Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.Br.[C:3]([C:7]1[N:11]=[C:10]([S:12][CH2:13][CH2:14][NH2:15])[NH:9][N:8]=1)([CH3:6])([CH3:5])[CH3:4].C(N(CC)CC)C.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1>C(Cl)Cl>[C:3]([C:7]1[N:11]=[C:10]([S:12][CH2:13][CH2:14][NH:15][C:32](=[O:33])[NH:31][C:28]2[CH:29]=[CH:30][C:25]([C:24]([F:23])([F:35])[F:34])=[CH:26][CH:27]=2)[NH:9][N:8]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)c1n[nH]c(SCCN)n1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Agent: Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)c1n[nH]c(SCCNC(=O)Nc2ccc(C(F)(F)F)cc2)n1
Temperature: -40 °C
Yield: 86 %

Procedure:
To 10 g (27 mmole) of 3-t-butyl-5-(2-aminoethylthio)-1H-1,2,4-triazole dihydrobromide in 100 ml of methylene chloride was added 5.5 g (54 mmole) of triethylamine. The mixture was cooled to -40° C. and a solution of 5.2 g (27 mmole) of 4-trifluoromethylphenyl isocyanate in methylene chloride was slowly added. The stirred mixture was slowly allowed to warm to room temperature and was stirred at room temperature for eighteen hours. The reaction mixture was washed twice with water, dried over magnesium sulfate, filtered and concentrated in vacuo to yield 9 g of 3-t-butyl-5-(2-(4-trifluoromethylphenylcarbamoylamino)-ethylthio)-1H-1,2,4-triazole, m.p. 238°-240° C.
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:17][CH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:12][C:13]([OH:16])([CH3:15])[CH3:14])[N:8]=1)=[O:5].C(N(CC)C(C)C)(C)C.CC1(C)O[C@H](CN2C=CC(NC(=O)[C@@H](N3[CH2:56][C:55]([O:57][C:58]4[C:63]([F:64])=[CH:62][CH:61]=[C:60]([O:65][CH2:66][CH3:67])[C:59]=4[F:68])=[CH:54][C:53]3=[O:69])CC(C)C)=N2)CO1>C(#N)C>[CH2:66]([O:65][C:60]1[C:59]([F:68])=[C:58]([C:63]([F:64])=[CH:62][CH:61]=1)[O:57][C:55]1[CH2:56][N:2]([CH:3]([CH2:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:4]([NH:6][C:7]2[CH:11]=[CH:10][N:9]([CH2:12][C:13]([OH:16])([CH3:14])[CH3:15])[N:8]=2)=[O:5])[C:53](=[O:69])[CH:54]=1)[CH3:67]
Reactant: CCOc1ccc(F)c(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)Nc3ccn(C[C@@H]4COC(C)(C)O4)n3)C2)c1F
Reactant: CC(C)(O)Cn1ccc(NC(=O)C(N)CC2CCOCC2)n1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccc(F)c(OC2=CC(=O)N(C(CC3CCOCC3)C(=O)Nc3ccn(CC(C)(C)O)n3)C2)c1F
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 14 %

Procedure:
A suspension of 2-amino-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-3-(tetrahydro-pyran-4-yl)-propionamide hydrochloride salt (766 mg, 2.0 mmol) in acetonitrile (15 mL) was treated with N,N-diisopropylethylamine (1.0 mL) and the resulting mixture stirred at 60° C. for 15 min. After this time N,N-diisopropylethylamine (0.5 mL) and a solution of (E)-4-bromo-3-(3-ethoxy-2,6-difluoro-phenoxy)-but-2-enoic acid ethyl ester (prepared in Example 116, 705 mg, 1.93 mmol) in acetonitrile (10 mL) were added and the resulting solution refluxed for 20 h. The resulting mixture was concentrated in vacuo and the residue partitioned between ethyl acetate and water. The layers were separated and the organic layer was dried over anhydrous sodium sulfate. The mixture was filtered and concentrated in vacuo and the residue dissolved in tetrahydrofuran (4 mL) and transferred to an Emrys Optimizer microwave tube and microwaved at 160° C. for 6 h. The mixture was concentrated in vacuo and the residue was purified by ISCO flash chromatography (RediSep silica 40 g, 5% to 80% (10% methanol/dichloromethane)/hexanes) which afforded 2-[4-(3-ethoxy-2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-3-(tetrahydro-pyran-4-yl)-propionamide (148 mg, 14%): HR-ES-MS (m/z) calculated for C27H34F2N4O6 [M+H]+ 549.2519, observed 549.2520; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.05 (br. s., 3H), 1.07 (br. s., 3H), 1.13-1.31 (m, 3H), 1.35 (t, J=6.9 Hz, 3H), 1.55-1.74 (m, 3H), 1.75-1.88 (m, 1H), 3.09-3.31 (m, 2H), 3.82 (br. s., 2H), 3.90 (s, 2H), 4.14 (q, J=6.9 Hz, 2H), 4.32 (d, J=18.6 Hz, 1H), 4.66 (br. s., 1H), 4.64 (d, J=18.6 Hz, 1H), 4.91 (dd, J=10.8, 4.4 Hz, 1H), 5.06 (s, 1H), 6.45 (d, J=1.8 Hz, 1H), 7.17 (td, J=9.4, 4.9 Hz, 1H), 7.27 (td, J=9.4, 1.3 Hz, 1H), 7.54 (d, J=1.8 Hz, 1H), 10.81 (s, 1H).
Reaction SMILES: C(Br)C(C1C=CC=CC=1)=O.C1OC1C1C=CC=CC=1.[CH3:20][C:21]([C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([Cl:30])[CH:24]=1)=[O:22].CCOC(C)=O>C(Cl)(Cl)Cl>[Cl:30][C:25]1[CH:24]=[C:23]([CH:28]=[C:27]([Cl:29])[CH:26]=1)[CH:21]1[O:22][CH2:20]1
Reactant: CC(=O)c1cc(Cl)cc(Cl)c1
Agent: O=C(CBr)c1ccccc1
Agent: c1ccc(C2CO2)cc1
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: Clc1cc(Cl)cc(C2CO2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The phenacyl bromide intermediate for the above-mentioned styrene oxide is prepared by brominating 10 g of 3,5-dichloroacetophenone in 50 ml of CHCl3 /50 ml of EtOAc with 23.6 g of CuBr2. The mixture is heated at reflux for 2.5 hours and cooled to room temperature. After stirring for 16 hours at room temperature, the mixture is cooled in ice for 2 hours and filtered. The filter cake is washed with 50 ml of CHCl3 and the combined filtrates are twice decolorized with activated carbon, filtered, and evaporated to dryness in vacuo to afford the orange oil of the 3,5-dichlorostyrene oxide.
Reaction SMILES: [H-].[Na+].[C:3]([O:10][CH3:11])(=[O:9])[CH2:4][C:5]([O:7][CH3:8])=[O:6].F[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[N+:20]([O-:22])=[O:21].Cl>CS(C)=O.CCOC(C)=O>[CH3:8][O:7][C:5](=[O:6])[CH:4]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[N+:20]([O-:22])=[O:21])[C:3]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)CC(=O)OC
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COC(=O)C(C(=O)OC)c1ccc(F)cc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 2 h
Yield: 89.4 %

Procedure:
To a mixture of NaH (60%, 7 g, 0.16 mol) in dimethyl sulfoxide (150 mL) was added dropwise dimethyl malonate (20 mL, 0.16 mol). The mixture was heated to 100° C. for 10 min then cooled to room temperature, followed by the addition of 2,5-difluoronitrobenzene (14 g, 0.08 mol). After stirred at 90° C. for 2 h, the mixture was cooled and poured into 5% aq.HCl with ice cooling. EtOAc (50 mL) was added and the organic phase was separated, washed by water and dried with Na2SO4. The solvent was removed in vacuo to give 2-(4-fluoro-2-nitro-phenyl)-malonic acid dimethyl ester (19.4 g). 2-(4-fluoro-2-nitro-phenyl)-malonic acid dimethyl ester (6 g, 22 mmol) was dissolved in glacial acetic acid (30 mL), the aqueous HCl (6N, 30 mL) was added and the reaction mixture were heated ar refluxing for 4 h, Iron power (5 g, 88 mmol) was added portionwise to the mixture and the refluxing was allowed to continue for another 2 h. The solvent was removed in vacuo and the remaining residue was extracted by EtOAc. The organic phase washed with aqueous HCl (1N), brine and dried over Na2SO4. concentrated to give the titled compound as a yellow solid (3 g, 89%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[N:26]=[CH:25][N:24]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:23]=2)=[N:10]1.Cl.[NH:34]1[CH2:39][CH2:38][O:37][CH:36]([CH2:40][C:41]([OH:43])=[O:42])[CH2:35]1>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([C:22]2[N:26]=[CH:25][N:24]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:23]=2)[NH:12][C:13]([CH2:20][N:34]2[CH2:39][CH2:38][O:37][CH:36]([CH2:40][C:41]([OH:43])=[O:42])[CH2:35]2)=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: O=C(O)CC1CNCCO1
