Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C@@H:5]1[CH2:9][C@@H:8]([CH2:10][OH:11])[NH:7][C:6]1=[O:12].[N+:13]([C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1)([O-:15])=[O:14].C(N(CC)CC)C.S(C1C=CC([N+]([O-])=O)=CC=1)([O-])(=O)=O>CN(C1C=CN=CC=1)C.C1COCC1.CCOC(C)=O>[N+:13]([C:16]1[CH:17]=[CH:18][C:19]([S:22]([O:11][CH2:10][C@@H:8]2[CH2:9][C@@H:5]([CH2:4][CH2:3][CH2:2][Cl:1])[C:6](=[O:12])[NH:7]2)(=[O:24])=[O:23])=[CH:20][CH:21]=1)([O-:15])=[O:14]
Reactant: O=C1N[C@H](CO)C[C@H]1CCCCl
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Agent: O=[N+]([O-])c1ccc(S(=O)(=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1N[C@H](COS(=O)(=O)c2ccc([N+](=O)[O-])cc2)C[C@H]1CCCCl
Temperature: 25 °C
Reaction time: 17 h
Yield: 85.7 %

Procedure:
The (3R,5S)-3-(3-chloropropyl)-5-(hydroxymethyl)pyrrolidin-2-one (8.31 g, 43.4 mmol, 1.0 equiv), p-nitrobenzenesulfonylchloride (10.57 g, 47.7 mmol, 1.1 equiv) and DMAP (0.53 g, 4.4 mmol, 0.1 equiv) were added to a 500 mL round-bottom flask and dissolved in THF (100 mL) under nitrogen. Triethylamine (8.77 g, 12.1 mL, 86.7 mmol, 2.0 equiv) was added via syringe and the resulting solution stirred for 17 h at ambient temperature. After this time complete formation of the desired nosylate was observed by LC/MS analysis. The mixture was diluted with 50 mL of EtOAc and the amines quenched by addition of 100 mL of 1.0 M HCl. The layers were separated and the organic layer washed with brine, dried over Na2SO4, filtered and evaporated. The pale yellow solid was washed with ether and residual solvent removed in vacuo. This afforded 14.02 g (86% yield) of ((2S,4R)-4-(3-chloropropyl)-5-oxopyrrolidin-2-yl)methyl 4-nitrobenzenesulfonate.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[CH3:25][O:26][CH2:27][C:28]1([CH2:33][NH2:34])[CH2:32][CH2:31][CH2:30][CH2:29]1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:34][CH2:33][C:28]4([CH2:27][O:26][CH3:25])[CH2:32][CH2:31][CH2:30][CH2:29]4)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2]
Reactant: COCC1(CN)CCCC1
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Product: COCC1(CNC(=O)c2ccc(-n3ncc(-c4ccc(C#N)cc4C)c3O)nc2)CCCC1

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (1-(methoxymethyl)cyclopentyl)methanamine 1H NMR (400 MHz, DMSO-d6) δ ppm 1.26-1.38 (m, 2 H) 1.38-1.59 (m, 6 H) 2.37 (s, 3 H) 3.13 (s, 2 H) 3.21 (s, 3 H) 3.26 (d, J=6.32 Hz, 2 H) 7.59 (dd, J=7.83, 1.52 Hz, 1 H) 7.66 (s, 1 H) 7.73 (d, J=8.08 Hz, 1 H) 8.09 (s, 1 H) 8.33 (s, 2 H) 8.42 (t, J=6.06 Hz, 1 H) 8.82 (t, J=1.52 Hz, 1 H) 12.56-13.49 (m, 1 H). MS m/z [M+H]+ 446.2.
Reaction SMILES: C([O:4][C:5]1[C:6](=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:7]([OH:9])=O)(=O)C.[Br:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>>[Br:14][C:15]1[CH:21]=[CH:20][C:18]([NH:19][C:7](=[O:9])[C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[OH:4])=[CH:17][CH:16]=1
Reactant: Nc1ccc(Br)cc1
Reactant: CC(=O)Oc1ccccc1C(=O)O
Product: O=C(Nc1ccc(Br)cc1)c1ccccc1O

