Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[C:16]2[C:15]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=3)=[N:14][CH:13]=[N:12][C:11]=2[S:10][C:9]=1[CH3:28]>>[CH3:1][C:2]1[N:3]([C:13]2[N:14]=[C:15]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=3)[C:16]3[CH:8]=[C:9]([CH3:28])[S:10][C:11]=3[N:12]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1ncc[nH]1
Reactant: Cc1sc2ncnc(NCc3cccc([N+](=O)[O-])c3)c2c1Cl
Product: Cc1cc2c(NCc3cccc([N+](=O)[O-])c3)nc(-n3ccnc3C)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 5-chloro-6-methyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-6-methyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][NH:11][C:10](=[O:14])[CH:9]=2)=[CH:4][CH:3]=1.Br[C:18]1[CH:19]=[CH:20][C:21]2[N:25]=[C:24]([CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])[N:23]([CH3:31])[C:22]=2[CH:32]=1.CNCCNC.C(=O)([O-])[O-].[K+].[K+]>[Cu](I)I.CS(C)=O>[CH3:28][C:27]([CH3:30])([CH3:29])[CH2:26][C:24]1[N:23]([CH3:31])[C:22]2[CH:32]=[C:18]([N:11]3[CH:12]=[CH:13][C:8]([O:7][CH2:6][C:5]4[CH:15]=[CH:16][C:2]([F:1])=[CH:3][CH:4]=4)=[CH:9][C:10]3=[O:14])[CH:19]=[CH:20][C:21]=2[N:25]=1
Reactant: Cn1c(CC(C)(C)C)nc2ccc(Br)cc21
Reactant: O=c1cc(OCc2ccc(F)cc2)cc[nH]1
Agent: I[Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: Cn1c(CC(C)(C)C)nc2ccc(-n3ccc(OCc4ccc(F)cc4)cc3=O)cc21
Temperature: 150 °C
Yield: 33.5 %

Procedure:
A mixture of 4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one (78 mg), 6-bromo-2-(2,2-dimethylpropyl)-1-methyl-1H-benzimidazole (100 mg), N,N′-dimethylethylenediamine (31 mg), copper iodide (68 mg), potassium carbonate (147 mg) and DMSO (2 ml) was heated under Ar atmosphere at 150° C. for 2 h. The mixture was partitioned between 14% aqueous NH3 and EtOAc. The organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by NH silica gel column chromatography (hexane/EtOAc) to give the title compound (50 mg) as a white solid.
Reaction SMILES: C([O:4][CH2:5][C@H:6]1[O:10][C@@H:9](N2C=C(C)C(=O)NC2=O)[CH2:8][C@@H:7]1[F:20])(=O)C.[F:21][C:22]1[N:30]=[C:29]2[C:25]([NH:26][CH:27]=[N:28]2)=[C:24]([NH2:31])[N:23]=1.C[Si](C([Si](C)(C)C)C(N)=O)(C)C>C(#N)C>[F:20][C@@H:7]1[C@@H:6]([CH2:5][OH:4])[O:10][C@@H:9]([N:28]2[CH:27]=[N:26][C:25]3[C:29]2=[N:30][C:22]([F:21])=[N:23][C:24]=3[NH2:31])[CH2:8]1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@@H]1F
Reactant: Nc1nc(F)nc2nc[nH]c12
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Solvent: CC#N
Product: Nc1nc(F)nc2c1ncn2[C@H]1C[C@H](F)[C@@H](CO)O1

