Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[C@@H:10]([O:12]S(C)(=O)=O)[CH3:11].[N+:17]([C:20]1[N:25]=[CH:24][C:23]2[CH:26]=[CH:27][O:28][C:22]=2[C:21]=1O)([O-:19])=[O:18].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[C@H:10]([O:12][C:21]1[C:22]2[O:28][CH:27]=[CH:26][C:23]=2[CH:24]=[N:25][C:20]=1[N+:17]([O-:19])=[O:18])[CH3:11]
Reactant: C[C@H](OS(C)(=O)=O)c1c(Cl)ccc(F)c1Cl
Reactant: O=[N+]([O-])c1ncc2ccoc2c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@H](Oc1c([N+](=O)[O-])ncc2ccoc12)c1c(Cl)ccc(F)c1Cl
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Alternate synthesis: To a solution of Methanesulfonic acid (S)-1-(2,6-dichloro-3-fluorophenyl)-ethyl ester (109 mg, 0.380 mmol) and 6-nitrofuro[3,2-c]pyridin-7-ol (68.4 mg, 0.380 mmol) in DMF (1.0 mL) was added potassium carbonate (57.2 mg, 0.414 mmol), and the resulting suspension was stirred at ambient temperature for 1 h and at 60° C. overnight. Methanesulfonic acid (S)-1-(2,6-dichloro-3-fluorophenyl)ethyl ester (32.7 mg, 0.114 mmol) and potassium carbonate (16 mg, 0.12 mmol) were added to the reaction mixture, and the mixture was heated at 70° C. for 3 days. Water and EtOAc were added to the reaction mixture, the layers were separated, and the aqueous layer was extracted with EtOAc (3×15 mL). The combined EtOAc extracts were washed with 1N NaOH (2×), water (2×), and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel to afford the title compound.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[C:7]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:25])=[O:24])=[C:6]1[CH3:32].[OH-].[Li+]>O1CCCC1>[C:26]1([S:23]([C:17]2[CH:18]=[C:19]([Cl:22])[CH:20]=[CH:21][C:16]=2[CH2:15][C:7]2[C:8]3[C:13](=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=3)[N:5]([CH2:4][C:3]([OH:33])=[O:2])[C:6]=2[CH3:32])(=[O:24])=[O:25])[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COC(=O)Cn1c(C)c(Cc2ccc(Cl)cc2S(=O)(=O)c2ccccc2)c2cc(F)ccc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1c(Cc2ccc(Cl)cc2S(=O)(=O)c2ccccc2)c2cc(F)ccc2n1CC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.5 %

Procedure:
A solution of [3-(2-benzenesulfonyl-4-chlorobenzyl)-5-fluoro-2-methylindol-1-yl]acetic acid methyl ester (0.16 g) in tetrahydrofuran (5.0 mL) was treated with 1.0 M aqueous lithium hydroxide solution (0.5 mL), and the resulting mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure, pH adjusted to 4 by the addition of 0.1 M aqueous hydrochloric acid solution and extracted with ethyl acetate. The combined organic extract was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by preparative reverse-phase HPLC, eluting with a mixture of acetonitrile and water (1:19 to 49:1 by volume) to afford the title compound as a white solid (0.15 g).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11]I)[CH:6]=[CH:7][CH:8]=1.[C-:15]#[C-:16].[Na+].[Na+]>>[F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11][C:15]#[CH:16])[CH:6]=[CH:7][CH:8]=1
Reactant: [C-]#[C-]
Reactant: FC(F)(F)c1cccc(CCCI)c1
Agent: [Na+]
Product: C#CCCCc1cccc(C(F)(F)F)c1

Procedure:
The title compound was synthesized using 3-(3-trifluoromethylphenyl)-1-iodopropane and sodium acetylide by conducting the reactions similar to those mentioned in Reference example 29.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.C(Cl)(=O)C(Cl)=O.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[C:32](=[O:33])[CH2:31][C:30](=[O:34])[NH:29][C:28]3[C:35]4[C:40]([CH:41]=[CH:42][C:27]2=3)=[CH:39][CH:38]=[CH:37][CH:36]=4)=[CH:22][CH:21]=1>>[CH3:12][N:2]([CH3:1])[C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[C:32](=[O:33])[CH2:31][C:30](=[O:34])[NH:29][C:28]4[C:35]5[C:40]([CH:41]=[CH:42][C:27]3=4)=[CH:39][CH:38]=[CH:37][CH:36]=5)=[CH:22][CH:21]=2)=[O:9])=[CH:10][CH:11]=1
Reactant: CN(C)c1ccc(C(=O)O)cc1
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Agent: O=C(Cl)C(=O)Cl
Product: CN(C)c1ccc(C(=O)Nc2ccc(N3C(=O)CC(=O)Nc4c3ccc3ccccc43)cc2)cc1
Yield: 25.8 %

