g (4 mmol) of 9,9-dimethyl-2-fluoreneboronic acid, 1.87 g (4 mmol) of 2-(3,5-dibromophenyl)-4,6-diphenyl-1,3,5-triazine and 46.2 mg (0.04 mmol) of tetrakis(triphenylphosphine)palladium were suspended in a mixed solvent composed of 150 mL of toluene and 20 mL of ethanol, and the resultant suspension was heated to 50° C. To the suspension, 12 mL (12 mmol) of an aqueous 1M K2CO3 solution was gradually added dropwise, and the mixture was stirred for 18 hours. The resultant reaction mixture was cooled to room temperature, and then, 1.19 g (6 mmol) of 4-(2-pyridyl)phenylboronic acid and 12 mL (12 mmol) of an aqueous 1M K2CO3 solution were added to the reaction mixture. The resultant mixture was heated to 60° C., and maintained at that temperature for 2 hours while being stirred. The obtained reaction mixture was cooled to room temperature, and then distilled under a reduced pressure to remove all volatile materials. Methanol was added to the concentrate, and the thus-deposited solid was collected by filtration. The obtained crude product was purified by silica gel chromatography using a hexane/chloroform (1:2) mixed solvent as an eluent to give 1.61 g of the target 2-[5-(9,9-dimethylfluoren-2-yl)-4′-(2-pyridyl)biphenyl-3-yl]-4,6-diphenyl-1,3,5-triazine as a white solid (yield: 61.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]2[CH2:16][CH2:15][CH2:14][C@H:13]2[CH2:17][OH:18])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[CH:29][CH:28]=1.C(OCC)(=O)C>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[CH:29][CH:28]=2)[C@@H:12]2[CH2:16][CH2:15][CH2:14][C@H:13]2[CH2:17][OH:18])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: O=S(=O)(N[C@@H]1CCC[C@H]1CO)c1ccc(Cl)cc1
Reactant: N#Cc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1ccc(CN([C@@H]2CCC[C@H]2CO)S(=O)(=O)c2ccc(Cl)cc2)cc1
Reaction time: 2 h
Yield: 80.8 %

Procedure:
A suspension of 4-chloro-N-(trans-2-hydroxymethylcyclopentyl)benzenesulfonamide (290 mg, 1.0 mmol), cesium carbonate (652 mg, 2.0 mmol), and α-bromo-p-tolunitrile (253 mg, 1.2 mmol) in 2 mL dimethylformamide was stirred for 2 h. The reaction was diluted into 50 mL ethyl acetate and extracted with brine. The organic layer was concentrated and purified by flash chromatography on a 40 g silica gel column using a gradient of 20 to 70% ethyl acetate in hexane over 25 min. to give 4-chloro-N-(4-cyanobenzyl)-N-(trans-2-(hydroxymethyl)cyclopentyl)benzenesulfonamide (327 mg, 81%). 1H NMR (400 MHz, CDCl3) δ ppm 7.71 (2H, d, J=8.56 Hz), 7.57-7.63 (2H, m), 7.49 (3H, dd, J=10.83, 8.31 Hz), 4.64 (1H, d, J=16.62 Hz), 4.16 (1H, d, J=16.62 Hz), 3.99-4.12 (1H, m), 3.37-3.62 (2H, m), 1.99 (1H, t, J=6.17 Hz), 1.32-1.71 (7H, m). LC/MS R.T.=2.77 min; [M+H]+=404.12. HRMS [M+H]+ calc'd 405.1040, found 405.1054.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=O)=[CH:5][CH:4]=1.[CH2:18]([O:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([N+:30]([O-:32])=[O:31])[C:28]=1[OH:29])[CH:24]=O)[CH3:19].[NH2:33][C:34]([NH2:36])=[O:35].Cl>C(O)C>[CH2:18]([O:20][C:21]1[CH:22]=[C:23]([CH:24]2[C:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:36][C:34](=[O:35])[NH:33]2)[CH:26]=[C:27]([N+:30]([O-:32])=[O:31])[C:28]=1[OH:29])[CH3:19]
Reactant: NC(N)=O
Reactant: CCOc1cc(C=O)cc([N+](=O)[O-])c1O
Reactant: COc1ccc(CC(=O)c2ccccc2)cc1
Agent: Cl
Solvent: CCO
Product: CCOc1cc(C2NC(=O)NC(c3ccccc3)=C2c2ccc(OC)cc2)cc([N+](=O)[O-])c1O
Yield: 10.8 %

