Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH:2]1[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[C:8](=[S:11])([O-:10])[CH3:9].[K+]>CN(C=O)C>[C:8](=[O:10])([S:11][CH:2]1[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1)[CH3:9]
Reactant: ClC1CCOCC1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SC1CCOCC1

Procedure:
A mixrue of 4-chlorotetrahydro-2H-pyran (1 g, 8.29 mmol) and potassium ethanethioate (0.947 g, 8.29 mmol) in DMF (15 mL) was stirred at 80° C. for 24 h. The reaction mixture was cooled down and partitioned between hexane and cold 1N Na OH. The organic layer was washed with brine, dried (MgSO4), removed the solvent to afford S-tetrahydro-2H-pyran-4-yl ethanethioate as a pale brown oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.68 (2 H, m), 1.90 (2 H, m), 2.32 (3 H, s), 3.55 (2 H, m), 3.68 (1 H, m), 3.91 (2 H, dt, J=11.83, 3.90 Hz). Into a solution of S-tetrahydro-2H-pyran-4-yl ethanethioate in DCm (3 mL) and water (3 mL) at −10° C., chlorine gas was bubbled for ˜5 min slowly until persistent greenish color was maintained. The mixture was stirred for 0.5 h at r.t. and blown with air for 5 min and diluted with ether (5 mL). The mixture was added to concentrated ammonium hydroxide (5mL, 128 mmol) at 0° C. over 10 min. The mixture was stirred for 1 h and evaporated to dryness. The residue was taken up with EtOAc and filtered through 2″ silica gel pad and eluted with EtOAc/hexane (80% to 100%) to afford tetrahydro-2H-pyran-4-sulfonamide as a brown solid (113 mg). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.88 (2 H, m), 2.08 (2 H, ddd, J=12.72, 3.65, 1.76 Hz), 3.15 (1 H, tt, J=12.06, 3.81 Hz), 3.40 (2 H, td, J=11.96, 2.27 Hz), 4.11 (2 H, dd, J=11.33, 4.28 Hz), 4.48 (2 H, br. s.).
Reaction SMILES: [C:1]1([NH:7][C:8]([NH:10][C:11]2[CH:12]=[C:13]([C:17]3[CH:31]=[CH:30][C:20]4[N:21]=[C:22]([NH:24][C:25]([NH:27][CH2:28][CH3:29])=[O:26])[S:23][C:19]=4[CH:18]=3)[CH:14]=[CH:15][CH:16]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N[C:33]1C=C(C2C=CC3N=C(NC(NCC)=O)SC=3C=2)C=CC=1.C(N(CC)CC)C.C1(C)C=CC=C(N=C=O)C=1>C1(C)C=CC=CC=1>[C:5]1([CH3:33])[CH:4]=[CH:3][CH:2]=[C:1]([NH:7][C:8]([NH:10][C:11]2[CH:12]=[C:13]([C:17]3[CH:31]=[CH:30][C:20]4[N:21]=[C:22]([NH:24][C:25]([NH:27][CH2:28][CH3:29])=[O:26])[S:23][C:19]=4[CH:18]=3)[CH:14]=[CH:15][CH:16]=2)=[O:9])[CH:6]=1
Reactant: CCNC(=O)Nc1nc2ccc(-c3cccc(N)c3)cc2s1
Reactant: CCNC(=O)Nc1nc2ccc(-c3cccc(NC(=O)Nc4ccccc4)c3)cc2s1
Agent: Cc1cccc(N=C=O)c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCNC(=O)Nc1nc2ccc(-c3cccc(NC(=O)Nc4cccc(C)c4)c3)cc2s1
Yield: 26 %

