Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]([CH:25]([CH3:27])[CH3:26])[C:12]1[CH:17]=[CH:16][C:15]([C:18]([OH:24])([CH3:23])[C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=1)(=[O:10])=[O:9].[CH:28]1(B(O)O)[CH2:30][CH2:29]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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:28]1([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8]([N:11]([CH:25]([CH3:27])[CH3:26])[C:12]2[CH:17]=[CH:16][C:15]([C:18]([OH:24])([CH3:23])[C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=2)(=[O:10])=[O:9])[CH2:30][CH2:29]1
Reactant: CC(C)N(c1ccc(C(C)(O)C(F)(F)F)cc1)S(=O)(=O)c1ccccc1Br
Reactant: OB(O)C1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: CC(C)N(c1ccc(C(C)(O)C(F)(F)F)cc1)S(=O)(=O)c1ccccc1C1CC1
Temperature: 95 °C

Procedure:
To a vessel containing 2-bromo-N-isopropyl-N-(4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)benzenesulfonamide (ii) (prepared as in Example 1, 0.020 g, 0.043 mmol), cyclopropylboronic acid (0.0070 g, 0.086 mmol), K3PO4 (0.018 g, 0.086 mmol), and Pd(PPh3)4 (0.0050 mg, 0.0043 mmol) under nitrogen atmosphere was added degassed toluene (0.40 mL) and H2O (0.040 mL). The vessel was sealed under nitrogen atmosphere and heated in a 95° C. oil bath for 17.5 h. The reaction was cooled to room temperature, diluted with CH2Cl2 (2 mL), and extracted with H2O (1 mL). The combined organics were dried with Na2SO4, concentrated in vacuo, and purified by silica gel chromatography (gradient elution 5-20% ethyl acetate in hexanes) to afford 25. 1H NMR (400 MHz, CDCl3) δ 0.85-0.090 (m, 2H), 1.10-1.19 (m, 8H), 1.78 (s, 3 H), 2.42 (bs, 1 H), 2.70-2.80 (m, 1 H), 4.53 (septet, J=6.7, 1H), 6.86 (d, J=7.8 Hz, 1H), 7.14 (t, J=7.3, 1H), 7.21 (d, J=8.6, 2H), 7.41 (t, J=7 Hz, 1 H), 7.53 (d, J=8.4 Hz, 2H), 7.84 (d, J=8 Hz, 1H).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2=[C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:14]=[N:15][CH:16]=[C:11]2[C:10]([CH:25]=[O:26])=[C:9]1[CH3:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>C(O)C>[CH2:1]([N:8]1[C:12]2=[C:13]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:14]=[N:15][CH:16]=[C:11]2[C:10]([CH2:25][OH:26])=[C:9]1[CH3:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(C=O)c2cnnc(OCc3ccccc3)c2n1Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1c(CO)c2cnnc(OCc3ccccc3)c2n1Cc1ccccc1
Yield: 92 %

Procedure:
1.3 g (3.6 mmol) of 1-benzyl-7-benzyloxy-3-formyl-2-methylpyrrolo[2,3-d]pyridazine and 140 mg (3.7 mmol) of sodium borohydride are reacted in 125 ml of ethanol as described for Example 1a. Yield: 92%, m.p.: 130°-132° C.
Reaction SMILES: [O:1]=[CH:2][CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6]>CN(C=O)C>[CH:2]([CH:3]([CH:2]([OH:1])[CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6])[CH2:4][C:5]([O:7][CH3:8])=[O:6])=[O:1]
Reactant: COC(=O)CCC=O
Solvent: CN(C)C=O
Product: COC(=O)CCC(O)C(C=O)CC(=O)OC