Procedure:
This compound was obtained as a white solid starting from acetylsalicyclic acid and 4-bromoaniline using the same procedure described in example 5.
Reaction SMILES: [C:1]12([CH2:11][CH2:12][N:13]([CH2:26][CH2:27][NH:28][CH3:29])[C:14]([NH:16][CH2:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[O:15])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].[CH3:38][O:39][CH2:40][CH2:41]Cl>O.C(OCC)C.CN(C)C=O>[C:1]12([CH2:11][CH2:12][N:13]([CH2:26][CH2:27][N:28]([CH2:41][CH2:40][O:39][CH3:38])[CH3:29])[C:14]([NH:16][CH2:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[O:15])[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: CNCCN(CCC12CC3CC(CC(C3)C1)C2)C(=O)NCCCc1ccncc1
Reactant: COCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: COCCN(C)CCN(CCC12CC3CC(CC(C3)C1)C2)C(=O)NCCCc1ccncc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 32.1 %

Procedure:
To N,N-dimethylformamide (20 ml) were added 1-[2-(1-adamantyl)ethyl]-1-(2-methylaminoethyl)-3-[3-(4-pyridyl)propyl]urea (1.50 g, 3.76 mmol), which was a free base of Compound No. 3-1, potassium carbonate (1.56 g, 11.3 mmol) and sodium iodide (1.69 g, 11.3 mmol) at room temperature, then 2-chloroethyl methyl ether (412 μl, 4.51 mmol) was added to the mixture, and the whole was heated at 80° C. The whole was stirred overnight, diethyl ether (50 ml) and water (100 ml) were added to the reaction mixture, and the whole was extracted. The obtained organic layer was washed with water (100 ml) and a saturated aqueous sodium chloride solution (50 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 552 mg (32.1%) of the titled compound as a pale yellow oily matter.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:16]=[CH:15][C:14]3[C:9](=[C:10]([C:17]([O:19]C)=[O:18])[CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:2]=1.[Li+].[OH-]>C1COCC1.O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:16]=[CH:15][C:14]3[C:9](=[C:10]([C:17]([OH:19])=[O:18])[CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:2]=1
Reactant: COC(=O)c1cccc2cnc(-c3cccnc3)nc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cccc2cnc(-c3cccnc3)nc12
Temperature: 50 °C
Reaction time: 2 h
Yield: 90.5 %

Procedure:
A mixture of methyl 2-(pyridin-3-yl)quinazoline-8-carboxylate (3.5 g, 13.2 mmol) and LiOH (0.48 g, 19.8 mmol) in 1:1 THF/H2O (50 mL) was stirred at 50° C. for 2 hours. The solvent was removed in vacuo and water (20 mL) was added. Aqueous solution was adjusted to pH=3 with 1N aqueous hydrochloride solution. The mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried (Na2SO4), concentrated in vacuo, and purified by silica gel column chromatography (2.5% MeOH in CH2Cl2) to obtain 2-(pyridin-3-yl)quinazoline-8-carboxylic acid (3.0 g, 90% yield).
Reaction SMILES: Br[C:2]1[C:7]2[NH:8][C:9]([N:11]3[CH2:16][CH2:15][N:14]([C:17]4[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][N:18]=4)[CH2:13][C@H:12]3[CH3:24])=[N:10][C:6]=2[CH:5]=[C:4]([C:25]([F:28])([F:27])[F:26])[CH:3]=1.[F:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1>>[Cl:23][C:22]1[C:17]([N:14]2[CH2:15][CH2:16][N:11]([C:9]3[NH:8][C:7]4[C:2]([C:34]5[CH:33]=[CH:32][CH:31]=[C:30]([F:29])[CH:35]=5)=[CH:3][C:4]([C:25]([F:28])([F:26])[F:27])=[CH:5][C:6]=4[N:10]=3)[C@H:12]([CH3:24])[CH2:13]2)=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: C[C@@H]1CN(c2ncccc2Cl)CCN1c1nc2cc(C(F)(F)F)cc(Br)c2[nH]1
Product: C[C@@H]1CN(c2ncccc2Cl)CCN1c1nc2cc(C(F)(F)F)cc(-c3cccc(F)c3)c2[nH]1

