Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.N1C=CC=CC=1.Cl[C:15]([O:17][CH2:18][C:19]([Cl:22])([Cl:21])[Cl:20])=[O:16]>O1CCCC1>[N:3]1[CH:4]=[CH:5][N:6]=[CH:7][C:2]=1[NH:1][C:15](=[O:16])[O:17][CH2:18][C:19]([Cl:22])([Cl:21])[Cl:20]
Reactant: Nc1cnccn1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(Nc1cnccn1)OCC(Cl)(Cl)Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 3.4 %

Procedure:
To a solution of aminopyrazine (2.00 g, 21.0 mmol) and pyridine (5.10 ml, 63.1 mmol) in tetrahydrofuran was added 2,2,2-trichloroethyl chloroformate (4.34 ml, 31.5 mmol) with ice-cooling, the mixture was stirred for 2 hours with ice-cooling, the reaction mixture was poured into ice-water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain the desired product (193 mg, 3.4%) as a solid.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[CH3:14][N:15]1[C:19]([NH2:20])=[CH:18][CH:17]=[N:16]1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:14][N:15]1[C:19]([NH:20][C:7](=[O:8])[C:6]2[CH:10]=[CH:11][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=2)=[CH:18][CH:17]=[N:16]1
Reactant: Cn1nccc1N
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cn1nccc1NC(=O)c1ccc(C(F)(F)F)cc1
Reaction time: 2 h
Yield: 69.6 %

Procedure:
Under cooling in an ice bath, 4-(trifluoromethyl)benzoyl chloride (8.26 g) was added dropwise to a chloroform (35 mL) solution that contained 1-methyl-1H-pyrazol-5-amine (3.50 g) and triethylamine (5.50 mL), and the obtained solution was then stirred for 2 hours. Thereafter, the reaction solution was diluted with chloroform, and was then washed with a saturated sodium hydrogencarbonate aqueous solution and a saturated saline. The organic layer was dried over anhydrous sodium sulfate, and was then concentrated under a reduced pressure. The obtained solid was washed with diisopropyl ether, so as to obtain the title compound (6.75 g) in the form of a colorless solid.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13](=[O:35])[NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[S:27](=[O:34])(=[O:33])[NH:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:17][N:16]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl.C(Cl)(Cl)Cl>[C:29]([NH:28][S:27]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:13]([CH:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)=[O:35])=[N:16][CH:17]=1)(=[O:34])=[O:33])([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(NC(=O)C2CCCN2C(=O)OC(C)(C)C)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(NC(=O)C2CCCN2)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-[5-(2-tert-Butylsulfamoyl-phenyl)-pyridin-2-ylcarbamoyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.92 g, 1.83 mmol) was dissolved in 30 mL DCM, added 10 mL trifluoroacetic acid and stirred at ambient temperature for one hour. Concentrated solution, redissolved in CHCl3 and reconcentrated. Repeated co-concentration twice to yield title compound as an oil. (quant. yield) APCI (AP−): 401.1 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:14]([NH2:17])(=[O:16])=[O:15])[CH:5]=[N:6][C:7]=1[O:8][C@@H:9]1[CH2:13][CH2:12][NH:11][CH2:10]1.[F:18][CH:19]([F:22])[CH2:20]I.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([S:14]([NH2:17])(=[O:15])=[O:16])[CH:5]=[N:6][C:7]=1[O:8][C@@H:9]1[CH2:13][CH2:12][N:11]([CH2:20][CH:19]([F:22])[F:18])[CH2:10]1
Reactant: FC(F)CI
Reactant: NS(=O)(=O)c1cnc(O[C@@H]2CCNC2)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1cnc(O[C@@H]2CCN(CC(F)F)C2)c(Cl)c1
Temperature: 25 °C

