Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:9][C:10]1[O:11][C@H:12]([C:36]([F:39])([F:38])[F:37])[CH2:13][C@@:14]([C:19]2[N:24]=[C:23]([NH:25][C:26](=[O:34])[C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][N:28]=3)[CH:22]=[CH:21][C:20]=2[F:35])([CH:16]([F:18])[F:17])[N:15]=1)(=O)C1C=CC=CC=1.N12CCCN=C1CCCCC2>CO>[NH2:9][C:10]1[O:11][C@H:12]([C:36]([F:37])([F:39])[F:38])[CH2:13][C@@:14]([C:19]2[N:24]=[C:23]([NH:25][C:26](=[O:34])[C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][N:28]=3)[CH:22]=[CH:21][C:20]=2[F:35])([CH:16]([F:17])[F:18])[N:15]=1
Reactant: O=C(NC1=N[C@](c2nc(NC(=O)c3ccc(Cl)cn3)ccc2F)(C(F)F)C[C@@H](C(F)(F)F)O1)c1ccccc1
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Product: NC1=N[C@](c2nc(NC(=O)c3ccc(Cl)cn3)ccc2F)(C(F)F)C[C@@H](C(F)(F)F)O1
Temperature: 80 °C
Yield: 13.8 %

Procedure:
To a solution of N-(6-((4R,6S)-2-benzamido-4-(difluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-5-fluoropyridin-2-yl)-5-chloropicolinamide (16 mg, 0.028 mmol) in MeOH (74.60 in a flask was added 1,8-diazabicyclo-[5.4.0]undec-7-ene (336 μl, 2.249 mmol). The vial was sealed and was heated at 80° C. for 4 h. The reaction was diluted with MeOH and purified by reverse-phase preparative HPLC using a Phenomenex Gemini column, 10 micron, C18, 110 Å, 150×30 mm, 0.1% TFA in CH3CN/H2O, gradient 10% to 70% over 16 min, then neutralized with solid NaHCO3 and extracted with DCM to provide N-(6-((4R,6S)-2-amino-4-(difluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-5-fluoropyridin-2-yl)-5-chloropicolinamide (1.8 mg, 3.85 μmol, 13.75% yield) as a off-white solid. MS m/z=467, 469 M+; Calculated for C17H12ClF6N5O2: 467.75.
Reaction SMILES: CON(C)[C:4]([C@H:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][C@H:7]1[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)=[O:5].[CH3:27][Mg]Br.C[O-].[Na+]>CO>[CH2:12]([N:9]1[CH2:10][CH2:11][C@@H:6]([C:4](=[O:5])[CH3:27])[C@H:7]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[CH2:8]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CON(C)C(=O)[C@H]1CCN(Cc2ccccc2)C[C@H]1c1ccc(Cl)cc1
Reactant: C[Mg]Br
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)[C@@H]1CCN(Cc2ccccc2)C[C@H]1c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described for the synthesis of 1-[(3SR,4SR)-1-benzyl-3-(4-chloro-phenyl)-piperidin-4-yl]-ethanone (example 5 (c)) the title compound was prepared from (3R,4S)-1-Benzyl-3-(4-chloro-phenyl)-piperidine-4-carboxylic acid methoxy-methyl-amide and methylmagnesium bromide with subsequent epimerisation with NaOMe in methanol. The title compound was obtained as off-white solid. MS (m/e): 327.1 [(M+H)+].
Reaction SMILES: ClC1C=CC(C2NC(C3C=C[C:16]([O:19]C)=[CH:15]C=3OCC)=NC2CC(C)C)=CC=1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]2[N:39]([C:40]([N:42]3[CH2:47][CH2:46][N:45](C)[CH2:44][CH2:43]3)=[O:41])[C:38]([C:49]3[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][C:50]=3[O:57][CH2:58][CH3:59])=[N:37][CH:36]2[CH2:60][CH:61]2[CH2:65]CC[CH2:62]2)=[CH:31][CH:30]=1>>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]2[N:39]([C:40]([N:42]3[CH2:43][CH2:44][N:45]([C:16](=[O:19])[CH3:15])[CH2:46][CH2:47]3)=[O:41])[C:38]([C:49]3[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][C:50]=3[O:57][CH2:58][CH3:59])=[N:37][CH:36]2[CH2:60][CH:61]([CH3:62])[CH3:65])=[CH:31][CH:30]=1
Reactant: CCOc1cc(OC)ccc1C1=NC(CC2CCCC2)C(c2ccc(Cl)cc2)N1C(=O)N1CCN(C)CC1
Reactant: CCOc1cc(OC)ccc1C1=NC(CC(C)C)C(c2ccc(Cl)cc2)N1
Product: CCOc1cc(OC)ccc1C1=NC(CC(C)C)C(c2ccc(Cl)cc2)N1C(=O)N1CCN(C(C)=O)CC1