Procedure:
4-Dimethylaminobenzoic acid (33 mg, 0.2 mmol) was treated with oxalyl chloride in the same manner as that of Example 40, and then by using the resultant together with 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (32 mg, 0.1 mmol) obtained in Example 1, (3), the title compound (12 mg, yield 26%) was obtained as pale brown crystals in the same manner as that of Example 1, (4). The structure was confirmed by NMR and MS.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=[CH:12][C:10]=3[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[NH3:23].Cl>O1CCCC1.O.CN(C=O)C>[C:1]1([C:7]2[NH:8][C:9]3[C:15]([C:16]([NH2:23])=[O:18])=[CH:14][CH:13]=[CH:12][C:10]=3[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N
Reactant: O=C(O)c1cccc2nc(-c3ccccc3)[nH]c12
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1cccc2nc(-c3ccccc3)[nH]c12
Temperature: 25 °C
Reaction time: 12 h
Yield: 62 %

Procedure:
2-Phenylbenzimidazole-4-carboxylic acid (50 mg, 0.21 mmol) was dissolved in dry tetrahydrofuran (10 ml) and thionyl chloride (16.8 μl, 0.231 mmol) and DMF (0.05 ml) were added. The mixture was stirred at room temperature for 12 hours, when a white precipitate developed, and the suspension was added dropwise to stirred aqueous ammonia (10 ml) over 10 minutes. The mixture was stirred for a further 30 minutes, diluted with water (20 ml), and neutralised with hydrochloric acid (4M). The white solid which was precipitated upon cooling, was collected by filtration to afford 2-phenylbenzimidazole-4-carboxamide (31 mg, 62%); vmax /cm-1 3320, 3180, 1660 and 1600; δH (d6 -DMSO, 200 MHz) 7.45 (1H, t, Ar-5H), 7.72 (3H, d, 3-Ph-4H), 7.87 (1H, d, Ar-4H), 7.97 (1H, br s, CONH), 7.99 (2H, d, Ar-6H), 8.38 (2H, d, Ph-2-H and Ph-2-H), 9.5 (1H, br s, CONH); m/z (EI) 237 (M+), 220, 192, 165, 77.
Reaction SMILES: [F:1][C:2]([F:19])([CH:8]([F:18])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=1)[C:3](OCC)=[O:4].[BH4-].[Na+].C(OCC)(=O)C.Cl>C(O)C>[F:1][C:2]([F:19])([CH:8]([F:18])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=1)[CH2:3][OH:4]
Reactant: CCOC(=O)C(F)(F)C(F)c1cccc([N+](=O)[O-])c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cccc(C(F)C(F)(F)CO)c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 82.1 %

Procedure:
To a solution of ethyl 2,2,3-trifluoro-3-(3-nitrophenyl)propanoate (C30, 1.19 g) in ethanol (43 mL), sodium borohydride (811 mg) was added under ice cooling, and the mixture was stirred at room temperature for 40 minutes. To the reaction mixture, ethyl acetate and 1.0 mol/L aqueous hydrochloric acid were added. The organic layer was separated, washed successively with saturated aqueous sodium hydrogencarbonate and saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent, 100 to 40% hexane in ethyl acetate) to obtain 2,2,3-trifluoro-3-(3-nitrophenyl)propan-1-ol (C31, 829 mg).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:14]=3)[CH2:7][CH:6]3[CH2:20][O:21][CH2:22][CH2:23][N:5]3[C:4]=2[N:3]=1.[NH:24]1[C:32]2[C:27](=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25]1>O1CCOCC1.C([O-])(O)=O.[Na+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH:24]1[C:32]2[C:27](=[C:28]([C:2]3[N:11]=[CH:10][C:9]4[N:8]([CH2:12][C:13]5[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:14]=5)[CH2:7][CH:6]5[CH2:20][O:21][CH2:22][CH2:23][N:5]5[C:4]=4[N:3]=3)[CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25]1
Reactant: Cc1cccc(CN2CC3COCCN3c3nc(Cl)ncc32)n1
Reactant: OB(O)c1cccc2[nH]ccc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1COCCO1
Product: Cc1cccc(CN2CC3COCCN3c3nc(-c4cccc5[nH]ccc45)ncc32)n1