Procedure:
(S)-Proline (14.9 mg, 0.13 mmol) was added to a stirred solution of 16 (150 mg, 1.29 mmol) in THF (650 μl). The reaction mixture was stirred at r.t. for 14 h. The reaction mixture was purified directly by column chromatography, eluting with petrol/EtOAc (2:1), to give the aldehydes 17 and SI-3 (as a 3.6:1 mixture of anti:syn diastereoisomers, 91 mg, 61%) as a clear colourless oil. The reaction was also conducted on a 244 mg scale of aldehyde 16 in DMF which gave a 2:1 ratio of anti:syn diastereoisomers (100 mg, 41%).
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11](=O)[C:12]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[CH:15]=[C:14]([CH3:25])[C:13]=1[F:26]>C1COCC1>[F:1][C:2]1[C:3]([NH:10][CH2:11][C:12]2[CH:17]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)[CH:15]=[C:14]([CH3:25])[C:13]=2[F:26])=[C:4]([F:9])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: Cc1cc(-c2cccc(F)c2)cc(C(=O)Nc2c(F)ccc(O)c2F)c1F
Solvent: C1CCOC1
Product: Cc1cc(-c2cccc(F)c2)cc(CNc2c(F)ccc(O)c2F)c1F
Temperature: 55 °C
Yield: 78.3 %

Procedure:
To a solution of N-(2,6-difluoro-3-hydroxy-phenyl)-2-fluoro-5-(3-fluorophenyl)-3-methyl-benzamide (200 mg, 0.53 mmol, 1.0 eq) in THF (8 mL) was added a solution of BH3 (1M in THF, 5 mL, 5 mmol, 9.4 eq) dropwise. The reaction was heated at 55° C. for 2 h, then quenched by the addition of 1M HCl and EtOAc. The organic extract was separated, washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo to give the title compound (150 mg, 77%). This material was used without further purification.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[F:18][C:19]([F:29])([F:28])[C@@H:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1>>[F:29][C:19]([F:18])([F:28])[C@@H:20]([NH:27][C:15]([C:7]1[CH:6]=[N:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1
Reactant: N[C@@H](c1ccccn1)C(F)(F)F
Reactant: O=C(O)c1cnc(C2CC2)c(OCC2CC2)n1
Product: O=C(N[C@@H](c1ccccn1)C(F)(F)F)c1cnc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 6, using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (Example 10 g) and (S)-2,2,2-trifluoro-1-pyridin-2-yl-ethylamine (Example 48b) as starting materials, and isolated (71 mg, 85%) as light yellow gum; LC-MS (UV peak area, ESI) 100%, 393.1524 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:36]=[CH:35][C:17]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([P:27](=[O:34])([O:31]CC)[O:28]CC)([F:26])[F:25])=[CH:16][C:15]=3[CH3:37])=[CH:7][C:6]=2[C:5]2[CH:38]=[CH:39][C:40]([CH3:42])=[CH:41][C:4]=2[N:3]=1.C(O)(C(F)(F)F)=O>>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:36]=[CH:35][C:17]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([P:27](=[O:28])([OH:31])[OH:34])([F:25])[F:26])=[CH:16][C:15]=3[CH3:37])=[CH:7][C:6]=2[C:5]2[CH:38]=[CH:39][C:40]([CH3:42])=[CH:41][C:4]=2[N:3]=1
Reactant: CCOP(=O)(OCC)C(F)(F)CCCCCOc1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)c(C)c1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(OCCCCCC(F)(F)P(=O)(O)O)cc3C)cc12