Procedure:
1-{4-[5-(4-Chloro-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4-isobutyl-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-ethanone was prepared from 5-(4-chloro-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4-isobutyl-4,5-dihydro-1H-imidazole (Example 10) in an analogous manner as described for the preparation of [5-(4-chloro-phenyl)-4-cyclopentylmethyl-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro-imidazol-1-yl]-(4-methyl-piperazin-1-yl)-methanone (Example 24). HR-MS (ES, m/z) observed 541.2580, calculated for C26H32N4O4Cl [(M+H)+]541.2576.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[N:12]([O-])=O.[Na+].[Sn](Cl)Cl>Cl.O>[ClH:1].[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][NH2:12])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: O=N[O-]
Reactant: Nc1ccc(Cl)cc1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: NNc1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 116.4 %

Procedure:
4-Chloro-2-nitroaniline (40 g, 0.23 mol) prepared in Preparation 13 was dissolved in 12N hydrochloric acid (100 mL). Sodium nitrite (16 g, 0.23 mol) dissolved in water (50 mL) was slowly added in drops thereto at 0° C., and the mixture was stirred for 30 min at 0° C. to room temperature. The reaction mixture was cooled to 0° C., tin (II) chloride (132 g, 0.70 mol) dissolved in 12N hydrochloric acid (100 mL) was slowly added in drops thereto, and the mixture was stirred for 3 h at 0° C. to room temperature. The resulting yellow solid was filtered, washed with a small amount of 6N HCl, and dried to give the title compound (30 g, Yield 63%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:10])[NH2:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1B(O)O.C(N(CC)CC)C>ClCCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]([CH3:10])[NH:9][C:16]1[CH:17]=[C:12]([Cl:11])[CH:13]=[CH:14][C:15]=1[Cl:18])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1cc(Cl)ccc1Cl
Reactant: CN(N)C(=O)OC(C)(C)C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CN(Nc1cc(Cl)ccc1Cl)C(=O)OC(C)(C)C
Temperature: 50 °C
Yield: 46.6 %

Procedure:
A mixture of N-methyl-hydrazinecarboxylic acid tert-butyl ester (Intermediate 1; 650 mg, 4.45 mmol), 2,5-dichlorophenylboronic acid (Aldrich; 831 mg, 4.36 mmol), copper(II) acetate (807 mg, 4.45 mmol) and triethylamine (623 μL, 4.45 mmol) in 1,2-dichloroethane (4.5 mL) was heated in an oil bath at 50° C. for 3 h. The mixture was allowed to cool, and it was then adsorbed onto silica gel and purified by chromatography using an ISCO 40 g column, eluting with 20-40% ethyl acetate/hexanes, to give N′-(2,5-dichloro-phenyl)-N-methyl-hydrazinecarboxylic acid tert-butyl ester (592 mg, 46%) as a yellow oil that solidified on standing.
Reaction SMILES: [F:1][C:2]1[C:3]([N+:10]([O-:12])=[O:11])=[C:4]([OH:9])[CH:5]=[C:6]([F:8])[CH:7]=1.[CH3:13]N(C)C=O.C(=O)([O-])[O-].[K+].[K+].IC>O>[F:1][C:2]1[C:3]([N+:10]([O-:12])=[O:11])=[C:4]([O:9][CH3:13])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=[N+]([O-])c1c(O)cc(F)cc1F
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Product: COc1cc(F)cc(F)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 3,5 difluoro-2-nitrophenol(8.3 g), N,N-dimethylformamide(30 mL), potassium carbonate(10 g) and iodomethane(5 mL) was stirred vigorously at room temperature for 18 h. The mixture was diluted with water and extracted with ether. The extract was washed with brine, dried and evaporated to dryness to give the product(8.7 g) as a yellow solid.
Reaction SMILES: C([O:9][C:10]1[CH:15]=[C:14]([Br:16])[C:13]([O:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[CH:19]=2)=[C:12]([Br:34])[CH:11]=1)(=O)C1C=CC=CC=1.[OH-].[Na+].C(OCC)(=O)C>C1COCC1>[Br:16][C:14]1[CH:15]=[C:10]([OH:9])[CH:11]=[C:12]([Br:34])[C:13]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[CH:19]=1
Reactant: COc1ccc(Oc2c(Br)cc(OC(=O)c3ccccc3)cc2Br)cc1Cc1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(Oc2c(Br)cc(O)cc2Br)cc1Cc1ccc(F)cc1
Reaction time: 8 h
Yield: 92.9 %

