Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]([C:16]([C:18]2[CH:23]=[C:22]([O:24][C:25]([F:30])([F:29])[CH:26]([F:28])[F:27])[CH:21]=[C:20]([F:31])[CH:19]=2)=O)[CH:12]=[CH:13][C:14]=1[F:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:32][C:33]([S@:36]([NH2:38])=[O:37])([CH3:35])[CH3:34]>C1COCC1>[Si:1]([O:8][C:9]1[CH:10]=[C:11]([C:16]([C:18]2[CH:23]=[C:22]([O:24][C:25]([F:30])([F:29])[CH:26]([F:28])[F:27])[CH:21]=[C:20]([F:31])[CH:19]=2)=[N:38][S@@:36]([C:33]([CH3:35])([CH3:34])[CH3:32])=[O:37])[CH:12]=[CH:13][C:14]=1[F:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(C(=O)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Solvent: C1CCOC1
Product: CC(C)(C)[S@@](=O)N=C(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(F)c(O[Si](C)(C)C(C)(C)C)c1
Temperature: 75 °C
Yield: 80 %

Procedure:
A round bottom flask was charged with (3-(tert-butyldimethylsilyloxy)-4-fluorophenyl)(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)methanone (2.09 g, 4.50 mmol), (R)-2-methylpropane-2-sulfinamide (653 mg, 5.4 mmol), Ti(OEt)4 (1.54 g, 6.76 mmol) and anhydrous THF (40 mL). The resulting solution was heated at 75° C. under argon for 14 h. The solvents were removed and the residue was diluted with ether (50 mL) and sat. NaCl (20 mL). The resulting mixture was filtered through a glass frit and the filtrate transferred to a separatory funnel. The organic portion was separated and the aqueous extracted with ether (2×20 mL). The combined organic portions were dried over Na2SO4, filtered and concentrated. The residue was dissolved in hexane:EtOAc and purified by ISCO chromatography (2×120 g column) using hexanes/EtOAc (0-100% over 30 min) to yield (R)—N-((3-(tert-butyldimethylsilyloxy)-4-fluorophenyl)(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)methylene)-2-methylpropane-2-sulfinamide at a retention time of 14 min (2.05 g, 80% yield) LCMS: RT=2.37 min [M+H] 568.24 (Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm). NMR: 400 MHz 1H (CDCl3) 7.36 ppm, 1H, m; 7.11 ppm, 5H, m; 5.90 ppm, 1H, t, J=52.73 Hz; 0.97 ppm, 9H, s; 0.18 ppm, 6H, s.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[N+:10]([O-:12])=[O:11].Cl.[CH3:14][C:15]1[S:16][C:17]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19][C:18]=2[N:24]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:8][C:6]1[NH:5][C:4](=[O:9])[C:3]([N+:10]([O-:12])=[O:11])=[C:2]([N:21]2[CH2:22][CH2:23][C:17]3[S:16][C:15]([CH3:14])=[N:24][C:18]=3[CH2:19][CH2:20]2)[N:7]=1
Reactant: Cc1nc(Br)c([N+](=O)[O-])c(=O)[nH]1
Reactant: Cc1nc2c(s1)CCNCC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(N2CCc3nc(C)sc3CC2)c([N+](=O)[O-])c(=O)[nH]1
Temperature: 25 °C
Reaction time: 60 h
Yield: 78.5 %

