Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:9][CH2:8][N:7]([C:10]3[S:11][C:12]([C:15]([OH:17])=O)=[CH:13][N:14]=3)[C:6]2=[O:18])[CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[N:50]1[CH:55]=[CH:54][CH:53]=[C:52]([CH2:56][NH2:57])[CH:51]=1>CN(C)C=O>[CH:1]1([CH2:4][N:5]2[CH2:9][CH2:8][N:7]([C:10]3[S:11][C:12]([C:15]([NH:57][CH2:56][C:52]4[CH:51]=[N:50][CH:55]=[CH:54][CH:53]=4)=[O:17])=[CH:13][N:14]=3)[C:6]2=[O:18])[CH2:2][CH2:3]1
Reactant: O=C(O)c1cnc(N2CCN(CC3CC3)C2=O)s1
Reactant: NCc1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCc1cccnc1)c1cnc(N2CCN(CC3CC3)C2=O)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40 %

Procedure:
To a solution of 2-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)thiazole-5-carboxylic acid (0.10 g, 0.37 mmol) in anhydrous N,N-dimethylformamide (10 mL) was added N,N-diisopropylethylamine (0.17 mL, 1.34 mmol), followed by the addition of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.11 g, 0.59 mmol). The reaction was stirred at ambient temperature for 0.5 hours, 1-Hydroxybenzotriazole (0.07 g, 0.52 mmol) was added, followed by the addition of pyridin-3-ylmethanamine (0.06 g, 0.56 mmol). The reaction mixture was stirred at ambient temperature for 18 hours. The solvent was concentrated in vacuo. The residue was diluted with dichloromethane (150 mL), washed with water (100 mL) and brine (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was crystallized in dichloromethane and hexane to yield the title compound as a colorless solid in 40% yield (0.065 g): mp 190-192° C. (dichloromethane/hexanes); 1H NMR (300 MHz, DMSO-d6) δ 8.98 (t, J=5.8 Hz 1H), 8.49 (m, 1H), 8.43-8.39 (m, 1H), 7.98 (s, 1H), 7.68-7.65 (m, 1H), 7.34-7.30 (m, 1H), 4.40 (d, J=5.8 Hz, 2H), 4.01-3.95 (m, 2H), 3.65-3.59 (m, 2H), 3.07 (d, J=7.1 Hz, 2H), 1.01-0.85 (m, 1H), 0.53-0.39 (m, 2H), 0.21-0.16 (m, 2H); 13C NMR (75 MHz, DMSO-d6) δ 161.5, 161.3, 155.1, 149.3, 148.6, 140.1, 135.7, 135.3, 127.1, 123.9, 48.2, 42.5, 42.3, 9.31, 3.63; MS (ES+) m/z 358.2 (M+1).
Reaction SMILES: [C:1]([NH:24][CH:25]([CH2:40][CH:41]([CH3:43])[CH3:42])[C:26]([O:28][C:29]1[CH:39]=[CH:38][CH:37]=[CH:36][C:30]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:27])(=[O:23])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6]/[CH:7]=[CH:8]\[CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH3:22].OC1C=C([C:54]([F:57])([F:56])[F:55])C=CC=1C(O)=O>>[C:1]([NH:24][CH:25]([CH2:40][CH:41]([CH3:43])[CH3:42])[C:26]([O:28][C:29]1[CH:39]=[C:38]([C:54]([F:57])([F:56])[F:55])[CH:37]=[CH:36][C:30]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:27])(=[O:23])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6]/[CH:7]=[CH:8]\[CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH3:22]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)NC(CC(C)C)C(=O)Oc1ccccc1C(=O)OCC
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1O
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)NC(CC(C)C)C(=O)Oc1cc(C(F)(F)F)ccc1C(=O)OCC

Procedure:
Ethyl 2-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido-4-methylpentanoyloxy)-4-(trifluoromethyl)benzoate was prepared as described for ethyl 2-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido-4-methylpentanoyloxy)benzoate, using the appropriate 2-hydroxy-4-(trifluoromethyl)benzoic acid starting material. Mass calculated for C38H50F3NO5=657.80. found: [M+H]+=658.4.
Reaction SMILES: [C:1](=[O:17])([O:14][CH2:15]Cl)[O:2][CH2:3][CH2:4][CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[I-:18].[Na+].O>C(#N)C>[C:1](=[O:17])([O:14][CH2:15][I:18])[O:2][CH2:3][CH2:4][CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: [I-]
Reactant: O=C(OCCl)OCCCOCc1ccccc1
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=C(OCI)OCCCOCc1ccccc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 92.4 %

