Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[CH:6][C:5]=1[O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].[H][H]>C(O)C.[Pd]>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:5]=1[O:13][Si:14]([C:17]([CH3:19])([CH3:18])[CH3:20])([CH3:15])[CH3:16]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1O[Si](C)(C)C(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1cc(N)ccc1O[Si](C)(C)C(C)(C)C
Yield: 100.4 %

Procedure:
A solution of 2-(tert-butyl-dimethyl-silanyloxy)-5-Nitrobenzoic acid methyl ester (4.9 g, 16 mmol) in ethanol (100 mL) was treated with hydrogen gas (60 psi) for 48 h in the presence of palladium on carbon catalyst (0.31 g, 10% Pd). The catalyst was removed by filtration through CELITE®, and the filtrate was concentrated to a syrup and dried in vacuo to afford the intermediate 5-amino-2-(tert-butyl-dimethyl-silanyloxy)-benzoic acid methyl ester as a dark brown solid (4.52 g, 99%).
Reaction SMILES: I[C:2]1[N:3]=[C:4]([NH2:20])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].[O:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH:23]=[C:22]1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(O)C.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>[NH2:20][C:4]1[N:3]=[C:2]([C:22]2[O:21][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[CH:23]=2)[N:19]=[C:18]2[C:5]=1[N:6]=[CH:7][N:8]2[C@H:9]1[C@H:10]([OH:11])[C@H:12]([OH:13])[C@@H:14]([CH2:15][OH:16])[O:17]1
Reactant: Nc1nc(I)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: OB(O)c1cc2ccccc2o1
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: [Cs+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Nc1nc(-c2cc3ccccc3o2)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 2.5 %

Procedure:
A solution of 2-iodo adenosine (200 mg, 0.51 mmol), 2-benzofuranylboronic acid (99 mg, 0.61 mmol), cesium carbonate (364 mg, 1.12 mmol) and Pd(PPh3)4 (59 mg, 0.051 mmol) in toluene (1.2 mL) and ethanol (2.4 mL) was heated in a Biotage microwave (120° C., absorption high, pre-stirring 15 s) for 40 min. The solvents were then removed in vacuo and the residue dissolved in EtOAc (15 mL) and washed with sat. aq. NaHCO3 (15 mL×2) and brine (15 mL) and dried over MgSO4. Purification by flash column chromatography (normal phase, ICN silica, 20 g, 18-32μ, gradient 0-20% ethanol in DCM, residue dry loaded, product eluted in 15% ethanol) and by reverse phase prep HPLC (Phenomenex Synergi, RP-Hydro 150×10 mm, 10%, 20 mL per min, gradient 5-100% acetonitrile in water over 10 min, product eluted in 35% acetonitrile) afforded the title compound 13 as a white solid (4.9 mg, 3%).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:5]=1[OH:12])[CH:2]=[CH2:3].C(OO)(=[O:15])C.O.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C.C([O-])(=O)C.[Na+]>[CH3:11][O:10][C:6]1[C:5]2[O:12][CH:2]([CH2:3][OH:15])[CH2:1][C:4]=2[CH:9]=[CH:8][CH:7]=1
Reactant: CC(=O)OO
Reactant: C=CCc1cccc(OC)c1O
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1cccc2c1OC(CO)C2
Temperature: 15 °C
Reaction time: 48 h
Yield: 16 %

Procedure:
124 g of 2-allyl-6-methoxyphenol, dissolved in 80 ml of acetic acid, are added to a mixture, cooled to 15° C., containing 160 ml of 32% strength peracetic acid in acetic acid and 2.4 g of sodium acetate. The mixture is left at room temperature for 48 hours and then hydrolyzed with 2 1 of water containing 400 g of sodium carbonate. The mixture is extracted with ethyl ether and the organic phase is washed with sodium hydroxide. It is dried, the ether is evaporated off and the residue is distilled at 110° C. and at 0.02 mmHg to obtain 7-methoxy-2,3-dihydro-2-benzofuranylmethanol.
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)Cl.[OH-:6].[Na+]>O>[CH2:1]([O:6][CH2:1][CH:3]1[O:5][CH2:4]1)[CH:3]1[O:5][CH2:4]1
Reactant: [OH-]
Reactant: ClCC1CO1
Agent: [Na+]
Solvent: O
Product: C(OCC1CO1)C1CO1
Yield: 94.6 %