Reactant: CCOC(=O)Cn1cnc(C2=NC(c3ccc(F)cc3Br)C(C(=O)OCC)=C(CBr)N2)n1
Agent: Cl
Product: CCOC(=O)Cn1cnc(C2=NC(c3ccc(F)cc3Br)C(C(=O)OCC)=C(CN3CCOC(CC(=O)O)C3)N2)n1
Yield: 53.3 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(1-(2-ethoxy-2-oxoethyl)-1H-1,2,4-triazol-3-yl)-1,4-dihydropyrimidine-5-carboxylate (0.57 g, 1 mmol) was reacted with 2-(morpholin-2-yl)acetic acid hydrochloride (0.3 g, 1.65 mmol) according to the procedure as described in Example 1, Step C to give the title compound as a yellow solid (0.34 g, 53%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [Cl-:1].[Mn+2:2].[Cl-].[S:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH:6]=[N:5]1.[OH2:13]>>[Cl-:1].[Mn+2:2].[S:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6](=[O:13])[NH:5]1.[Cl-:1]
Reactant: c1ccc2sncc2c1
Reactant: O
Agent: [Mn+2]
Agent: [Cl-]
Product: O=c1[nH]sc2ccccc12
Yield: 77 %

Procedure:
To a solution of 1.26 g (0.01 mol) of anhydrous manganese chloride was added 4.5 g (0.03 mol) of 1,2-benzisothiazolin in 30 ml of water. The solution was concentrated to give a tan colored solid. The solid was thoroughly washed with dry acetone, filtered and dried at room temperature to yield 3.47 g (77%) of product, m.p. >250° C.
Reaction SMILES: [CH3:1][SH:2].[CH2:3]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]Br)[C:4]1[CH:12]=[CH:11][C:10]2[O:9][CH2:8][O:7][C:6]=2[CH:5]=1.[OH-].[K+]>C(COC)OC>[CH2:3]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][S:2][CH3:1])[C:4]1[CH:12]=[CH:11][C:10]2[O:9][CH2:8][O:7][C:6]=2[CH:5]=1
Reactant: CS
Reactant: BrCCCCCCCCCCCCOCc1ccc2c(c1)OCO2
Agent: [K+]
Agent: [OH-]
Solvent: COCCOC
Product: CSCCCCCCCCCCCCOCc1ccc2c(c1)OCO2

Procedure:
Methyl mercaptan, 1.6 g. (0.032 mole) was bubbled into a solution of 13.0 g. (0.032 mole) of 12-bromododecyl piperonyl ether, and 5.6 g. (0.1 mole) of potassium hydroxide in 150 ml. of dimethoxyethane. When all had been added the resulting mixture was heated at reflux for 3 hours. After cooling and filtering, the solvent was removed by evaporation. The crude product was then dissoved in hexane and filtered. The filtrate was evaporated to give 8.5 g. of oily product. The NMR spectra was consistent with the assigned structure. The infrared spectra had strong adsorption peaks at 3.4, 3.5, 6.7, 6.95, 8.0, 9.0, 9.6, 10.6 and 12.2 microns. Analysis was as follows:
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C:2]#[C:3][CH3:4].[CH2:8]([SH:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]>C1CCN2C(=NCCC2)CC1.CCOCC>[CH2:8]([S:16]/[C:3](/[CH3:4])=[CH:2]/[C:1]([O:6][CH3:7])=[O:5])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CC#CC(=O)OC
Reactant: CCCCCCCCS
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOCC
Product: CCCCCCCCS/C(C)=C/C(=O)OC
Reaction time: 8 h

Procedure:
Two drops of DBU is added to methyl 2-butynoate (6.0 g) under N2. 1-Octanethiol (8.96 g, 61.2 mmol) is added dropwise over 20 min. with cooling with an ice bath. The mixture is allowed to come to RT and is stirred overnight. It is then diluted with ether, washed, dried and stripped and the product is purified by prep. TLC to give methyl (E)-3-octylthio-2butenoate.
