Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][S:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)=[CH:5][C:4]=1[O:18][CH3:19].C([Li])(C)(C)C.[Br:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]Br>O1CCCC1>[Br:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([O:18][CH3:19])[CH:5]=1)[S:10][C:11]1[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=1
Reactant: COc1ccc(CSc2ccc(C)cc2)cc1OC
Reactant: BrCCCCCBr
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COc1ccc(C(CCCCCBr)Sc2ccc(C)cc2)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 13.72 g of 1,2-dimethoxy-4-[[(4-methylphenyl)thio]methyl]benzene in 200 mL of tetrahydrofuran (dried over 3A sieves), under nitrogen, is cooled to -78° C. and 30 mL of 1.7M t-butyl lithium is added. After 30 minutes, the solution is transferred, via a canula, into a stirred solution of 14.0 mL of 1,5-dibromopentane in 25 ml of tetrahydrofuran, under nitrogen at -78° C. The reaction is slowly warmed to room temperature, and the reaction is quenched by the addition of 4 mL of acetone. The reaction is concentrated in vacuo and the residual material is dissolved in ethyl acetate and is washed with brine. Drying (sodium sulfate) and solvent removal affords 33.22 g of oil. The residue is purified via chromatography on silica gel with gradient elution progressing from hexane to chloroform to methyl alcohol to afford 10.82 g of the desired product as a tan gum.
Reaction SMILES: C([N:4]([C:11]1[C:35]([F:36])=[C:34]([NH:37]C(=O)C(C)(C)C)[C:14]2[C:15](=[O:33])[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25]C(=O)C(C)(C)C)=[C:21]([F:32])[CH:20]=3)[O:18][C:13]=2[C:12]=1[F:44])[CH2:5][CH2:6][CH2:7][N:8]([CH3:10])[CH3:9])(=O)C>S(=O)(=O)(O)O>[NH2:37][C:34]1[C:14]2[C:15](=[O:33])[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH2:25])=[C:21]([F:32])[CH:20]=3)[O:18][C:13]=2[C:12]([F:44])=[C:11]([NH:4][CH2:5][CH2:6][CH2:7][N:8]([CH3:10])[CH3:9])[C:35]=1[F:36]
Reactant: CC(=O)N(CCCN(C)C)c1c(F)c(NC(=O)C(C)(C)C)c2c(=O)cc(-c3ccc(NC(=O)C(C)(C)C)c(F)c3)oc2c1F
Agent: O=S(=O)(O)O
Product: CN(C)CCCNc1c(F)c(N)c2c(=O)cc(-c3ccc(N)c(F)c3)oc2c1F
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 82.1 %

Procedure:
549 mg (0.890 mmol) of the above 7-[N-acetyl-N-(3-dimethylaminopropyl)amino]-6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-5-pivaloylamino-4H-1-benzopyran-4-one was dissolved in 15 mL of concentrated sulfuric acid and the solution was stirred at 50° C. for 10 minutes. The reaction solution was poured into ice water, the mixture was adjusted to pH 8 and extracted once with ethyl acetate. The organic layer was washed once with water and once with an aqueous saturated solution of sodiumchloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol:aqueous ammonia=20:1:1) to give 297 mg of Compound 97 (yield: 82%). This compound was converted into hydrochloride according to the same manner as that in Example 96 (2).
Reaction SMILES: Br[CH:2]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[F:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19]>>[F:14][C:10]1[CH:9]=[C:8]([CH:2]([NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[C:16]([F:15])[CH:17]=2)[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:13]=[CH:12][CH:11]=1
Reactant: Nc1cccc(F)c1
Reactant: CCOC(=O)C(Br)c1cccc(F)c1
Product: CCOC(=O)C(Nc1cccc(F)c1)c1cccc(F)c1
Yield: 99 %