Procedure:
The title compound was prepared in a manner similar to EXAMPLE 3 using 2-chloro-5-((6-methylpyridin-2-yl)methyl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (PREPARATION x28, 36 mg, 0.108 mmol), 1H-indol-4-ylboronic acid (34.9 mg, 0.217 mmol) and PdCl2(dppf) (7.94 mg, 10.85 μmol) in dioxane (2 mL) and aqueous saturated NaHCO3 (0.4 mL). 1H NMR (400 MHz, DMSO-d6) δ 2.50 (s, 3 H), 3.26-3.44 (m, 3 H), 3.54-3.68 (m, 2 H), 3.95-4.06 (m, 1 H), 4.06-4.17 (m, 1 H), 4.55-4.81 (m, 4 H), 6.93-7.05 (m, 1 H), 7.20-7.37 (m, 3 H), 7.54-7.64 (m, 3 H), 7.64-7.70 (m, 1 H), 7.70-7.81 (m, 1 H), 11.47-11.66 (m, 1 H). ESI-MS m/z [M+H]+ calc'd for C24H24N6O, 412.20; found 412.3.
Reaction SMILES: [N+:1]([C:4]1[C:5]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[N:6][NH:7][CH:8]=1)([O-])=O>CO>[N:11]1[CH:12]=[CH:13][CH:14]=[C:9]([C:5]2[C:4]([NH2:1])=[CH:8][NH:7][N:6]=2)[CH:10]=1
Reactant: O=[N+]([O-])c1c[nH]nc1-c1cccnc1
Solvent: CO
Product: Nc1c[nH]nc1-c1cccnc1
Reaction time: 3 h
Yield: 95.3 %

Procedure:
Compound 38 (0.37 g, 1.9 mmol) was dissolved in MeOH (containing Pd(OH)2/C (0.03 g)). Hydrogenation was accomplished within 3 hours (1 atm) at room temperature. The reaction mixture was filtered, washed with ethyl acetate/MeOH (1/1) and concentrated in vacuo. The resulting residue was purified by flash chromatography (ethyl acetate followed by ethyl acetate/MeOH 1/1) to afford compound 39 as an oil (0.29 g, 95%). 1H-NMR (200 MHz, CDCl3 and D6DMSO 1/1): δ 9.05 (d, J=2 Hz, 1H), 8.51 (d, J=5 Hz, 2 Hz, 1H), 8.09 (dt, J=8 Hz, 2 Hz, 1H), 7.43 (s, 1H), 7.37-7.32 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.[Li]CCCC.[Sn:14](Cl)([CH2:23][CH2:24][CH2:25][CH3:26])([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][CH2:16][CH2:17][CH3:18]>C1COCC1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([Sn:14]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:15][CH2:16][CH2:17][CH3:18])=[CH:3][CH:4]=1
Reactant: Brc1ccc(Br)cc1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1ccc(Br)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 81.3 %

Procedure:
To p-dibromobenzene (932 mg, 4.00 mmol, 1.00 equiv) in THF (10 mL) at −78° C. was added nBuLi (2.5 M in hexane, 1.6 mL, 4.0 mmol, 1.0 equiv). The reaction mixture was stirred at −78° C. for 30 min before the addition of nBu3SnCl (1.30 g, 4.00 mmol, 1.00 equiv). After stirring for 1.0 hr at −78° C., the reaction mixture was warmed to 23° C. and the solvent was removed in vacuo. the residue was purified by fractional distillation to afford 1.45 g of the title compound as a colorless oil (81% yield).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[F:9])[CH3:2].[S:10]([Cl:14])(=O)(=[O:12])[OH:11]>>[CH2:1]([C:3]1[CH:8]=[C:7]([S:10]([Cl:14])(=[O:12])=[O:11])[CH:6]=[CH:5][C:4]=1[F:9])[CH3:2]
Reactant: O=S(=O)(O)Cl
Reactant: CCc1ccccc1F
Product: CCc1cc(S(=O)(=O)Cl)ccc1F

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 65a by using 1-ethyl-2-fluorobenzene (2.30 g, 19.0 mmol) and chlorosulfuric acid (4.9 mL, 74.0 mmol), to yield the title compound in a crude form.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH2:9][C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1.Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>>[CH2:19]([O:18][C:16](=[O:17])[CH2:15][C:9]([C:10]#[N:11])([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:12])([F:13])[F:1])[CH:4]=1)[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH3:20]
Reactant: CCOC(=O)CBr
Reactant: N#CCc1cccc(C(F)(F)F)c1
Product: CCOC(=O)CC(C#N)(CC(=O)OCC)c1cccc(C(F)(F)F)c1