Procedure:
[3-(Benzyloxy)propyl] chloromethyl carbonate (2.0 g) was dissolved in acetonitrile (3 ml), and sodium iodide (4.6 g) was added. The mixture was stirred under a nitrogen atmosphere at 60° C. for 2 hours. The reaction mixture was poured into water (100 ml) and extracted with ethyl acetate (100 ml). The ethyl acetate layer was washed with an aqueous 5% sodium thiosulfate solution (50 ml×2), water (50 ml×2), and a saturated sodium chloride aqueous solution (50 ml). After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain [3-(benzyloxy)propyl] iodomethyl carbonate (2.5 g) as a pale yellow liquid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[S:25](Cl)(=[O:27])=[O:26]>>[C:9]([C:3]1[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=1[NH:1][S:25]([C:19]1[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:18]=1[Cl:17])(=[O:27])=[O:26])(=[O:10])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Product: O=C(c1ccccc1)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(Cl)cc1Cl

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 115 mg of (2-amino-5-chloro-phenyl)-phenyl-methanone and 123 mg of 2,4-dichloro-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 7.24 (m, 1H), 7.31 (m, 1H), 7.45 (m, 2H), 7.54 (m, 2H), 7.60–7.65 (m, 2H), 7.97 (d, 1H, J=8.4 Hz), 10.23 (s, 1H). MS: m/z 440.7 (M++1).
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([NH:11][C@@H:12]([C:16]2[O:17][C:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=3)=[N:19][N:20]=2)[C@@H:13]([OH:15])[CH3:14])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].N1C=CC=CC=1.[C:35](Cl)(=[O:39])[CH2:36][CH2:37][CH3:38]>C(Cl)Cl>[C:35]([O:15][C@@H:13]([CH3:14])[C@@H:12]([NH:11][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[C:9]=1[CH3:10])[C:16]1[O:17][C:18]([C:21]2[CH:22]=[CH:23][C:24]([C:27]#[N:28])=[CH:25][CH:26]=2)=[N:19][N:20]=1)(=[O:39])[CH2:36][CH2:37][CH3:38]
Reactant: Cc1c(N[C@@H](c2nnc(-c3ccc(C#N)cc3)o2)[C@H](C)O)ccc(C#N)c1Cl
Reactant: CCCC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCC(=O)O[C@@H](C)[C@@H](Nc1ccc(C#N)c(Cl)c1C)c1nnc(-c2ccc(C#N)cc2)o1
Temperature: 25 °C
Reaction time: 18 h
Yield: 60 %

Procedure:
To a 50 mL round bottomed flask was added 2-chloro-4-((1R,2S)-1-(5-(4-cyanophenyl)-1,3,4-oxadiazol-2-yl)-2-hydroxypropylamino)-3-methylbenzonitrile (200 mg, 0.508 mmol, pyridine (1 mL, 12.41 mmol) and methylene chloride (15 mL). Butyryl chloride (0.26 mL, 2.54 mmol) was then added dropwise and the mixture was stirred at room temperature for 18 h. The reaction mixture was then quenched with 10% aq HCl (15 mL) and methylene chloride (30 mL) was added. The phases were partitioned and the aqueous phase extracted with methylene chloride (30 mL) (×2). The combined organics were washed with a saturated solution of sodium hydrogen carbonate, dried (Na2SO4) and concentrated to furnish a yellow oil (0.139 g, 60%). 1H NMR (Acetone d6, 400 MHz) δ 8.23 (d, J=9 Hz, 2 H), 8.02 (d, J=9 Hz, 1 H), 7.54 (d, J=9 Hz, 1 H), 7.02 (d, J=9 Hz, 1 H), 5.74 (d, J=9 Hz, 1 H), 5.72-5.64 (m, 1H), 5.48 (dd, J=5 and 8 Hz, 1H), 2.37 (s, 3 H), 2.33-2.25 (m, 2H), 1.64-1.50 (m, 2 H), 1.47 (d, J=6 Hz, 3 H) and 0.92 (t, J=8 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])=[CH:9][C:8]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([C@H:28](/[CH:35]=[CH:36]/[CH3:37])[CH2:29][C:30]([O:32]CC)=[O:31])=[CH:24][CH:23]=2)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].C1COCC1.CCO.[OH-].[Li+]>>[CH3:4][C:2]([C:5]1[C:10]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])=[CH:9][C:8]([CH2:20][O:21][C:22]2[CH:23]=[CH:24][C:25]([C@H:28](/[CH:35]=[CH:36]/[CH3:37])[CH2:29][C:30]([OH:32])=[O:31])=[CH:26][CH:27]=2)=[CH:7][CH:6]=1)([CH3:1])[CH3:3]
Reactant: C/C=C/[C@H](CC(=O)OCC)c1ccc(OCc2ccc(C(C)(C)C)c(-c3cc(OC)ccc3F)c2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: C/C=C/[C@H](CC(=O)O)c1ccc(OCc2ccc(C(C)(C)C)c(-c3cc(OC)ccc3F)c2)cc1
Reaction time: 22 h
Yield: 93.9 %