Procedure:
A mixture of EXAMPLE 261B (353 mg), 1,1-difluoro-2-iodoethane (268 mg), sodium carbonate (283 mg) in N,N-dimethylformamide (10 mL) was heated at 80° C. overnight. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The organic phase was washed with water, brine, dried over magnesium sulfate, filtered, and concentrated. The residue was loaded onto silica gel column and eluted using a gradient of 0.5 to 3% methanol in dichloromethane to provide the title compound.
Reaction SMILES: [CH2:1]([C:9]1[CH:25]=[CH:24][C:12]([C:13]([N:15]2[CH2:20][CH2:19][C:18]3[CH:21]=[CH:22][O:23][C:17]=3[CH2:16]2)=[O:14])=[CH:11][CH:10]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1.[CH2:31]=O>C(O)(=O)C>[CH2:1]([C:9]1[CH:25]=[CH:24][C:12]([C:13]([N:15]2[CH2:20][CH2:19][C:18]3[CH:21]=[C:22]([CH2:31][N:26]4[CH2:30][CH2:29][CH2:28][CH2:27]4)[O:23][C:17]=3[CH2:16]2)=[O:14])=[CH:11][CH:10]=1)[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: C=O
Reactant: C1CCNC1
Reactant: O=C(c1ccc(CCc2ccccc2)cc1)N1CCc2ccoc2C1
Solvent: CC(=O)O
Product: O=C(c1ccc(CCc2ccccc2)cc1)N1CCc2cc(CN3CCCC3)oc2C1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of 1.078 g (3.253 mmol) of the above 6-(4-phenethylbenzoyl)-4,5,6,7-tetrahydrofuro[2,3-c]pyridine in 10 ml of acetic acid, 0.41 ml (4.88 mmol) of pyrrolidine and 0.40 g (4.88 mmol) of 37% aqueous formaldehyde were added, followed by stirring at 100° C. for 1 hour. After the solvent was distilled off under reduced pressure, the residual solution was alkalified with aqueous sodium hydroxide and extracted with ethyl acetate 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (ethyl-acetate to ethyl acetate/methanol=4/1) to yield the desired product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([O:23][CH3:24])[CH2:9][C@H:10]([CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[C:11]([O:13][CH3:14])=[O:12])=[CH:4][CH:3]=1.[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][C:27]=1[CH3:34].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>>[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][N:20]2[CH2:19][CH2:18][N:17]([CH2:16][CH2:15][C@@H:10]([CH2:9][C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[O:23][CH3:24])[C:11]([O:13][CH3:14])=[O:12])[CH2:22][CH2:21]2)=[CH:28][C:27]=1[CH3:34]
Reactant: Cc1cc(C=O)ccc1F
Reactant: COC(=O)[C@@H](CCN1CCNCC1)C[C@@H](OC)c1ccc(F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)[C@@H](CCN1CCN(Cc2ccc(F)c(C)c2)CC1)C[C@@H](OC)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (2S,4R)-methyl 4-(4-fluorophenyl)-4-methoxy-2-(2-(piperazin-1-yl)ethyl)butanoate (62 mg, 0.11 mmol) and 4-Fluoro-3-methyl-benzaldehyde (19.3 mg, 0.14 mmol) was added NaBH(OAc)3 (32.5 mg, 0.15 mmol) and AcOH (6.6 mg, 6 μL, 0.11 mmol) at room temperature. The mixture was stirred for 8 h at the room temperature. The reaction was quenched by pouring into 20 mL 5% aqueous NaOH and diluted with ethylacetate. The mixture was extracted with more ethyl acetate (3×15 mL) and the combined organic layers washed with brine (2×10 mL) and dried over Na2SO4. The mixture was concentrated under reduced pressure and the crude product was used directly in the next reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]3[S:11][C:10]([C:12]#[N:13])=[C:9]([OH:14])[C:7]=3[S:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][C:25]([O:27][CH3:28])=[O:26]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]3[S:11][C:10]([C:12]#[N:13])=[C:9]([O:14][CH2:24][C:25]([O:27][CH3:28])=[O:26])[C:7]=3[S:8][C:4]=2[CH:3]=1
Reactant: COC(=O)CBr
Reactant: N#Cc1sc2c(sc3cc(Cl)ccc32)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)COc1c(C#N)sc2c1sc1cc(Cl)ccc12
Yield: 90 %