Procedure:
To a mixture of 3,5-dibromo-4-[3′-(4-fluorobenzyl)-4′-methoxyphenoxy]phenyl benzoate (2.14 gm, 3.75 mmol) in THF 60 mL was added 1 N NaOH 20 mL. The reaction was stirred at r.t overnight, then poured into 120 mL ethyl acetate. The aqueous layer was removed and the organic was washed 2× with aqueous NaHCO3, 1× with 1 N HCl 30 mL. The ethyl acetate was dried over Na2SO4, filtered and concentrated under reduced pressure to give 3,5-dibromo-4-[3′-(4-fluorobenzyl)-4′-methoxyphenoxy]phenol (1.68 gm, 93%); 1H NMR (300 MHz, DMSO-d6): δ 10.27 (s, 1H), 7.20 (m, 2H), 7.05 (m, 4H), 6.87 (d, J=9 Hz, 1H), 6.65 (d, J=3.3 Hz, 1H), 6.46 (dd, J=9, 3 Hz, 1H), 3.84 (s, 2H), 3.71 (s, 3H); TLC conditions: Uniplate silica gel, 250 microns; hexane-ethyl acetate [3:1]; Rf=0.65.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH:16]=[CH2:17])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:23]([O:22][C:20](=[O:21])[CH2:19][O:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:10][C:11]=1[CH:16]=[CH2:17])[CH3:24]
Reactant: C=Cc1cc(OCc2ccccc2)ccc1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C=Cc1cc(OCc2ccccc2)ccc1OCC(=O)OCC
Temperature: 55 °C
Yield: 101.3 %

Procedure:
4-Benzyloxy-2-vinylphenol (0.40 g, 1.77 mmol) was dissolved in anhydrous DMF (4 mL), followed by the addition of ethyl bromoacetate (0.29 mL, 2.65 mmol), and cesium carbonate (0.75 g, 2.30 mmol). The mixture was then heated for 18 h (55° C.). The reaction mixture was then cooled and concentrated in vacuo. The crude residue was partitioned between EtOAc (70 mL) and water (40 mL). The organic layer was washed with brine, dried (Na2SO4), and removed in vacuo to give 0.56 g (100%) of a yellow solid: 1H NMR (400 MHz, CDCl3) δ 7.44-7.31 (m, 4H), 7.13 (d, J=2.9 Hz, 1H), 7.10-7.06 (m, 1H), 6.82 (dd, J=8.8, 2.9 Hz, 1H), 6.73 (d, J=9.3 Hz, 1H), 5.76 (dd, J=17.1 Hz, 1.5 Hz, 1H), 5.30 (dd, J=11.2, 1.5 Hz, 1H), 5.03 (s, 2H), 4.58 (s, 2H), 4.26 (q, J=7.2 Hz, 2H), 1.30 (t, J=7.1 Hz, 3H); MS (FIA) m/e 313 (M+1).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=3[OH:21])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[CH3:22][C:23]1[CH:24]=[CH:25][C:26]([OH:32])=[C:27](B(O)O)[CH:28]=1>>[OH:21][C:15]1[CH:16]=[C:17]([CH3:20])[CH:18]=[CH:19][C:14]=1[C:10]1[N:9]=[C:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:25]3[CH:24]=[C:23]([CH3:22])[CH:28]=[CH:27][C:26]=3[OH:32])[N:7]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Cc1ccc(-c2cccc(-c3cccc(Br)n3)n2)c(O)c1
Reactant: Cc1ccc(O)c(B(O)O)c1
Product: Cc1ccc(-c2cccc(-c3cccc(-c4cc(C)ccc4O)n3)n2)c(O)c1
Yield: 44 %