Procedure:
A solution of ethyl 2-bromo-2-(3-fluorophenyl)acetate (I9) (1.80 g, 6.84 mmol) in 3-fluoroaniline (6.50 mL, 68.0 mmol) is heated at 100° C. for 5 minutes under MW irradiation (LC-MS monitoring: complete conversion). The solvent is evaporated and the resulting crude is purified by flash chromatography (Hexane/EtOAc=9/1) in order to obtain 2.00 g of I10 as a yellow oil (99% yield).
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[CH:10]12[O:17][CH:14]([CH2:15][CH2:16]1)[CH2:13][NH:12][CH2:11]2>>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([N:12]2[CH2:11][CH:10]3[O:17][CH:14]([CH2:15][CH2:16]3)[CH2:13]2)[N:7]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: C1CC2CNCC1O2
Product: Clc1nc(Cl)nc(N2CC3CCC(C2)O3)n1
Yield: 47 %

Procedure:
The title compound was prepared by following the procedure of example 462 step 3 using cyanuric chloride and 8-oxa-3-azabicyclo[3.2.1]octane. Yield 10 g, 47% yield.
Reaction SMILES: [C:1]([C:4]1[C:13]([OH:14])=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)(=[O:3])[CH3:2].Cl[C:16]1[C:25]2[C:20](=[CH:21][C:22]([O:28][CH3:29])=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[CH:18][CH:17]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:27][O:26][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][C:22]=1[O:28][CH3:29])[N:19]=[CH:18][CH:17]=[C:16]2[O:14][C:13]1[C:4]([C:1](=[O:3])[CH3:2])=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: CC(=O)c1nc2ccccc2cc1O
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Solvent: O
Product: COc1cc2nccc(Oc3cc4ccccc4nc3C(C)=O)c2cc1OC
Temperature: 130 °C
Reaction time: 8 h
Yield: 13.6 %