Reaction SMILES: [H-].[Na+].[CH:3]1[C:12]2[C:7](=[CH:8][C:9]([N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:10][CH:11]=2)[CH:6]=[CH:5][N:4]=1.[Cl:19][C:20]1[CH:40]=[CH:39][C:23]([CH2:24][C@H:25]2[CH2:29]OS(=O)(=O)[N:26]2C(OC(C)(C)C)=O)=[CH:22][CH:21]=1.O>CN(C=O)C>[NH2:26][C@@H:25]([CH2:24][C:23]1[CH:22]=[CH:21][C:20]([Cl:19])=[CH:40][CH:39]=1)[CH2:29][NH:18][C:16]1[CH:15]=[N:14][N:13]([C:9]2[CH:8]=[C:7]3[C:12](=[CH:11][CH:10]=2)[CH:3]=[N:4][CH:5]=[CH:6]3)[CH:17]=1
Reactant: CC(C)(C)OC(=O)N1[C@@H](Cc2ccc(Cl)cc2)COS1(=O)=O
Reactant: Nc1cnn(-c2ccc3cnccc3c2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N[C@H](CNc1cnn(-c2ccc3cnccc3c2)c1)Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 22.8 %

Procedure:
A 60% dispersion of sodium hydride in mineral oil (9.6 mg, 251 μmol) was added to a mixture of 1-(isoquinolin-6-yl)-1H-pyrazol-4-amine (44 mg, 209 μmol) and (S)-tert-butyl 4-(4-chlorobenzyl)-1,2,3-oxathiazolidine-3-carboxylate-2,2-dioxide (109 mg, 314 μmol) in DMF (1 mL) at ambient temperature and the mixture was stirred at ambient temperature for 1.5 hours. H2O (15 mL) was added, and the mixture was extracted with DCM (4×15 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure. The resulting yellow solid was dissolved in DCM (3 mL), TFA (2 mL) was added, and the mixture was stirred at ambient temperature for 2 hours. Toluene (3 mL) was added, and the mixture was concentrated under reduced pressure. The resulting orange oil was dissolved in DCM, evaporated onto a silica gel plug, and purified by flash chromatography (Biotage Si 25+M, 5% to 10% 2 N NH3 in MeOH/DCM) to provide N-((S)-2-amino-3-(4-chlorophenyl)propyl)-1-(isoquinolin-6-yl)-1H-pyrazol-4-amine (18 mg, 23% yield) as an off-white solid. LCMS (API-ES) m/z (%): 412.2 (100%, M++H); 1H NMR (300 MHz, CDCl3) δ ppm 1.54 (br s, 3H), 2.62 (dd, J=13.1, 8.1 Hz, 1H), 2.79-2.94 (m, 2H), 3.15 (dd, J=11.8, 2.6 Hz, 1H), 3.25 (d, J=4.1 Hz, 1H), 7.17 (d, J=7.8 Hz, 2H), 7.31 (d, J=7.8 Hz, 2H) 7.45 (s, 2H), 7.64 (d, J=5.5 Hz, 1H), 7.89 (s, 1H), 8.00 (s, 2H), 8.51 (d, J=5.5 Hz, 1H), 9.20 (s, 1H). (S)-tert-Butyl 4-(4-chlorobenzyl)-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide was prepared in a similar manner as that described for (S)-tert-butyl 4-(4-(trifluoromethyl)benzyl)-1,2,3-oxathiazolidine-3-carboxylate-2,2-dioxide in Scheme 1, using (S)-2-(tert-butoxycarbonylamino)-3-(4-chlorophenyl)propanoic acid (commercially available from 3B Scientific Corporation Product List (Order Number 3B3-011434)) instead of (S)-2-(tert-butoxycarbonylamino)-3-(4-(trifluoromethyl)phenyl)propanoic acid.