Procedure:
A suspension of 0.234 g (1.00 mmol) of the 6-bromo-2-methyl-5-nitro-3H-pyrimidin-4-one, 0.205 g (1.00 mmol) of the 2-methyl-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepine hydrochloride and 0.304 g (2.20 mmol) of potassium carbonate in 2.0 ml of N,N-dimethylformamide was stirred at room temperature for 60 hours. The reaction mixture was then poured into 50 ml of an ice/water mixture and the crystals formed collected by filtration. Thus, a first crop of the 2-methyl-6-(2-methyl-4,5,7,8-tetrahydro-thiazolo[4,5-d]azepin-6-yl)-5-nitro-3H-pyrimidin-4-one was obtained. The mother liquor was then evaporated and the residue chromatographed on silica gel using a 9:1 v/v mixture of dichloromethane and methanol as eluent giving a second crop of the 2-methyl-6-(2-methyl-4,5,7,8-tetrahydro-thiazolo[4,5-d]azepin-6-yl)-5-nitro-3H-pyrimidin-4-one, in total 0.252 g (0.785 mmol, yield 78.5%) as light yellow solid; m.p. >200° C.; MS: [M+H]+=322.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][C@H:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:3]1.[F:15][C:16]([F:29])([C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)[C:17](OCC)=[O:18].CCOCC.CCCCCC>CCO>[F:15][C:16]([F:29])([C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)[C:17]([NH:1][C@H:2]1[CH2:6][CH2:5][C@H:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:3]1)=[O:18]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)C1
Reactant: CCOC(=O)C(F)(F)c1ccc(C)cc1
Solvent: CCOCC
Solvent: CCCCCC
Solvent: CCO
Product: Cc1ccc(C(F)(F)C(=O)N[C@H]2CC[C@H](NC(=O)OC(C)(C)C)C2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 42 %

Procedure:
A solution of tert-butyl [(1S,3S)-3-aminocyclopentyl]carbamate (1.36 g, 6.8 mmol) and ethyl difluoro(4-methylphenyl)acetate (1.45 g, 6.8 mmol) in EtOH (5 mL) was stirred at reflux for 16 h. The solution was cooled to rt. whereupon it solidified. Et2O (6 mL) and hexane (3 mL) were added and the mixture was stirred for 3 h and the solids collected by filtration, rinsing with Et2O (2 mL), and dried to give the title compound (1.051 g) as a solid; MS=313.4 (M+1-isobutylene).
Reaction SMILES: [NH2:1][C@@H:2]1[C@@H:6]([C:7]([OH:9])=[O:8])[O:5][C@@H:4]([N:10]2[CH:18]=[N:17][C:16]3[C:11]2=[N:12][CH:13]=[N:14][C:15]=3[NH:19][C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@@H:3]1[OH:28].[CH2:29]([O:36][C:37]([NH:39][C@@H:40]([C:48](O)=[O:49])[CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[C:20]([NH:19][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[C:16]=1[N:17]=[CH:18][N:10]2[C@@H:4]1[O:5][C@H:6]([C:7]([OH:9])=[O:8])[C@@H:2]([NH:1][C:48](=[O:49])[C@@H:40]([CH2:41][C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[NH:39][C:37]([O:36][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:38])[C@H:3]1[OH:28])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: N[C@H]1[C@@H](O)[C@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)O[C@@H]1C(=O)O
Reactant: O=C(N[C@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Product: O=C(N[C@H](Cc1ccccc1)C(=O)N[C@H]1[C@@H](O)[C@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)O[C@@H]1C(=O)O)OCc1ccccc1
Yield: 60.9 %

Procedure:
1-(6-Benzoylamino-9H-purin-9-yl)-1,3-dideoxy-3-(N-benzyloxycarbonyl-D-phenylalanylamino)-β-D-ribofuranuronic acid (405 mg) was prepared by reacting 1-(6-benzoylamino-9H-purin-9-yl)-1,3-dideoxy-3-amino-β-D-ribofuranuronic acid (384 mg) prepared in Example 1 with N-hydroxysuccinimide ester of N-benzyloxycarbonyl-D-phenylalanine (543 mg) according to a similar manner to that of Example 5, mp. 206°-210° C. (dec.).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:1][C:2]2[CH:3]=[C:4]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10]2[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]3=2)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Product: CN(C)C1CCc2[nH]c3ccc(NS(=O)(=O)c4ccc(Cl)cc4)cc3c2C1
Yield: 61.9 %