Procedure:
A mixture of 2.88 g (10 mMoles) 1-(5-O-acetyl-2,3-dideoxy-3-fluoro-β-D-ribofuranosyl) thymine, 4.6 g (30 mMoles) 2-fluoroadenine, 7.4 ml bistrimethylsilyl acetamide, and 250 ml acetonitrile was heated on reflux for 25 minutes. Subsequently, 6.5 ml (33 mMoles) trifluoromethanesulfonic acid trimethyl ester was added and the reaction mixture heated on reflux for further 8 hours. After removal of the solvent under vacuum the residue was suspended in 100 ml chloroform and neutralized with NaHCO3 solution. The organic phase was dried over sodium sulfate filtered and the chloroform removed under vacuum. The residue was separated by column chromatography on silica gel, eluting with chloroform (1 l of 5% n-hexane; 15 l of 2.5% n-hexane; 1 l of 1% n-hexane). The obtained mixture was deacetylated in a conventional manner by means of ammonia/methanol and was subjected to column chromatographic separation. Chloroform (1% methanol) was used as eluent. 0.51 g was isolated of the β anomer, the title compound. Further compound remained in the mixture with the α anomer.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:4][C:3]=1[C:17](=O)[CH2:18][C:19](=O)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].O.[NH2:32][NH2:33]>C(O)C>[CH2:8]([C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([C:17]2[CH:18]=[C:19]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[NH:33][N:32]=2)[CH:4]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCC(=O)CC(=O)c1cc(CCCCCCCCC)ccc1O
Reactant: NN
Solvent: CCO
Solvent: O
Product: CCCCCCCCCc1ccc(O)c(-c2cc(CCCCCCCCC)[nH]n2)c1

Procedure:
1-(2-hydroxy-5-nonyl-phenyl)dodecane-1,3-dione (0.1M) dissolved in ethanol (50 ml), hydrazine hydrate (0.105M) added and the reaction solution heated to reflux. Held at reflux for 2 hours, cooled to ambient and organic phase washed with water (2×25 ml). Toluene removed by vacuum evaporation to produce a brown oil.
Reaction SMILES: C([N:8]1[CH2:12][C:11]([CH3:14])([CH3:13])[C@H:10]([OH:15])[CH2:9]1)C1C=CC=CC=1.[H][H].[ClH:18]>C(O)C.[Pd]>[ClH:18].[CH3:13][C:11]1([CH3:14])[CH2:12][NH:8][CH2:9][C@H:10]1[OH:15]
Reactant: CC1(C)CN(Cc2ccccc2)C[C@H]1O
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CC1(C)CNC[C@H]1O
Yield: 99 %

Procedure:
To a solution of 6.34 g (41.7 mmol) of (3S)-1-benzyl-4,4-dimethyl-3-pyrrolidinol in 250 mL of ethanol and 50 mL of 1N hydrochloric acid was added 300 mg of 10% palladium on carbon. The reaction mixture was stirred under 40 psi of hydrogen gas for 18 h. To the reaction mixture was added 300 mg of 10% palladium on carbon and 2 mL of concentrated hydrochloric acid. The reaction mixture was stirred under 40 psi of hydrogen gas for 72 h. The catalyst was filtered off over celite, and the filtrate was concentrated. Several portions of toluene were distilled from the residue, which was then dried under high vacuum to afford 4.74 g (>99%) of (3S)-4,4-dimethyl-3-pyrrolidinol hydrochloride. 1H-NMR (300 MHz, DMSO-d6): δ 9.46 (d, J=40 Hz, 2H), 5.43 (br s, 1H), 3.75 (m, 1H), 3.36 (m, 1H), 2.88 (m, 3H), 0.96 (d, J=10 Hz, 6H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:30][C:31]([O:33]CC)=O)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][S:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=4[Cl:28])(=[O:20])=[O:19])=[C:13]([F:29])[CH:12]=3)[C:3]=12.[CH3:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:30][C:31]([N:40]3[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]3)=[O:33])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][S:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=4[Cl:28])(=[O:19])=[O:20])=[C:13]([F:29])[CH:12]=3)[C:3]=12
Reactant: CCOC(=O)Cn1nc(-c2ccc(NS(=O)(=O)c3cccc(Cl)c3Cl)c(F)c2)c2c(N)ncnc21
Reactant: CN1CCNCC1
Product: CN1CCN(C(=O)Cn2nc(-c3ccc(NS(=O)(=O)c4cccc(Cl)c4Cl)c(F)c3)c3c(N)ncnc32)CC1