Procedure:
To a stirred solution of 1.1 (0.050 g, 0.099 mmol) in THF (2.00 mL, 24 mmol) and EtOH (2.00 mL, 34 mmol) at 23° C. was added 1N lithium hydroxide (1.00 mL, 1.0 mmol). Stirring was continued for 22 hours. The reaction was concentrated in vacuo. 1N HCl was added to reach pH 1, and the resulting mixture was extracted with EtOAc (3×10 mL), dried over MgSO4 and concentrated in vacuo. The residue was then purified by flash chromatography (SiO2 gel 60, eluted with 0%-20% EtOAc in hexanes) to give a clear oil (0.0443 g, 94% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.58 (1H, d, J=8.6 Hz), 7.40 (1H, dd, J=8.2, 2.0 Hz), 7.13 (2H, d, J=8.6 Hz), 7.08 (1H, d, J=1.5 Hz), 7.00 (1H, t, J=8.8 Hz), 6.92 (2H, d, J=8.6 Hz), 6.86 (1H, m), 6.79 (1H, m), 5.57 (1H, m), 5.50 (1H, m), 4.99 (2H, s), 3.79 (3H, s), 3.76 (1H, dd, J=14.5, 7.6 Hz), 2.71 (2H, dd, J=7.6, 2.5 Hz), 1.66 (3H, d, J=5.9 Hz), 1.23 (9H, m). MS ESI (neg.) m/e: 951.4.1 (2M−H)+, 475.1 (M−H)+.
Reaction SMILES: [CH:1]1([C:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([F:15])[CH:8]=2)(O)[CH3:5])[CH2:3][CH2:2]1.FC(F)(F)C(O)=O.[CH3:23][S:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]2[C:34]=1[NH:33][CH:32]=[CH:31]2>ClCCl>[CH:1]1([C:4]([C:31]2[C:30]3[C:34](=[C:26]([CH2:25][S:24][CH3:23])[CH:27]=[CH:28][CH:29]=3)[NH:33][CH:32]=2)([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([F:15])[CH:8]=2)[CH3:5])[CH2:3][CH2:2]1
Reactant: COc1ccc(C(C)(O)C2CC2)cc1F
Reactant: CSCc1cccc2cc[nH]c12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C(C)(c2c[nH]c3c(CSC)cccc23)C2CC2)cc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
100 mg (0.48 mmol) of the compound from Example 140A and 0.04 ml (0.57 mmol) of trifluoroacetic acid were added to 84 mg (0.48 mmol) of the compound from Example 8A in 2.5 ml of dichloromethane. The reaction mixture was stirred at RT for 30 min, and the crude product was then purified directly by preparative HPLC (mobile phase: acetonitrile/water gradient). 63 mg (361% of theory) of the title compound were obtained.
Reaction SMILES: C([O:3][C:4](=[O:29])[C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)[C:8]([O:18][CH2:19][CH2:20][OH:21])=[C:7]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)[CH:6]=1)C.[OH-].[K+]>C1COCC1.CCO>[Cl:17][C:13]1[CH:12]=[C:11]([C:9]2[CH:10]=[C:5]([CH:6]=[C:7]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)[C:8]=2[O:18][CH2:19][CH2:20][OH:21])[C:4]([OH:29])=[O:3])[CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)c1cc(-c2cccc(Cl)c2)c(OCCO)c(-c2cccc(Cl)c2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)c1cc(-c2cccc(Cl)c2)c(OCCO)c(-c2cccc(Cl)c2)c1
Reaction time: 18 h