Procedure:
Similar to the synthesis of 1-(6-(3-phenylaminocarbonylaminophenyl)-2-benzothiazolyl)-3-ethylurea, a mixture of 1-(6-(3-aminophenyl)-2-benzothiazolyl)-3-ethylurea, triethylamine, and 3-tolyl isocyanate in toluene was reacted to give the desired compound 0.023 g (26%). LC/MS 446.2 (M+1); LC retention time 3.76 min.
Reaction SMILES: Br[C:2]1[N:3]([CH:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:16])[C:4]2[C:9]([C:10]=1[C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[Br-].[CH:24]1([Zn+])[CH2:26][CH2:25]1>O1CCCC1.O.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>[CH:24]1([C:2]2[N:3]([CH:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])[C:4]3[C:9]([C:10]=2[C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:26][CH2:25]1
Reactant: [Zn+]C1CC1
Reactant: COC(=O)c1c(Br)n(C(C)c2ccccc2)c2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1c(C2CC2)n(C(C)c2ccccc2)c2ccccc12
Temperature: 25 °C
Yield: 82 %

Procedure:
To a solution of methyl 2-bromo-1-(1-phenylethyl)-1H-indole-3-carboxylate (0.30 g, 0.84 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.09 g, 0.08 mmol) in tetrahydrofuran (20 mL) was added cyclopropylzinc(II) bromide (6.0 mL, 0.5 mol/L in tetrahydrofuran). The reaction mixture was stirred at reflux for 12 hours. After the reaction, it was cooled to room temperature and diluted with water (100 mL). The product was extracted with ethyl acetate (100 mL), dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (silica gel: ethyl acetate:petroleum ether=1:10) to give the crude product methyl 2-cyclopropyl-1-(1-phenylethyl)-1H-indole-3-carboxylate (0.22 g, 82%) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]=O)=[CH:4][CH:3]=1.[CH3:16][NH:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[BH4-].[Na+].O>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][N:17]([CH3:16])[CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:4][CH:3]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=O
Reactant: CNCCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1noc(-c2ccc(Br)cc2)c1CN(C)CCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-(4-Bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde (0.150 g, 0.56 mmol) and N-methyl-phenethylamine (0.10 mL, 0.67 mmol) were combined in MeOH and stirred at room temperature overnight. Once no starting material was seen by analytical LCMS, sodium borohydride (0.064 g, 1.69 mmol) was added and the reaction was stirred at room temperature for 1 hour. H2O was added and the mixture was extracted with EtOAc. The combined organic layers were dried and concentrated, and the residue was purified by silica gel chromatography to give the title compound.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]#[N:7])[CH:3]=[C:2]1[C:8]#[N:9].[H-].[Na+].[NH2:12]OP(=O)(C1C=CC=CC=1)C1C=CC=CC=1>CN(C=O)C>[NH2:12][N:1]1[CH:5]=[C:4]([C:6]#[N:7])[CH:3]=[C:2]1[C:8]#[N:9]
Reactant: NOP(=O)(c1ccccc1)c1ccccc1
Reactant: N#Cc1c[nH]c(C#N)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cc(C#N)n(N)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 81.7 %

Procedure:
To a solution of DMF (100 mL) was added 1H-pyrrole-2,4-dicarbonitrile (1.00 g, 8.54 mmol) followed by NaH, 60% dispersion in mineral oil (0.51 g, 12.8 mmol). The solution was stirred at rt for 15 min and then (aminooxy)(diphenyl)phosphine oxide (2.99 g, 12.8 mmol) was added, and the solution was heated to 80° C. for 2 h. Upon cooling to rt the solution was filtered washing with CH2Cl2. The solution was partially concentrated and a white precipitate formed which was filtered. The mother liquor was then evaporated under vacuum and subsequently purified by MPLC (Isco) 100% CH2Cl2 ramping to 9:1 v/v CH2Cl2-EtOAc. The resulting purified fractions were combined and concentrated in vacuo yielding 0.92 g of a white solid (6.98 mmol, yield 82%). 1H-NMR (DMSO-d6) (17.92 (d, J=1.8 Hz, 1H), 7.39 (d, J=1.9 Hz, 1H), 6.66 (s, 2H); MS [M+H]+=133.0; LCMS RT=0.96 min.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([O:15][C:16]1[CH:17]=[C:18]([CH2:24][C@H:25]([NH:30]C(OC(C)(C)C)=O)[C:26]([O:28][CH3:29])=[O:27])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>ClCCl>[NH2:30][C@@H:25]([CH2:24][C:18]1[CH:19]=[CH:20][C:21]([O:22][CH3:23])=[C:16]([O:15][CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:17]=1)[C:26]([O:28][CH3:29])=[O:27].[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4]
Reactant: COC(=O)[C@H](Cc1ccc(OC)c(OCc2ccccc2)c1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@@H](N)Cc1ccc(OC)c(OCc2ccccc2)c1