Procedure:
To a solution of 2-(4-methoxyphenyl)-1-phenylethanone (100 mg, 0.44 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (93 mg, 0.44 mmol), and urea (60 mg, 1.32 mmol) in 20 mL of ethanol was added 0.2 mL of concentrated HCl, the mixture was stirred at reflux for 4 days. After the solvent was removed under reduced pressure, the residue was purified by thin layer chromatography (PE:EtOAc=1:2) to give Compound 19 (22 mg, yield 10.8%). 1H NMR (CD3OD 400 MHz): δ7.55 (s, 1H), 7.20 (s, 5H), 7.12 (s, 1H), 6.73 (d, J=8.4 Hz, 2H), 6.57 (d, J=8.8 Hz, 2H), 5.25 (s, 1H), 4.05-4.00 (m, 2H), 3.61 (s, 3H), 1.35 (t, J=6.8 Hz, 3H); MS (ESI): m/z 462.2 [M+1]+.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3](=[O:18])[CH:4]([CH3:17])[N:5]1[C:9](C)=[CH:8][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:6]1.Cl[O:21][C:22](C)(C)C.BrBr.C(Cl)(Cl)(Cl)[Cl:29]>C(O)(=O)C>[Cl:29][C:8]1[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:21][CH3:22])=[N:6][N:5]([CH:4]([CH3:17])[C:3]([N:2]([CH3:19])[CH3:1])=[O:18])[CH:9]=1
Reactant: CC(C)(C)OCl
Reactant: Cc1cc(-c2ccccc2)nn1C(C)C(=O)N(C)C
Reactant: ClC(Cl)(Cl)Cl
Agent: BrBr
Solvent: CC(=O)O
Product: COc1ccccc1-c1nn(C(C)C(=O)N(C)C)cc1Cl

Procedure:
Following the procedure of Example 108, but substituting N,N,α-trimethyl-3-(o-methoxyphenyl)pyrazole-1-acetamide for N,N,α,5-tetramethyl-3-phenylpyrazole-1-acetamide, tert-butyl hypochlorite for bromine, and carbon tetrachloride for acetic acid as the reaction solvent, there was obtained 4-chloro-N,N,α-trimethyl-3-(o-methoxyphenyl)pyrazole-1-acetamide having a melting point of 74°-77° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([O:12][CH3:13])=[O:11])[CH:3]=[CH:2]1.[N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[CH2:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Cl)=[CH:28][CH:27]=1>>[CH3:13][O:12][C:10]([C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[N:1]([CH2:30][C:29]1[CH:28]=[CH:27][C:26]([O:25][CH2:24][C:15]3[CH:16]=[CH:17][C:18]4[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:14]=3)=[CH:33][CH:32]=1)[CH:2]=[CH:3]2)=[O:11]
Reactant: COC(=O)c1cccc2cc[nH]c12
Reactant: ClCc1ccc(OCc2ccc3ccccc3n2)cc1
Product: COC(=O)c1cccc2ccn(Cc3ccc(OCc4ccc5ccccc5n4)cc3)c12

Procedure:
This compound was prepared from methyl 7-indole carboxylate and 4-(quinolin-2-ylmethoxy)benzyl chloride (Example 1a) by the method described in Example 1b, part i. The residue was purified by chromatography on flash silica using petroleum spirit 40°-60° C./diethyl ether (2:1, 7:5) as eluent.
Reaction SMILES: Cl.N[CH2:3][CH2:4][SH:5].C1(C)C=CC=CC=1.C(N(CC)CC)C.[CH3:20][C:21]1[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][C:22]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31](=[N:34][O:35][CH3:36])[C:32]#[N:33]>O.O.C([O-])(=O)C.[Zn+2].C([O-])(=O)C.O>[CH3:36][O:35][N:34]=[C:31]([C:32]1[S:5][CH2:4][CH2:3][N:33]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[CH2:24][O:23][C:22]1[CH:37]=[C:38]([CH3:41])[CH:39]=[CH:40][C:21]=1[CH3:20]
Reactant: CON=C(C#N)c1ccccc1COc1cc(C)ccc1C
Reactant: NCCS
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Zn+2]
Solvent: O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CON=C(C1=NCCS1)c1ccccc1COc1cc(C)ccc1C
Yield: 79 %