Procedure:
Ethyl 2-[4-amino-3-(4-{[(2,3-dichlorophenyl)sulfonyl]amino}-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]acetate was treated with 1-methylpiperazine using the representative procedure for amide formation. Purification by preparative HPLC (25 to 100% CH3CN in 0.1 M aqueous ammonium acetate over 20 min at 21 mL/min using an 8Hypersi1HS C18, 250×21 mm column, Rt 6.4-7.0 min) afforded N1-(4-{4-amino-1-[2-(4-methylpiperazino)-2-oxoethyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-fluorophenyl)-2,3-dichloro-1-benzenesulfonamide as a white solid (0.005 g, 0.009 mmol): RP-HP (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate over 10 min at 1 mL/min using a Hypersil HS C18, 250×4.6 mm column) Rt 6.83 min. 1H NMR (DMSO-d6, 400 MHz) δ 8.20 (s, 1H), 7.96 (d, 1H), 7.88 (d, 1H), 7.50 (t, 1H), 7.36 (m, 3H), 5.31 (s, 2H), 3.45 (m, 4H), 2.50 (m, 4H), 2.30 (s, 3H), MS: MH+ 593.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=2[C:11]#[N:12])[CH:5]=[CH:6][C:7]=1[NH2:8].C(O[CH2:21][CH3:22])(=O)C>C(O)C.[Cl-].[Na+].O>[CH2:21]([C:22]1[NH:8][C:7]2[CH:6]=[CH:5][C:4]([C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[C:11]#[N:12])=[CH:3][C:2]=2[N:1]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ccccc1-c1ccc(N)c(N)c1
Reactant: CCOC(C)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N#Cc1ccccc1-c1ccc2[nH]c(Cc3ccccc3)nc2c1

Procedure:
2-(3,4-Diaminophenyl)benzonitrile (2.4 mmoles, 0.50 g) was dissolved in 3 ml ethanol. Ethyl phenylacetamidate hydrochloride (2.88 mmoles, 0.573 g) (prepared from HCl gas bubbled through benzyl cyanide and ethanol) was added. The reaction was warmed on a steam bath for 10 minutes. Ethyl acetate and brine were added. The organic phase was separated dried and concentrated. The product was precipitated from ethyl acetate and hexane and filtered to yield 290 mg of 2-benzyl-5-(2-cyanophenyl)-1H-benzimidazole. (MS)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[NH:10][S:9]1(=[O:18])=[O:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:39][CH2:40][CH:41]([N:48]([CH3:56])[C:49](=[O:55])[O:50][C:51]([CH3:54])([CH3:53])[CH3:52])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]([CH2:39][CH2:40][CH:41]([N:48]([CH3:56])[C:49](=[O:55])[O:50][C:51]([CH3:53])([CH3:52])[CH3:54])[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[S:9]1(=[O:18])=[O:17]
Reactant: O=S1(=O)Nc2ccccc2N1c1ccccc1F
Reactant: CN(C(=O)OC(C)(C)C)C(CCO)c1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CN(C(=O)OC(C)(C)C)C(CCN1c2ccccc2N(c2ccccc2F)S1(=O)=O)c1ccccc1

Procedure:
In an analogous manner to general procedure II, 1-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (prepared in an analogous manner as described in general procedure I, 108 mg, 0.41 mmol) was treated with triphenylphosphine (0.13 g, 0.49 mmol), tert-butyl (3-hydroxy-1-phenylpropyl)methylcarbamate (0.12 g, 0.45 mmol), and diisopropylazodicarboxylate (0.095 mL, 0.49 mmol) to provide 0.13 g tert-butyl {3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-phenylpropyl}methylcarbamate.
Reaction SMILES: Cl[C:2]1([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[O:3]1.C(N(CC)CC)C.[NH2:26][CH2:27][C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=1>>[CH:7]1[CH:6]=[C:5]2[C:4]([N:33]([CH2:32][C:31]3[CH:34]=[CH:35][C:28]([C:27]#[N:26])=[CH:29][CH:30]=3)[C:2]([OH:3])([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[C:10]2=[CH:9][CH:8]=1)=[O:11]
Reactant: O=C1OC(Cl)(c2ccc(Cl)cc2)c2ccccc21
Reactant: N#Cc1ccc(CN)cc1
Solvent: CCN(CC)CC
Product: N#Cc1ccc(CN2C(=O)c3ccccc3C2(O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 47.7 %