Procedure:
Trifluoroacetic acid (TFA; 25 mL) was added to a solution of (S)-methyl 3-(3-(benzyloxy)-4-methoxyphenyl)-2-((tert-butoxycarbonyl)amino)propanoate (5.00 g, 12.0 mmol) in dichloromethane (CH2Cl2; 50 mL) at 0° C. with stirring. The mixture was stirred for 1 h and then concentrated to dryness. The residue was azeotroped three times with EtOAc (20 mL for each portion) to remove residual TFA to afford crude compound (S)-methyl 2-amino-3-(3-(benzyloxy)-4-methoxyphenyl)propanoate as its TFA salt.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]([O:13][CH3:14])=[O:12])[NH:6]2.[H-].[Na+].I[CH3:18]>>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]([O:13][CH3:14])=[O:12])[N:6]2[CH3:18]
Reactant: CI
Reactant: COC(=O)c1cc2c(Br)cccc2[nH]1
Agent: [H-]
Agent: [Na+]
Product: COC(=O)c1cc2c(Br)cccc2n1C

Procedure:
The preparation is carried out as in Example 1.1, from 20 g (79 mmol) of methyl 4-bromo-1H-indole-2-carboxylate, from 3.8 g of 60% sodium hydride and from 6 ml of iodomethane. After reaction, the solvent is evaporated under reduced pressure and the residue is taken up in water. The mixture is extracted with ethyl acetate. The organic phase is dried and the solvent is evaporated under reduced pressure. The product is dried under reduced pressure. 20.6 g (77 mmol) of solid are obtained.
Reaction SMILES: [CH:1](=[C:3]1[CH2:8][C:7]2[CH2:9][CH:4]1[CH2:5][CH:6]=2)[CH3:2].[CH2:10]=[CH:11][CH3:12].C=C.C1(/C=C/C=C/C2C=CC=CC=2)C=CC=CC=1.B(C1C(F)=C(F)C(F)=C(F)C=1F)(C1C(F)=C(F)C(F)=C(F)C=1F)C1C(F)=C(F)C(F)=C(F)C=1F>C1(C)C=CC=CC=1>[CH2:1]=[CH2:2].[CH2:10]=[CH:11][CH3:12].[CH:1](=[C:3]1[CH2:8][CH:7]2[CH2:9][CH:4]1[CH:5]=[CH:6]2)[CH3:2]
Reactant: CC=C1CC2=CCC1C2
Agent: C(/C=C/c1ccccc1)=C\c1ccccc1
Agent: C=C
Agent: Fc1c(F)c(F)c(B(c2c(F)c(F)c(F)c(F)c2F)c2c(F)c(F)c(F)c(F)c2F)c(F)c1F
Solvent: C=CC
Solvent: Cc1ccccc1
Product: CC=C1CC2C=CC1C2
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
A 2 L batch reactor is charged with 500 mL of mixed alkanes, 75 mL of 5-ethylidene-1-norbornene, and 500 mL of liquefied propylene. The reactor is heated to 60° C., and is saturated with ethylene at 500 psig (3.4 MPa). In an inert atmosphere drybox, 10 μmol of a 0.005M solution in toluene of rac-[1,2-ethanediylbis(1-(2-methyl-4-phenyl)indenyl)]zirconium (trans,trans-1,4-diphenyl-1,3-butadiene and 10 μmol of a 0.005 m solution of B(C6F5)3 in toluene are combined and the mixture is transferred to the reactor to initiate polymerization. After 15 minutes, the reactor is vented and the solution is drained from the reactor. The polymer solution is combined with 100 mg of antioxidant and the volatiles are removed under reduced pressure in order to isolate the rubbery terpolymer of ethylene/propylene/ethylidene norbornene.
Reaction SMILES: [OH:1][CH:2]([C:9]1[CH:18]=[CH:17][C:16]([OH:19])=[C:15]2[C:10]=1[CH:11]=[CH:12][C:13](=[O:20])[NH:14]2)[CH:3]([NH:6][CH2:7][CH3:8])[CH2:4][CH3:5].[CH3:21][O-:22].[Na+].[Na]>CO>[CH:9]1([CH2:2][CH2:3][C:21]([O:19][C:16]2[CH:17]=[CH:18][C:9]([CH:2]([OH:1])[CH:3]([NH:6][CH2:7][CH3:8])[CH2:4][CH3:5])=[C:10]3[C:15]=2[NH:14][C:13](=[O:20])[CH:12]=[CH:11]3)=[O:22])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:10]1
Reactant: CCNC(CC)C(O)c1ccc(O)c2[nH]c(=O)ccc12