Procedure:
6-(2-Hydroxy-4-methylphenyl)-6′-(2-hydroxy-5-methylphenyl)-2,2′-bipyridine was prepared from 6-bromo-6′-(2-hydroxy-4-methylphenyl)-2,2′-bipyridine and 5-methyl-2-hydroxyphenylboronic acid in 44% yield using method F; δH [2H6]-DMSO 13.60,(1H, b), 13.10,(1H, b), 8.32,(2H, t), 8.23,(2H, m), 8.13,(2H, d), 8.03,(1H, d), 7.95,(1H, s), 7.18,(1H, d), 6.92,(1H, d), 6.83,(2H, m), 2.33,(3H, s), 2.34,(3H, s); MS 369 (MH)+; HPLC retention time (system 1) 4.46 minutes.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=[C:11]([N:19]([CH3:21])[CH3:20])[N:10]=1.[CH3:22][C:23]1[CH:24]=[CH:25][C:26]([C:32]2[N:37]=[CH:36][CH:35]=[CH:34][N:33]=2)=[C:27]([CH:31]=1)[C:28](O)=[O:29]>>[CH3:20][N:19]([CH3:21])[C:11]1[N:10]=[C:9]([N:2]2[CH2:3][CH:4]3[CH:5]([CH2:6][N:7]([C:28]([C:27]4[CH:31]=[C:23]([CH3:22])[CH:24]=[CH:25][C:26]=4[C:32]4[N:33]=[CH:34][CH:35]=[CH:36][N:37]=4)=[O:29])[CH2:8]3)[CH2:1]2)[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=1
Reactant: Cc1ccc(-c2ncccn2)c(C(=O)O)c1
Reactant: CN(C)c1nc(N2CC3CNCC3C2)cc(C(F)(F)F)n1
Product: Cc1ccc(-c2ncccn2)c(C(=O)N2CC3CN(c4cc(C(F)(F)F)nc(N(C)C)n4)CC3C2)c1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 36 and 5-methyl-2-pyrimidin-2-yl-benzoic acid. MS (ESI): mass calculated for C25H26F3N7O, 497.53; m/z found 498.0 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.67 (dd, J=20.0, 4.9, 2H), 8.20 (d, J=10.1, 1H), 7.34-7.30 (m, 1H), 7.19-7.15 (m, 1H), 7.13-7.03 (m, 1H), 5.85 (br s, 1H), 3.98-2.83 (m, 16H), 2.42 (s, 3H).
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]([NH:14][CH3:15])=[O:13])=[C:10]([CH2:16][CH:17]([OH:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>[Pd].C(O)C>[NH2:8][C:7](=[C:11]([C:10](=[O:9])[CH2:16][CH:17]([OH:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:12]([NH:14][CH3:15])=[O:13])[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CNC(=O)c1c(-c2ccccc2)noc1CC(O)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CNC(=O)C(C(=O)CC(O)c1ccccc1)=C(N)c1ccccc1