Procedure:
Compound A prepared in the same manner as in Reference Example 2 was allowed to place at 10° C. for a week to obtain precipitated crystals. The crystal was filtered and washed with trichlorotrifluoroethane to obtain 26 g (0.063 mole) of 1,4-bis(1,1,1,3,3,3-hexafluoro-2-hydroxyisopropyl)cyclohexane (Compound B). To a mixture of Compound B and 117 g (1.26 moles) of epichlorohydrin were added 5.1 g (0.13 mole) of sodium hydroxide and 0.6 ml of water and the mixture was refluxed for 10 hours with stirring. The resulting sodium chloride was removed by filtration and the excess of epichlorohydrin was distilled off. The residue was distilled to obtain 16 g of diglycidyl ether of Compound B having a boiling point of 147° to 151° C./1 mmHg.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:16]2[C@H:20]([CH2:21][O:22][CH3:23])[CH2:19][O:18][C:17]2=[O:24])[CH:5]=[CH:6][C:7]=1[C:8]([N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:9].Cl[C:26]1[C:31]([Cl:32])=[CH:30][C:29]([Cl:33])=[CH:28][N:27]=1>>[Cl:32][C:31]1[C:26]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:7]3[CH:6]=[CH:5][C:4]([N:16]4[C@H:20]([CH2:21][O:22][CH3:23])[CH2:19][O:18][C:17]4=[O:24])=[CH:3][C:2]=3[F:1])=[O:9])[CH2:11][CH2:12]2)=[N:27][CH:28]=[C:29]([Cl:33])[CH:30]=1
Reactant: COC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCNCC2)c(F)c1
Reactant: Clc1cnc(Cl)c(Cl)c1
Product: COC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCN(c3ncc(Cl)cc3Cl)CC2)c(F)c1
Yield: 59.5 %

Procedure:
By reaction and treatment in the same manner as in Example 147 and using (R)-3-[3-fluoro-4-(piperazine-1-carbonyl)phenyl]-4-methoxymethyloxazolidin-2-one (875 mg) described in Preparation Example 158 and 2,3,5-trichloropyridine (945 mg), the title compound (746 mg) was obtained. MS(ESI)m/z:483(M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:14])[CH:11]=NO)[CH:5]=[C:6]([Cl:8])[CH:7]=1.S(=O)(=O)(O)[OH:16]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]2[C:3]=1[C:11](=[O:16])[C:10](=[O:14])[NH:9]2
Reactant: O=S(=O)(O)O
Reactant: O=C(C=NO)Nc1cc(Cl)cc(Cl)c1
Product: O=C1Nc2cc(Cl)cc(Cl)c2C1=O
Temperature: 90 °C
Yield: 81 %

Procedure:
The N-(3,5-dichlorophenyl)-2-hydroxyiminoacetamide just prepared (12.1 g, 0.052 mol) was added to 96 per cent strength sulfuric acid (56 ml) at 50-75° C. in the course of 15 min. The reaction mixture was then heated at 90° C. for 15 min, while stirring. After cooling, the mixture was poured slowly on to ice (500 g). The solid formed was filtered off with suction after 30 min. The desired isatin was isolated in a yield of 81% (9.12 g) as an orange-coloured solid. It was not possible to determine a melting point.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:7](=[O:14])[NH:6][C:5]2=[O:15].Cl.[CH3:17][N:18]([CH3:23])[CH:19]([CH3:22])[CH2:20]N.N1C=CN=C1.CCN(CC)CC>O1CCOCC1>[NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:7](=[O:14])[N:6]([CH2:20][CH:19]([N:18]([CH3:23])[CH3:17])[CH3:22])[C:5]2=[O:15]
Reactant: Nc1cc2c(cc1[N+](=O)[O-])C(=O)NC2=O
Reactant: CC(CN)N(C)C
Agent: Cl
Agent: c1c[nH]cn1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(CN1C(=O)c2cc(N)c([N+](=O)[O-])cc2C1=O)N(C)C
Temperature: 130 °C
Yield: 15 %