Procedure:
Distilled THF (25 mL) was added to 3-chloro-3-(4-chlorophenyl)-3H-isobenzofuran-1-one (1.071 g, 3.84 mmol) followed by triethylamine (777.14 mg, 7.68 mmol, 1.07 mL) and 4-(aminomethyl)benzonitrile (507.6 mg, 3.84 mmol). The mixture was stirred at room temperature under nitrogen for 4 hours and monitored by TLC. Upon completion the mixture was then extracted with EtOAc (15 mL) and washed with saturated sodium bicarbonate (3×10 mL), water (3×10 mL) and dried (Na2SO4). Removal of solvent after washing produced a viscous orange oil. Trituration under petrol yielded a yellow/orange solid which was recrystallised from a minimum amount of boiling ethyl acetate and excess petrol to produce the title product as a fine pale yellow crystalline solid (665 mg, 1.83 mmol, 50%). 1H NMR: (300 MHz, DMSO) δ ppm 4.31 (d, 2H, J=16.12 Hz, H9), 4.55 (d, 2H J=16.15 Hz, H9′), 7.26 (m, 5H, H1-H5), 7.37 (d, 2H J=8.29 Hz, H10, H13), 7.58 (m, 2H, H6-H7), 7.64 (d, 2H J=8.26 Hz, H11-H12), 7.77 (d, 1H, H8). 13C NMR: (75 Hz, DMSO); δ 42.51 (N—CH2), 60.02 (CN) 90.57 (O—C—N), 109.82, 119.08, 123.06, 123.25, 128.40, 128.62, 129.16, 129.83, 130.54, 132.03, 133.19, 133.26, 133.52, 139.19, 144.24, 149.48 (Ar), 167.23 (C═O). IR: 1397, 1655, 2227 cm−1.
Reaction SMILES: [C:1]([C@@H:4]([N:8]([C:27](=[O:32])[CH2:28][CH2:29][CH2:30][CH3:31])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]2[NH:26][N:25]=[N:24][N:23]=2)=[CH:12][CH:11]=1)[CH:5]([CH3:7])[CH3:6])([OH:3])=[O:2].[OH-].[Mg+2:34].[OH-].CO>O>[Mg:34].[C:1]([C@@H:4]([N:8]([C:27](=[O:32])[CH2:28][CH2:29][CH2:30][CH3:31])[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]2[NH:23][N:24]=[N:25][N:26]=2)=[CH:14][CH:15]=1)[CH:5]([CH3:6])[CH3:7])([OH:3])=[O:2]
Reactant: [Mg+2]
Agent: CCCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)[C@H](C(=O)O)C(C)C
Agent: [OH-]
Solvent: CO
Solvent: O
Product: [Mg]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5 g of (S)-N-(1-carboxy-2-methyl-prop-1-yl)-N-pentanoyl-N-[2′-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-amine are added to a suspension of 0.666 g of magnesium hydroxide in 20 ml of water. 40 ml of methanol are added, then the mixture is stirred for 2 hours at room temperature and concentrated. The residue is dissolved in methanol, filtered through a hard filter, concentrated and evaporated with acetonitrile. The product is stirred with hot acetonitrile, filtered by suction at room temperature and dried in a high vacuum at 90° C. over night. (S)-N-(1-carboxy-2-methyl-prop-1-yl)-N-pentanoyl-N-[2′-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-amine magnesium salt is obtained as a white powder. Melting point: The sample becomes brownish upon heating and vitrifies towards 300° C.
Reaction SMILES: CN(C)C=O.[Cl:6][C:7]1[CH:26]=[CH:25][C:10]([CH2:11][N:12]2[CH:17]=[N:16][C:15]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[N:14][C:13]2=[O:24])=[CH:9][CH:8]=1.Cl[C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][N:29]=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.O>[Cl:6][C:7]1[CH:26]=[CH:25][C:10]([CH2:11][N:12]2[CH:17]=[N:16][C:15]([N:18]3[CH2:23][CH2:22][N:21]([C:28]4[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][N:29]=4)[CH2:20][CH2:19]3)=[N:14][C:13]2=[O:24])=[CH:9][CH:8]=1
Reactant: O=c1nc(N2CCNCC2)ncn1Cc1ccc(Cl)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: O=c1nc(N2CCN(c3ccc([N+](=O)[O-])cn3)CC2)ncn1Cc1ccc(Cl)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 4.9 %