Procedure:
A solution of 6-chloro-3-hydroxythieno[3,2-b][1]benzothiophene-2-carbonitrile (200 mg, 0.8 mmol), potassium carbonate (156 mg, 1.5 eq), methyl bromoacetate (110 μL, 1.5 eq) in DMF was heated at 60° C. for 1.5 h. The solution was diluted with ethyl acetate, washed with water and brine, dried, filtered, evaporated, and flash chromatographed (20-30% ethyl acetate/hexanes) to provide methyl [(6-chloro-2-cyanothieno[3,2-b][1]benzothien-3-yl)oxy]acetate (230 mg, 90%) as a white, fibrous solid.
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[N:20]=[CH:19][C:18]([O:21][CH2:22][CH:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)=[CH:17][N:16]=3)[CH:10]=2)[N:6]=[C:5]([C:29]2[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=2)[C:32]#[N:33])[CH:4]=[CH:3]1.C(O[BH-](O[C:47](=O)[CH3:48])OC(=O)C)(=O)C.[Na+].[C:51](O)(=O)C>CC(C)=O>[CH:47]([N:26]1[CH2:25][CH2:24][CH:23]([CH2:22][O:21][C:18]2[CH:17]=[N:16][C:15]([C:11]3[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=3)[CH2:8][N:7]3[C:2](=[O:1])[CH:3]=[CH:4][C:5]([C:29]4[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=4)[C:32]#[N:33])=[N:6]3)=[N:20][CH:19]=2)[CH2:28][CH2:27]1)([CH3:48])[CH3:51]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: N#Cc1cccc(-c2ccc(=O)n(Cc3cccc(-c4ncc(OCC5CCNCC5)cn4)c3)n2)c1
Reactant: CC(=O)O
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)N1CCC(COc2cnc(-c3cccc(Cn4nc(-c5cccc(C#N)c5)ccc4=O)c3)nc2)CC1
Temperature: 40 °C
Reaction time: 15 h

Procedure:
150 mg (0.22 mmol) of 3-(6-oxo-1-{3-[5-(piperidin-4-ylmethoxy)pyrimidin-2-yl]benzyl}-1,6-dihydropyridazin-3-yl)benzonitrile is suspended in 5 ml of acetone, and 94 mg (0.45 mmol) of sodium triacetoxyborohydride are added. 200 μl of acetic acid are added to the reaction mixture, which is then stirred at 40° C. for 15 h. A further 94 mg (0.45 mmol) of sodium triacetoxyborohydride are subsequently added, and the mixture is stirred at 40° C. for 24 h. The reaction mixture is filtered, and the residue is washed with THF. The filtrate is stripped off to dryness and purified by means of preparative HPLC.
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH2:14][CH2:13][C:12]2([CH2:23][C:22](=O)[C:21]3[C:16](=[CH:17][CH:18]=[C:19](/[CH:25]=[CH:26]/[C:27]([NH:29][OH:30])=[O:28])[CH:20]=3)[O:15]2)[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH2:31][O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.N1C=CC=CC=1>CCO>[CH2:2]([N:9]1[CH2:14][CH2:13][C:12]2([CH2:23][C:22](=[N:31][O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:21]3[C:16](=[CH:17][CH:18]=[C:19](/[CH:25]=[CH:26]/[C:27]([NH:29][OH:30])=[O:28])[CH:20]=3)[O:15]2)[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: NOCc1ccccc1
Reactant: O=C(/C=C/c1ccc2c(c1)C(=O)CC1(CCN(Cc3ccccc3)CC1)O2)NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: O=C(/C=C/c1ccc2c(c1)C(=NOCc1ccccc1)CC1(CCN(Cc3ccccc3)CC1)O2)NO
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.6 %

Procedure:
A mixture of (E)-3-{1′-benzyl-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-N-hydroxy-acrylamide hydrochloride (150 mg, 0.35 mmol), NH2OCH2Ph (94 mg, 0.76 mmol) and pyridine (61 μl, 0.700 mmol) in EtOH (10 ml) was heated to reflux. After 2 h, the solution was cooled down to RT and evaporated under vacuum. The crude residue was triturated with Et2O/H2O 90/10 to give (E)-3-{1′-benzyl-4-benzyloxyimino-spiro[chromane-2,4′-piperidine]-6-yl}-N-hydroxy-acrylamide (55 mg) as a 70/30 mixture of the two isomers (hydrochloride salts).
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[OH:15][C:16]1[CH:17]=[C:18]([CH:23]=[CH:24][C:25]=1[O:26][C:27]([F:30])([F:29])[F:28])[C:19]([O:21][CH3:22])=[O:20].[CH:31]1(O)[CH2:35][CH2:34][CH2:33][CH2:32]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH:31]1([O:15][C:16]2[CH:17]=[C:18]([CH:23]=[CH:24][C:25]=2[O:26][C:27]([F:28])([F:29])[F:30])[C:19]([O:21][CH3:22])=[O:20])[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: COC(=O)c1ccc(OC(F)(F)F)c(O)c1
Reactant: OC1CCCC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC(F)(F)F)c(OC2CCCC2)c1