Procedure:
A mixture of 5-amino-6-nitro-isoindole-1,3-dione (1.66 g, 8.0 mmol), HCl salt of 2-dimethylamino-propylamine (5.5 g, crude, <30 mmol), imidazole (1.36 g, 20 mmol) and Et3N (8.4 mL, 6.07 g, 60 mmol) in dioxane (80 mL) was sealed in a ChemGlass heavy wall pressure flask. After it was heated at 130° C. for 69 h, the reaction mixture was evaporated to dryness at 95° C. (the bath temperature) under reduced pressure. The chromatography of the residue with CH2Cl2/MeOH/28% aqueous NH4OH (240:10:1) afforded the title compound (360 mg, 15%). 1H NMR (DMSO-d6) δ 0.88 (d, J=6 Hz, 3H, CH3), 2.13 (s, 6H, 2CH3), 3.32 (m, 2H), 3.65 (m, 1H), 7.45 (s, 1H), 8.30 (s, 1H), 8.40 (br s, 2H, NH). ESI-MS m/z 293.3 (MH+).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][C@@H:7]1[NH:12][CH2:11][CH2:10][N:9]([C:13]2[C:22]3[CH:21]=[C:20]([CH3:23])[S:19][C:18]=3[NH:17][C:16]3[CH:24]=[CH:25][CH:26]=[CH:27][C:15]=3[N:14]=2)[CH2:8]1.[CH2:28]=O>ClC(Cl)C.O.[OH-].[Na+]>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][C@@H:7]1[N:12]([CH3:28])[CH2:11][CH2:10][N:9]([C:13]2[C:22]3[CH:21]=[C:20]([CH3:23])[S:19][C:18]=3[NH:17][C:16]3[CH:24]=[CH:25][CH:26]=[CH:27][C:15]=3[N:14]=2)[CH2:8]1
Reactant: COCCCC[C@H]1CN(C2=Nc3ccccc3Nc3sc(C)cc32)CCN1
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(Cl)Cl
Product: COCCCC[C@H]1CN(C2=Nc3ccccc3Nc3sc(C)cc32)CCN1C
Reaction time: 8 h

Procedure:
Into a room temperature, stirred solution of (S)-10-[3-(4-methoxybutyl)-piperazin-1-yl]-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene (0.031 g, 0.08 mmol), and formaldehyde solution (0.082 mL, 0.10 mmol, 37% in H2O) in dichloroethane (0.5 mL) was added NaHB(OAc)3 (0.026 g, 0.12 mmol) and stirred overnight. Dilute the solution with H2O (20 mL), 1.0 N NaOH (1 mL) and extract with CH2Cl2 (3×40 mL). Dry the combined organic layers over Na2SO4, and filter. Concentrate the mixture under reduced pressure and purify by silica gel chromatography eluting with 10% (33% 2 M NH3 in MeOH/64% EtOH)/CH2Cl2. Combine the purified fractions, concentrate under reduced pressure, and place under vacuum to give the title compound: orange solid (0.014 g), mass spectrum (m/e):399.3 (M+H).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15](=O)[CH2:16][CH2:17][C:18]([OH:20])=O)=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.O.[NH2:23][NH2:24]>O>[N:1]1([CH2:6][CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH2:16][CH2:17][C:18](=[O:20])[NH:23][N:24]=3)=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: NN
Reactant: O=C(O)CCC(=O)c1ccc(CCCn2ccnc2)cc1
Solvent: O
Product: O=C1CCC(c2ccc(CCCn3ccnc3)cc2)=NN1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
2 g of 4-{4-[3-(1-imidazolyl)-propyl]-phenyl}-4-oxo-butyric acid are suspended in 10 ml of water, 0.68 g of hydrazine hydrate are added and the mixture is then stirred at 90° C. for 2 hours. After the mixture has been cooled, it is extracted with chloroform and the chloroform solution is washed with water, dried over Na2SO4 and concentrated to dryness.
Reaction SMILES: C(O[C:6]([N:8]([C:42](OC(C)(C)C)=O)[C:9](=[O:41])[C:10]1[CH:15]=[C:14]([N:16]2[CH2:20][CH2:19][CH2:18][S:17]2(=[O:22])=[O:21])[CH:13]=[CH:12][C:11]=1[C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:31]2[C:36]([CH3:37])=[CH:35][C:34]([CH:38]3[CH2:40][CH2:39]3)=[CH:33][N:32]=2)[CH2:27][CH2:26]1)=[O:24])=O)(C)(C)C.O1CCCC1.CNC>>[CH:38]1([C:34]2[CH:35]=[C:36]([CH3:37])[C:31]([N:28]3[CH2:27][CH2:26][N:25]([C:23]([C:11]4[CH:12]=[CH:13][C:14]([N:16]5[CH2:20][CH2:19][CH2:18][S:17]5(=[O:22])=[O:21])=[CH:15][C:10]=4[C:9]([N:8]([CH3:42])[CH3:6])=[O:41])=[O:24])[CH2:30][CH2:29]3)=[N:32][CH:33]=2)[CH2:40][CH2:39]1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCCS3(=O)=O)cc2C(=O)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CC1
Agent: CNC
Solvent: C1CCOC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCCS3(=O)=O)cc2C(=O)N(C)C)CC1
Yield: 54.8 %