Reactant: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: CCNC(CC)C(O)c1ccc(OC(=O)CCC2CCCCC2)c2[nH]c(=O)ccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5 g of 5-(1-hydroxy-2-ethylaminobutyl)-8-hydroxycarbostyril was suspended in 20 ml of methanol, and sodium methylate prepared from 458 mg of sodium metal and 9.6 ml of absolute methanol was added to the suspension. The mixture was then concentrated to dryness, and the resulting residue was dissolved in 30 ml of dimethylformamide. 3.3 g of β-cyclohexylpropionyl chloride was then added dropwise to the mixture while cooling with ice-water. The mixture was then stirred for 1 hour at room temperature, and diethyl ether was added to the mixture. The precipitate formed was separated by filtration, washed with diethyl ether and recrystallized from a mixture of methanol and diethyl ether to obtain 3.86 g of 8-(β-cyclohexylpropionyloxy)-5-(1-hydroxy-2-ethylaminobutyl)carbostyril having a melting point of 233°-234° C. (with decomposition).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](/[CH:10]=[N:11]/[C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH2:22]=[C:23]([CH3:25])[CH3:24].B(F)(F)F.CCOCC>C(#N)C>[CH3:22][C:23]1([CH3:25])[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]([F:19])([F:20])[F:21])[CH:16]=2)[NH:11][CH:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH2:24]1
Reactant: C=C(C)C
Reactant: O=[N+]([O-])c1cccc(/C=N/c2ccc(C(F)(F)F)cc2)c1
Agent: FB(F)F
Solvent: CC#N
Solvent: CCOCC
Product: CC1(C)CC(c2cccc([N+](=O)[O-])c2)Nc2ccc(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 27.1 %

Procedure:
A mixture of [1-(3-nitro-phenyl)-meth-(E)-ylidene]-(4-trifluoromethyl-phenyl)-amine (18.2 g of crude, 62.1 mmol), isobutene (52 mL, 620.6 mmol) and boron trifluoride etherate (1.6 mL, 12.4 mmol) in acetonitrile in a hydrogenated kettle was stirred for two days at room temperature. The solution was evaporated in vacuo and the residue was crystallized by treating with ethyl acetate to give 5.9 g of 4,4-Dimethyl-2-(3-nitro-phenyl)-6-trifluoromethyl-1,2,3,4-tetrahydro-quinoline (yield: 27.1%).
Reaction SMILES: C(N(CC)C(C1C=CC=CC=1S([C:14]1[C@H:15]([CH3:38])[C@@H:16]2[C@@H:33]([C@H:34]([OH:36])[CH3:35])[C:32](=[O:37])[N:17]2[C:18]=1[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:20])=O)=O)C.[SH:41][C@@H:42]1[CH2:46][N:45]([CH3:47])[C@H:44]([C:48]([N:50]2[CH2:54][CH2:53][C@H:52]([NH:55][C:56]([O:58][CH2:59][C:60]3[CH:65]=[CH:64][C:63]([N+:66]([O-:68])=[O:67])=[CH:62][CH:61]=3)=[O:57])[CH2:51]2)=[O:49])[CH2:43]1>>[N+:66]([C:63]1[CH:62]=[CH:61][C:60]([CH2:59][O:58][C:56]([NH:55][C@H:52]2[CH2:53][CH2:54][N:50]([C:48]([C@H:44]3[N:45]([CH3:47])[CH2:46][C@@H:42]([S:41][C:14]4[C@H:15]([CH3:38])[C@@H:16]5[C@@H:33]([C@H:34]([OH:36])[CH3:35])[C:32](=[O:37])[N:17]5[C:18]=4[C:19]([O:21][CH2:22][C:23]4[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=4)=[O:20])[CH2:43]3)=[O:49])[CH2:51]2)=[O:57])=[CH:65][CH:64]=1)([O-:68])=[O:67]
Reactant: CCN(CC)C(=O)c1ccccc1S(=O)C1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@@H](C)O)[C@H]2[C@H]1C
Reactant: CN1C[C@@H](S)C[C@H]1C(=O)N1CC[C@H](NC(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CC[C@H](NC(=O)OCc5ccc([N+](=O)[O-])cc5)C4)N(C)C3)[C@H](C)[C@H]12
Yield: 60 %