Procedure:
To a stirred solution of 3,5-bis-(m-chlorophenyl)-4-(2-hydroxyethoxy)benzoic acid ethyl ester (0.620 g, 1.44 mmol) in THF:EtOH (3:2, 30 mL) at room temperature was added 1 N KOH (7.20 mL, 7.20 mmol) dropwise. After 18 h at this temperature, the reaction mixture was concentrated and diluted with H2O (100 mL). The aqueous solution was acidified to pH 1 with 2 N HCl. The solid [3,5-bis-(m-chlorophenyl)-4-(2-hydroxyethoxy)benzoic acid] that formed was filtered off, washed with excess H2O, and then dried on the high vacuum pump (0.450 g, 78%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:19](=[O:20])[N:18]([CH:21]([CH3:23])[CH3:22])[C:11]3[N:12]=[C:13](SC)[N:14]=[CH:15][C:10]=3[CH:9]=2)=[CH:4][C:3]=1[N+:24]([O-:26])=[O:25].C1C=C(Cl)C=C(C(OO)=O)C=1.[NH3:38]>O1CCOCC1>[NH2:38][C:13]1[N:14]=[CH:15][C:10]2[CH:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[C:3]([N+:24]([O-:26])=[O:25])[CH:4]=3)[C:19](=[O:20])[N:18]([CH:21]([CH3:23])[CH3:22])[C:11]=2[N:12]=1
Reactant: CSc1ncc2cc(-c3ccc(F)c([N+](=O)[O-])c3)c(=O)n(C(C)C)c2n1
Reactant: N
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: C1COCCO1
Product: CC(C)n1c(=O)c(-c2ccc(F)c([N+](=O)[O-])c2)cc2cnc(N)nc21
Yield: 69 %

Procedure:
Using a procedure analogous to Example A1, 6-(4-fluoro-3-nitrophenyl)-8-isopropyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (0.82 g, 2.2 mmol), MCPBA (0.38 g, 2.2 mmol) and 0.5 M ammonia in dioxane (8 mL) were combined to afford 2-amino-6-(4-fluoro-3-nitrophenyl)-8-isopropylpyrido[2,3-d]pyrimidin-7(8H)-one as a yellow solid (0.52 g, 69% yield). 1H NMR (400 MHz, MeOH-d4): δ 8.61 (s, 1H), 8.44 (dd, J=7.6 Hz, 2.4 Hz, 1H), 8.03-8.00 (m, 1H), 7.95 (s, 1H), 7.48 (dd, J=10.8 Hz, 7.6 Hz, 1H), 5.96-5.92 (m, 1H), 2.63 (s, 3H), 1.64 (d, J= 6.4 Hz, 6H); MS (ESI) m/z: 344.3 (M+H+).
Reaction SMILES: [S:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][C:9]=2[NH2:15].[F:16][C:17]([F:29])([F:28])[C:18]1[CH:19]=[C:20]([S:24](Cl)(=[O:26])=[O:25])[CH:21]=[CH:22][CH:23]=1>N1C=CC=CC=1>[S:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][C:9]=2[N:15]([S:24]([C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:17]([F:16])([F:28])[F:29])[CH:19]=1)(=[O:26])=[O:25])[S:24]([C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:17]([F:29])([F:28])[F:16])[CH:19]=1)(=[O:26])=[O:25]
Reactant: Nc1cccc2cc(C3=NCCS3)[nH]c12
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Solvent: c1ccncc1
Product: O=S(=O)(c1cccc(C(F)(F)F)c1)N(c1cccc2cc(C3=NCCS3)[nH]c12)S(=O)(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.3 %