Procedure:
2-Aminoethanethiol hydrochloride (2.80 g, 24.6 mmol), zinc acetate dihydrate (600 mg, 2.7 mmol), toluene (12 ml) and triethylamine (3.12 g, 30.8 mmol) were added to 2-(2,5-dimethylphenoxymethyl)-α-methoxyiminophenylacetonitrile (6.00 g, 20.4 mmol), and the mixture was stirred under reflux for 14 hours. After completion of the reaction, water (100 ml) was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 2-(2,5-dimethylphenoxymethyl)phenyl 2-thiazolin-2-yl ketone O-methyloxime (5.71 g, 79.0%) as crystals.
Reaction SMILES: C([BH-](CCCCC)CCCCC)CCCC.[K+].C1COCC1.[CH3:23][C:24](=[O:45])[C@@H:25]1[C@:42]2([CH3:43])[C@H:28]([C@H:29]3[C@H:39]([CH2:40][CH2:41]2)[C@:37]2([CH3:38])[C@H:32]([CH2:33][C:34](=[O:44])[CH2:35][CH2:36]2)[CH2:31][CH2:30]3)[CH2:27][CH2:26]1>C(Cl)(Cl)Cl>[OH:44][C@@H:34]1[CH2:35][CH2:36][C@@:37]2([CH3:38])[C@@H:32]([CH2:31][CH2:30][C@@H:29]3[C@@H:39]2[CH2:40][CH2:41][C@@:42]2([CH3:43])[C@H:28]3[CH2:27][CH2:26][C@@H:25]2[C:24](=[O:45])[CH3:23])[CH2:33]1
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CCCCC[BH-](CCCCC)CCCCC
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 0 °C
Reaction time: 2 h
Yield: 33 %

Procedure:
The reaction was carried out under a dry N2 atmosphere. Potassium trisamylborohydride solution (KS-Selectide) in THF (6 cc, 5.83 mmol) was introduced into a three neck round bottom flask and cooled to 0° C. 5α-Pregnan-3,20-dione (1.58 g, 5 mmol) dissolved in 10 ml of anhydrous chloroform was added to the cooled reducing agent. The resulting mixture was stirred vigorously for 2 hours at 0° C. and then allowed to equilibrate to room temperature for 1 hour. The reaction was quenched with 3 ml of water and 7 ml of ethanol. The organoborane was oxidized with 5 ml of 6 M NaOH and 7 ml of 30% H2O2. The reaction mixture was saturated with anhydrous potassium carbonate, and the organic layer was separated. The aqueous phase was neutralized with 0.1 N HCl and extracted with 20 ml of chloroform twice. The combined organic layers were dried over anhydrous MgSO4 and the solvent removed by rotary evaporation. Acetone was added to effect crystallization to produce a yield of 33%. The product has been identified by co-migration with authentic samples using silica based TLC and capillary GC. Melting point is 174°-175°. Elemental analysis: Calc. C=79.19, H=10.76. Obs. C=78.86, H=10.70, NMR: 200 MHz ppm delta; 0.59 (s)(CH3), 0.77 (s)(CH3). 0.9-2.0 (m) (CH2), 2.1 (s) (CH3--C=O), 2.5 (t) (17-H), 4.02 (t) (3-H equatorial). The preparation method is a modification of the method shown in Gyermek et al., "Steroids CCCX. Structure-Activity Relationship of Some Steroidal Hypnotic Agents," J. Med. Chem., 11:117-125 (1968).
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=[O:2].[F:24][C:25]1[C:32]([F:33])=[C:31]([F:34])[C:30]([F:35])=[C:29]([F:36])[C:26]=1[CH2:27]Br>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:10][CH2:11][C:4]([C:1]([O:3][CH2:27][C:26]4[C:29]([F:36])=[C:30]([F:35])[C:31]([F:34])=[C:32]([F:33])[C:25]=4[F:24])=[O:2])([CH2:9][CH2:8]2)[CH2:5][CH2:6]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: Fc1c(F)c(F)c(CBr)c(F)c1F
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)OCc3c(F)c(F)c(F)c(F)c3F)(CC1)CC2
Yield: 89.7 %