Reaction SMILES: [CH3:1][Si:2]([CH3:14])([CH3:13])[C:3]#[C:4][CH2:5][O:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][O:8]1.Br[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH3:21]>>[CH3:14][Si:2]([CH3:13])([CH3:1])[C:3]#[C:4][CH:5]([O:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][O:8]1)[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH3:21]
Reactant: C[Si](C)(C)C#CCOC1CCCCO1
Reactant: CCC/C=C\CBr
Product: CCC/C=C\CC(C#C[Si](C)(C)C)OC1CCCCO1

Procedure:
Reaction of trimethyl(3-(tetrahydro-2H-pyran-2-yloxy)prop-1-ynyl)silane and (Z)-1-bromohex-2-ene according to General Procedure 11.A provided (Z)-trimethyl(3-(tetrahydro-2H-pyran-2-yloxy)non-5-en-1-ynyl)silane.
Reaction SMILES: [CH3:1][C@@:2]12[C:9]([CH3:11])([CH3:10])[CH:6]([CH2:7][CH2:8]1)[C:5](=[O:12])[CH2:4][C:3]2=[O:13].C(N(CC)CC)C.[Cl:21][C:22]1[CH:23]=[C:24]([N:29]=[C:30]=[O:31])[CH:25]=[CH:26][C:27]=1[Cl:28].Cl>CN(C)C1C=CN=CC=1.ClCCl>[Cl:21][C:22]1[CH:23]=[C:24]([NH:29][C:30]([CH:4]2[C:5](=[O:12])[CH:6]3[C:9]([CH3:10])([CH3:11])[C@:2]([CH3:1])([CH2:8][CH2:7]3)[C:3]2=[O:13])=[O:31])[CH:25]=[CH:26][C:27]=1[Cl:28]
Reactant: CC1(C)C2CC[C@]1(C)C(=O)CC2=O
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)C2CC[C@]1(C)C(=O)C(C(=O)Nc1ccc(Cl)c(Cl)c1)C2=O
Temperature: 30 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
To an ice-cooled solution of (1S)-1,8,8-trimethylbicyclo[3.2.1]octane-2,4-dione (0.18 g, 1.0 mmole), triethylamine (0.10 g, 1.0 mmole) and 4-(dimethylamino)pyridine (0.12 g, 1.0 mmole) in dry dichloromethane (25 mL) was added a solution of 3,4-dichlorophenyl isocyanate (0.19 g, 1.0 mmole) in dry dichloromethane (5 mL). The resulting mixture was allowed to stir overnight under a nitrogen atmosphere, during which time it came up to room temperature, and then was heated at 30° C. for 7 hours. The reaction mixture was treated with 2N aqueous HCl and the layers separated. The acidic aqueous layer was extracted with two additional portions of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated on a rotary evaporator to give a yellow oil, which was purified by chromatography on silica gel (10% ethyl acetate/hexane) to yield a yellow oil, which was crystallized from 95% ethanol to yield the title compound as a tan solid (0.21 g, 57% yield), mp=88–90° C.; MS (−) ESI m/z=366 (M−H)−; [α]D25=−24.8° (c=1, EtOH).