Procedure:
2-Acetyl-3-quinolinol (22 mg), 4-chloro-6,7-dimethoxyquinoline (54 mg), and 4-dimethylaminopyridine (88 mg) were suspended in o-dichlorobenzene (5 ml), and the suspension was stirred at 130° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-hexane to give the title compound (6 mg, yield 13%).
Reaction SMILES: [CH2:1]([C:3]1[S:4][CH:5]=[C:6](/[CH:8]=[CH:9]/[C:10]2[C:11]([O:21][CH2:22][C:23]3[O:27][N:26]=[C:25]([O:28][CH2:29][C:30]4[N:31]=[C:32]([C:36]5[CH:41]=[CH:40][C:39]([CH2:42][C:43]([O:45]CC)=[O:44])=[CH:38][CH:37]=5)[O:33][C:34]=4[CH3:35])[CH:24]=3)=[N:12][N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:14]=2)[N:7]=1)[CH3:2].O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[CH2:1]([C:3]1[S:4][CH:5]=[C:6](/[CH:8]=[CH:9]/[C:10]2[C:11]([O:21][CH2:22][C:23]3[O:27][N:26]=[C:25]([O:28][CH2:29][C:30]4[N:31]=[C:32]([C:36]5[CH:41]=[CH:40][C:39]([CH2:42][C:43]([OH:45])=[O:44])=[CH:38][CH:37]=5)[O:33][C:34]=4[CH3:35])[CH:24]=3)=[N:12][N:13]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:14]=2)[N:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(-c2nc(COc3cc(COc4nn(-c5ccccc5)cc4/C=C/c4csc(CC)n4)on3)c(C)o2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CCc1nc(/C=C/c2cn(-c3ccccc3)nc2OCc2cc(OCc3nc(-c4ccc(CC(=O)O)cc4)oc3C)no2)cs1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a mixture of ethyl (4-{4-[({5-[({4-[(E)-2-(2-ethyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]isoxazol-3-yl}oxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenyl)acetate (193 mg), tetrahydrofuran (3 mL) and ethanol (3 mL) was added 1N aqueous sodium hydroxide solution (0.9 mL), and the mixture was stirred at 50° C. for 1 hr. To the reaction mixture were added 1N hydrochloric acid (0.9 mL) and water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was recrystallized from ethyl acetate-diethyl ether gave (4-{4-[({5-[({4-[(E)-2-(2-ethyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]isoxazol-3-yl}oxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenyl)acetic acid as colorless prism crystals (112 mg, yield 61%). melting point: 156-158° C.
Reaction SMILES: OS(O)(=O)=O.[Br:6][C:7]1[C:12]([C:13]#[N:14])=[C:11]([NH2:15])[CH:10]=[C:9]([NH2:16])[N:8]=1.[N+:17](OS(=O)(=O)O)([O-:19])=[O:18].[OH-].[Na+]>>[Br:6][C:7]1[C:12]([C:13]#[N:14])=[C:11]([NH2:15])[C:10]([N+:17]([O-:19])=[O:18])=[C:9]([NH2:16])[N:8]=1
Reactant: N#Cc1c(N)cc(N)nc1Br
Reactant: O=[N+]([O-])OS(=O)(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: N#Cc1c(Br)nc(N)c([N+](=O)[O-])c1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
460 Parts of concentrated H2SO4 are charged into a reaction vessel and 106.5 parts of 2-bromo-3-cyano-4,6-diamino-pyridine are added by small amounts whilst the temperature is kept at 15°-20° C by cooling with ice. After the starting material has dissolved completely, the solution is cooled to 10° to 15° C and at this temperature 69.1 g of nitrosulphuric acid (50%) are added dropwise in the course of 45 minutes. When the addition is complete, the reaction solution is stirred for 11/2 hours at room temperature, then poured onto 500 parts of ice so that the temperature does not exceed 20°-25° C (ice bath). The suspension is neutralised with 1000 parts of concentrated NaOH while cooling, whereupon the product precipitates completely. The brown product is filtered off, washed free of salt with 1500 parts of water and dried in vacuo at 70° C.
Reaction SMILES: [CH3:1][N:2]([CH2:10][C:11]([NH:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]1[N:19]=[C:20]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[CH:31]=2)[C:21]2[C:27](=[O:28])[NH:26][CH:25]=[CH:24][C:22]=2[N:23]=1)=[O:12])C(=O)OC(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:1][NH:2][CH2:10][C:11]([NH:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]1[N:19]=[C:20]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[CH:31]=2)[C:21]2[C:27](=[O:28])[NH:26][CH:25]=[CH:24][C:22]=2[N:23]=1)=[O:12]
Reactant: Cc1cccc(Nc2nc(NCCCNC(=O)CN(C)C(=O)OC(C)(C)C)nc3cc[nH]c(=O)c23)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCC(=O)NCCCNc1nc(Nc2cccc(C)c2)c2c(=O)[nH]ccc2n1
Reaction time: 1.5 h
Yield: 124.4 %

Procedure:
To a solution of 1,1-dimethylethyl methyl(2-{[3-({4[(3-methylphenyl)amino]-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidin-2-yl}amino)propyl]amino}-2-oxoethyl)carbamate (30 mg, 0.061 mmol) in Dichloromethane (DCM) (1 mL) was added TFA (0.5 mL, 6.49 mmol), and the reaction mixture was stirred for 1.5 h. It was concentrated and the residue was further dried under high vacuum to give 30 mg of pure product.
Reaction SMILES: ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[F:23][C:24]([F:28])([F:27])[CH2:25][NH2:26].[Cl:29][C:30]1[CH:35]=[CH:34][N:33]=[C:32]([C:36](O)=[O:37])[CH:31]=1>O.ClCCl>[F:23][C:24]([F:28])([F:27])[CH2:25][NH:26][C:36]([C:32]1[CH:31]=[C:30]([Cl:29])[CH:35]=[CH:34][N:33]=1)=[O:37]
Reactant: O=C(O)c1cc(Cl)ccn1
Reactant: NCC(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: O=C(NCC(F)(F)F)c1cc(Cl)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.5 %