Procedure:
In a similar manner to Example 8, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (30.0 mg) and 2,3,4,5,6-pentafluorobenzyl bromide (26.6 mg) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-(2,3,4,5,6-pentafluorobenzyl)oxycarbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (41.9 mg).
Reaction SMILES: [H-].[Na+].CN(C)C=O.[C:8]1([SH:14])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[NH2:15][C:16]1[CH:21]=[C:20](Cl)[CH:19]=[CH:18][C:17]=1[N+:23]([O-:25])=[O:24]>O>[NH2:15][C:16]1[CH:21]=[C:20]([S:14][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:19]=[CH:18][C:17]=1[N+:23]([O-:25])=[O:24]
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: Sc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cc(Sc2ccccc2)ccc1[N+](=O)[O-]
Reaction time: 3 h

Procedure:
2.53 G. 57% sodium hydride in oil suspension in 20 ml. dimethylformamide is treated with 6.2 ml. thiophenol under nitrogen. 5.0 G. 2-amino-4-chloro-1-nitrobenzene is added and the mixture stirred for three hours. Water is added and the product filtered off and washed with water and hexane. Recrystallization from methanol gives pure 2-amino-4-phenylthio-1-nitrobenzene.
Reaction SMILES: C1COCC1.[C:6]([O:10][C:11](=[O:38])/[C:12](=[CH:23]/[C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH:34]=[C:33]([CH3:35])[N:32]=[CH:31]2)=[C:26]([O:36][CH3:37])[CH:25]=1)/[CH2:13][CH2:14][O:15][Si](C(C)(C)C)(C)C)([CH3:9])([CH3:8])[CH3:7].CCCC[N+](CCCC)(CCCC)CCCC.[F-].O>C(OCC)(=O)C>[C:6]([O:10][C:11](=[O:38])/[C:12](=[CH:23]/[C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH:34]=[C:33]([CH3:35])[N:32]=[CH:31]2)=[C:26]([O:36][CH3:37])[CH:25]=1)/[CH2:13][CH2:14][OH:15])([CH3:9])([CH3:8])[CH3:7]
Reactant: COc1cc(/C=C(\CCO[Si](C)(C)C(C)(C)C)C(=O)OC(C)(C)C)ccc1-n1cnc(C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(/C=C(\CCO)C(=O)OC(C)(C)C)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.7 %

Procedure:
To a THF (10 mL) solution of (E)-4-(tert-butyldimethylsilanyloxy)-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)butyric acid tert-butyl ester (122 mg), TBAF (1M THF solution, 318 μL) was added, and the reaction solution was agitated at room temperature for 1 hour. After confirming disappearance of the starting materials, water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: ethyl acetate->ethyl acetate:ethanol=10:1), and 49.7 mg of the title compound was obtained. The physical properties of the compound are as follows.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:20])/[CH:9]=[CH:10]/[C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=2)=[C:4]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:3]=1.[NH2:28][CH:29]1[CH2:34][CH2:33][CH:32]([OH:35])[CH2:31][CH2:30]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:20])/[CH:9]=[CH:10]/[C:11]2[CH:12]=[CH:13][C:14]([C:15]([NH:28][CH:29]3[CH2:34][CH2:33][CH:32]([OH:35])[CH2:31][CH2:30]3)=[O:17])=[CH:18][CH:19]=2)=[C:4]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:3]=1
Reactant: O=C(O)c1ccc(/C=C/C(=O)c2ccc(Cl)cc2Nc2ccccc2)cc1
Reactant: NC1CCC(O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CCC(O)CC1)c1ccc(/C=C/C(=O)c2ccc(Cl)cc2Nc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.3 %