Procedure:
A mixture of 30.0 grams (0.093 mole) of 3-phenyl-5-(β-hydroxyphenethyl)-N-methyl-isoxazole-4-carboxamide, 600 milliliters of ethanol and 3.0 grams of 10 percent Palladium on carbon in hydrogenated at 50 p.s.i. until 1 equivalent of hydrogen is absorbed (about 5 hours). The mixture is filtered and the filtrate evaporated in vacuo. The residue is then crystallized from methylene chloride petroleum ether to give 2-(α-aminobenzylidene)-5-hydroxy-N-methyl-3-oxo-5-phenylvaleramide, m.p. 72° C.-76° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:14]=[C:13]([N:15]3[CH2:20][CH2:19][NH:18][C@@H:17]([CH2:21][CH2:22][CH2:23][O:24][CH3:25])[CH2:16]3)[C:12]3[CH:11]=[C:10]([CH3:26])[S:9][C:8]=3[NH:7][C:6]=2[CH:27]=1.C=O.[C:30](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.C(=O)(O)[O-].[Na+]>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:14]=[C:13]([N:15]3[CH2:20][CH2:19][N:18]([CH3:30])[C@@H:17]([CH2:21][CH2:22][CH2:23][O:24][CH3:25])[CH2:16]3)[C:12]3[CH:11]=[C:10]([CH3:26])[S:9][C:8]=3[NH:7][C:6]=2[CH:27]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: COCCC[C@H]1CN(C2=Nc3ccc(F)cc3Nc3sc(C)cc32)CCN1
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: COCCC[C@H]1CN(C2=Nc3ccc(F)cc3Nc3sc(C)cc32)CCN1C
Yield: 88.9 %

Procedure:
Combine (S)-6-fluoro-10-[3-(3-methoxy-propyl)-piperazin-1-yl]-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene (0.105 g, 0.270 mmol), formaldehyde (31 μL, 0.378 mmol, 37%), and sodium triacetoxyborohydride (0.086 g, 0.405 mmol) in dichloroethane (6 mL) and stir at room temperature overnight. Dilute the mixture with saturated sodium bicarbonate and extract three times with methylene chloride. Combine the organic layers, dry over sodium sulfate and concentrate under reduced pressure to give the crude product. Purification by flash chromatography, eluting with a step gradient starting with dichloromethane going to 5% 2N ammonia-methanol in dichloromethane gives (S)-6-fluoro-10-[3-(3-methoxy-propyl)-4-methyl-piperazin-1-yl]-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene (0.097 g, 0.240 mmol, 89%) as a yellow oil. Mass spectrum (APCI): m/z=403.1 (M+1). Isolate clean product as the corresponding dihydrochloride in the following manner: dissolve the yellow foam in ethanol (5 mL) and add a solution of about 5 equivalents of HCl in ethanol (5 mL). Evaporate the mixture to obtain (S)-6-fluoro-10-[3-(3-methoxy-propyl)-4-methyl-piperazin-1-yl]-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene dihydrochloride.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][C:11](=[O:13])[CH:10]([C:14](=[O:26])[CH:15]=[CH:16][C:17]3[CH:22]=[CH:21][C:20]4[O:23][CH2:24][O:25][C:19]=4[CH:18]=3)[C:9](=[O:27])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>O1CCCC1.[C].[Pd]>[C:1]1([CH:7]2[CH2:12][C:11](=[O:13])[CH:10]([C:14](=[O:26])[CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]4[O:23][CH2:24][O:25][C:19]=4[CH:18]=3)[C:9](=[O:27])[CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: O=C(C=Cc1ccc2c(c1)OCO2)C1C(=O)CC(c2ccccc2)CC1=O
Agent: [Pd]
Solvent: C1CCOC1
Product: O=C(CCc1ccc2c(c1)OCO2)C1C(=O)CC(c2ccccc2)CC1=O

Procedure:
In 200 ml of tetrahydrofuran was dissolved 10.8 g of 5-phenyl-2-[3-(3,4-methylenedioxyphenyl)-propenoyl]-cyclohexane-1,3-dione prepared in step (1) above, and 2 g of a 5% palladium-carbon catalyst was added to the solution and catalytic reduction was carried out for 7 hours with hydrogen under atmospheric pressure. The catalyst was removed by filtration and tetrahydrofuran was removed by distillation. Recrystallization from isopropyl alcohol have 7.5 g (the yield being 70%) of the desired 5-phenyl-2-[3-(3,4-methylenedioxyphenyl)-propionyl]-cyclohexane-1,3-dione.
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][C:7]([CH2:8][O:9][C:10](=[O:21])[CH2:11][N:12](C(OC(C)(C)C)=O)[CH3:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].[ClH:24].C(OCC)C>O1CCOCC1>[ClH:24].[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10](=[O:21])[CH2:11][NH:12][CH3:13])=[CH:22][CH:23]=1)([O-:3])=[O:2]
Reactant: CN(CC(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CNCC(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 88 %