Reaction SMILES: [CH3:1][N:2]([CH3:33])[C:3]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:8][CH2:7][CH:6]([CH2:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][CH:19]=2)=[O:11])[CH2:5][CH2:4]1.[Cl:34][Si](C)(C)C.CCOCC>CC(CC)=O>[ClH:34].[CH3:33][N:2]([CH3:1])[C:3]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:8][CH2:7][CH:6]([CH2:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][CH:19]=2)=[O:11])[CH2:5][CH2:4]1
Reactant: C[Si](C)(C)Cl
Agent: CN(C)C1(c2ccccc2)CCC(CC(=O)NCCCCCc2c[nH]c3ccccc23)CC1
Solvent: CCC(C)=O
Solvent: CCOCC
Product: Cl

Procedure:
2-(4-Dimethylamino-4-phenylcyclohexyl)-N-[5-(1H-indol-3-yl)pentyl]-acetamide (112 mg, 0.25 mmol) was dissolved in ethyl methyl ketone (5 ml), and chlorotrimethylsilane (0.048 ml, 0.38 mmol) was added. After 1 h ether (15 ml) was added to the reaction mixture. The product was obtained as a pink-coloured solid in a yield of 90% (108 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][CH2:14][C:15]3[N:19]4[N:20]=[C:21]([C:24]5[S:28][C:27]([C:29](Cl)=[O:30])=[CH:26][CH:25]=5)[CH:22]=[CH:23][C:18]4=[N:17][N:16]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[CH2:32]([N:34](C(C)C)[CH:35](C)C)C.CNC>ClCCl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][CH2:14][C:15]3[N:19]4[N:20]=[C:21]([C:24]5[S:28][C:27]([C:29]([N:34]([CH3:35])[CH3:32])=[O:30])=[CH:26][CH:25]=5)[CH:22]=[CH:23][C:18]4=[N:17][N:16]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1ccc2c(OCc3nnc4ccc(-c5ccc(C(=O)Cl)s5)nn34)ccnc2c1
Agent: CNC
Solvent: ClCCl
Product: COc1ccc2c(OCc3nnc4ccc(-c5ccc(C(=O)N(C)C)s5)nn34)ccnc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)thiophene-2-carbonyl chloride (0.260 g, 0.58 mmol) in dichloromethane was added N-ethyl-N-isopropylpropan-2-amine (0.20 ml, 1.2 mmol) and dimethylamine (1.4 ml, 2.9 mmol). The solution was stirred at room temperature for one hour then was concentrated in vacuo. The residue was triturated with water and filtered; the resulting precipitate was triturated with acetonitrile and filtered to yield the product as an off-white solid. MS m/z=461.0 [M+1]+. Calc'd for C23H20N6O3S: 460.1.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH2:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(Cl)(Cl)Cl.ClC1C=C(C=CC=1)C(OO)=[O:22]>O>[C:1]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]2[O:22][CH2:10]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: C=Cc1ccc(OC(C)=O)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(=O)Oc1ccc(C2CO2)cc1
Reaction time: 24 h
Yield: 83.7 %

Procedure:
30 g of 4-acetoxy styrene and 1 L of chloroform were added into a 2 L reactor, and was stirred and cooled in iced water. 47 g of 3-chloroperoxybenzoicacid were added into the cooled solution, and the reaction was carried out at room temperature for 24 hours. After completion of the reaction, the 3-chlorobenzoicacid (by-product) was removed by filtering the product, and then the residual 3-chlorobenzoicacid was removed by washing 2 times with saturated sodium sulfite aqueous solution, 1 time with saturated sodium bicarbonate aqueous solution, 1 time with saturated sodium chloride aqueous solution, and 1 time with distilled water. Next, the product was dried with magnesium sulfate, and chloroform was removed under reduced pressure, and then the product was vacuum dried for 1 day to obtain 27.6 g of the pure 4-acetoxy styreneoxide.