Procedure:
A mixture of 4-[(E)-3-(4-chloro-2-phenylamino-phenyl)-3-oxo-propenyl]-benzoic acid (0.2 g, 0.53 mmol), 4-amino-cyclohexanol (61 mg, 0.53 mmol), EDCI (152 mg, 0.8 mmol), HOBt (25 mg), DIPEA (1 mL) in THF (50 mL) was stirred at RT overnight. The resulting mixture was evaporated under reduced pressure, and the residue partitioned between water and EtOAc. The resulting precipitate was collected by filtration and dried in a vacuum oven, the filtrate separated, the organic layer dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by preparative TLC (EtOAc/hexane, 75:25) and combined with the solid collected to yield 4-[(E)-3-(4-chloro-2-phenylamino-phenyl)-3-oxo-propenyl]-N-(4-hydroxy-cyclohexyl)-benzamide (197 mg). MS=475 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH3:8])[CH2:5][CH2:6][OH:7].[CH2:9](Br)[CH:10]=[CH2:11]>CC(C)=O>[CH2:11]([O:7][CH2:6][CH2:5][N:4]([CH3:8])[CH3:3])[CH:10]=[CH2:9]
Reactant: CN(C)CCO
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)=O
Product: C=CCOCCN(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (17.5 g) and dimethyl formaldehyde (400 mL) were added to a 2-L round-bottom flask. After cooling the flask to 0° C. by immersing in an ice bath, 2-dimethylaminoethanol (0.398 mol) was added. After stirring for about 30 minutes and adding allyl bromide (0.4378 mol), the mixture was stirred for 3 hours after raising the temperature of the reactor to room temperature. Upon completion of reaction, the reaction was terminated by adding water to the flask and the product was extracted using diethyl ether. The extract was concentrated under reduced pressure and used in the next step without further purification. After filtration under reduced pressure, 2-(allyloxy)-N,N-dimethylethanamine was obtained through fractional distillation. Structural analysis was performed by nuclear magnetic resonance (NMR) spectroscopy.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:8])=[N:4][CH:5]=[CH:6][CH:7]=1.I[CH3:10]>C1C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[Br:1][C:2]1[C:3]([O:8][CH3:10])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ncccc1Br
Reactant: CI
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: c1ccccc1
Product: COc1ncccc1Br
Reaction time: 24 h
Yield: 62.5 %

Procedure:
Under an argon atmosphere, a mixture of 3-bromo-2-hydroxypyridine (3.49 g, 20 mmol), silver carbonate (3.67 g, 13.31 mmol), and iodomethane (1.5 mL, 24.1 mmol) in benzene (30 mL) was stirred in the dark at 40° C. to 50° C. for 24 hours, cooled in an ice bath, and filtered. The filtrate was washed once with 2% aqueous sodium bicarbonate and twice with water, dried (MgSO4), the benzene was evaporated at atmospheric pressure, and the residue was purified by flash chromatography (eluting with hexane/ethyl acetate, 2:1) to 10 obtain the title compound (2.35 g, 12.5 mmol, 62%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1F)[CH3:2].[CH2:13]([O:15][CH2:16][CH2:17][NH2:18])[CH3:14].C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:18][CH2:17][CH2:16][O:15][CH2:13][CH3:14])[CH3:2]
Reactant: CCOC(=O)c1ccccc1F
Reactant: CCOCCN
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCOCCNc1ccccc1C(=O)OCC
Temperature: 120 °C

Procedure:
To a stirred solution of commercially available 2-Fluoro-benzoic acid ethyl ester (1 g, 6.01 mmol) and 2-Ethoxy-ethylamine (0.500 g, 2.97 mmole) in dry N,N′dimethylformamide (10 mL) in a screw cap vial was added diisopropylethylamine (1.1 eq, 0.223 g, 3.27 mmole, 1.1 mL). The resulting solution was heated to 120° C. for 4 hours. Reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate (25 mL×3). Combined organic phase was washed consecutively with water, brine before drying over sodium sulfate. Organic phase was evaporated and the residue was purified by flash chromatography to afford 2-(2-Ethoxy-ethylamino)-benzoic acid ethyl ester as a clear liquid (0.493 g, 70%, LCMS calc M+H 238, obs M+H 238).
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:9](=[O:11])C.[O-]C#N.[Na+].[C:16]1([N:22]2CC(=O)NN2)C=CC=C[CH:17]=1.[Cl-].[Na+]>C(O)(C)(C)C.O.O.C(O)(=O)C>[CH3:17][C:16]1[NH:22][C:9](=[O:11])[N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=1
Reactant: NNc1ccccc1
Reactant: CC=O
Reactant: O=C1CN(c2ccccc2)NN1
Agent: N#C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(C)(C)O
Solvent: O
Product: Cc1nn(-c2ccccc2)c(=O)[nH]1
Temperature: 5 °C
Yield: 91 %