Procedure:
Beginning with 10.4 mg (0.046 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 14.1 mg (0.067 mMol) 4-chlorobenzenesulfonyl chloride, 11.5 mg (64%) of the title compound were recovered as a light beige solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][CH:12]3[CH2:14][CH2:13]3)[C:6]=2[CH:5]=[CH:4][C:3]=1[C:15]1[CH:31]=[CH:30][C:18]([CH2:19][NH:20][C:21]([NH:23][CH2:24][C:25]([O:27]CC)=O)=[O:22])=[CH:17][CH:16]=1.C(=O)(O)[O-].[Na+]>Cl>[Cl:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][CH:12]3[CH2:14][CH2:13]3)[C:6]=2[CH:5]=[CH:4][C:3]=1[C:15]1[CH:16]=[CH:17][C:18]([CH2:19][N:20]2[C:25](=[O:27])[CH2:24][NH:23][C:21]2=[O:22])=[CH:30][CH:31]=1
Reactant: CCOC(=O)CNC(=O)NCc1ccc(-c2ccc3c(nnn3CC3CC3)c2Cl)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C1CNC(=O)N1Cc1ccc(-c2ccc3c(nnn3CC3CC3)c2Cl)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Ethyl N-({4-[4-chloro-1-(cyclopropylmethyl)-1H-benzotriazol-5-yl]benzyl}carbamoyl)glycinate (Example 83, 30 mg, 0.068 mmol) was dissolved in hydrochloric acid (1.4 mL, 1 N aqueous) and placed into an oil-bath preheated at 100° C. for 1.5 hours. The mixture was cooled to ambient temperature, treated with sodium bicarbonate (aqueous saturated) and extracted with ethyl acetate (3×30 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative reverse phase HPLC (85:15 to 36:64; water containing 0.1% trifluoroacetic acid:acetonitrile containing 0.1% trifluoroacetic acid) to afford the titled compound: 1H-NMR (400 MHz, d6-DMSO) δ 8.17 (1H, s); 8.00 (1H, d, J=8.5 Hz); 7.58 (1H, d, J=8.6 Hz); 7.49 (2H, d, J=8.2 Hz); 7.41 (2H, d, J=8.2 Hz); 4.67 (2H, d, J=7.2 Hz); 4.62 (2H, s); 4.02 (2H, s); 1.43-1.37 (1H, m); 0.59-0.55 (2H, m); 0.51-0.48 (2H, m) ppm; high resolution mass spectrometry (ES+) m/z 396.1242 [(M+H)+; calculated for C20H19ClN5O2: 396.1222].
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([Cl:12])[CH:6]=1)C.[NH2:14][NH2:15]>>[Cl:12][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][C:8]=1[OH:11])[C:4]([NH:14][NH2:15])=[O:3]
Reactant: CCOC(=O)c1ccc(O)c(Cl)c1
Reactant: NN
Product: NNC(=O)c1ccc(O)c(Cl)c1
Yield: 69 %

Procedure:
Ethyl-3-chloro-4-hydroxybenzoate (4.95 g, 25 mmol) was reacted with hydrazine as described for the preparation of intermediate 22b to afford the product as white crystals (3.15 g, 69%). 1H NMR (400 MHz, DMSO-d6, δ in ppm) 10.71 (br s, 1H), 9.64 (br s, 1H), 7.83 (d, J=2.1 Hz, 1H), 7.65 (dd, J=2.1, 8.4 Hz, 1H), 6.99 (d, J=8.4 Hz, 1H), 4.43 (br s, 2H).
Reaction SMILES: [Cl:1][C:2]1C=C[C:5](C)=[C:6](N2CCN(C/C=C\CN)CC2)[CH:7]=1.[K].[C:21]1(=[O:31])[NH:25][C:24](=[O:26])[C:23]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]12>>[Cl:1][CH2:2]/[CH:7]=[CH:6]\[CH2:5][N:25]1[C:21](=[O:31])[C:22]2=[CH:30][CH:29]=[CH:28][CH:27]=[C:23]2[C:24]1=[O:26]
Reactant: Cc1ccc(Cl)cc1N1CCN(C/C=C\CN)CC1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Product: O=C1c2ccccc2C(=O)N1C/C=C\CCl