Procedure:
7-Bromo-2-[(2R)-4-(3-chloropyridin-2-yl)-2-methylpiperazin-1-yl]-5-(trifluoromethyl)-1H-benzoimidazole (95 mg, 0.2 mmol, Example 77) and 3-fluoro-phenylboronic acid (35 mg, 0.25 mmol, Aldrich) reacted under the conditions of Example 51a to give the title compound as a white amorphous solid. MS (ESI, pos. ion) m/z: 490 (M+1).
Reaction SMILES: [C:1]1([CH2:11][C:12]([OH:14])=[O:13])[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]([OH:10])=[O:9])[CH:2]=1.Cl.[CH2:16](O)[CH3:17]>O1CCOCC1>[CH2:16]([O:9][C:8](=[O:10])[CH2:7][C:3]1[CH:2]=[C:1]([CH2:11][C:12]([OH:14])=[O:13])[CH:6]=[CH:5][CH:4]=1)[CH3:17]
Reactant: O=C(O)Cc1cccc(CC(=O)O)c1
Reactant: CCO
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)Cc1cccc(CC(=O)O)c1

Procedure:
A solution of the diester from preparation 1 (44.3 g, 177 mmol) and 2,2′-(1,3-phenylene)diacetic acid (59.2 g, 308 mmol) in ethanol (24 mL) and dioxan (290 mL) was treated dropwise with 12M hydrochloric acid (4.9 mL, 58.8 mmol). The reaction mixture was stirred and heated under reflux for 18 hours before being allowed to cool and concentrated to low volume. The reaction mixture was diluted with toluene (125 mL) and the resulting slurry filtered. The filtrate was concentrated under reduced pressure and the residue taken up in water and neutralised with sodium bicarbonate. The mixture was diluted with ethyl acetate (200 mL) and the organic layer was separated and washed with sodium bicarbonate solution (5×30 mL) and brine (50 mL). The combined aqueous extracts were acidified to pH 3 with 6M hydrochloric acid and extracted with ether (3×30 mL). The organics were combined, dried over magnesium sulphate and concentrated under reduced pressure. The residue was triturated with pentane giving the title compound as a colourless solid 10.8 g.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([NH2:8])[CH2:3]1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C.Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>O>[CH2:25]([O:24][C:22](=[O:23])[NH:8][CH:4]1[CH2:5][CH2:6][CH2:7][CH:2]([OH:1])[CH2:3]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: NC1CCCC(O)C1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(NC1CCCC(O)C1)OCc1ccccc1
Yield: 88.1 %

Procedure:
Treat a mixture of 3-hydroxycyclohexyl amine (10 g, 86.96 mmol), potassium carbonate (18 g, 130 mmol), ethyl acetate (150 mL) and water (70 mL) with benzyl chloroformate (22.17 g, 130 mmol). Stir the reaction at room temperature for 12 hours. Separate the organic layer, dry the organic over sodium sulfate, filter and concentrate. Add diethyl ether to the residuer. Filter the resulting white precipitate and air dry to afford 19.1 g of the title compound (88%). MS (m/z): 250 (M+).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[N:5]1[CH:10]=[CH:9][N:8]=[C:7]2[NH:11][C:12]([C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]([CH2:23][CH2:24][CH2:25][NH2:26])[CH:15]=3)=[CH:13][C:6]=12.C(N(CC)CC)C>ClCCl>[N:5]1[CH:10]=[CH:9][N:8]=[C:7]2[NH:11][C:12]([C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]([CH2:23][CH2:24][CH2:25][NH:26][C:1](=[O:3])[CH3:2])[CH:15]=3)=[CH:13][C:6]=12
Reactant: CC(=O)Cl
Reactant: NCCCn1cc(-c2cc3nccnc3[nH]2)c2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCCCn1cc(-c2cc3nccnc3[nH]2)c2ccccc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Acetyl chloride (31 μl) was added dropwise to a solution of 3-[3-(5H-pyrrolo[2,3-b]pyrazin-6-yl)-indol-1-yl]-propylamine [100 mg, Example 3(a)] and triethylamine (52.2 μl) and dichloromethane (20 mL) at ambient temperature under a nitrogen atmosphere. After stirring for 24 hours at ambient temperature the reaction mixture was evaporated. The residue was subjected to flash chromatography on silica eluting with a mixture of dichloromethane and methanol (9:1, v/v) to give the title compound (82 mg) as a yellow solid, m.p. 260° C. MS: 334 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:23]([NH2:26])([CH3:25])[CH3:24]>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([NH:26][CH:23]([CH3:25])[CH3:24])=[O:8])=[CH:9][CH:10]=1
Reactant: CC(C)N
Reactant: O=C(O)c1ccc(Cl)nc1
Agent: O=C(n1ccnc1)n1ccnc1
Product: CC(C)NC(=O)c1ccc(Cl)nc1