Procedure:
Diisopropyl azodicarboxylate (0.61 mL) is added to a solution of methyl 3-hydroxy-4-trifiuoromethoxybenzoate (0.74 g), cyclopentanol (0.19 g) and triphenylphosphine (0.81 g) in tetrahydrofuran (10 mL) and the mixture is heated overnight at reflux. Solvent is evaporated off under reduced pressure and the resulting yellow oil is triturated with diethyl ether. The white solid thus formed is filtered off, and the flitrate is evaporated under reduced pressure and subjected to mplc, to give methyl 3-cyclopentyloxy-4-trifluoromethoxy-benzoate in the form of a pale yellow oil (0.6 g).
Reaction SMILES: [NH2:1][C:2]1[S:10][C:5]2[CH2:6][NH:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1.CCN(CC)CC.[C:27]1([N:33]=[C:34]=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(Cl)Cl>[NH2:1][C:2]1[S:10][C:5]2[CH2:6][N:7]([C:34]([NH:33][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:35])[CH2:8][CH2:9][C:4]=2[C:3]=1[C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1
Reactant: Nc1sc2c(c1C(=O)c1ccc(Cl)cc1)CCNC2
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Nc1sc2c(c1C(=O)c1ccc(Cl)cc1)CCN(C(=O)Nc1ccccc1)C2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 2-amino-3-(4-chlorobenzoyl)-4,5,6,7-tetrahydrothieno(2,3-c)pyridine) (1.02 mmol) in dry CH2Cl2 (20 mL), Et3N (1.2 eq) and phenylisocyanate (1.2 eq) were added. The mixture was stirred at room temperature for 4 hours, then was concentrated at reduced pressure and the residue purified by flash chromatography (EtOAc/light petroleum 3/7) to afford the desired compound as a solid (mp 216-217 ° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].C(N(C(C)C)CC)(C)C.[F:20][C:21]1[CH:22]=[C:23]2[C:28](=[C:29]([O:43][CH3:44])[C:30]=1[N:31]1[CH2:36][CH2:35][N:34]([CH2:37][CH2:38][O:39][CH2:40][CH2:41][OH:42])[CH2:33][CH2:32]1)[N:27]([C@@H:45]1[CH2:47][C@@H:46]1[F:48])[CH:26]=[C:25]([C:49](O)=[O:50])[C:24]2=[O:52]>CN(C)C=O.O>[Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH:5][C:49]([C:25]1[C:24](=[O:52])[C:23]2[C:28](=[C:29]([O:43][CH3:44])[C:30]([N:31]3[CH2:32][CH2:33][N:34]([CH2:37][CH2:38][O:39][CH2:40][CH2:41][OH:42])[CH2:35][CH2:36]3)=[C:21]([F:20])[CH:22]=2)[N:27]([C@@H:45]2[CH2:47][C@@H:46]2[F:48])[CH:26]=1)=[O:50]
Reactant: COc1c(N2CCN(CCOCCO)CC2)c(F)cc2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Reactant: NCc1ccc(Cl)cc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COc1c(N2CCN(CCOCCO)CC2)c(F)cc2c(=O)c(C(=O)NCc3ccc(Cl)cc3Cl)cn([C@@H]3C[C@@H]3F)c12
Temperature: 25 °C
Reaction time: 48 h
Yield: 59.4 %

Procedure:
140 mg (0.27 mmol) of 1-benzotriazolyloxytripyrrolidinophosphonium hexafluorophosphate, 47 mg (0.27 mmol) of 2,4-dichlorobenzylamine and 35 mg (0.27 mmol) of diisopropylethylamine are added under argon to 105 mg (0.14 mmol) of the carboxylic acid of Example 6A in 2 ml of dimethylformamide and the mixture is stirred at room temperature for 2 days. The reaction mixture is diluted with 2 ml of water and without further work-up purified by preparative HPLC (Method 4). 52 mg of the target compound are obtained.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:9][C:10]([F:22])([F:21])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17](Cl)(=[O:19])=[O:18].[OH-].[Na+]>>[F:22][C:10]([F:9])([F:21])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17]([N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)(=[O:18])=[O:19]
Reactant: O=S(=O)(Cl)c1ccccc1C(F)(F)F
Reactant: CNc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: CN(c1ccccc1)S(=O)(=O)c1ccccc1C(F)(F)F
Yield: 96 %