Procedure:
Using N,N-di-tert-butyloxycarbonyl-2-[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]-5-(1,1-dioxo-1λ6-isothiazolidin-2-yl)benzamide (100 mg) described in Example 805 and 2 mol/L dimethylamine tetrahydrofuran solution (88 μL) and by the reaction and treatment in the same manner as in Example 770, the title compound (41 mg) was obtained.
Reaction SMILES: [O:1]1[CH2:7][CH2:6][CH2:5][O:4][C:3]2[C:8]([CH2:12][NH:13][CH3:14])=[CH:9][CH:10]=[CH:11][C:2]1=2.Cl.[O:16]=[C:17]1[NH:26][C:25]2[N:24]=[CH:23][C:22](/[CH:27]=[CH:28]/[C:29]([OH:31])=O)=[CH:21][C:20]=2[CH2:19][CH2:18]1>>[O:1]1[CH2:7][CH2:6][CH2:5][O:4][C:3]2[C:8]([CH2:12][N:13]([CH3:14])[C:29](=[O:31])[CH:28]=[CH:27][C:22]3[CH:23]=[N:24][C:25]4[NH:26][C:17](=[O:16])[CH2:18][CH2:19][C:20]=4[CH:21]=3)=[CH:9][CH:10]=[CH:11][C:2]1=2
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Reactant: CNCc1cccc2c1OCCCO2
Agent: Cl
Product: CN(Cc1cccc2c1OCCCO2)C(=O)C=Cc1cnc2c(c1)CCC(=O)N2
Yield: 78.9 %

Procedure:
According to the procedure of Example 35g (3,4-dihydro-2H-benzo[b][1,4]dioxepin-6-ylmethyl)-methyl-amine (239 mg, 1.24 mmol) and (E)-3-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-3yl)acrylic acid hydrochloride (318 mg, 1.25 mmol), were coupled to give crude product. Purification by column chromatography (silica gel, 5% MeOH/CH2Cl2) gave the title compound (385 mg, 79%) as a yellow solid and a mixture of amide rotomers: 1H NMR (400 MHz, DMSO-d6) δ 10.66-10.63 (m, 1H), 8.36-8.32 (m, 1H), 8.07-8.03 (m, 1H), 7.51-7.46 (m, 1H), 7.30-721 (m, 1H), 6.93-6.88 (m, 2H), 6.78-6.76 (m, 1H), 4.76-4.59 (m, 2H), 4.13-4.06 (m, 4H), 3.11-2.84 (m, 5H), 2.54-2.52 (m, 2H), 2.11-2.07 (m, 2H); ESI MS m/e 394 [C22H23N3O4+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1([OH:18])[CH2:17][CH2:16][CH2:15][CH:14]2[CH:10]1[CH2:11][NH:12][CH2:13]2.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([CH2:28][C:29](O)=[O:30])=[CH:20]1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1([OH:18])[CH2:17][CH2:16][CH2:15][CH:14]2[CH:10]1[CH2:11][N:12]([C:29](=[O:30])[CH2:28][C:21]1[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[NH:19][CH:20]=1)[CH2:13]2
Reactant: O=C(O)Cc1c[nH]c2ccccc12
Reactant: COc1ccccc1C1(O)CCCC2CNCC21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COc1ccccc1C1(O)CCCC2CN(C(=O)Cc3c[nH]c4ccccc34)CC21
Temperature: 25 °C
Reaction time: 18 h
Yield: 49.3 %