Procedure:
6-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)-1,1-difluorohexylphosphonic acid (24) was prepared according to the procedure described in Example 1—Step 3, but using diethyl 6-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)-1,1-difluorohexylphosphonate from the previous step 2. TFA was added to the 1H NMR sample to solubilize the compound for analysis. The 1H NMR (MeOD-d4) obtained for 6-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)-1,1-difluorohexylphosphonic acid (24) was: δ 8.73 (s, 1H), 8.60 (s, 1H), 8.31 (d, 1H, J=8.4 Hz), 7.48 (s, 1H), 7.43 (d, 1H, J=8.3 Hz), 6.91 (d, 1H, J=8.4 Hz), 6.70 (s, 1H), 6.61 (d, 1H, J=11.0 Hz), 3.90 (t, 2H, J=6.3 Hz), 3.20 (t, 2H, J=7.3 Hz), 3.03 (t, 2H, J=7.5 Hz), 2.54 (s, 2H), 2.22 (s, 3H), 1.79-1.71 (m, 2H), 1.69-1.59 (m, 2H), 1.57-1.47 (m, 2H). LRMS [M+H]=544.2
Reaction SMILES: [NH2:1][C@H:2]([C:6]([CH3:9])([SH:8])[CH3:7])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[CH3:17][O:18][C:19]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([O:29][CH3:30])[C:20]=1[CH2:21]O>C(Cl)Cl>[NH2:1][C@H:2]([C:6]([CH3:9])([S:8][CH2:21][C:20]1[C:23]([O:29][CH3:30])=[CH:24][C:25]([O:27][CH3:28])=[CH:26][C:19]=1[O:18][CH3:17])[CH3:7])[C:3]([OH:5])=[O:4]
Reactant: COc1cc(OC)c(CO)c(OC)c1
Reactant: CC(C)(S)[C@@H](N)C(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(OC)c(CSC(C)(C)[C@@H](N)C(=O)O)c(OC)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 95.1 %

Procedure:
A suspension of (2S)-2-amino-3-methyl-3-sulfanylbutanoic acid (5.0 g, 703 mnuol) in CH2Cl2 (150 mL) was cooled to 0° C. Trifluoroacetic acid (54 mL, 703 mmol) was added dropwise over a period of 5 min. 2,4,6-trimethoxybenzyl alcohol (6.64 g, 34 mmol) in CH2Cl2 (137 mL) was added dropwise at 0° C. with stirring. The stirring was continued for 1 hour at 0° C. and 2 hours at room temperature, the solvent removed in vacuo and the residue was dried under high vacuum for 3 hours. The crude red solid was recrystallized from 1:1:1 CH2Cl2:MeOH:EtOAc to give the title compound 10.5 g (95%) as a white solid which was used for the next step without further purification. 1H NMR (300 MHz, CDCl3) δ 6.10 (s, 2H), 3.84 (s, 6H), 3.76 (s, 3H), 3.40—4.10 (mult, 3H), 1.69 (s, 3H), 1.23 (s, 3H); mass spectrum (API-TIS) m/z 330 (M+H).
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1)([CH3:5])[CH3:4])#[N:2].COCCO[AlH2-]OCCOC.[Na+]>C1COCC1>[NH2:11][CH2:10][C:9]1[CH:12]=[CH:13][C:6]([C:3]([CH3:5])([CH3:4])[C:1]#[N:2])=[CH:7][CH:8]=1
Reactant: CC(C)(C#N)c1ccc(C#N)cc1
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C#N)c1ccc(CN)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 38.6 %

Procedure:
4-(1-cyano-1-methylethyl)benzonitrile (2.28 g, 13.41 mmol) is dissolved in dry THF and the solution cooled to 0° C. Red-Al (85% soln in toluene, 2.62 ml, 13.41 mmol of hydride) is added and the reaction stirred at 0° C. for 4 hours. The mixture is quenched with methanol and concentrated under vacuo. The residue is dissolved in CH2Cl2, washed with 2 portions of water, dried over magnesium sulfate, filtered and evaporated to dryness. The crude is purified by normal phase MPLC (SiO2, DCM to DCM/MeOH 3:1), giving 2-[4-(aminomethyl)phenyl]-2-methylpropanenitrile (900 mg, 5.17 mmol, 39%) as a colorless oil. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.68 (s, 6H) 4.00-4.05 (m, 2H) 7.55 (q, J=8.59 Hz, 4H) 8.35 (broad s, 2H).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]1[C:14](=[O:26])[C@@H:15]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16][CH3:17])=O.[CH3:27][S:28][CH2:29][CH2:30][NH2:31].ClCCl>CO.C(OCC)C>[CH3:27][S:28][CH2:29][CH2:30][NH:31][C:3]([C@@H:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]1[C:14](=[O:26])[C@@H:15]([NH:18][C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[CH2:16][CH3:17])=[O:2]
Reactant: CSCCN
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)N1c2ccccc2C[C@H]1C(=O)OC
Solvent: CCOCC
Solvent: CO
Solvent: ClCCl
Product: CC[C@H](NC(=O)OC(C)(C)C)C(=O)N1c2ccccc2C[C@H]1C(=O)NCCSC
Temperature: 60 °C
Reaction time: 48 h