Procedure:
An N,N-dimethylformamide suspension (1 mL) of 1-(4-chlorobenzyl)-4-(piperazin-1-yl)-1,3,5-triazin-2(1H)-one (31 mg, 0.10 mmol) synthesized in Reference Synthesis Example 9, 2-chloro-5-nitropyridine (16 mg, 0.10 mmol) and potassium carbonate (18 mg, 0.20 mmol) was stirred at 100° C. for 1 hour. After the completion of the reaction, water was added to the reaction solution and extraction with ethyl acetate from the resultant reaction solution was performed three times. The organic layer was washed with brine, was dried over anhydrous sodium sulfate, and was concentrated under reduced pressure. The resultant residue was purified by preparative silica gel thin-layer chromatography to obtain the title compound (2.1 mg, yield: 4.9%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[CH2:5][CH2:6][NH2:7])[CH3:2].CCN(CC)CC.[Cl:16][C:17]1[CH:18]=[C:19]([NH:23][C:24]2[O:25][C:26]([C:29]3[CH:34]=[CH:33][C:32]([CH:35]4[CH2:40][CH2:39][CH:38]([CH2:41][C:42](O)=[O:43])[CH2:37][CH2:36]4)=[CH:31][CH:30]=3)=[CH:27][N:28]=2)[CH:20]=[CH:21][CH:22]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O.O>[CH2:1]([O:3][C:4](=[O:8])[CH2:5][CH2:6][NH:7][C:42](=[O:43])[CH2:41][CH:38]1[CH2:37][CH2:36][CH:35]([C:32]2[CH:31]=[CH:30][C:29]([C:26]3[O:25][C:24]([NH:23][C:19]4[CH:20]=[CH:21][CH:22]=[C:17]([Cl:16])[CH:18]=4)=[N:28][CH:27]=3)=[CH:34][CH:33]=2)[CH2:40][CH2:39]1)[CH3:2]
Reactant: O=C(O)CC1CCC(c2ccc(-c3cnc(Nc4cccc(Cl)c4)o3)cc2)CC1
Reactant: CCOC(=O)CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCNC(=O)CC1CCC(c2ccc(-c3cnc(Nc4cccc(Cl)c4)o3)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 113 %