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH:17]1([NH:20][CH3:21])[CH2:19][CH2:18]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13](=[O:15])[N:20]([CH:17]1[CH2:19][CH2:18]1)[CH3:21])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CNC1CC1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CN(C(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C1CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of (S)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (1 eq.), cyclopropyl-methyl-amine hydrochloride (1.2 eq.), HOBt (1.5 eq.), EDAC (1.5 eq.) and TEA (3 eq.) in DMF was stirred at rt for 48 hours. The reaction was concentrated, diluted with sodium bicarbonate and extracted with DCM. The combined DCM was washed with brine, dried, concentrated, purified on a silica gel column to give (S)-2-(cyclopropyl-methyl-carbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH:1]([C@:3]12[CH2:41][CH2:40][C@@H:39]([C:42]([CH3:44])=[CH2:43])[C@@H:4]1[C@@H:5]1[C@@:18]([CH3:21])([CH2:19][CH2:20]2)[C@@:17]2([CH3:22])[C@@H:8]([C@:9]3([CH3:38])[C@@H:14]([CH2:15][CH2:16]2)[C:13]([CH3:24])([CH3:23])[C:12]([C:25]2[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:27][CH:26]=2)=[CH:11][CH2:10]3)[CH2:7][CH2:6]1)=O.C(O)(=O)C.[NH2:49][CH2:50][CH:51]1[CH2:55][CH2:54][CH2:53][N:52]1[CH2:56][CH3:57].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C([O-])(O)=O.[Na+]>[CH2:56]([N:52]1[CH2:53][CH2:54][CH2:55][CH:51]1[CH2:50][NH:49][CH2:1][C@:3]12[CH2:41][CH2:40][C@@H:39]([C:42]([CH3:44])=[CH2:43])[C@@H:4]1[C@@H:5]1[C@@:18]([CH3:21])([CH2:19][CH2:20]2)[C@@:17]2([CH3:22])[C@@H:8]([C@:9]3([CH3:38])[C@@H:14]([CH2:15][CH2:16]2)[C:13]([CH3:23])([CH3:24])[C:12]([C:25]2[CH:26]=[CH:27][C:28]([C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])=[CH:36][CH:37]=2)=[CH:11][CH2:10]3)[CH2:7][CH2:6]1)[CH3:57]
Reactant: C=C(C)[C@@H]1CC[C@]2(C=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CCN1CCCC1CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: C=C(C)[C@@H]1CC[C@]2(CNCC3CCCN3CC)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of tert-butyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-formyl-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (0.1 g, 0.167 mmol) in DCE (2 ml) was added acetic acid (1M in DCM) (0.167 ml, 0.167 mmol) and 2-(aminomethyl)-1-ethylpyrrolidine (0.029 ml, 0.200 mmol). The mixture was stirred for 15 minutes at rt and sodium triacetoxyborohydride (0.071 g, 0.334 mmol) was added. The mixture was stirred at rt for 1.5 h then an additional 0.1 g of sodium triacetoxyborohydride was added and the mixture was stirred at rt overnight. After 24 h of stirring, some starting material still remained by TLC. To the mixture was added acetic acid (1M in DCM) (0.167 ml, 0.167 mmol), 2-(aminomethyl)-1-ethylpyrrolidine (0.029 ml, 0.200 mmol), and sodium triacetoxyborohydride (0.071 g, 0.334 mmol). The mixture was stirred at rt for an additional 19 h then was diluted with 7 ml of sat. NaHCO3. The mixture was extracted with dichloromethane (3×7 ml) and the combined organic layers were dried with Na2SO4. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The mixture was purified by flash chromatography using a 0-10% MeOH in dichloromethane gradient. Two products were isolated as white foams. LC/MS indicated the same mass for both, with different retention times. 1H NMR confirmed that two diastereomers were isolated. 44 mg of diastereomer 1 (less polar spot by TLC) was isolated while 55 mg of diastereomer 2 (more polar spot) was isolated. Diastereomer 1: LCMS: m/e 711.4 (M+H)+, 3.34 min (method 6). Diastereomer 2: LCMS: m/e 711.6 (M+H)+, 3.27 min (method 6).