Procedure:
To a solution of 1.5 g of (3aRS,4RS,7aSR)-4-(2-methoxyphenyl)-4-perhydroisoindolol and 1.27 g of 3-indoleacetic acid in 40 cm3 of dichloromethane, cooled to 0° C., are added 0.08 g of 1-hydroxybenzotriazole and 1.4 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. The mixture is stirred for 18 hours at room temperature and the organic phase is then washed with twice 80 cm3 of water and then with 80 cm3 of saturated aqueous sodium chloride solution, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel (particle size 0.04-0.06 mm, diameter 4 cm, height 40 cm), eluting under a pressure of 0.5 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (70/30 by volume) and collecting 40 cm3 fractions. Fractions 24 to 48 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 1.21 g of (3aRS,4RS,7aSR)-4-(2-methoxyphenyl)-2-(3-indolylacetyl)-4-perhydroisoindolol are obtained in the form of an off-white foam.
Reaction SMILES: COCCOC.Br[C:8]1[C:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:10][CH:11]=[CH:12][CH:13]=1.[C:19]([O:23][C:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O)=[O:25])([CH3:22])([CH3:21])[CH3:20].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.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:19]([O:23][C:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:8]1[C:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:10][CH:11]=[CH:12][CH:13]=1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: CCOC(=O)c1ncccc1Br
Reactant: CC(C)(C)OC(=O)NCc1ccccc1B(O)O
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: ClCCl
Solvent: COCCOC
Product: CCOC(=O)c1ncccc1-c1ccccc1CNC(=O)OC(C)(C)C
Reaction time: 0.17 h
Yield: 63.6 %

Procedure:
150 ml of 1,2-dimethoxyethane were aerated with argon, and 874 mg (0.75 mmol) of Pd(PPh3)4 and 3.45 g (15 mmol) ethyl 3-bromopyridine-2-carboxylate were added. After 10 min, 5.53 g (22.5 mmol) of 2-(tert-butoxycarbonylaminomethyl)phenylboronic acid and finally 15 ml of a 2M sodium carbonate solution were added. The mixture was heated to reflux for 18 h under argon, diluted with dichloromethane after cooling and washed with water. The organic phase was dried, concentrated and purified by chromatography on silica gel. 3.4 g (66%) of a viscous oil were obtained. MS (ES+): m/z=357 (M+1).
Reaction SMILES: [F:1][S:2]([F:17])([F:16])([F:15])([F:14])[C:3]1[CH:4]=[C:5]([NH:9]S(C)(=O)=O)[CH:6]=[CH:7][CH:8]=1.F[C:19]1[C:28]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]([CH3:33])[CH:20]=1>CN1C(=O)CCC1.CC(=O)OCC>[CH3:32][S:29]([C:28]1[C:19]([NH:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([S:2]([F:1])([F:14])([F:15])([F:16])[F:17])[CH:4]=2)=[CH:20][C:21]([CH3:33])=[C:22]([CH:27]=1)[C:23]([O:25][CH3:26])=[O:24])(=[O:30])=[O:31]
Reactant: COC(=O)c1cc(S(C)(=O)=O)c(F)cc1C
Reactant: CS(=O)(=O)Nc1cccc(S(F)(F)(F)(F)F)c1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(S(C)(=O)=O)c(Nc2cccc(S(F)(F)(F)(F)F)c2)cc1C
Temperature: 150 °C
Reaction time: 7 h
Yield: 25.6 %