Procedure:
To a solution of 1-(N-t-butoxycarbonyl-2(S)-aminobutyryl)-indoline-2(S)-carboxylic acid methyl ester (0.5 g, 1.4 mmol) in methanol (2 ml), was added 2-methylthioethylamine (3 ml) under nitrogen, and the resulting solution was stirred at 60° C. for 48 hours. The solution was poured into dichloromethane (20 ml), and washed with 1M potassium hydrogen sulphate, the aqueous layer was extracted with dichloromethane (3×15 ml). The combined organic layers were dried over Na2SO4, and then the solvent was evaporated. A white solid was obtained after column chromatography on silica gel using diethyl ether as eluent.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:13][CH:12]([C:14]([O:16][CH3:17])=[O:15])[CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[CH2:11][CH:12]([C:14]([O:16][CH3:17])=[O:15])[CH2:13]2)=[CH:8][CH:9]=1
Reactant: COC(=O)C1CC(c2ccc([N+](=O)[O-])cc2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)C1CC(c2ccc(N)cc2)C1

Procedure:
A solution of this nitro compound (750mg.) in ethyl acetate (20ml.) was stirred for 16 hours with a 5% palladium on carbon catalyst (250mg.) in an atmosphere of hydrogen. The solution was filtered through a pad of "Hyflo" and evaporated to give methyl 3-(4-aminophenyl)-cyclobutanecarboxylate. A solution of this amine (800mg.) in dry benzene (20ml.) was stirred under argon at room temperature during the dropwise addition of amyl nitrite (0.755ml.). The temperature of the reaction mixture was slowly (over 21/2 hours) raised to its boiling point and the mixture was then refluxed for 1 hour. The solvent was evaporated under reduced pressure and the residue was chromatographed on a dry column of silica gel `MFC` (supplied commercially by Hopkin and Williams) (25g.), eluting with toluene to give a mixture of cis and trans isomers of methyl 3-(4-biphenylyl)cyclobutanecarboxylate, RF = 0.70 (9:1 v/v toluene/ethyl acetate). The n.m.r. spectrum in deuteriochloroform showed the following characteristic features (δ values):-
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]2[CH:23]=[CH:22][C:14]([C:15]([O:17]C(C)(C)C)=[O:16])=[C:13]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH:12]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]>FC(F)(F)C(O)=O>[CH3:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]2[CH:23]=[CH:22][C:14]([C:15]([OH:17])=[O:16])=[C:13]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH:12]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(/C=C/c2ccc(C(=O)OC(C)(C)C)c(Nc3ccc(F)cc3)c2)cc1C
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(/C=C/c2ccc(C(=O)O)c(Nc3ccc(F)cc3)c2)cc1C