Procedure:
To 0.88 g (˜0.01 mole) of freshly prepared N-methylaniline (b.p. 196° C.) is added 2.0 g (˜0.01 mole) of 2-trifluoromethylbenzene-sulfonyl chloride (98 w/w %). The mixture is stirred until hot. Ten percent sodium hydroxide is then added dropwise with stirring until the solution is slightly alkaline. The 2-trifluoromethyl-N-methylbenzene-sulfonanilide is formed as a viscous light brown liquid. It is next washed with water several times until the wash water is neutral to litmus paper, and the viscous light brown liquid is extracted with ether. The ether layer is dried over magnesium sulfate, filtered and the solvent removed by evaporation. The yield of light brown oil is 2.5 g (96% yield). 1H NMR (deuterioacetone): δ 7.8.2 (m, 9 ArH), 3.2 (s, 3H, N—CH3)
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([CH2:11][O:12][CH3:13])[C:3]=1[C:4]#[N:5].CO.[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([CH2:11][O:12][CH3:13])[C:3]=1[CH2:4][NH2:5]
Reactant: COCc1cc(Cl)cc(Cl)c1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COCc1cc(Cl)cc(Cl)c1CN
Temperature: 60 °C

Procedure:
A solution of BH3 (3.5 mL, 1M in THF) was added to a solution of 2,4-dichloro-6-(methoxymethyl)benzonitrile (0.88 mmol) in 3 mL THF. The reaction mixture was heated to 60° C. for 2 h. At 0° C., 3.5 mL MeOH was dropwise added and the mixture was stirred until gas evolution was finished. An aq. solution of 10% NaOH was added still under cooling. The solvent was removed under vacuo, the residue was diluted with water and extracted 3 times with EtOAc. The combined organic layers were dried over MgSO4 and concentrated in vacuo to give the desired product as orange oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:27]=[CH:26][C:12]([O:13][C:14]2[C:22]3[CH2:21][CH2:20][CH2:19][C:18]=3[C:17](C=O)=[CH:16][C:15]=2[CH3:25])=[CH:11][C:10]=1[CH:28]([CH3:30])[CH3:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:31](=O)([O-:33])[OH:32].[Na+].ClC1C=CC=C(C(OO)=O)C=1>ClCCl>[CH:31]([O:33][C:17]1[CH:16]=[C:15]([CH3:25])[C:14]([O:13][C:12]2[CH:26]=[CH:27][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:10]([CH:28]([CH3:29])[CH3:30])[CH:11]=2)=[C:22]2[C:18]=1[CH2:19][CH2:20][CH2:21]2)=[O:32]
Reactant: Cc1cc(C=O)c2c(c1Oc1ccc(OCc3ccccc3)c(C(C)C)c1)CCC2
Reactant: O=C([O-])O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(OC=O)c2c(c1Oc1ccc(OCc3ccccc3)c(C(C)C)c1)CCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.7 %