Procedure:
Prepare by the method of example 1.1.2 using 3-trifluoromethyl-phenylacetonitrile (0.161 mol) and ethyl bromoacetate (0.325 mol). Chromatograph on silica gel to give the title compound.
Reaction SMILES: O.O.O.O.O.O.[Ni:7](Cl)Cl.[NH2:10][C:11]1[C:24]2[C:23](=[O:25])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16](=[O:26])[C:15]=2[C:14]([NH2:27])=[CH:13][CH:12]=1.C(N(CC)CC)C>CN(C)C=O>[Ni+2:7].[NH2:10][C:11]1[C:24]2[C:23](=[O:25])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16](=[O:26])[C:15]=2[C:14]([NH2:27])=[CH:13][CH:12]=1
Reactant: Cl[Ni]Cl
Agent: Nc1ccc(N)c2c1C(=O)c1ccccc1C2=O
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: [Ni+2]

Procedure:
Nickel (II) chloride hexahydrate (0.5 g) is dissolved in dimethylformamide (25 ml) containing 1,4-diamino anthraquinone (0.5 g) and triethylamine (0.84 g). A precipitate forms and is collected and washed repeatedly with methylene chloride until the washings are colorless. The yield is 0.66 g of a dark blue-black powder having a conductivity of 4.72×10-3S/cm. Analysis shows a composition of C--59.34 percent, H--3.76 percent, N--9.38 percent, Ni--17.2 percent and Cl--2.6 percent.
Reaction SMILES: Cl[CH2:2][N:3]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[S:4]1(=[O:6])=[O:5].C1([N:21]2[C:25]([SH:26])=[N:24][N:23]=[N:22]2)CCCCC1.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH:7]1([CH:2]([S:26][C:25]2[NH:24][N:23]=[N:22][N:21]=2)[N:3]2[C:13](=[O:14])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:4]2(=[O:6])=[O:5])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: O=C1c2ccccc2S(=O)(=O)N1CCl
Reactant: Sc1nnnn1C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=C1c2ccccc2S(=O)(=O)N1C(Sc1nnn[nH]1)C1CCCCC1
Yield: 81.7 %

Procedure:
A mixture of 2-(chloromethyl) saccharin (3 g, 12.9 mmol) , 1-cyclohexyl-5-mercapto-1H-tetrazole (2.37 g, 12.9 mmol) and potassium carbonate (4.45 g, 32.2 mmol) was heated under reflux in methyl ethyl ketone (50 ml) for 1 hour. The reaction mixture was cooled, poured into dilute sodium bicarbonate/ice solution and extracted twice with ethyl acetate. The combined organic extracts were washed with water, dried (Na2SO4) and freed of solvent under vacuum. Chromatography (silica gel; MDC) afforded 2 g of 2-(1-cyclohexyl-1H-tetrazol-5-ylthiomethyl) saccharin as a white foam that was crystallized from hot cyclohexane, mp 103°-105° C. 1H nmr (90 MHz, CDCl3):5.65 (2H, s). FDMS: m/e 379 (M+).
Reaction SMILES: C[O:2][C:3](=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[CH2:22]([CH2:24][NH2:25])[OH:23]>CCCC[O-].CCCC[O-].CCCC[O-].CCCC[O-].[Ti+4]>[CH2:22]([CH2:24][NH2:25])[OH:23].[C:3]([OH:21])(=[O:2])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCCCCCCCCCC(=O)OC
Agent: [Ti+4]
Agent: CCCC[O-]
Solvent: NCCO
Product: CCCCCCCCCCCCCCCCCC(=O)O