Procedure:
A fifty gallon reactor was charged with 61.1 pounds of tert-butanol/water (88/12) which was stirred and cooled to 5° C. To this was added 22.0 pounds (0.203 lb-mole) of phenylhydrazine. While maintaining the temperature of the reaction mixture at 0 to 5° C., a solution of 9.3 pounds (0.211 lb-mole) of acetaldehyde in 20 pounds of tert-butanol/water (88/12) was added during a 90 minute period. After this time a mixture of 15.6 pounds (0.240 lb-mole) of 85% pure sodium cyanate in 44.5 pounds of water was added during a five-minute period. The addition caused the temperature of the reaction mixture to rise about 5° to 10° C. The reaction mixture was again cooled to 5° C. as it was stirred during a 30 minute period. While maintaining the reaction mixture at about 10° C., 14.8 pounds (0.247 lb-mole) of acetic acid was added during about a 30-45 minute period. Upon completion of the addition, the reaction mixture was stirred for three hours at about 10° C. until the reaction was complete. The reaction endpoint and the concentration of the phenyltriazolidinone intermediate was determined by gas chromatography. Upon completion of the reaction, a solution of 12.6 pounds of sodium chloride in 35.8 pounds of water was stirred into the reaction mixture. The aqueous phase was separated when the temperature of the reaction mixture was about 15° C. While maintaining the temperature of the reaction mixture at 20° C., 120.5 pounds of aqueous 11.1% (wt/wt) sodium hypochlorite (0.180 lb-mole) was added to the reaction mixture during a three-hour period. Upon completion of addition, the reaction mixture, was stirred for one hour at 20° C. After this time, 67.8 pounds of water was added to the reaction mixture and 73.4 pounds of tert-butanol/water (88/12) was removed by distillation at an overhead temperature of 80° C. The residue was cooled to 0° C., and a solid was collected by filtration. The solid was dried at 80° C./ 5mm Hg for 24 hours, yielding 32.2 pounds (91% yield) of 4,5-dihydro-3-methyl-1-phenyl-1,2,4-triazol-5(1H)-one.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[NH:12]=[C:13]1[N:17]([CH2:18][CH2:19][S:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:16]2[CH:27]=[CH:28][C:29]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:30][C:15]=2[S:14]1>C(O)C>[NH:12]=[C:13]1[N:17]([CH2:18][CH2:19][S:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:9])[C:16]2[CH:27]=[CH:28][C:29]([O:31][C:32]([F:34])([F:35])[F:33])=[CH:30][C:15]=2[S:14]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: N=c1sc2cc(OC(F)(F)F)ccc2n1CCSc1ccccc1
Solvent: CCO
Product: N=c1sc2cc(OC(F)(F)F)ccc2n1CCS(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 52.1 %

Procedure:
m-Chloroperbenzoic acid (0.6 g) is added in the course of approximately 10 minutes to 2-imino-3-(2-phenylthioethyl)-6-trifluoromethoxybenzothiazoline (1.3 g) in absolute ethanol (20 cc) cooled to 0° C. The reaction is continued for 3 hours at a temperature in the region of 20° C. The reaction medium is concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) and the residue obtained purified by chromatography on a silica column with ethyl acetate as eluent. (RS)-2-Imino-3-(2-phenylsulphinylethyl)-6-trifluoromethoxybenzothiazoline (0.7 g) is obtained in the form of a yellowish oil, which is converted to a hydrochloride, m.p. 210° C.