Procedure:
1-hydroxybenzotriazole (0.53 g, 3.5 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (WSC) (0.67 g, 3.5 mmol) and 2,2,2-trifluoroethyl amine (0.51 ml. 6.35 mmol) were added to a dichloromethane solution (5 ml) of 4-chloropyridine-2-carboxylic acid (0.5 g, 3.17 mmol) and the mixture was stirred at room temperature for one hour. Water was added to the reaction solution, which was then extracted with ethyl acetate. The extraction solution with ethyl acetate was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=11:1→5:1). The purified product was concentrated to dryness under reduced pressure to obtain N-(2,2,2-trifluoroethyl)-4-chloropyridine-2-carboxamide (435 mg) as white powder.
Reaction SMILES: C(C1(COC2C(C3CC3)=CC(C(O)=O)=C(F)C=2)C2CC3CC(CC1C3)C2)#N.[CH:28]1([C:31]2[C:32]([O:41][CH2:42][CH:43]3[CH2:49][CH2:48][CH:47]4[CH:45]([C:46]4([F:51])[F:50])[CH2:44]3)=[CH:33][C:34]([F:40])=[C:35]([CH:39]=2)[C:36]([OH:38])=O)[CH2:30][CH2:29]1.CS(N)(=O)=O.[N:57]1([S:61]([NH2:64])(=[O:63])=[O:62])[CH2:60][CH2:59][CH2:58]1>>[N:57]1([S:61]([NH:64][C:36](=[O:38])[C:35]2[CH:39]=[C:31]([CH:28]3[CH2:29][CH2:30]3)[C:32]([O:41][CH2:42][CH:43]3[CH2:49][CH2:48][CH:47]4[CH:45]([C:46]4([F:50])[F:51])[CH2:44]3)=[CH:33][C:34]=2[F:40])(=[O:63])=[O:62])[CH2:60][CH2:59][CH2:58]1
Reactant: NS(=O)(=O)N1CCC1
Reactant: O=C(O)c1cc(C2CC2)c(OCC2CCC3C(C2)C3(F)F)cc1F
Agent: CS(N)(=O)=O
Agent: N#CC1(COc2cc(F)c(C(=O)O)cc2C2CC2)C2CC3CC(C2)CC1C3
Product: O=C(NS(=O)(=O)N1CCC1)c1cc(C2CC2)c(OCC2CCC3C(C2)C3(F)F)cc1F

Procedure:
Following the procedure as described in Example 332 Step 7 and making non-critical variations to replace 4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid with 5-cyclopropyl-4-((7,7-difluorobicyclo[4.1.0]heptan-3-yl)methoxy)-2-fluorobenzoic acid and to replace methanesulfonamide with azetidine-1-sulfonamide, the title compound was obtained as a colorless solid (0.025 g, 22%): 1H NMR (300 MHz, CDCl3) δ11.59 (br s, 1H), 7.11 (d, J=8.2 Hz, 1H), 7.03-6.87 (m, 1H), 4.14-3.77 (m, 6H), 2.94-2.50 (m, 1H), 2.43-1.49 (m, 8H), 1.48-1.06 (m, 2H), 1.06-0.75 (m, 3H), 0.75-0.56 (m, 2H); MS (ES+) m/z 459.07 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:17]2[C:22]([N+:23]([O-:25])=O)=[CH:21][CH:20]=[CH:19][N:18]=2)[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=O)=[CH:4][CH:3]=1>C(O)C.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:22]3[N:23]([OH:25])[C:9]=2[C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: O=C(c1ccncc1)C(c1ccc(F)cc1)c1ncccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: On1c(-c2ccncc2)c(-c2ccc(F)cc2)c2ncccc21
Reaction time: 6 h
Yield: 33.6 %