Procedure:
Trifluoroacetic acid 10 mL solution of tert-butyl 4-((E)-2-(3,4-dimethylphenyl)vinyl)-2-(4-fluoroanilino)benzoate was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, and the obtained residue was refined by reversed-phase silica gel column chromatography [eluent; 85-100% acetonitrile/0.1% trifluoroacetic acid aqueous solution] to give 4-((E)-2-(3,4-dimethylphenyl)vinyl)-2-(4-fluoroanilino)benzoic acid.
Reaction SMILES: S([O-])([O-])(=O)=O.[Mg+2].[C-:7]#[N:8].[Na+].[O:10]1[CH:12]([CH:13]2[O:19][C:18]([CH3:21])([CH3:20])[O:17][CH:14]2[CH:15]=[CH2:16])[CH2:11]1>CO>[CH3:20][C:18]1([CH3:21])[O:17][CH:14]([CH:15]=[CH2:16])[CH:13]([CH:12]([OH:10])[CH2:11][C:7]#[N:8])[O:19]1
Reactant: C=CC1OC(C)(C)OC1C1CO1
Reactant: [C-]#N
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Agent: [Na+]
Solvent: CO
Product: C=CC1OC(C)(C)OC1C(O)CC#N
Temperature: 10 °C
Reaction time: 0.75 h
Yield: 23.9 %

Procedure:
Fifty milliliters of a saturated magnesium sulfate aqueous solution were cooled to 10° C., and 10.23 g of sodium cyanide was gradually added not to proceed over 10° C. After stirring at 10° C. for 45 minutes, a solution of 7.61 g of 1,2-epoxy-3,4-(dimethylmethylenedioxy)-5-hexene in 30 ml of methanol was gradually added to the above mixture not to proceed over 10° C. After stirring at room temperature for 2 hours, the reaction mixture was extracted with ethyl acetate. The extract was washed with a sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to afford 2.11 g of 4,5-(dimethylmethylenedioxy)-3-hydroxy-6-heptenenitrile having the following properties.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:10][CH:9]([NH:24][C:25]([C:27]2[NH:28][C:29]3[C:34]([CH:35]=2)=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:26])[C:8]1=[O:36].[C:37]1(=[O:47])[NH:41][C:40](=[O:42])[C:39]2=[CH:43][CH:44]=[CH:45][CH:46]=[C:38]12.[K].CN(C)C=O>O>[C:37]1(=[O:47])[N:41]([CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[C:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:10][CH:9]([NH:24][C:25]([C:27]3[NH:28][C:29]4[C:34]([CH:35]=3)=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:26])[C:8]2=[O:36])[C:40](=[O:42])[C:39]2=[CH:43][CH:44]=[CH:45][CH:46]=[C:38]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=C(NC1N=C(c2ccccc2)c2ccccc2N(CCOCCCl)C1=O)c1cc2ccccc2[nH]1
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NC1N=C(c2ccccc2)c2ccccc2N(CCOCCN2C(=O)c3ccccc3C2=O)C1=O)c1cc2ccccc2[nH]1
Reaction time: 7 h
Yield: 105.3 %

Procedure:
A mixture of (3RS)-1-[2-(2-chloroethoxy)ethyl]-1,3-dihydro-3-(2-indolylcarbonylamino)-5-phenyl-2H-1,4-benzodiazepine-2-one (700 mg), potassium phthalimide (610 mg) and N,N-dimethylformamide (5 ml) was stirred for 7 hours at 80°-90° C. The reaction mixture was poured into a cold water (100 ml) and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and evaporated to give (3RS)-1-[2-(2-phthalimidoethoxy)ethyl]-1,3-dihydro-3-(2-indolylcarbonylamino)-5-phenyl-2H-1,4-benzodiazepine-2-one (0.9 g).
Reaction SMILES: Cl.[N:2]([C@H:5]1[CH2:33][N:8]2[C@H:9]([CH:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:10][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:12][C@@H:7]2[CH2:6]1)=[N+]=[N-]>CO.[Pd]>[NH2:2][C@H:5]1[CH2:33][N:8]2[C@H:9]([CH:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:10][N:11]([C:13]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14])[CH2:12][C@@H:7]2[CH2:6]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@@H](N=[N+]=[N-])CN2[C@H](C(c2ccccc2)c2ccccc2)C1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@@H](N)CN2[C@H](C(c2ccccc2)c2ccccc2)C1
Reaction time: 4 h
Yield: 102.7 %