Procedure:
Cis-4-[4-(5-chloro-2-methylphenyl)piperazinyl]-2-buten-1-amine: according to the method of Example 5, phthalimide potassium salt was reacted with cis-1,4-dihydro-2-butene to obtain N-(cis-4-chloro-2-buten-1-yl)phthalimide; which was then reacted with 5-chloro-2-methylphenylpiperazine to obtain N-{4-[4-(5-chloro-2-methylphenyl)piperazinyl]-cis-2-buten-1-yl}phthalimide, which was then reacted with hydrazine hydrate. Yield: 85.7%. Hydrochloride mp: 127-129° C. 1HNMR (ppm, CDCl3) δ: 1.56 (br-s, 4H), 2.23 (s, 3H), 2.71 (br-s, 2H, NH2), 2.96 (m, 4H), 3.12 (d, J=7.0 Hz), 3.41 (d, J=6.72 Hz, 2H), 5.60 (m, 1H), 5.73 (m, 1H), 6.96 (m, 2H), 7.08 (d, J=7.84, 1H).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][C:9]([O:10][C:11]3[CH:12]=[C:13]4[C:18](=[CH:19][CH:20]=3)[C:17]([NH2:21])=[CH:16][CH:15]=[CH:14]4)=[C:4]2[CH:3]=[N:2]1.[Cl:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([NH:21][C:17]2[C:18]3[C:13](=[CH:12][C:11]([O:10][C:9]4[CH:8]=[CH:7][N:6]=[C:5]5[NH:1][N:2]=[CH:3][C:4]=45)=[CH:20][CH:19]=3)[CH:14]=[CH:15][CH:16]=2)=[O:28])=[CH:25][CH:24]=1
Reactant: Nc1cccc2cc(Oc3ccnc4[nH]ncc34)ccc12
Reactant: O=C(O)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cccc2cc(Oc3ccnc4[nH]ncc34)ccc12)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
6-(1H-Pyrazolo[3,4-b]pyridin-4-yloxy)naphthalen-1-amine (25 mg, 0.09 mmol), 4-chlorobenzoic acid (16 mg, 0.10 mmol) and TBTU (35 mg, 0.108 mmol) were dissolved in DMF (0.75 mL). Hunig's base (18 mg, 0.14 mmol) was then added and the reaction mixture was stirred at RT for 16 h. Additional 4-chlorobenzoic acid (6 mg, 0.036 mmol) and TBTU (12 mg, 0.036 mmol) were added to the reaction and stirring was continued for 3 days. The reaction mixture was concentrated in vacuo. The remaining dark brown residue was purified by silica gel chromatography (0% to 2% MeOH in DCM) to yield 4-chloro-N-(6-(1H-pyrazolo[3,4-b]pyridin-4-yloxy)-1-naphthalenyl)benzamide as an off-white solid. MS (ESI, pos. ion) m/z: 415.0 (M+1). MS (ESI pos. ion) m/z: 415.0 (M+H). Calc'd for C23H15ClN4O2−414.85.
Reaction SMILES: [NH2:1][C:2]1[C:7](C(O)=O)=[CH:6][C:5]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[CH:4][N:3]=1>[Cu].N1C2C(=CC=CC=2)C=CC=1>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[N:3][CH:4]=2)=[CH:12][CH:13]=1
Reactant: Nc1ncc(-c2ccc(Cl)cc2)cc1C(=O)O
Agent: [Cu]
Solvent: c1ccc2ncccc2c1
Product: Nc1ccc(-c2ccc(Cl)cc2)cn1
Temperature: 230 °C