Procedure:
23 g (68.2 mmoles) of 2-(4-Fluoro-phenyl)-2-(3-nitro-pyridin-2-yl)-1-pyridin-4-yl-ethanone is dissolved in 700 mL of absolute ethanol. 2.2 g of 10% Palladium on charcoal is added to the solution which is stirred for 6 hours under a hydrogen atmosphere. The reaction mixture is filtered over celite, concentrated and the brown residue is purified by chromatography on silica gel (ethylacetate) to give 7 g of 3-(4-Fluoro-phenyl)-2-pyridin-4-yl-pyrrolo[3,2-b]pyridin-1-ol and 13 g of the starting material is recovered.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][C:16](=[O:18])[N:15]([CH3:19])[C:14]([CH3:20])=[C:13]1[C:21]([O:23]C)=[O:22]>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][C:16](=[O:18])[N:15]([CH3:19])[C:14]([CH3:20])=[C:13]1[C:21]([OH:23])=[O:22]
Reactant: COC(=O)C1=C(C)N(C)C(=O)CC1c1ccc(C(F)(F)F)cc1F
Solvent: C1CCOC1
Product: CC1=C(C(=O)O)C(c2ccc(C(F)(F)F)cc2F)CC(=O)N1C

Procedure:
The title compound was synthesized using the procedure stated in Example 1, Step 2 except that the product from Step 1 was used and THF was not used to yield product as an off white solid. MS (ES+) m/e 332 [M+H]+
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]([OH:10])=O)[N:5]=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.C(N(C(C)C)CC)(C)C.C[NH3+].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.Cl.[CH2:58]([O:60][C:61](=[O:74])[C:62]1[CH:67]=[CH:66][CH:65]=[C:64]([CH:68]2[CH2:73][CH2:72][NH:71][CH2:70][CH2:69]2)[CH:63]=1)[CH3:59]>CN(C=O)C>[CH2:58]([O:60][C:61](=[O:74])[C:62]1[CH:67]=[CH:66][CH:65]=[C:64]([CH:68]2[CH2:69][CH2:70][N:71]([C:8](=[O:10])[CH2:7][N:6]3[C:2]([CH3:1])=[CH:3][C:4]([C:11]([F:14])([F:13])[F:12])=[N:5]3)[CH2:72][CH2:73]2)[CH:63]=1)[CH3:59]
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)O
Reactant: CCOC(=O)c1cccc(C2CCNCC2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C[NH3+]
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cccc(C2CCN(C(=O)Cn3nc(C(F)(F)F)cc3C)CC2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 49.5 %

Procedure:
To a solution of (5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid (5.23 g, 20.75 mmol) in DMF (50 mL) was added diisopropylethylamine (43 mL, 207.58 mmol), followed by 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (10.52 g, 22.83 mmol) at RT. After stirring 15 min. at RT, 3-piperidin-4-yl-benzoic acid ethyl ester hydrochloride salt (5.6 g, 20.75 mmol) was added to the reaction mixture. After stirring overnight at RT, solvent was evaporated and the resulting brown oil was dissolved in ethylacetate (200 mL), washed with aq. sat. sodium bicarbonate solution (100 mL) and the aqueous phase was re-extracted with ethylacetate (200 mL). The combined organic layers were washed with 1M HCl solution (400 mL) and brine (400 mL), dried over sodium sulfate, filtered, and evaporated under reduce pressure. The crude mixture was purified by column chromatography on silica gel (ethylacetate/cyclohexane 0:1 to 1:1) to give 3-{1-[2-(5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-piperidin-4-yl}-benzoic acid ethyl ester (4.35 g, 49.5%). 1H-NMR (400 MHz, d6-DMSO): δ=1.28-1.39 (t, 3H), 1.45-1.55 (m, 1H), 1.65-1.1.79 (m, 1H), 1.80-1.91 (m, 2H), 2.22 (s, 3H), 2.68-2.73 (m, 1H), 2.89-2.95 (m, 1H), 3.99-4.04 (m, 1H), 4.29-4.33 (q, 2H), 4.46-4.52 (m, 1H), 5.21-5.38 (dd, 2H, diastereotopic), 6.50 (s, 1H), 7.47 (t, 1H), 7.55 (d, 1H), 7.80 (s, 1H), 7.81 (d, 1H). MS: m/z=424 (M+1).
Reaction SMILES: CC(C)([O-])C.[K+].[OH:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[CH:11]2.C(OC([N:27]1[CH2:32][CH2:31][C:30](=O)[CH2:29][CH2:28]1)=O)C1C=CC=CC=1>C(O)(C)(C)C.C(OCC)(=O)C>[OH:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[C:30]1[CH2:31][CH2:32][NH:27][CH2:28][CH:29]=1
Reactant: Oc1ccc2[nH]ccc2c1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: CCOC(C)=O
Product: Oc1ccc2[nH]cc(C3=CCNCC3)c2c1
Reaction time: 16 h
Yield: 92 %