Procedure:
The product was prepared from 6-chloro-nicotinic acid (1.0 g), carbonyldiimidazole (0.8 g) and isopropylamine (0.6 ml) using the method of example 115 step (i). Yield 0.75 g.
Reaction SMILES: [C:1]([NH:11][C@@H:12]([C:19]([OH:21])=O)[CH2:13][C:14]1[N:18]=[CH:17][NH:16][CH:15]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C1C=C2N=NN(O)C2=CC=1.O.C1CCC(N=C=NC2CCCCC2)CC1.[C:48]1([CH2:54][O:55][CH2:56][CH2:57][NH:58][C:59](=[O:77])[CH2:60][NH:61][CH2:62][C:63]2[CH:68]=[CH:67][C:66]([O:69][CH2:70][C:71]3[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=3)=[CH:65][CH:64]=2)[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>CN(C=O)C>[C:5]1([CH2:4][O:3][C:1]([NH:11][C@@H:12]([C:19]([N:61]([CH2:62][C:63]2[CH:64]=[CH:65][C:66]([O:69][CH2:70][C:71]3[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=3)=[CH:67][CH:68]=2)[CH2:60][C:59]([NH:58][CH2:57][CH2:56][O:55][CH2:54][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)=[O:77])=[O:21])[CH2:13][C:14]2[N:18]=[CH:17][NH:16][CH:15]=2)=[O:2])[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=C(CNCc1ccc(OCc2ccccc2)cc1)NCCOCc1ccccc1
Reactant: O=C(N[C@H](Cc1c[nH]cn1)C(=O)O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CN(Cc1ccc(OCc2ccccc2)cc1)C(=O)[C@@H](Cc1c[nH]cn1)NC(=O)OCc1ccccc1)NCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45 %

Procedure:
To a suspension of CBZ-D-histidine (0.093 g, 0.32 mmol) in DMF (2 mL) was added HOBT hydrate (0.059 g, 0.39 mmol) followed by DCC (0.080 g, 0.39 mmol). A solution of the compound from Step 3 above (0.13 g, 0.32 mmol) in DMF (2 mL) was added and the mixture was stirred overnight at room temperature. The mixture was filtered, and the filtrate was diluted with CHCl3, washed twice with saturated aqueous NaHCO3, brine, dried over MgSO4, and concentrated. Flash chromatography (2-5% MeOH/CHCl3) gave 0.10 g (45%) of the title compound as a white powder; ES-MS 676 (m+1).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:21])[N:5]([CH:13]1[CH2:18][CH2:17][C:16](=[O:19])[NH:15][C:14]1=[O:20])[C:6]([CH3:12])=[N:7]2.[Cl:22][CH2:23][C:24](Cl)=[O:25].C(#N)C>CO>[Cl:22][CH2:23][C:24]([NH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:21])[N:5]([CH:13]1[CH2:18][CH2:17][C:16](=[O:19])[NH:15][C:14]1=[O:20])[C:6]([CH3:12])=[N:7]2)=[O:25]
Reactant: O=C(Cl)CCl
Reactant: Cc1nc2cccc(N)c2c(=O)n1C1CCC(=O)NC1=O
Solvent: CC#N
Solvent: CO
Product: Cc1nc2cccc(NC(=O)CCl)c2c(=O)n1C1CCC(=O)NC1=O
Temperature: 100 °C
Yield: 88.6 %