Procedure:
As in Example 1, 597 g (2 mol) of stearic acid methyl ester (94%), 245.5 g (4 mol) of ethanolamine and 4 g (0.012 mol, 0.6 mol-%) of titanium tetrabutylate were reacted under nitrogen and normal pressure at 140°-175° C. to form stearic acid ethanolamine with removal of methanol by distillation. The excess ethanolamine was then distilled off in a water jet pump vacuum (20 hPa) at 115°-200° C. The temperature was then increased in an oil pump vacuum (0.007 hPa) to 220°-300° C., 2-heptadecyl-2-oxazoline and water distilling over.
Reaction SMILES: [ClH:1].[CH2:2]([O:7][C:8]1[CH:9]=[C:10]([CH:12]=[CH:13][C:14]=1[O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[NH2:11])[CH2:3][CH2:4][CH2:5][CH3:6].[NH4+].[OH-].Cl.N([C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[C:38]3[N:43]=[CH:42][NH:41][C:39]3=2)[N:34]=[C:33]([CH3:44])[CH:32]=1)C1C=CC=CC=1>C(O)C>[ClH:1].[CH2:2]([O:7][C:8]1[CH:9]=[C:10]([CH:12]=[CH:13][C:14]=1[O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[NH:11][C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[C:38]3[N:43]=[CH:42][NH:41][C:39]3=2)[N:34]=[C:33]([CH3:44])[CH:32]=1)[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCOc1ccc(N)cc1OCCCCC
Reactant: Cc1cc(Nc2ccccc2)c2c(ccc3nc[nH]c32)n1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCOc1ccc(Nc2cc(C)nc3ccc4nc[nH]c4c23)cc1OCCCCC
Reaction time: 8 h

Procedure:
Ten grams (0.033 m.) of 3,4-dipentoxyaniline hydrochloride was dissolved in 500 ml. of ethanol, then neutralized with 28% NH4OH. After adding 7.2 g. (0.033 m.) of the compound of Example I, C., the mixture was refluxed with stirring overnight. Concentration in vacuo gave 17 g. The crude product was recrystallized from 300 ml. of MeOH to yield 16 g. m.p. 236°-238°C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.[N:14]([O-])=O.[Na+].Cl>O>[NH:1]([C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1)[NH2:14]
Reactant: O=N[O-]
Reactant: COC(=O)c1ccc(N)cc1OC
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COC(=O)c1ccc(NN)cc1OC
Yield: 108113 %

Procedure:
The title compound was prepared according to the procedure described in step-2 of Intermediate-7 by using methyl 4-amino-2-methoxybenzoate (10.0 g, 0.055 mol), stannous chloride (31.00 g, 0.138 mmol), sodium nitrite (4.57 g, 0.066 mmol), 6 N HCl (200 mL) and water (100 mL) to afford 14.0 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 3.73 (s, 3H), 3.80 (s, 3H), 6.51 (d, J=8.4 Hz, 1H), 6.69 (s, 1H), 7.68 (d, J=8.4 Hz, 1H), 8.75 (br s, 1H), 10.28 (br hump, 2H); MS (m/z): 197.01 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)=[N:8][C:7](=[O:17])[C:6]=2[CH:18]=1.Br[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[OH:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][O:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)=[N:8][C:7](=[O:17])[C:6]=2[CH:18]=1
Reactant: OCCCCCCBr
Reactant: O=c1nc(-c2ccccn2)sc2ccc(O)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1nc(-c2ccccn2)sc2ccc(OCCCCCCO)cc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 95 %