Procedure:
Potassium tert-butoxide (2.81 g, 25.02 mmol) was added to a solution of 5-hydroxyindole (1.11 g, 8.34 mmol) in tert-butyl alcohol. 1-Benzyloxycarbonyl-4-piperidone (3.89 g, 16.67 mmol) was added to the purple reaction mixture at RT. After 16 h, the reaction mixture was diluted with ethyl acetate (100 ml) and washed with saturated sodium bicarbonate, brine, dried over MgSO4 and concentrated in vacuo. The residue was chromatographed (SiO2, 25-45% ethyl acetate/hexanes) to give 4-(5-hydroxyindol-3-yl)-1,2,3,6-tetrahydropyridine as a white solid (92%).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:12]=[CH:13][CH:14]=1)[O:6][CH2:7][C:8](=[O:11])[CH2:9][CH3:10].Cl.[H][H]>CO.C(OCC)(=O)C.CCCCCC>[F:1][C:2]([F:15])([F:16])[C:3]1[CH:4]=[C:5]([CH:12]=[CH:13][CH:14]=1)[O:6][CH2:7][CH:8]([OH:11])[CH2:9][CH3:10]
Reactant: CCC(=O)COc1cccc(C(F)(F)F)c1
Reactant: [H][H]
Agent: Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CO
Product: CCC(O)COc1cccc(C(F)(F)F)c1
Reaction time: 69 h

Procedure:
Using a steel capillary, 87.9 g of 1-(3-trifluoromethylphenoxy)butan-2-on, dissolved in 130 ml of methanol and 0.641 g of Ru2Cl4 [(R)-2,2'-bis(diphenylphosphino)-1,1'-dinaphthyl]2 [N(C2 H5)3 ]=Ru2Cl4 [(R)-BINAP]2 [N(C2 H5)3 ] and 1.2 ml of 1N hydrochloric acid are transferred in succession into a steel autoclave under an argon atmosphere. In 3 cycles (20 bar, atmospheric pressure), the argon inert gas is displaced by hydrogen, and the mixture is subsequently hydrogenated at 20° C. under a hydrogen pressure of 80 bar. After 69 hours, the hydrogen uptake has ended. The reaction mixture is removed from the steel autoclave and evaporated on a rotary evaporator. The residue obtained is dissolved in ethyl acetate/n-hexane 1/4 and filtered through a short silica gel column to remove the catalyst. After the collected fractions have been evaporated, the desired product is obtained in a yield of 87.9 g (99% of theory); refractive index nD22 1.4611; [α]36520 -18.7+0.2° (c=1.0 in methanol).
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[Cl:23][C:24]1[CH:44]=[CH:43][C:27]2[C:28](=[O:42])[C:29]3[C:36]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[N:35][NH:34][C:30]=3[C:31](=O)[NH:32][C:26]=2[CH:25]=1>C1(C)C=CC=CC=1>[Cl:23][C:24]1[CH:44]=[CH:43][C:27]2[C:28](=[O:42])[C:29]3[C:36]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[N:35][NH:34][C:30]=3[C:31](=[S:10])[NH:32][C:26]=2[CH:25]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)c1n[nH]c2c(=O)[nH]c3cc(Cl)ccc3c(=O)c12
Solvent: Cc1ccccc1
Product: CCOC(=O)c1n[nH]c2c(=S)[nH]c3cc(Cl)ccc3c(=O)c12
Yield: 82 %