Procedure:
The stirred mixture of 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione (4.0 g, 14 mmol) and chloroacetyl chloride (7.7 mL, 98 mmol) was heated in a 100° C. oil bath for 15 minutes. The mixture was allowed to cool to room temperature. Acetonitrile (5 mL) was added to the mixture. The suspension was filtered and washed with ethyl acetate (2×10 mL) to give a white solid. The solid was stirred in methanol (50 mL) overnight. The suspension was filtered and washed with methanol (20 mL) to give 2-chloro-N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-yl]-acetamide as a white solid (4.5 g, 90% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 20/80 CH3CN/0.1% H3PO4, 12.79 min (97.6%); mp: 275-277° C.; 1H NMR (DMSO-d6) δ 2.18-2.25 (m, 1H, CH2), 2.61-2.80 (m, 5H, CH3, 2CHH), 2.86-2.91 (m, 1H, CHH), 4.48-4.53 (m, 2H, CH2), 5.36 (dd, J=6, 11 Hz, 1H, NCH), 7.39 (dd, J=1, 8 Hz, 1H, Ar), 7.83 (t, J=8 Hz, 1H, Ar), 8.57 (dd, J=1, 8 Hz, 1H, Ar), 10.7 (brs, 1H, HCl), 11.11 (s, 1H, NH), 12.26 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.66, 23.10, 30.60, 43.56, 56.84, 107.89, 115.65, 120.87, 135.77, 138.87, 147.17, 155.49, 162.67, 165.55, 169.14. 172.60; LCMS: MH=363, 365; Anal Calcd for C16H15N4O4Cl+1.05HCl: C, 47.92; H, 4.03; N, 13.97; Cl, 18.12. Found: C, 48.24; H, 3.79; N, 13.84; Cl, 18.27.
Reaction SMILES: [CH3:1][N:2]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([C:14]2[C:19]([F:20])=[C:18]([F:21])[C:17]([F:22])=[C:16]([F:23])[C:15]=2[F:24])(=[O:13])=[O:12])=[CH:6][CH:5]=1)[CH3:3].[CH3:25][Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[CH3:3][N:2]([C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH3:25])[S:11]([C:14]2[C:15]([F:24])=[C:16]([F:23])[C:17]([F:22])=[C:18]([F:21])[C:19]=2[F:20])(=[O:13])=[O:12])=[CH:6][CH:5]=1)[CH3:1]
Reactant: CN(C)c1ccc(NS(=O)(=O)c2c(F)c(F)c(F)c(F)c2F)cc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(C)c1ccc(N(C)S(=O)(=O)c2c(F)c(F)c(F)c(F)c2F)cc1
Reaction time: 0.17 h
Yield: 60 %

Procedure:
4-(N,N-Dimethylamino)-1-(pentafluorophenylsulfonamido)benzene (100 mg, 0.273 mmol) was dissolved in dry THF (2.5 mL) and to the system was added under N2 at room temperature a 1M solution of lithium bis(trimethylsilyl)amide (0.274 mL). The reaction mixture was stirred for 10 min followed by addition of Mel (65 mg, 0.028 mL). The reaction mixture was stirred overnight, the solvent was evaporated under reduced pressure and the crude product purified by HPLC using silica as the stationary phase and eluting with 20% EtOAc/Hex (v/v) to afford the product as a white solid in 60% yield (62 mg). EI m/z: 380(35, M+), 149(100). 1H NMR (CD3OD) 7.05(d, J=8 Hz, 2H), 6.68(d, J=8 Hz, 2H), 3.33(s, 3H) 2.93(s, 6H). Anal. calcd. for C15H13F5SO2N2 : C, 47.37, H, 3.45, N 7.37. Found: C, 47.37, H, 3.49, N, 7.32.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[C:9](Cl)(=[O:13])[C:10](Cl)=[O:11]>ClC1C=CC=CC=1Cl>[O:8]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][C:10](=[O:11])[C:9]1=[O:13]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Nc1ccccc1O
Solvent: Clc1ccccc1Cl
Product: O=c1[nH]c2ccccc2oc1=O
Temperature: 70 °C
Reaction time: 1.5 h