Procedure:
Following a procedure similar to that described in Example 27(b), but using 4-nitrobenzyl (1R,5S,6S)-2-(2-diethylcarbamoylphenylsulfinyl)-1-methyl-6-[1(R)-hydroxyethyl]-1-carbapen-2-em-3-carboxylate [prepared as described in Example 27(a)] and (2S,4S)-4-mercapto-2-[3 (S)-(4-nitrobenzyloxycarbonyl)aminopyrrolidin-1-ylcarbonyl]-1-methylpyrrolidine as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as a powder in a yield of 60%.
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH3:13])=[N+:2]=[N-:3].[C:14]1([C:20]#[CH:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>C(O)CCC>[CH3:13][O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][N:1]1[CH:21]=[C:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=[N:2]1
Reactant: C#Cc1ccccc1
Reactant: COCCOCCOCCN=[N+]=[N-]
Solvent: CCCCO
Solvent: O
Product: COCCOCCOCCn1cc(-c2ccccc2)nn1

Procedure:
1-azido-2-(2-(2-methoxyethoxy)ethoxy)ethane (15.0 g, 79 mmol) was mixed with phenylacetylene (8.10 g, 79 mmol) in a 1:3 solution of water:butanol. The mixture was rotovap and the product extracted in ethanolamine and washed multiple times with water and brine, producing 1-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-4-phenyl-1H-1,2,3-triazole.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([Cl:17])[CH:3]=1.[CH3:18][N:19]([CH3:29])[C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[Cl:17][C:4]1[CH:3]=[C:2]([C:23]2[CH:24]=[CH:25][C:20]([N:19]([CH3:29])[CH3:18])=[CH:21][CH:22]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: CN(C)c1ccc(B(O)O)cc1
Reactant: Cc1c2n(c3c(Br)cc(Cl)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4ccc(N(C)C)cc4)cc(Cl)cc13)CCNC2=O