Procedure:
2-Amino-5-(4-chlorophenyl)-3-pyridinecarboxylic acid (1.0 gram), copper powder (0.2 gram), and 10 ml quinoline were heated in an oil bath at 205° C. After 21/2 hours, the temperature was raised to 230° C. for an additional hour. A solid precipitate formed which was collected and then washed with ethyl acetate. The solution was then stripped and the residue chromatographed on 300 ml of silica gel. The gum-like solid was applied to the top of the column with ether and then eluted with additional ether until all the quinoline was removed. Elution with ethyl acetate very slowly produced a brown solid which was recrystallized from methanol-water giving tan plate-like crystals, yield 400 mg, m.p. 122°-124° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17]CC3C=CC=CC=3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C(O)C.[H][H]>[Pd].O1CCOCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][OH:17])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: [H][H]
Reactant: COc1ccc(-c2ccc(CCOCc3ccccc3)cc2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: C1COCCO1
Product: COc1ccc(-c2ccc(CCO)cc2)cc1
Yield: 92 %

Procedure:
2,59 g (7.85 mol) of 2-{4-(4-methoxyphenyl) phenyl}ethylbenzylether, 0.4 g of 5% palladium activated carbon, 70 ml of ethanol and 6 ml of dioxane were injected and stirred at room temperature for 7 hours under presence of hydrogen. After the reactions had been completed, the catalyst was removed by tuck filtration and the solvent was removed by filtration so that 1.64 g of 2-{4-(4-methoxyphenyl) phenyl}ethanol was obtained (yield 92%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)([C:10]2[NH:11][CH:12]=[CH:13][N:14]=2)[OH:9])=[CH:4][CH:3]=1.[C:22]1(C(O)=C([N+]([O-])=O)C=C([N+]([O-])=O)C=1)[N+]([O-])=O.[I-].[K+].[OH-].[Na+].CI>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)([C:10]2[N:14]([CH3:22])[CH:13]=[CH:12][N:11]=2)[OH:9])=[CH:6][CH:7]=1
Reactant: OC(c1ccc(Cl)cc1)(c1ccc(Cl)cc1)c1ncc[nH]1
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(O)c([N+](=O)[O-])c1
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CC#N
Solvent: CI
Product: Cn1ccnc1C(O)(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reaction time: 1 h

Procedure:
To a suspension of 9.6 g (0.030 mol) of α,α-bis(p-chlorophenyl)imidazole-2-methanol (prepared according to Example III) in 100 ml. of acetonitrile, 500 mg of picric acid, 300 mg of potassium iodide and 1.45 g (0.036 mol) of sodium hydroxide were added at 60° C. The reaction mixture was stirred for one hour and then 4.7 g (0.033 mol) of methyl iodide in 25 ml. of acetonitrile were added dropwise at 55° C. The mixture was refluxed for four hours, the solvent was distilled off and the residue was extracted with a mixture of water and diethyl ether. The solid matter was filtered off and the ethereal phase was dried over sodium sulphate and concentrated. Diethyl ether was added to the residue and the solid matter was filtered off. The two portions of solid material were combined and twice crystallised from isopropyl alcohol and twice from toluene and rewashed with petroleum ether (boiling range 60°-80° C.). α,α-Bis(p-chlorophenyl)-1-methylimidazole-2-methanol was obtained. Melting point 190°-191° C.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[F:7][C:8]1[CH:13]=[C:12](B(O)O)[CH:11]=[CH:10][N:9]=1.[Br:17][C:18]1[CH:31]=[CH:30][C:29]2[O:28][C:27]3[C:22](=[CH:23][C:24](I)=[CH:25][CH:26]=3)[C@@:21]3([N:37]=[C:36]([NH2:38])[CH2:35][O:34][CH2:33]3)[C:20]=2[CH:19]=1>COCCOC.O.[Cl-].[Na+].O.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>[Br:17][C:18]1[CH:31]=[CH:30][C:29]2[O:28][C:27]3[C:22](=[CH:23][C:24]([C:12]4[CH:11]=[CH:10][N:9]=[C:8]([F:7])[CH:13]=4)=[CH:25][CH:26]=3)[C@@:21]3([N:37]=[C:36]([NH2:38])[CH2:35][O:34][CH2:33]3)[C:20]=2[CH:19]=1
Reactant: NC1=N[C@@]2(COC1)c1cc(Br)ccc1Oc1ccc(I)cc12
Reactant: OB(O)c1ccnc(F)c1
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: [Cl-]
Solvent: COCCOC
Solvent: O
Product: NC1=N[C@@]2(COC1)c1cc(Br)ccc1Oc1ccc(-c3ccnc(F)c3)cc12
Temperature: 80 °C
Reaction time: 6 h