Procedure:
To a solution of (N-t-butoxycarbonyl-N-methyl-amino)acetic acid p-nitrobenzyl ester (4.30 g, 133 mmol) (obtained as described in Reference Example 43(1)) was added a solution of 4N hydrogen chloride in 1,4-dioxane (4.3 ml) in an ice bath, and the mixture was stirred at room temperature for 2.5 hours. After checking the completion of the reaction, diethyl ether was added thereto and the reaction mixture was stirred for 30 minutes. The resulting reaction mixture was filtered and the obtained residue was washed with diethyl ether and dried to give sarcosine p-nitrobenzyl ester hydrochloride (3.04 g, yield 88%).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12][CH:13]2[CH2:18][O:17]C(C)(C)[O:15][CH2:14]2)=[C:4](Cl)[N:3]=1>C(O)C.C1CCCCC=1.[Pd]>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12][CH:13]([CH2:18][OH:17])[CH2:14][OH:15])=[CH:4][N:3]=1
Reactant: CC1(C)OCC(CCn2cnc3c(Cl)nc(N)nc32)CO1
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CCO
Product: Nc1ncc2ncn(CCC(CO)CO)c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.1 %

Procedure:
To a solution of 2-amino-6-chloro-9-[2-(2,2-dimethyl-1, 3-dioxan-5-yl)ethyl]purine (0.54 g, 1.75 mmol) in ethanol (10 ml) and cyclohexene (20 ml) was added 10% palladium-on-charcoal (400 mg) and the solution was refluxed for 7 hours. A further quantity of catalyst (200 mg) was added and the solution was refluxed overnight. The solution was filtered and washed through with methanol. To the filtrate was added hydrochloric acid (5 M, 0.3 ml) and water (0.7 ml) and the solution was stirred for 30 minutes at room temperature. The solution was neutralised by addition of aqueous sodium bicarbonate and the solvent was removed. The residue was purified by column chromatography on silica gel eluting with chloroform-methanol (5:1, 4:1) to afford 2-amino-9-(4-hydroxy-3-hydroxymethylbut-1-yl)purine as a crystalline solid (150 mg, 36%), m.p. 156°-158° C.; λmax (H2O) 242 and 303 nm; νmax (KBr) 3320, 3210, 1640, 1610, 1580, and 1430 cm1 ; δH [(CD3)2SO] 1.47 (1H, m, 3'-H), 1.78 (2H, q, J 7.2Hz, 2'-H), 3.3-3.5 (4H, m, 2×4'-H), 4.12 (2H, t, J 7.4Hz, 1'-H), 4.42 (2H, t, J 5.2Hz, D2O exchangeable, 2 x OH), 6.45 (2H, s, D2O exchangeable, 2-NH2), 8.06 (1H, s, 8-H), and 8.56 (1H, s, 6-H); (Found: C, 50.61; H, 6.45; N, 29.62 %. C10H15N5O2 requires: C, 50.62; H, 6.37; N, 29.52
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[N:8]=[C:9](/[O:16][CH2:17][CH3:18])\[CH2:10][C:11]([O:13]CC)=O)=[CH:4][C:3]=1[O:19][CH3:20]>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][C:3]=1[O:19][CH3:20])[N:8]=[C:9]([O:16][CH2:17][CH3:18])[CH:10]=[C:11]2[OH:13]
Reactant: CCOC(=O)C/C(=N\c1ccc(Br)c(OC)c1)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: CCOc1cc(O)c2cc(Br)c(OC)cc2n1
Temperature: 250 °C
Reaction time: 0.08 h