Procedure:
To a mixture of 2-(4,5-dihydro-1,3-thiazol-2-yl)-1H-indole-7-amine (100 mg) and pyridine (3 mL) was added 3-(trifluoromethyl)benzenesulfonyl chloride (140 mg) at 0° C., and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated, and the residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:1) to give the title compound (93 mg, yield 32%) as pale-yellow crystals. M+1=634.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][S:13][C:14]1[N:26]=[CH:25][C:17]2=[CH:18][C:19]3[C:24]([N:16]2[N:15]=1)=[CH:23][CH:22]=[CH:21][CH:20]=3.C([O-])(O)=O.[Na+]>ClCCl.O>[CH3:12][S:13]([C:14]1[N:26]=[CH:25][C:17]2=[CH:18][C:19]3[C:24]([N:16]2[N:15]=1)=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:9]
Reactant: CSc1ncc2cc3ccccc3n2n1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CS(=O)c1ncc2cc3ccccc3n2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
261 g) Into a round-bottom flask, m-chloroperbenzoic acid (77% by weight in benzoic acid, 853 mg, 3.80 mmol) was added to a solution of 2-methylsulfanyl-[1,2,4]triazino[1,6-a]indole (780 mg, 3.60 mmol) in dichloromethane (20 mL), at 0° C. The reaction was stirred for 1 hour at room temperature. Saturated NaHCO3 in water was added and the reaction mixture was stirred for 30 minutes. The organic phase was separated, washed with brine, and dried over magnesium sulfate, then filtered. The solvent was removed under vacuum to afford 2-methanesulfinyl-[1,2,4]triazino[1,6-a]indole (820 mg, 98%) as an orange solid, which was used without further purification. 1H-NMR (CDCl3) δ 9.28 (s, 1H), 8.34 (d, J=8.5 Hz, 1H), 7.95 (d, J=8.1 Hz, 1H), 7.60 (m, 1H), 7.52 (m, 1H), 7.21 (s, 1H), 3.06 (s, 3H); LC/MS (ESI+): 254.5 (M+Na).
Reaction SMILES: C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[Si]([O:21][C@H:22]([CH2:35][CH2:36][C:37]1[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=1)[C@H:23]([CH3:34])[O:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)(C(C)(C)C)(C)C.[CH3:43][N:44]([C:46]1[CH:51]=[CH:50][CH:49]=[C:48](Br)[N:47]=1)[CH3:45]>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.C(O)C>[CH3:43][N:44]([CH3:45])[C:46]1[N:47]=[C:48]([C:28]2[CH:27]=[CH:26][C:25]([O:24][C@@H:23]([CH3:34])[C@H:22]([OH:21])[CH2:35][CH2:36][C:37]3[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=3)=[CH:30][CH:29]=2)[CH:49]=[CH:50][CH:51]=1
Reactant: C[C@H](Oc1ccc(B(O)O)cc1)[C@@H](CCc1cccnc1)O[Si](C)(C)C(C)(C)C
Reactant: CN(C)c1cccc(Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: C[C@H](Oc1ccc(-c2cccc(N(C)C)n2)cc1)[C@H](O)CCc1cccnc1
Temperature: 120 °C
Yield: 50.1 %

Procedure:
Prepared according to the method described in Example 15g) from toluene (4 ml), 2M aqueous sodium carbonate (0.5 ml), (1S,2R)-4-[2-(tert-butyldimethylsilanyloxy)-1-methyl-4-pyridin-3-yl-butoxy]benzeneboronic acid (0.200 g, Example 15f)), ethanol (1 ml), 6-bromo-2-N,N-dimethylaminopyridine (0.201 g, Example 18a)) and tetrakis(triphenylphosphine)palladium(0) (0.020 g) with heating at 120° C. for 4 hours. The product was purified by normal-phase HPLC eluting with a gradient of 0-25% ethanol in dichloromethane to give the title compound as an oil (0.091 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13]Br)=[C:9]([Cl:15])[CH:8]=2)[CH:6]=1.[C-:16]#[N:17].[Na+].O>CS(C)=O>[Cl:15][C:9]1[CH:8]=[C:7]([N:5]2[CH:6]=[C:2]([Cl:1])[CH:3]=[N:4]2)[CH:12]=[CH:11][C:10]=1[CH2:13][C:16]#[N:17]
Reactant: Clc1cnn(-c2ccc(CBr)c(Cl)c2)c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCc1ccc(-n2cc(Cl)cn2)cc1Cl
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 99.5 %