Procedure:
In a microwave vial, sodium carbonate (0.094 g, 0.885 mmol), 2-fluoropyridin-4-ylboronic acid (0.048 g, 0.339 mmol), Pd(PPh3)4 (0.034 g, 0.030 mmol), and (S)-2′-bromo-7′-iodo-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthen]-5-amine (0.139 g, 0.295 mmol) were suspended in DME (2.5 mL) and water (0.5 mL). Argon gas was blown through the vessel which was sealed and heated in an 80° C. oil bath. After 6 h, the reaction mixture was diluted with brine (10 mL) and the aqueous phase was extracted with 7.5% MeOH-dcm (3×25 mL). The organics were combined, washed with dilute brine (5 mL), dried over sodium sulfate and concentrated. The material was purified through silica gel (33 mL) using 3.5 to 4.5 to 7% MeOH-DCM to afford (R)-2′-bromo-7′-(2-fluoropyridin-4-yl)-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthen]-5-amine
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][OH:6])=[NH:4].[CH3:7][C:8]([CH3:14])([CH3:13])[CH2:9][C:10](Cl)=O.C(N(CC)CC)C.[Cl-].[Na+]>CN(C)C=O>[Cl:1][CH2:2][C:3]1[N:4]=[C:10]([CH2:9][C:8]([CH3:14])([CH3:13])[CH3:7])[O:6][N:5]=1
Reactant: CC(C)(C)CC(=O)Cl
Reactant: N=C(CCl)NO
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)Cc1nc(CCl)no1
Temperature: 130 °C
Reaction time: 5 h
Yield: 8.1 %

Procedure:
2.0 g of 2-chloro-N-hydroxyacetoamidine and 2.6 g of 3,3-dimethylbutyryl chloride were dissolved in 30 ml of N,N-dimethylformamide, and 2.05 g of triethylamine was added dropwise under ice-cooling. After completion of the addition, the mixture was stirred at 130° C. for 5 hours and then cooled to room temperature. After aqueous saturated sodium chloride was added, the reaction mixture was extracted with methyl-t-butyl ether. The organic layer was washed with aqueous saturated sodium chloride, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.28 g of 3-(chloromethyl)-5-(2,2-dimethylpropyl)-1,2,4-oxadiazole.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:16])[C:7]([C:13]([OH:15])=[O:14])=[CH:8][N:9]2[CH3:12])=[CH:4][C:3]=1[F:17].[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.CS(C)=O>O>[F:17][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[N:22]1[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]1)[N:9]([CH3:12])[CH:8]=[C:7]([C:13]([OH:15])=[O:14])[C:6]2=[O:16]
Reactant: Cn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)cc21
Reactant: CN1CCNCC1
Solvent: O
Solvent: CS(C)=O
Product: CN1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C)CC1
Yield: 40.7 %