Procedure:
A solution of ethyl (3E)-3-[(4-bromo-3-methoxyphenyl)imino]-3-ethoxypropanoate (30.0 g, 87 mmol) in DOWTHERM (30 mL) was added to a stirred solution of DOWTHERM (300 mL) at 250° C. The resulting solution was stirred at 250° C. for 5 minutes, cooled to RT and filtered, and the cake was washed with hexane (3×50 mL), then dried to give the title product. 1H NMR (400 MHz, CD3OD) δ 8.25 (s, 1H); 6.92 (s, 1H); 5.80 (s, 1H); 4.27 (q, J=7.1 Hz, 2H); 3.97 (s, 3H); 1.46 (t, J=7.0 Hz, 3H) ppm. LRMS (ESI) m/z 298.0 [(M+H)+; calcd for C12H13BrNO3: 298.0].
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([CH2:17][CH2:18][O:19]C)(=[O:16])=[O:15])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1.B(Br)(Br)Br>C(=O)(O)[O-]>[Cl:1][C:2]1[C:3]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)=[N:4][C:5]([N:8]2[CH2:9][CH2:10][N:11]([S:14]([CH2:17][CH2:18][OH:19])(=[O:16])=[O:15])[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: COCCS(=O)(=O)N1CCN(c2ccc(Cl)c(-c3ccccn3)n2)CC1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Product: O=S(=O)(CCO)N1CCN(c2ccc(Cl)c(-c3ccccn3)n2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 67.3 %

Procedure:
To a cooled −78° C. solution of 3-chloro-6-(4-((2-methoxyethyl)sulfonyl)piperazin-1-yl)-2,2′-bipyridine (134 mg, 0.338 mL) in (2 mL), boron tribromide (0.139 mL, 0.737 mmol) was added. After 1 h, the reaction mixture was warmed to 0° C. and stirred for an additional 1 h. Saturated aqueous bicarbonate (10 mL) was added and extracted with CH2Cl2 (2×10 mL). The combined organic layer was washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure and purified by column chromatography (60 to 100% ethyl acetate/heptane) to obtain pure product (87 mg, 67% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.65 (d, J=4.80 Hz, 1 H) 7.92 (td, J=7.71, 1.77 Hz, 1 H) 7.75 (d, J=9.09 Hz, 1 H) 7.69 (d, J=7.83 Hz, 1 H) 7.44 (td, J=6.19, 1.01 Hz, 1 H) 6.99 (d, J=8.84 Hz, 1 H) 5.02 (t, J=5.43 Hz, 1 H) 3.75 (q, J=6.06 Hz, 2 H) 3.59-3.67 (m, 4 H) 3.24-3.30 (m, 4 H) 3.21 (t, J=6.19 Hz, 2 H). LCMS (M+H)+: 383.0.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:12]([CH3:15])(=[O:14])=[O:13])=[C:6]([NH:8][C:9](=O)[CH3:10])[CH:7]=1.[N-:16]=[N+:17]=[N-:18].[Na+].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:12]([CH3:15])(=[O:14])=[O:13])=[C:6]([N:8]2[C:9]([CH3:10])=[N:18][N:17]=[N:16]2)[CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)Nc1cc(Br)ccc1S(C)(=O)=O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: CC#N
Product: Cc1nnnn1-c1cc(Br)ccc1S(C)(=O)=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 66.7 %

Procedure:
A solution of N-(5-bromo-2-methanesulfonyl-phenyl)-acetamide (350 mg, 1.2 mmol) in acetonitrile (6 mL) at 25° C. was treated with sodium azide (78 mg, 1.2 mmol). The reaction mixture was cooled to 0° C. and then treated with trifluoromethanesulfonic anhydride (0.24 mL, 1.2 mmol). The resulting reaction mixture was allowed to warm to 25° C. where it was stirred overnight, at which time, thin layer chromatography analysis of the reaction mixture indicated the absence of starting material. The reaction mixture was then concentrated in vacuo. The resulting residue was diluted with ethyl acetate (50 mL) and water (50 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×30 mL). The combined organic extracts were washed with a saturated aqueous sodium chloride solution (1×100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 8/1 hexanes/ethyl acetate) afforded 1-(5-bromo-2-methanesulfonyl-phenyl)-5-methyl-1H-tetrazole (254 mg, 67%) as a white solid: mp 174-184° C.; EI-HRMS m/e calcd for C9H9BrN4O2S (M+) 315.9630, found 315.9634.