Procedure:
1.0 g of N-(3-pentafluorosulfanylphenyl)methanesulfonamide, 0.8 g of methyl 4-fluoro-5-methanesulfonyl-2-methylbenzoate and 1.4 ml of TBTMG were dissolved in 10 ml of NMP (anhydrous) and stirred at 150° C. for 7 h. The mixture was then diluted with 100 ml of EA and washed firstly 3 times with 30 ml of a saturated aqueous Na2CO3 solution each time and then 3 times with 30 ml of a saturated aqueous NaHSO4 solution each time. The residue after drying over MgSO4 and removal of the solvent in vacuo was chromatographed on silica gel with DIP. 370 mg of a resinous solid were obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:23])[C:8]2[CH:9]=[C:10]([F:22])[C:11]([F:21])=[C:12]3[O:17][CH2:16][CH:15]([CH2:18][OH:19])[N:14]([CH:20]=1)[C:13]=23)=[O:5])[CH3:2].N1C=CC=CC=1.[N+:30]([C:33]1[CH:34]=[C:35]([CH:39]=[C:40]([N+:42]([O-:44])=[O:43])[CH:41]=1)[C:36](Cl)=[O:37])([O-:32])=[O:31]>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:23])[C:8]2[CH:9]=[C:10]([F:22])[C:11]([F:21])=[C:12]3[O:17][CH2:16][CH:15]([CH2:18][O:19][C:36](=[O:37])[C:35]4[CH:34]=[C:33]([N+:30]([O-:32])=[O:31])[CH:41]=[C:40]([N+:42]([O-:44])=[O:43])[CH:39]=4)[N:14]([CH:20]=1)[C:13]=23)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn2c3c(c(F)c(F)cc3c1=O)OCC2CO
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cn2c3c(c(F)c(F)cc3c1=O)OCC2COC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 75.2 %

Procedure:
One gram of (±)-9,10-difluoro-3-hydroxymethyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid ethyl ester (I) and 500 mg of pyridine were suspended in 100 ml of anhydrous tetrahydrofuran (THF), and 1.6 g of 3,5-dinitrobenzoyl chloride was added thereto, followed by refluxing at 90° C. The suspension was once dissolved, and a colorless precipitate was then formed. The reaction was continued for 1.5 hours. After cooling, the precipitate was collected by filtration, washed with methanol and diethyl ether and dried to obtain 1.2 g of (±)-9,10-difluoro-3-(3,5-dinitrobenzoyloxy)methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid ethyl ester (II) as a colorless powder having a melting point of 240°-242° C. NMR (CDCl3 /5% DMSO-d6) δ(ppm); 1,30 (3H, t, J=7.0 Hz, --CH2CH3), 4.26 (2H, q, J=7.0 Hz, --CH2CH3), 4.4-4.5 (5H, m), 7.76 (1H, dd, J=11.0 Hz, 7.0 Hz, C8 -H), 8.8 (1H, s, C5 -H), 9.0 (2H, d, J=3.0 Hz, aromatic ring proton) and 9.2 (1H, t, J=3.0 Hz, aromatic ring proton).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[NH:18][CH3:19])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=1)=[O:6].[Cl:20][C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][C:30]=1[N:31]=[C:32]=S)[C:24]([O:26][CH3:27])=[O:25].C(Cl)CCl>CN(C=O)C>[Br:14][C:11]1[CH:12]=[CH:13][C:8]([NH:7][C:5]([C:4]2[CH:15]=[CH:16][C:17]3[N:18]([CH3:19])[C:32]([NH:31][C:30]4[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][C:21]=4[Cl:20])=[N:1][C:2]=3[CH:3]=2)=[O:6])=[CH:9][CH:10]=1
Reactant: COC(=O)c1ccc(N=C=S)c(Cl)c1
Reactant: CNc1ccc(C(=O)Nc2ccc(Br)cc2)cc1N
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Nc2nc3cc(C(=O)Nc4ccc(Br)cc4)ccc3n2C)c(Cl)c1

Procedure:
Prepared analogously to example 106a from 3-amino-N-(4-bromophenyl)-4-(methylamino)-benzamide and methyl 3-chloro-4-isothiocyanatobenzoate in DMF with EDC.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10](S(C)=O)SC)=[CH:5][CH:4]=1.S(=O)(=O)(O)[OH:17]>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]=[O:17])=[CH:5][CH:4]=1
Reactant: COc1ccc(CC(SC)S(C)=O)cc1
Reactant: O=S(=O)(O)O
Solvent: CO
Product: COc1ccc(CC=O)cc1
Yield: 53 %