Procedure:
Ortho-aminophenol (21.8 g) in 200 ml of ortho-dichlorobenzene was added as a slurry to 18.3 ml oxalyl dichloride (1.05 mol eq) in 150 ml ortho-dichlorobenzene at about 100° C. with stirring. After the addition (about 30 min.), the reaction mixture was heated to about 70° C. and then kept at this temperature for approximately 1.5 hours. The reaction mixture was then cooled, filtered and the solid product, 4H-1,4-benzoxazin-2,3-dione was washed with ether to give 27 g., m.p. 265°-268° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:55])/[C:4](/[N:41]1[CH2:45][CH2:44][C@H:43]([NH:46][C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[C:42]1=[O:54])=[CH:5]\[C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][C:17]([F:20])([F:19])[F:18])[C:12]([NH:21][C:22]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[N:11][CH:10]=[CH:9]2>CO>[CH3:1][O:2][C:3](=[O:55])[C@H:4]([N:41]1[CH2:45][CH2:44][C@H:43]([NH:46][C:47]([O:49][C:50]([CH3:51])([CH3:52])[CH3:53])=[O:48])[C:42]1=[O:54])[CH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][C:17]([F:20])([F:19])[F:18])[C:12]([NH:21][C:22]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[N:11][CH:10]=[CH:9]2
Reactant: COC(=O)/C(=C\c1cc2ccnc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)c2cc1OC(F)(F)F)N1CC[C@H](NC(=O)OC(C)(C)C)C1=O
Solvent: CO
Product: COC(=O)[C@@H](Cc1cc2ccnc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)c2cc1OC(F)(F)F)N1CC[C@H](NC(=O)OC(C)(C)C)C1=O

Procedure:
1.35 g (1.8 mmol) of (E)-2-((S)-3-tert-Butoxycarbonylamino-2-oxo-pyrrolidin-1-yl)-3-[7-trifluoromethoxy-1-(trityl-amino)-isoquinolin-6-yl]acrylic acid methyl ester are dissolved in 50 ml abs. Methanol.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[C:4]([C:6]1[S:10][C:9]([NH:11][C:12]([C:14]2([C:17]3[CH:25]=[CH:24][C:20]4[O:21][CH2:22][O:23][C:19]=4[CH:18]=3)[CH2:16][CH2:15]2)=[O:13])=[N:8][CH:7]=1)=[O:5].[BH4-].[Na+]>CO>[O:23]1[C:19]2[CH:18]=[C:17]([C:14]3([C:12]([NH:11][C:9]4[S:10][C:6]([CH:4]([C:3]5[CH:26]=[CH:27][CH:28]=[CH:29][C:2]=5[Cl:1])[OH:5])=[CH:7][N:8]=4)=[O:13])[CH2:16][CH2:15]3)[CH:25]=[CH:24][C:20]=2[O:21][CH2:22]1
Reactant: O=C(c1cnc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)s1)c1ccccc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=C(Nc1ncc(C(O)c2ccccc2Cl)s1)C1(c2ccc3c(c2)OCO3)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.2 %

Procedure:
1-Benzo[1,3]dioxol-5-yl-cyclopropanecarboxylic acid [5-(2-chloro-benzoyl)-thiazol-2-yl]-amide (1.0 g, 2.3 mmol) was suspended in 150 mL of anhydrous methanol. Sodium borohydride (1.3 g, 35 mmol) was slowly added and the resulting pale yellow solution was allowed to stir for 1 hour at room temperature. The crude product was evaporated to dryness and then dissolved in a minimum of ethyl acetate. The organic was washed three times with an equal volume of 1N hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride. The organic layer was then dried over sodium sulfate, filtered, and evaporated to dryness to yield the product as a beige solid (0.64 g, 1.5 mmol, 63%). 1H NMR (400 MHz, DMSO-d6) δ 1.10-1.14 (m, 2H), 1.41-1.45 (m, 2H), 6.00 (s, 2H), 6.14 (s, 1H), 6.86 (d, J=1.0 Hz, 2H), 6.95 (t, J=1.0 Hz, 1H), 7.14 (d, J=0.6 Hz, 1H), 7.29-7.34 (m, 1H), 7.38-7.43 (m, 2H), 7.71 (d, J=7.5 Hz, 1H), 10.93 (s, 1H) ESI-MS m/z calc. 428.1. found; 429.5 (M+1)+ Retention time 3.17 minutes.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6](O)[N:5]2[N:9]=[N:10][N:11]=[C:4]2[N:3]=1.P(Cl)(Cl)([Cl:14])=O>C(Cl)(Cl)Cl>[Cl:14][C:6]1[N:5]2[N:9]=[N:10][N:11]=[C:4]2[N:3]=[C:2]([CH3:1])[CH:7]=1
Reactant: Cc1cc(O)n2nnnc2n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cc1cc(Cl)n2nnnc2n1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 92 %