Procedure:
2.55 g (0.01 mol) of 7-chloro-6-fluoro-1-methyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid, 4.5 cm3 of 1-methylpiperazine (0.011 mol) and 32 cm3 of DMSO were heated at 110° C. for 4 hours. After cooling, the mixture was taken up in 150 cm3 of water. The crystalline precipitate was filtered off, washed and recrystallised from 100 cm3 of methylcellosolve. 1.3 g of 6-fluoro-1-methyl-7-(4-methylpiperazinyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, m.p. 304° C. (decomposition), were obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[NH2:8][C:9]1[C:10]([C:16](OC)=[O:17])=[N:11][C:12]([Br:15])=[CH:13][N:14]=1.N12CCCN=C1CCCCC2>O>[NH2:8][C:9]1[C:10]([C:16]([NH:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)=[O:17])=[N:11][C:12]([Br:15])=[CH:13][N:14]=1
Reactant: COC(=O)c1nc(Br)cnc1N
Reactant: Nc1cccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: Nc1ncc(Br)nc1C(=O)Nc1cccnc1
Reaction time: 4 h
Yield: 59.3 %

Procedure:
To 3-aminopyridine (10 g, 106 mmol) at 70° C. were added methyl 3-amino-6-bromo-2-pyrazinecarboxylate (1.0 g, 4.3 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (645 μL, 4.3 mmol). The reaction solution was stirred for 4 h, diluted with water (75 mL) and extracted with methylene chloride. The combined organic layers were washed with a saturated ammonium chloride solution, dried (MgSO4), filtered and evaporated in vacuo. The crude product was purified on a silica gel column using methylene chloride/ethanol, (9:1), as the eluent to give 750 mg (59% yield) of the title compound as a yellow solid: 1H NMR (CDCl3, 400 MHz) δ 9.50 (br s, 1H), 8.82 (d, J=3 Hz, 1H), 8.43 (dd, J=5 and 1 Hz, 1H), 8.31 (s, 1H), 8.23 (ddd, J=8, 3 and 2 Hz, 1H), 7.34 (dd, J=8, 5 Hz, 1H); MS (TSP) m/z 294 (M++1).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:18]=[C:17]3[C:12]([CH2:13][CH2:14][CH2:15][NH:16]3)=[CH:11][CH:10]=2)O1.[CH2:20]([O:27][C:28]1[C:29]([C:35]([O:37][CH3:38])=[O:36])=[N:30][C:31](Br)=[CH:32][CH:33]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH2:20]([O:27][C:28]1[C:29]([C:35]([O:37][CH3:38])=[O:36])=[N:30][C:31]([C:9]2[CH:18]=[C:17]3[C:12]([CH2:13][CH2:14][CH2:15][NH:16]3)=[CH:11][CH:10]=2)=[CH:32][CH:33]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC1(C)OB(c2ccc3c(c2)NCCC3)OC1(C)C
Reactant: COC(=O)c1nc(Br)ccc1OCc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1nc(-c2ccc3c(c2)NCCC3)ccc1OCc1ccccc1
Temperature: 90 °C

Procedure:
To 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroquinoline (27B) (1.16 g, 4.48 mmol), methyl 3-(benzyloxy)-6-bromopicolinate (29A) (1.44 g, 4.48 mmol), K2CO3 (1.546 g, 11.2 mmol), tetrabutylammonium bromide (0.144 g, 0.45 mmol), and dichlorobis(triphenylphosphine)palladium(II) (126 mg, 0.18 mmol) was added 1,4-dioxane (30 mL) and water (15 mL). The reaction mixture was heated to 90° C. for 1.5 hours, cooled to rt, concentrated, diluted with EtOAc, washed sequentially with water, brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was precipitated from EtOAc/PE to provide the product methyl 3-(benzyloxy)-6-(1,2,3,4-tetrahydroquinolin-7-yl)picolinate (29B). Additional material was isolated from the filtrate by column chromatography on silica gel eluting with a gradient of PE:EtOAc 73:27-63:37, to provide the desired product (29B): 1H NMR (300 MHz, CDCl3) δ7.67 (1H, d), 7.48-7.44 (2H, m), 7.43-7.31 (4H, m), 7.21 (1H, d), 7.16 (1H, dd), 7.01 (1H, d) 5.21 (2H, s), 3.98 (3H, s), 3.34 (2H, m), 2.79 (2H, t), 1.96 (2H, m).