Procedure:
15 g of 4-chloro-1-(4-bromomethyl-3-chlorophenyl)pyrazole are added to 2.8 g of sodium cyanide in 67 ml of dimethylsulfoxide and stirred for 6.5 hours at room temperature. 300 ml of water are added dropwise and 12.3 g of 2-chloro-4-(4-chloropyrazol-1-yl)phenylacetonitrile are thus obtained. Chromatographing the latter with a mixture of cyclohexane/ethanol/ethyl acetate on silica gel, yields a product with a m.p. 139.5° to 140° C. (As by-product, 1,2-bis-[2-chloro-4-(4-chloropyrazol-1-yl)phenyl]propionic acid nitrile has formed; from this by-product the appropriate amide with m.p. 248° to 249.5° C. is obtained by saponification with concentrated sulfuric acid.)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][C:6]2[C:7](=O)[NH:8][CH:9]=[CH:10][C:11]=2[CH:12]=1.P(Cl)(Cl)([Cl:16])=O>C(#N)C>[Cl:16][C:7]1[N:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:12]2
Reactant: COc1cnc2c(=O)[nH]ccc2c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: COc1cnc2c(Cl)nccc2c1
Temperature: 85 °C
Yield: 60.4 %

Procedure:
To a mixture of 3-methoxy-1,7-naphthyridin-8(7H)-one (4.50 g, 25.5 mmol) in acetonitrile (102 ml) was added phosphorus oxychloride (11.69 ml, 128 mmol). The reaction mixture was heated to 85° C. for 5 h. The solution was cooled to rt and concentrated in vacuo. The resulting brown residue was partitioned between CH2Cl2 and aqueous saturated NaHCO3 solution; the aqueous layer was back-extracted with DCM (3×). The combined organic extracts were dried over sodium sulfate, the filtrate was concentrated in vacuo, and the residue was purified by silica gel chromatography (5%-30% of 9:1 DCM:MeOH in DCM) to afford 8-chloro-3-methoxy-1,7-naphthyridine (3.00 g, 15.41 mmol, 60.3% yield) as an off-white solid. MS m/z=195 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([Br:18])[N:15]=[C:14](Br)[CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:20][NH2:21]>>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C:12]2[CH:13]=[C:14]([NH:21][CH3:20])[N:15]=[C:16]([Br:18])[CH:17]=2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: Nc1ccc(S(=O)(=O)Nc2cc(Br)nc(Br)c2)cc1
Reactant: CN
Product: CNc1cc(NS(=O)(=O)c2ccc(N)cc2)cc(Br)n1
Yield: 88 %

Procedure:
0.81 g (0.002 mol) of 4-amino-N-(2,6-dibromo-pyridin-4-yl)-benzenesulfonamide was stirred in 35 ml of liquid methylamine in an autoclave at 130° C. for 44 hours. The methylamine was left to evaporate, the residue was dissolved in ethanol, treated with 2 g of silica gel, concentrated and the residue was chromatographed on silica gel, firstly with ethyl acetate/hexane 1:2, then with pure ethyl acetate. There was obtained 0.63 g (88%) of 4-amino-N-(2-bromo-6-methylamino-pyridin-4-yl)-benzenesulfonamide as a beige foam. 0.33 g (0.00092 mol) of this was dissolved in 10 ml of methanol, treated with 5 ml of 2M HCl in methanol, concentrated and again treated with 4 ml of methanol. The precipitate obtained was filtered off under suction, rinsed with a small amount of methanol and dried in a high vacuum. There was obtained 0.27 g (69%) of 4-amino-N-(2-bromo-6-methylamino-pyridin-4-yl)-benzenesulfonamide hydrochloride as white crystals; m.p.: 226-228° C. (dec.).
Reaction SMILES: CN([CH:4]=[O:5])C.P(Cl)(Cl)(Cl)=O.[CH2:11]1[O:19][C:18]2[CH:17]=[CH:16][C:15]([CH3:20])=[CH:14][C:13]=2[O:12]1>>[CH3:20][C:15]1[CH:14]=[C:13]2[O:12][CH2:11][O:19][C:18]2=[CH:17][C:16]=1[CH:4]=[O:5]
Reactant: Cc1ccc2c(c1)OCO2
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc2c(cc1C=O)OCO2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 11 %