Procedure:
A mixture of 67.88 g (0.45 mole) of 5-methyl-7-hydroxytetrazolo[1,5-a]pyrimidine and 300 ml of phosphorus oxychloride was stirred for 1.5 hours in a bath of 100° C. and then concentrated. The residue obtained was dissolved in 600 ml of chloroform, ice-cooled and then washed with water, followed by drying over anhydrous magnesium sulfate to evaporate the solvent. The set residue was collected by filtration with addition of n-hexane and dried to obtain 70.2 g of the title compound (Yield: 92%).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:13]([CH2:14][O:15]C(=O)C)[O:12][C@H:11]2[C@H:7]([N:8]=[C:9]([NH:19][C:20](=[O:24])/[CH:21]=[CH:22]/[CH3:23])[S:10]2)[C@H:6]1[O:25]C(=O)C)(=O)C.C[O-].[Na+]>CO>[OH:4][C@@H:5]1[C@@H:13]([CH2:14][OH:15])[O:12][C@H:11]2[C@H:7]([N:8]=[C:9]([NH:19][C:20](=[O:24])/[CH:21]=[CH:22]/[CH3:23])[S:10]2)[C@H:6]1[OH:25]
Reactant: C/C=C/C(=O)NC1=N[C@@H]2[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](COC(C)=O)O[C@@H]2S1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: C/C=C/C(=O)NC1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]2S1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 10 mL reaction vial was added (3aR,5R,6S,7R,7aR)-5-[(acetyloxy)methyl]-2-[(2E)-but-2-enoylamino]-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazole-6,7-diyl diacetate (40.00 mg; 0.10 mmol; 1.00 eq.) in methanol (2.00 ml) followed by sodium methanolate (0.00 ml; 0.01 mmol; 0.10 eq.). The obtained clear solution was stirred at room temperature for 1 h. LCMS showed a strong peak of SM plus desired product and byproduct (m/z=331). After 5 h, LMCS only showed the product's peak. The solution was diluted with 10 mL MeOH before it was transferred into a 50 mL round-bottom flask. Half spoon resin (Dowex 50WX8) was added. The mixture was gently stirred for 10 sec before it was filtered. 30 mL MeOH was used to rinsed the cake. The obtained solution was concentrated and lyophilized to afford 90.6% of the title compound as a white solid.
Reaction SMILES: N1C=CC=CC=1P([CH2:14][P:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)C1C=CC=CC=1.Cl[CH2:29][CH2:30][CH2:31]Cl>ClCCl>[N:17]1[CH:18]=[CH:19][CH:31]=[CH:30][C:29]=1[P:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:16][CH2:21][CH2:14][P:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: ClCCCCl
Reactant: c1ccc(P(CP(c2ccccc2)c2ccccn2)c2ccccn2)cc1
Solvent: ClCCl
Product: c1ccc(P(CCCP(c2ccccc2)c2ccccn2)c2ccccn2)cc1

Procedure:
An amount of 1,3-bis[(2-pyridyl)(phenyl)phosphino]propane was prepared substantially in the same way as the diphosphine of Example 2, except that instead of dichloromethane, 1,3-dichloropropane was employed.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl:25][CH2:26][CH2:27][CH2:28][CH2:29]I>>[Cl:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:11]([C:8]1[CH:9]=[CH:10][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[CH:6][CH:7]=1)[C:12]([OH:14])=[O:13]
Reactant: ClCCCCI
Reactant: CC(C)Oc1ccc(CC(=O)O)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Product: CC(C)Oc1ccc(C(CCCCCl)C(=O)O)cc1
Yield: 37.6 %

Procedure:
Step AV (1): 2-(4-Isopropoxyphenyl)acetic acid (7.7 g, 39.6 mmol, reference G. Solladie et al. Tetrahedron (2003), 59, 3315) was deprotonated with NaHMDS (2.0 M in THF, 39.5 mL, 79 mmol) and reacted with 1-chloro-4-iodobutane (10.8 g, 49.6 mmol) using a procedure analogous to Step AC (1) to afford 6-chloro-2-(4-isopropoxyphenyl)hexanoic acid (4.24 g, 37% yield) as a clear viscous oil. LC-MS (M−H)− 193.0.