Procedure:
To a suspension of Lawesson's Reagent [(2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide) (0.32 g. 0.80 mmol) in dry toluene (15 mL) at room temperature was added 7-chloro-3-(ethoxycarbonyl)pyrazolo-[3,4-c][1]benzazepine-4,10(1H,9H)-dione (0.51 g, 1.59 mmol) in one portion. The resulting slurry was heated to reflux for 1.5 hours. The reaction mixture was filtered to remove insoluble material. The filtrate was concentrated via rotary evaporator to give a green oil which was purified by flash chromatography using chloroform:methanol (9:1) as the eluent. The yellow-green solid recovered was recrystallized from methanol to give the title compound (0.44 g, 82%, mp 248.0-252.6° C.).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:4].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.I[CH2:28][CH2:29][CH2:30][CH3:31]>C1COCC1>[CH3:1][O:2][C:3]([C:5]1([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:9][CH2:8][CH2:7][N:6]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:4]
Reactant: CCCCI
Reactant: COC(=O)C1CCCN1C(=O)OC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCC1(C(=O)OC)CCCN1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 68.8 %

Procedure:
To a stirred solution of pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (3.00 g, 13.1 mmol) in THF (50 mL) at −78° C. and under nitrogen was added LHMDS (14.4 mL of 1.0 M solution in THF, 14.4 mmol) dropwise. After 30 minutes, a solution of 1-iodobutane (2.23 mL, 19.7 mmol) in THF (1 mL) was added dropwise. The reaction mixture was stirred for 30 minutes at −78° C., warmed to ambient temperature over 90 minutes, then quenched by the addition of saturated aqueous NH4Cl and extracted with EtOAc. The combined extracts were washed with saturated aqueous NaHCO3 and brine then dried (MgSO4), filtered and concentrated in vacuo to a yellow oil (4.5 g). Purification by chromatography (silica, 10% EtOAc in hexanes) gave 2-butyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (2.57 g, 9.01 mmol, 69%) as a clear colourless oil.
Reaction SMILES: [CH3:1][Si:2]([CH2:5][CH2:6][O:7][CH2:8]Cl)([CH3:4])[CH3:3].[Br:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[NH:18][CH:17]=[CH:16]2>CN(C=O)C>[Br:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[N:18]([CH2:8][O:7][CH2:6][CH2:5][Si:2]([CH3:4])([CH3:3])[CH3:1])[CH:17]=[CH:16]2
Reactant: Brc1cccc2cc[nH]c12
Reactant: C[Si](C)(C)CCOCCl
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ccc2cccc(Br)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
Sodium hydride in mineral oil (60% by wt., 0.62 g; 15.5 mmol) was washed with hexanes and suspended in DMF (40 mL). SEM-Cl (2.0 mL, 11.3 mmol) was added followed by a solution of 7-bromoindole in DMF (15 mL) dropwise over 5 min. The resultant white suspension was stirred overnight at room temperature and then the reaction was quenched with saturated aqueous NaHCO3. The mixture was poured into EtOAc and the organic layer was separated and washed with pH 7 buffer, saturated aqueous NaHCO3, brine dried (MgSO4) and concentrated to a light yellow oil. Flash chromatography (2 to 5% EtOAc/hexanes) afforded the title compound as a colorless oil (2.58 g, 79%). 1H NMR (400 MHz, DMSO-d6) 7.58–7.61 (m, 2H), 7.36 (d, J=8 Hz, 1H), 6.70 (dd, J=8, 8 Hz, 1H), 6.55 (d, J=3 Hz, 1H), 5.80 (2, 2H), 3.45 (t, J=8 Hz, 2H), 0.80 (t, J=8 Hz, 2H), 0.01 (s, 9H). 13C NMR (75.7 MHz, DMSO-d6) 132.58, 132.31, 131.92, 126.69, 121.19, 120.26, 103.50, 102.03, 75.69, 64.45, 17.18, −1.46. MS (FD+, m/z) 327, 325 (M+). HRMS 326.0570 (M++1, calcd for C14H21NOSiBr 326.0576).