Procedure:
To DMF (6.5 ml, 83 mmoles) at 0° C. was added phosphorus oxychloride (3.9 ml, 42 mmoles). The solution was stirred 15 minutes at 0° C. followed by the addition of 3,4-(methylenedioxy)toluene (1.0 ml, 8.3 mmoles). The solution was heated to 110° C. upon which it became dark brown. 1.5 hours later the thick dark brown mixture was cooled to ambient temperature then added to ice (100 ml), and extracted with ether (100 ml). The organic layer was dried (MgSO4), filtered and concentrated. Flash chromatography (5% EtOAc/hexanes) provided 0.15 g (11%) of the title compound as a colorless oil.
Reaction SMILES: [OH:1][C:2]([CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]1[C@@H:16]2[C@@H:11]([NH:12][C:13]([NH:15]2)=[O:14])[CH2:10][S:9]1)=[O:3].C(N(CC)CC)C.FC(F)(F)C(O[C:29]1[C:34]([F:35])=[C:33]([F:36])[CH:32]=[C:31]([F:37])[C:30]=1[F:38])=O>CN(C=O)C>[F:35][C:34]1[C:33]([F:36])=[CH:32][C:31]([F:37])=[C:30]([F:38])[C:29]=1[O:3][C:2]([CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]1[C@@H:16]2[C@@H:11]([NH:12][C:13]([NH:15]2)=[O:14])[CH2:10][S:9]1)=[O:1]
Reactant: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Reactant: O=C(Oc1c(F)c(F)cc(F)c1F)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1N[C@H]2[C@H](CS[C@H]2CCCCC(=O)Oc2c(F)c(F)cc(F)c2F)N1
Yield: 65 %

Procedure:
A 2.5 g (10.3 mmol) quantity of d-biotin in 20 mL anhydrous DMF under argon atmosphere was warmed to 60° C. with stirring to effect dissolution. 1.7 mL (12.5 mmol) triethylamine was added, followed by 3.4 g (12.5 mmol) 1. The mixture was stirred for 2 hours, after which the solvent was removed by rotary evaporation. The resultant semi-solid was triturated with 15 mL ether twice to produce a white solid (2.6 g, 65%). 1H-NMR. (Ref. Wilbur, D. S., Bioconj. Chem., v8 pp572-584)
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1.[CH3:14][S:15]([NH:18][C:19]1[CH:28]=[CH:27][C:22]([O:23][CH2:24][CH2:25]Cl)=[CH:21][CH:20]=1)(=[O:17])=[O:16].C(=O)(O)[O-].[Na+].[I-].[Na+]>C(#N)C>[CH3:14][S:15]([NH:18][C:19]1[CH:28]=[CH:27][C:22]([O:23][CH2:24][CH2:25][N:2]([CH3:1])[CH2:3][CH2:4][C:5]2[CH:6]=[CH:7][C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=2)=[CH:21][CH:20]=1)(=[O:17])=[O:16]
Reactant: CS(=O)(=O)Nc1ccc(OCCCl)cc1
Reactant: CNCCc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CN(CCOc1ccc(NS(C)(=O)=O)cc1)CCc1ccc([N+](=O)[O-])cc1
Yield: 38.1 %

Procedure:
A suspension of N-methyl-4-nitrophenethylamine (1.1 g), 2-(4-methanesulphonamidophenoxy)ethyl chloride (1.5 g), sodium bicarbonate (0.5 g) and sodium iodide (0.9 g) in acetonitrile (100 ml) was stirred at reflux for 4 days. On evaporation to dryness the resultant oil was partitioned between 2N aqueous sodium bicarbonate solution and methylene chloride. After two further extractions with methylene chloride, the organic portions were combined, washed with saturated brine solution, dried over anhydrous magnesium sulphate, filtered and evaporated to dryness. The resultant brown oil was chromatographed on silica ("Kieselgel 60"-Trade Mark) eluting with ethyl acetate followed by collection and evaporation of suitable fractions to give the title compound as a yellow solid, (0.9 g).