Procedure:
To a solution of 3-aminopropionic acid ethyl ester (41 mg, 0.268 mmol) and Et3N (0.082 mL, 0.730 mmol) is added a solution of (4-{4-[2-(3-Chlorophenylamino)-oxazol-5-yl]-phenyl}-cyclohexyl)-acetic acid (100 mg, 0.243 mmol) in DMF (4 mL), HATU (102 mg, 0.268 mmol) and iPr2NEt (0.127 mL, 0.73 mmol). The reaction mixture is allowed to stir at ambient temperature for 18 h. Water is added and EtOAc is used to extract. The organic layer is washed with brine, dried with Na2SO4 and concentrated to give the title compound (140 mg) as a tan solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.02-1.13 (m, 2H) 1.18 (t, J=7.07 Hz, 3H) 1.38-1.50 (m, 2H) 1.71 (dd, J=7.71, 4.17 Hz, 1H) 1.78 (t, J=12.63 Hz, 4H) 1.98 (d, J=6.57 Hz, 2H) 2.44 (t, J=6.82 Hz, 2H) 3.25-3.28 (m, 2H) 4.06 (q, J=7.07 Hz, 2H) 6.99 (ddd, J=7.89, 1.96, 1.01 Hz, 1H) 7.27-7.35 (m, 1H) 7.29 (d, J=8.59 Hz, 2H) 7.40 (s, 1H) 7.50 (d, J=8.34 Hz, 1H) 7.47-7.52 (m, 1H) 7.85 (t, J=2.02 Hz, 1H) 7.88 (t, J=5.81 Hz, 1H) 10.52 (s, 1H); (M+H)+510.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[N:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH:8]3[CH2:15][CH2:16][CH2:17][N:7]3[CH2:6][C:5]2=1.[H-].[Na+].[O:20]1[CH2:22][CH:21]1[C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1>CN(C=O)C>[Cl:1][C:2]1[CH:14]=[N:13][C:12]2[N:11]([CH2:22][CH:21]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[OH:20])[C:10]3[CH2:9][CH:8]4[N:7]([CH2:17][CH2:16][CH2:15]4)[CH2:6][C:5]=3[C:4]=2[CH:3]=1
Reactant: Clc1cnc2[nH]c3c(c2c1)CN1CCCC1C3
Reactant: c1cc(C2CO2)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: OC(Cn1c2c(c3cc(Cl)cnc31)CN1CCCC1C2)c1ccncc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 6-chloro-2,3,4,9,10,10a-hexahydro-1H-3a,8,9-triaza-cyclopenta[b]fluorene (700 mg, 2.82 mmol) in DMF (10 mL) were added portionwise NaH (60%, 338 mg 8.46 mmol) and 4-oxiranyl-pyridine (511 mg, 3.38 mmol). The reaction mass was stirred at RT for 16 h. The progress of reaction was monitored by LCMS. The reaction mass was quenched with ice cold water (200 mL) and extracted with EtOAc (3×150 mL). The combined organic layer was washed with water (10×100 mL) followed by brine (2×100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (0-15% DCM/MeOH) followed by reverse phase HPLC to yield the title compound;
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH2:8][O:9][CH2:10][CH2:11][CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:7]=1.C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[C:39]3[C:44](=[N:45][CH:46]=2)[N:43]([C:47]([NH2:49])=[O:48])[CH2:42][CH2:41][CH2:40]3)O1.CCOC(C)=O>O>[CH3:16][S:13]([CH2:12][CH2:11][CH2:10][O:9][CH2:8][C:6]1[CH:7]=[C:2]([C:37]2[CH:38]=[C:39]3[C:44](=[N:45][CH:46]=2)[N:43]([C:47]([NH2:49])=[O:48])[CH2:42][CH2:41][CH2:40]3)[CH:3]=[N:4][CH:5]=1)(=[O:15])=[O:14]
Reactant: CC1(C)OB(c2cnc3c(c2)CCCN3C(N)=O)OC1(C)C
Reactant: CS(=O)(=O)CCCOCc1cncc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CS(=O)(=O)CCCOCc1cncc(-c2cnc3c(c2)CCCN3C(N)=O)c1
Yield: 51.9 %