Procedure:
10% Palladium-charcoal (50% wet, 40 mg) and 0.1N hydrochloric acid (0.1 ml) were added into a solution of tert-butyl (4R,7R,8aS)-7-azido-4-benzhydrylhexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate (200 mg) in methanol (2.5 ml) at room temperature. The mixture was hydrogenated at room temperature under atmospheric pressure for 4 hours. The palladium was filtered and washed with methanol. The filtrate and washings were combined and concentrated in vacuo. The resulting residue was partitioned between aqueous sodium hydrogen carbonate and ethyl acetate. The organic layer was separated, dried over magnesium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography with a mixture of dichloromethane and methanol (15:1) as an eluent. The fractions containing the objective compound were collected to give tert-butyl (4R,7R,8aS)-7-amino-4-benzhydrylhexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate (193 mg).
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]([NH:6][C:7](=[O:11])[CH2:8][C:9]#[N:10])=[CH:4][C:3]=1[CH3:14].[H-].[Na+].[C:17](Cl)(=[O:21])[C:18]([CH3:20])=[CH2:19].C1C2NC3C(=CC=CC=3)SC=2C=CC=1>O1CCCC1.N1C=CN=C1>[C:9]([C:8](=[C:17]([OH:21])[C:18]([CH3:20])=[CH2:19])[C:7]([NH:6][C:5]1[CH:12]=[CH:13][C:2]([Br:1])=[C:3]([CH3:14])[CH:4]=1)=[O:11])#[N:10]
Reactant: C=C(C)C(=O)Cl
Reactant: Cc1cc(NC(=O)CC#N)ccc1Br
Agent: [H-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: C=C(C)C(O)=C(C#N)C(=O)Nc1ccc(Br)c(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
A solution of 6.3 g of 4'-bromo-3'-methyl-cyanoacetanilide (0.025 mole) in 200 ml of dry tetrahydrofuran was stirred under nitrogen during the addition of 0.02 g of imidazole as a catalyst and 1.85 g (0.0625 mole) of sodium hydride 80% oil dispersion. The suspension was stirred at room temperature for 1 hour, then was cooled to -78° C. 2.95 ml (0.03 mole) of methacryloyl chloride freshly distilled from phenothiazine were added dropwise and the mixture was warmed to -20° C. over 90 minutes. The mixture was poured onto dilute hydrochloric acid/ice, and filtered. The solid was dissolved in dichloromethane, washed with water, dried over magnesium sulfate and evaporated under reduced pressure to obtain 8.0 g (99.7%) of the title compound as colorless crystals.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][N:7]=[C:6]2[NH2:12].[C:15]([O:19][CH2:20][CH3:21])(=[O:18])[CH:16]=O.C([BH3-])#N.[Na+]>CC(O)=O.CO.C1(C)C=CC=CC=1>[F:14][C:2]([F:1])([F:13])[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][N:7]=[C:6]2[NH:12][CH2:16][C:15]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)C=O
Reactant: Nc1n[nH]c2ccc(C(F)(F)F)cc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)CNc1n[nH]c2ccc(C(F)(F)F)cc12
Temperature: 100 °C
Reaction time: 2.5 h