Procedure:
2.65 g of methyl 2-(p-methoxyphenyl)-1-methylthioethyl sulfoxide was dissolved in 50 ml. of methanol, and with the addition of 20 ml. of 1N sulfuric acid, the solution was heated for 6 hours at 50°C. The reaction mixture was concentrated at reduced pressure to 20 ml., and extracted with ether (150 ml., 2 times). The extracted layer was washed with water and then with an aqueous solution of sodium hydrogencarbonate, and dried with anhydrous sodium sulfate. It was then concentrated at reduced pressure, and the residue was subjected to column chromatography (silica gel, benzene and methylene chloride) to give 774 mg of p-methoxyphenylacetaldehyde as a colorless liquid. The yield was 53%, b.p. 61°-63°C/2.5 mmHg.
Reaction SMILES: Br.[Br:2][CH2:3][CH2:4][CH2:5][NH2:6].Cl.[CH2:8]([NH:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26])[CH2:9][CH2:10][CH:11]=[CH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.COCCOC>[Br:2][CH2:3][CH2:4][CH2:5][NH:6][C:25](=[O:26])[C:24]1[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=1[NH:22][CH2:8][CH2:9][CH2:10][CH:11]=[CH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCCC=CCCCNc1ccccc1C(=O)Cl
Reactant: NCCCBr
Agent: Br
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: CCCCCCCCCC=CCCCNc1ccccc1C(=O)NCCCBr

Procedure:
To a slurry of 21.80 g. of 3-bromopropylamine hydrobromide in 200 ml. of glyme at 3° C. is added a solution of 23.9 g. of 2-(4-tetradecenylamino)benzoyl chloride hydrochloride in 65 ml. of glyme, concurrently with 26 ml. of triethylamine diluted to 39 ml. with 1,2-dimethoxyethane. The solution is warmed to reflux and 0.2 g. of 4-dimethylaminopyridine is added. The solution is heated for four hours and cooled overnight. The solid is removed and the mother liquor diluted with 200 ml. of water to yield a solid which is crystallized from cyclohexane and recrystallized from acetonitrile to yield the product.
Reaction SMILES: [F:1][C@H:2]1[C@H:8]([NH:9]C(=O)OC(C)(C)C)[CH2:7][CH2:6][C@@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[N+:23]([O-])=O)[O:4][CH2:3]1.C(OC([NH:33][C:34]1[S:38][C:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[C:45]([F:48])([F:47])[F:46])=[N:36][C:35]=1[C:49](O)=[O:50])=O)(C)(C)C>>[NH2:33][C:34]1[S:38][C:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[C:45]([F:48])([F:47])[F:46])=[N:36][C:35]=1[C:49]([NH:23][C:18]1[CH:19]=[N:20][N:21]([CH3:22])[C:17]=1[C@@H:5]1[CH2:6][CH2:7][C@@H:8]([NH2:9])[C@H:2]([F:1])[CH2:3][O:4]1)=[O:50]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2ccccc2C(F)(F)F)nc1C(=O)O
Reactant: Cn1ncc([N+](=O)[O-])c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Product: Cn1ncc(NC(=O)c2nc(-c3ccccc3C(F)(F)F)sc2N)c1[C@@H]1CC[C@@H](N)[C@H](F)CO1

Procedure:
Following the procedure for Example 111 starting from tert-butyl ((3S,4R,7S)-3-fluoro-7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-yl)carbamate (Intermediate 80), and replacing 5-((tert-butoxycarbonyl)amino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid with 5-((tert-butoxycarbonyl)amino)-2-(2-(trifluoromethyl)phenyl)thiazole-4-carboxylic acid (Example 19) gave 323. 1H NMR (400 MHz, DMSO-d6) δ 9.05 (s, 1H), 7.87 (d, J=7.8 Hz, 1H), 7.81-7.73 (m, 3H), 7.70-7.64 (m, 1H), 7.43 (s, 2H), 4.74 (dd, J=11.0, 3.4 Hz, 1H), 4.50-4.30 (m, 1H), 4.19-3.89 (m, 2H), 3.76 (s, 3H), 2.06-1.97 (m, 1H), 1.91-1.79 (m, 1H), 1.76-1.66 (m, 2H). LCMS (ES+) m/z 499 (M+1).