Procedure:
7-(4-benzyloxy-3-isopropylphenoxy)-6-methylindan-4-carbaldehyde (712 mg) was dissolved in dichloromethane (10 mL). To the solution were added sodium hydrogen carbonate (582 mg) and m-chloroperbenzoic acid (399 mg), and the resulting mixture was stirred at room temperature overnight. Adding water, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the title compound (694 mg).
Reaction SMILES: OC(C(F)(F)F)=O.[F:8][C:9]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:10]=1[O:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[N:19]=[C:20]3[CH2:31][CH2:30][NH:29][CH2:28][C:21]3=[N:22][C:23]=2[NH:24][CH:25]([CH3:27])[CH3:26])[CH2:14][CH2:13]1.C(N(CC)CC)C.[N:44]1([C:49](Cl)=[O:50])[CH2:48][CH2:47][CH2:46][CH2:45]1>C(Cl)Cl>[F:8][C:9]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:10]=1[O:11][CH:12]1[CH2:13][CH2:14][N:15]([C:18]2[N:19]=[C:20]3[CH2:31][CH2:30][N:29]([C:49]([N:44]4[CH2:48][CH2:47][CH2:46][CH2:45]4)=[O:50])[CH2:28][C:21]3=[N:22][C:23]=2[NH:24][CH:25]([CH3:27])[CH3:26])[CH2:16][CH2:17]1
Reactant: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CCNC2
Reactant: O=C(Cl)N1CCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CCN(C(=O)N1CCCC1)C2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine TFA salt (45 mg, 0.087 mmol) in DCM (870 μL) at 0° C. was treated with triethylamine (36.4 μL, 0.261 mmol), followed by pyrrolidine-1-carbonyl chloride (19.2 μL, 0.174 mmol). The reaction mixture was allowed to stir for 30 min, gradually warming to room temperature. The reaction mixture was concentrated under reduced pressure and purified directly by HPLC Method B, with the exception that a Phenomenex Gemini® C18, 5 μm, ID 30×75 mm column was used, using a 50% to 80% ACN gradient to give the title compound, as a TFA salt, as a pale yellow solid (10.6 mg, 19.8%). 1H NMR (400 MHz, methanol-d4) δ ppm 1.33 (d, J=6.3 Hz, 6H), 1.89 (m, 4H), 1.97 (m, 2H), 2.14 (m, 2H), 2.81 (t, J=5.8 Hz, 2H), 3.13 (m, 2H), 3.46 (m, 6H), 3.61 (t, J=5.8 Hz, 2H), 4.12 (septet, J=6.4 Hz, 1H), 4.38 (s, 2H), 4.51 (tt, J=7.2, 3.6 Hz, 1H), 6.88 (m, 1H), 6.99 (ddd, J=11.4, 8.5, 3.0 Hz, 1H), 7.18 (td, J=9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]+ 501.6.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH2:5][OH:6])[CH2:3][OH:4].N1C=CN=C1.[C:13]([Si:17]([CH3:20])([CH3:19])Cl)([CH3:16])([CH3:15])[CH3:14].O>ClCCl>[C:13]([Si:17]([CH3:20])([CH3:19])[O:4][CH2:3][C:2]([CH3:7])([CH3:1])[CH2:5][OH:6])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(CO)CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: CC(C)(CO)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 881.2 %

Procedure:
A mixture of 2,2-dimethyl-propane-1,3-diol (Aldrich) (10 g, 96 mmol) and imidazole (9.8 g, 140 mmol) in dichloromethane (200 mL) was added tert-butyldimethylchlorosilane (15.9 g, 10.6 mmol). The reaction mixture was stirred at room temperature for 0.5 h. Water was added. The organic layer was separated, the aqueous layer was then extracted with dichloromethane. The combined organic layers were washed with brine, dried over MgSO4, concentrated to give 3-(tert-butyl-dimethyl-silanyloxy)-2,2-dimethyl-propan-1-ol as a colorless oil (20.4 g, 97%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)=[CH:9][CH:10]=O)[CH:5]=[CH:6][CH:7]=1.[C:19]([CH:24]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:21][CH2:22][CH3:23])=[O:20]>C(O)C>[CH2:22]([O:21][C:19](=[O:20])/[CH:24]=[CH:10]\[CH:9]=[C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[CH3:23].[CH2:22]([O:21][C:19](=[O:20])/[CH:24]=[CH:10]/[CH:9]=[C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[CH3:23]
Reactant: O=CC=C(c1cccc(Cl)c1)c1cccc(Cl)c1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCO
Product: CCOC(=O)/C=C/C=C(c1cccc(Cl)c1)c1cccc(Cl)c1
Product: CCOC(=O)/C=C\C=C(c1cccc(Cl)c1)c1cccc(Cl)c1

Procedure:
In the manner described in Example 99, 3,3-bis(3-chlorophenyl)-2-propenal (14.6 g) was reacted with (carbethoxymethylene)triphenylphosphorane (19.15 g) in ethanol (50 ml) for 30 minutes at ambient temperature. The mixture of esters obtained from the usual work up was purified by HPLC (dichloromethanehexane; 1:2) to provide 3.2 g of the less polar (Z)-5,5-bis(3-chlorophenyl)-2,4-pentadienoic acid ethyl ester as an oil, and 11.2 g of (E)-5,5-bis(3-chlorophenyl)-2,4-pentadienoic acid ethyl ester. A portion of the (E)-isomer (E)-5,5-bis(3-chlorophenyl)-2,4-pentadienoic acid ethyl ester was crystallized from 2-propanol to give the ester, mp 68°-69° C. Anal. Calculated for C19H16Cl2O2 :C, 65.72; H, 4.64; Cl, 20.42 Found: C, 65.26; H, 5.09; Cl, 20.00.