Procedure:
Preparation I6, Step 2: A solution of 5-(trifluoromethyl)-1H-indazol-3-amine (2.08 g, 10.3 mmol) in 50 mL of 1% AcOH/MeOH was charged with ethyl glyoxylate (2.05 mL of a 50% solution in toluene, 10.3 mmol; note: the commercially available material is polymeric and was heated at 100° C. for 90 min before being used immediately in this reaction) and sodium cyanoborohydride (777 mg, 12.4 mmol). The mixture was stirred for 2.5 h, quenched with sat. NaHCO3, and extracted with EtOAc (2×). The organic extracts were combined, washed with brine, dried (sodium sulfate), filtered, and concentrated in vacuo. Purification by flash chromatography provided ethyl 2-(5-(trifluoromethyl)-1H-indazol-3-ylamino)acetate (819 mg).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][N:9]=2)[S:4][N:3]=1.[NH2:11][CH2:12][CH2:13][CH2:14][NH2:15]>CO>[S:4]1[C:5]2=[N:6][CH:7]=[CH:8][N:9]=[C:10]2[C:2]([NH:11][CH2:12][CH2:13][CH2:14][NH2:15])=[N:3]1
Reactant: NCCCN
Reactant: Brc1nsc2nccnc12
Solvent: CO
Product: NCCCNc1nsc2nccnc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 3-bromoisothiazolo[5,4-b]pyrazine in methanol (25 mL) was added 1,3-diaminopropane (6 mL). The reaction mixture was stirred at room temperature for 15 min, then heated to 50° C. After 1 h, the starting material was consumed as judged by LC-MS. The reaction mixture was concentrated under reduced pressure and then partitioned between ethyl acetate and brine. The aqueous layer was back-extracted twice with ethyl acetate and once with methylene chloride. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate and filtered. Concentration under reduced pressure gave N1-(isothiazolo[5,4-b]pyrazin-3-yl)propane-1,3-diamine (410 mg) as a yellow solid. 1H NMR (300 MHz, CDCl3-DMSO-d6): 8.62 (d, 1H), 8.54 (d, 1H), 2.66 (m, 4H), 2.49 (br s, 2H), 1.51 ppm (m, 2H). MW=209 confirmed by LC-MS, tr=2.51 min (Method Y) MH+=208-210.
Reaction SMILES: Cl[CH:2]([C:15]1[CH:19]=[C:18]([Si:20]([CH3:23])([CH3:22])[CH3:21])[O:17][CH:16]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[CH3:24][SH:25].C[O-].[K+]>O1CCCC1>[CH3:24][S:25][CH:2]([C:15]1[CH:19]=[C:18]([Si:20]([CH3:23])([CH3:22])[CH3:21])[O:17][CH:16]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CS
Reactant: CCCCCCCCCCCCC(Cl)c1coc([Si](C)(C)C)c1
Agent: C[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCC(SC)c1coc([Si](C)(C)C)c1
Temperature: 25 °C

Procedure:
A mixture of 3-(1-chlorotridecyl)-5-trimethylsilylfuran, methyl mercaptan and potassium methoxide in tetrahydrofuran is stirred at room temperature to give 3-(1-methylthiotridecyl)-5-trimethylsilylfuran. Oxidizing using Rose Bengal by the procedure of Example 1 gives 4-(1-methylthiotridecyl)-5-hydroxy-2(5H)-furanone.
Reaction SMILES: [CH3:1][NH2:2].C([O-])([O-])=O.[Na+].[Na+].[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=2[CH2:23]Br)=[C:12]([CH2:25]Br)[CH:11]=1>C1COCC1>[Br:9][C:10]1[CH:15]=[CH:14][C:13]2[C:16]3[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=3[CH2:23][N:2]([CH3:1])[CH2:25][C:12]=2[CH:11]=1
Reactant: BrCc1cc(Br)ccc1-c1ccc(Br)cc1CBr
Reactant: CN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1Cc2cc(Br)ccc2-c2ccc(Br)cc2C1
Yield: 99.4 %

Procedure:
MeNH2 (4.9 mL, 9.87 mmol) and Na2CO3 (0.349 g, 3.29 mmol) were added to a THF (6.5 mL) solution of 4,4′-dibromo-2,2′-bis(bromomethyl)biphenyl (0.328 g, 0.658 mmol), and the reaction mixture was refluxed for 3 hours. The volatile component was removed in vacuo, and the residue was passed through MCX (CH3OH wash; 2.0 M NH3/CH3OH elution) to afford 3,9-dibromo-6-methyl-6,7-dihydro-5H-dibenzo[c,e]azepine as a white solid (0.24 g). 1H NMR (DMSO-d6, δ=2.50, 500 MHz): 2.31 (s, 3H), 3.24 (s, 4H), 7.47 (d, J=7.9, 2 H), 7.55-7.82 (m, 4H).