Procedure:
A mixture of 6-hydroxy-2-(2-pyridyl)-4H-1,3-benzothiazine-4-one (0.35 g, 1.3 mmol), 6-bromohexanol (1.28 g, 7.0 mmol) and potassium carbonate (0.38 g, 2.7 mmol) and DMF (10 ml) was stirred at room temperature for 24 hrs. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water and dried. The solvent was evaporated under reduced pressure. The obtained crystals were recrystallized from tetrahydrofuran-hexane to give the titled compound (0.44 g, 91%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH:14]2[CH2:17][NH:16][CH2:15]2)[C:10]([F:13])([CH3:12])[CH3:11])[CH:5]=[C:6]([F:8])[CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH:25]([C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)[C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[C:29]#[N:30]>C(#N)C>[Cl:40][C:37]1[CH:36]=[CH:35][C:34]([C@H:25]([N:16]2[CH2:15][CH:14]([C@@H:9]([C:4]3[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=3)[C:10]([F:13])([CH3:12])[CH3:11])[CH2:17]2)[C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[C:29]#[N:30])=[CH:39][CH:38]=1
Reactant: CC(C)(F)[C@H](c1cc(F)cc(F)c1)C1CNC1
Reactant: N#Cc1cccc(C(Br)c2ccc(Cl)cc2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)(F)[C@H](c1cc(F)cc(F)c1)C1CN([C@@H](c2ccc(Cl)cc2)c2cccc(C#N)c2)C1
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
A solution of the crude amine from Step 1 and 3.4 g (1.1 mmole) of Cs2CO3 in 10 mL dry acetonitrile was stirred at rt in a flask fitted with a small Dean-Stark trap. After 15 minutes, 2.3 g (7.5 mmole) of 3-[bromo(4-chlorophenyl)methyl]benzonitrile was added and the mixture was heated at 60° C. After 18 h, the solution was filtered through CELITE and the residue was washed with acetonitrile. The combined filtrates were concentrated and the residue was purified by flash chromatography using a step gradient of 5 to 20% ethyl acetate-hexane. Fractions containing the faster product diastereomer were pooled and concentrated to afford the title compound; 1NMR(CDCl3) δ 1.25 (t, J=22 Hz, 6H), 2.33 (t, J=6.5 Hz, 1H), 2.83-2.89 (m, 2H), 3.09-3.11 (m, 2H), 3.60 (m, 1H), 4.24 (s, 1H), 6.68-6.71 (m, 3H), 7.21-7.8 (m, 8H); Mass Spectrum: m/e=469 (M+1, 35Cl) and 471 (M+1, 37Cl).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:5][CH2:4]1.Cl[CH2:7][C:8]1[N:13]=[C:12]([NH2:14])[CH:11]=[CH:10][N:9]=1.O>C1COCC1.[H-].[Na+]>[CH:3]1([CH2:2][O:1][CH2:7][C:8]2[N:13]=[C:12]([NH2:14])[CH:11]=[CH:10][N:9]=2)[CH2:5][CH2:4]1
Reactant: OCC1CC1
Reactant: Nc1ccnc(CCl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccnc(COCC2CC2)n1
Reaction time: 0.5 h
Yield: 21.6 %

Procedure:
Hydroxymethylcyclopropane (0.17 g) was dissolved in THF (2 mL) and at 0° C. sodium hydride dispersion (55% in oil, 0.1 g) was added. The mixture was allowed to stir for 30 minutes and subsequently, a solution of 2-chloromethyl-pyrimidin-4-ylamine (0.2 g, Eur. Pat. Appl. EP 61318 A2, 1982; Eur. Pat. Appl. 60094 A2, 1982) in THF (7 mL) was added dropwise. The resulting mixture was heated to reflux for 2 hours, cooled and water was added. The mixture was extracted with ethyl acetate and the organic layers were combined, dried over Na2SO4, filtered and evaporated. The residue was purified by flash chromatography (ethyl acetate/methanol 9:1) to give 2-cyclopropylmethoxymethyl-pyrimidin-4-ylamine as colorless solid (54 mg). 1H NMR (δ, CDCl3): 8.22 (d, 1H), 6.32 (d, 1H), 4.98 (br s, 2H), 4.58 (s, 2H), 3.46 (d, 2H), 1.21-1.12 (m, 1H), 0.59-0.53 (m, 2H), 0.27-0.24 (m, 2H). MS (ESI): 180.3 (MH+).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])=[O:17])=[C:12]([Cl:25])[CH:11]=1.[CH2:26]([O:28][P:29]([CH2:34][C:35](O)=[O:36])([O:31][CH2:32][CH3:33])=[O:30])[CH3:27].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[Cl:25][C:12]1[CH:11]=[C:10]([NH:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[CH2:2][NH:1][C:35](=[O:36])[CH2:34][P:29](=[O:30])([O:31][CH2:32][CH3:33])[O:28][CH2:26][CH3:27])[CH:15]=[CH:14][C:13]=1[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:24])=[O:17]
Reactant: Cc1ccccc1C(=O)c1ccc(Nc2ccccc2CN)cc1Cl
Reactant: CCOP(=O)(CC(=O)O)OCC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCOP(=O)(CC(=O)NCc1ccccc1Nc1ccc(C(=O)c2ccccc2C)c(Cl)c1)OCC
Temperature: 25 °C
Reaction time: 7 h

Procedure:
Compound 148 (0.20 g, 0.56 mmol) was dissolved in dry DCM (1 mL) in oven dried glass ware under an argon atmosphere. Diethylphosphonoacetic acid (0.09 mL, 0.56 mmol) was added followed by dropwise addition of dicyclohexylcarbodiimide (0.13 g, 0.61 mmol dissolved in 1 mL dry DCM). The suspension was stirred at room temperature for 7 h after which it was filtered. The filtrate was diluted with 5 mL DCM and washed with 10% aqueous NaHCO3, H2O and brine. The organic phase was dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography using EtOAc as the eluent to afford the title compound as a slightly coloured oil.