Procedure:
The title compound, white solid (31 mg, 35%), MS (ISP) m/z=354.5 [(M+H)+], mp 227° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-chloro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 12) (78.4 mg, 0.25 mmol) and commercially available 4-dimethylamino-phenylboronic acid (53.6 mg, 0.325 mmol).
Reaction SMILES: N#N.C([Si](C)(C)[O:8][CH2:9][C:10]1[S:11][CH:12]=[C:13]([C:15]2([CH3:20])[O:19][CH2:18][CH2:17][O:16]2)[CH:14]=1)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CC(=O)OCC>[CH3:20][C:15]1([C:13]2[CH:14]=[C:10]([CH2:9][OH:8])[S:11][CH:12]=2)[O:16][CH2:17][CH2:18][O:19]1
Reactant: CC1(c2csc(CO[Si](C)(C)C(C)(C)C)c2)OCCO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: N#N
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1(c2csc(CO)c2)OCCO1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of tert-butyl-dimethyl-[4-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-2-ylmethoxy]-silane (545 mg, 1.73 mmol) in dry THF (5.0 mL) was treated at 0° C. with TBAF (2.6 mL of a 1M solution in THF, 2.60 mmol). The reaction mixture was stirred at 0° C. for 2 h. The mixture was then diluted with EA (10 mL), washed with brine (3×20 mL), dried over MgSO4, filtered and concentrated under reduced pressure. Purification of the residue by FC (1:5 EA-Hept) gave the title compound as a colorless oil. TLC:rf (1:1 EA-Hept)=0.36. LC-MS-conditions 02: tR=0.70 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[S:14][CH2:13][CH:12]([C:15]([O:17]CC)=O)[NH:11][C:10]3[N:20]([CH3:29])[N:21]=[C:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)[C:9]2=3)=[C:4]([CH3:30])[CH:3]=1.[OH-].[Na+].[N:33]1(C(N2C=CN=C2)=O)C=CN=C1>O1CCOCC1.CN(C1C=CN=CC=1)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[S:14][CH2:13][CH:12]([C:15]([NH2:33])=[O:17])[NH:11][C:10]3[N:20]([CH3:29])[N:21]=[C:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)[C:9]2=3)=[C:4]([CH3:30])[CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCOC(=O)C1CSC(c2ccc(Br)cc2C)c2c(-c3ccccn3)nn(C)c2N1
Agent: CN(C)c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1cc(Br)ccc1C1SCC(C(N)=O)Nc2c1c(-c1ccccn1)nn2C
Temperature: 25 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
A mixture of rac-(4R,7S)-ethyl 4-(4-bromo-2-methylphenyl)-1-methyl-3-(pyridin-2-yl)-4,6,7,8-tetrahydro-1H-pyrazolo[3,4-e][1,4]thiazepine-7-carboxylate (0.170 g, 0.174 mmol, Preparation #39) and 2 M NaOH (1 mL, 2.00 mmol) in 1,4-dioxane (2 mL) was stirred at rt for about 2 h. The reaction was partitioned between 1 M HCl (40 mL) and EtOAc (50 mL). The organic layer was washed with brine (50 mL), dried with Na2SO4, filtered and was concentrated in vacuo. The residue was suspended in THF (4 ml) and di(1H-imidazol-1-yl)methanone (0.085 g, 0.52 mmol) was added followed by DMAP (0.026 g, 0.21 mmol). The reaction was stirred at rt for about 1 h. The reaction was quenched with NH4OH (5.0 mL) and extracted with EtOAc (50 mL). The organic layer was washed with brine (50 mL), dried with Na2SO4, filtered and was concentrated in vacuo. The residue was recrystallized from DCM/Et2O to give rac-(4R,7S)-4-(4-bromo-2-methylphenyl)-1-methyl-3-(pyridin-2-yl)-4,6,7,8-tetrahydro-1H-pyrazolo[3,4-e][1,4]thiazepine-7-carboxamide (0.080 g, 0.087 mmol, 50%), as a white solid: LC-MS (Table 1, Method g) Rt=2.12 min, m/z 458/460 (M+H)+; 1H-NMR (DMSO-d6, Bruker 400 MHz) δ 8.43-8.40 (m, 1H), 7.81-7.77 (m, 1H), 7.73-7.65 (m, 1H), 7.34 (d, J=1.8 Hz, 1H), 7.23-7.19 (m, 1H), 7.17-7.12 (m, 1H), 7.11-7.08 (m, 2H), 6.99 (s, 1H), 6.61 (s, 1H), 5.82 (d, J=5.0 Hz, 1H), 4.11-4.07 (m, 1H), 3.77 (s, 3H), 3.20 (dd, J=15.2, 5.5 Hz, 1H), 2.83 (dd, J=15.3, 2.8 Hz, 1H), 2.48 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C@H:6]1[O:8][CH2:7]1.[NH2:16][C:17]([CH3:36])([CH3:35])[CH2:18][C:19]1[CH:34]=[CH:33][C:22]([O:23][C:24]2[CH:32]=[CH:31][C:27]([C:28]([NH2:30])=[O:29])=[CH:26][CH:25]=2)=[CH:21][CH:20]=1>C(O)C>[NH2:1][C:2]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C@@H:6]([OH:8])[CH2:7][NH:16][C:17]([CH3:36])([CH3:35])[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([O:23][C:24]2[CH:32]=[CH:31][C:27]([C:28]([NH2:30])=[O:29])=[CH:26][CH:25]=2)=[CH:33][CH:34]=1
Reactant: CC(C)(N)Cc1ccc(Oc2ccc(C(N)=O)cc2)cc1
Reactant: Nc1c(OC[C@@H]2CO2)cccc1[N+](=O)[O-]
Solvent: CCO
Product: CC(C)(Cc1ccc(Oc2ccc(C(N)=O)cc2)cc1)NC[C@H](O)COc1cccc([N+](=O)[O-])c1N
Temperature: 55 °C
Yield: 61.7 %