Procedure:
3-Bromo-5-(3-methanesulfonyl-propoxymethyl)-pyridine (61 mg, 0.20 mmol) and 2.0 M Na2CO3 aqueous solution (0.20 mL, 0.40 mmol) are added into the crude 6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid amide 1,4-dioxane solution (2.0 mL, 0.24 mmol) which is synthesized according to the procedure for Step 3 of Example 16. Argon gas is bubbled through the solution for 5 min. Then PdCl2dppf (7.3 mg, 0.010 mmol) is added. The mixture is heated at 100° C. for 3.5 hrs before EtOAc (15 mL) and water (15 mL) are added. The aqueous layer is separated and extracted with EtOAc (2×10 mL). The organic layers are combined and concentrated to give the crude product. Purification by flash column chromatography affords 42 mg of the titled product.
Reaction SMILES: C(OC1C=CC([C@@H](O)CBr)=CC=1CO[Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])C1C=CC=CC=1.[N:28]([CH2:31][C@@H:32]([C:34]1[CH:35]=[CH:36][C:37]([O:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[C:38]([NH:40][CH:41]=[O:42])[CH:39]=1)[OH:33])=[N+:29]=[N-:30]>>[N:28]([CH2:31][C@@H:32]([C:34]1[CH:35]=[CH:36][C:37]([O:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[C:38]([NH:40][CH:41]=[O:42])[CH:39]=1)[O:33][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])=[N+:29]=[N-:30]
Reactant: [N-]=[N+]=NC[C@H](O)c1ccc(OCc2ccccc2)c(NC=O)c1
Reactant: CC(C)(C)[Si](C)(C)OCc1cc([C@@H](O)CBr)ccc1OCc1ccccc1
Product: CC(C)(C)[Si](C)(C)O[C@@H](CN=[N+]=[N-])c1ccc(OCc2ccccc2)c(NC=O)c1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 7, using Intermediate 11 in place of (R)-4-(2-bromo-1-hydroxyethyl)-2-(hydroxymethyl)phenol. ES/MS calcd. C22H31N4O3Si+ 427.2. Found m/z=427 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3]([Cl:18])=[C:4]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.[S:19]1(=[O:29])(=[O:28])[N:23]2[CH2:24][CH2:25][NH:26][CH2:27][CH:22]2[CH2:21][CH2:20]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:18][C:3]1[C:2]([N:26]2[CH2:25][CH2:24][N:23]3[S:19](=[O:29])(=[O:28])[CH2:20][CH2:21][CH:22]3[CH2:27]2)=[CH:7][C:6]([C:8]#[N:9])=[CH:5][C:4]=1[NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)Nc1cc(C#N)cc(Br)c1Cl
Reactant: O=S1(=O)CCC2CNCCN21
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1cc(C#N)cc(N2CCN3C(CCS3(=O)=O)C2)c1Cl
Temperature: 105 °C
Yield: 37.4 %

Procedure:
A mixture of tert-butyl (3-bromo-2-chloro-5-cyanophenyl)carbamate (160 mg, 0.482 mmol), hexahydro-2H-isothiazolo[2,3-a]pyrazine 1,1-dioxide (85 mg, 0.482 mmol), Pd2dba3 (44.2 mg, 0.048 mmol), BINAP (90 mg, 0.145 mmol), and Cs2CO3 (471 mg, 1.447 mmol) in Dioxane (5 mL) was evacuated and filled with nitrogen 3× and heated at 105° C. overnight. The reaction mixture was filtered through a plug of celite and the filtrate was concentrated. The crude product was purified by flash chromatography on silica gel using an automated ISCO system (40 g column, eluting with 1-10% Methanol in DCM) to give tert-butyl (2-chloro-5-cyano-3-(1,1-dioxidotetrahydro-2H-isothiazolo[2,3-a]pyrazin-5(3H)-yl)phenyl)carbamate (77 mg)
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([OH:3])=[O:2].[C:12]([C:15]1[CH:20]=[CH:19][C:18]([S:21]([NH2:24])(=[O:23])=[O:22])=[CH:17][CH:16]=1)([OH:14])=[O:13].CC1C=CC(S(O)(=O)=O)=CC=1>ClC1C=CC=CC=1>[C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[N:24][S:21]([C:18]2[CH:17]=[CH:16][C:15]([C:12]([OH:14])=[O:13])=[CH:20][CH:19]=2)(=[O:22])=[O:23])=[CH:6][CH:5]=1)([OH:3])=[O:2]
Reactant: NS(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Clc1ccccc1
Product: O=C(O)c1ccc(C=NS(=O)(=O)c2ccc(C(=O)O)cc2)cc1

Procedure:
In the same manner as Example 2, 0.60 g (4 mmol) of 4-carboxybenzaldehyde, 0.80 g (4 mmol) of 4-carboxybenzenesulfonamide and 15 mg of TsOH in 80 mL of chlorobenzene under nitrogen were heated to provide 80% of SULF-5 as a light tan powder: IR (Nujol) 3400-2600 (br), 3082, 1688, 1614, 1160 cm-1 ; 1H NMR (DMSO-d6, TMS ext std) δ 9.17 (s, 1), 8.2-7.8 (m, 8).