Procedure:
A suspension of (S)-3-(2-amino-3-nitrophenoxy)-1,2-epoxypropane (5 g, 23.8 mmol) and 4-(4-(2-amino-2-methylpropyl)phenoxy)benzamide (20.3 g 71.1 mmol) in absolute ethanol (200 mL) was heated to 55° C. for 12 h. All solids went into solution at 50° C. Upon completion of the reaction, the solvent was evaporated to dryness. The residue was redissolved in ethyl acetate and washed with a saturated solution of sodium bicarbonate. The layers were separated and the aqueous phase was extracted with ethyl acetate. The two organic layers were combined and washed with brine. The phases were separated and the organic layer was dried over sodium sulfate, filtered, and the solvent evaporated. Column chromatography eluting with 20% MeOH/CHCl3 gave 7.26 g (62%) of product. NMR. MS.
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][O:5][C:6]([CH2:8]P(OCC)(OCC)=O)=[O:7].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[CH:22]=O>O1CCCC1>[CH2:4]([O:5][C:6](=[O:7])[CH:8]=[CH:22][C:21]1[CH:24]=[CH:25][C:26]([O:27][CH3:28])=[C:19]([O:18][CH3:17])[CH:20]=1)[CH3:3]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: COc1ccc(C=O)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C=Cc1ccc(OC)c(OC)c1

Procedure:
16.5 g (0.55 mol) of sodium hydride (80%) are stirred in 500 ml of tetrahydrofuran and 123.3 g (0.55 mol) of phosphonoacetic acid triethyl ester are added dropwise to give a clear solution. Then over 15 minutes a solution of 83.1 g (0.50 mol) of 3,4-dimethoxybenzaldehyde in 200 ml of tetrahydrofuran are added. The mixture is then stirred under reflux for 30 minutes. After cooling, the clear solution is separated from the insoluble material which is dissolved in 500 ml of water and extracted twice with 250 ml of toluene. The tetrahydrofuran solution is evaporated to dryness and the residue is dissolved in the toluene extract. This solution is washed three times with water, dried and the solvent evaporated.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1.[CH3:15][NH2:16]>O1CCCC1>[CH3:15][NH:16][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Reactant: CN
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(SC)nc1NC
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.8 %

Procedure:
A mixture of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (5.0 g, 21.5 mmol) and 29% methylamine (5.75 g, 53.72 mmol, methanol (MeOH) solution) in tetrahydrofuran (THF) (100 mL) was stirred at room temperature for 2 hours. The reaction mixture was then concentrated, followed by the addition of sodium bicarbonate (NaHCO3) (aq., 20 mL), and the resulting solution was extracted with ethyl acetate (EtOAc) (3×50 mL). The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered, and concentrated to afford ethyl 4-(methylamino)-2-(methylthio)pyrimidine-5-carboxylate (4.68 g, 96%) as a yellowish solid. MS (ES+) C9H13N3O2S requires: 227. found: 228 [M+H]+.