Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B1(B2C3CCCC2CCC3)C2CCCC1CCC2.[NH2:19][C:20]1[C:21]2[C:28]([C:29]3[CH:30]=[N:31][C:32]4[C:37]([CH:38]=3)=[CH:36][CH:35]=[CH:34][CH:33]=4)=[C:27](Br)[N:26]([CH2:40][C@@H:41]([NH:44][C:45](=[O:51])[O:46][C:47]([CH3:50])([CH3:49])[CH3:48])[CH:42]=[CH2:43])[C:22]=2[N:23]=[CH:24][N:25]=1.[OH-].[Na+]>O1CCCC1>[NH2:19][C:20]1[C:21]2[C:28]([C:29]3[CH:30]=[N:31][C:32]4[C:37]([CH:38]=3)=[CH:36][CH:35]=[CH:34][CH:33]=4)=[C:27]3[N:26]([C:22]=2[N:23]=[CH:24][N:25]=1)[CH2:40][C@@H:41]([NH:44][C:45](=[O:51])[O:46][C:47]([CH3:50])([CH3:49])[CH3:48])[CH2:42][CH2:43]3
Reactant: C=C[C@@H](Cn1c(Br)c(-c2cnc3ccccc3c2)c2c(N)ncnc21)NC(=O)OC(C)(C)C
Agent: C1CC2CCCC(C1)B2B1C2CCCC1CCC2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CCc2c(-c3cnc4ccccc4c3)c3c(N)ncnc3n2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.1 %

Procedure:
9-Borabicyclo[3.3.1]nonane dimer (0.431 g) was added to a solution of (S)-tert-butyl (1-(4-amino-6-bromo-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)but-3-en-2-yl)carbamate (0.3 g) obtained in Reference Example 1 in tetrahydrofuran (4.5 ml) under a nitrogen atmosphere at room temperature, and the mixture was stirred at room temperature for 2 hours. A 4 N sodium hydroxide aqueous solution (2.12 ml) was slowly added to the reaction mixture at room temperature, and degassed under reduced pressure. Under a nitrogen atmosphere, (tetrakistriphenylphosphine)palladium(0) (0.136 g) was added to the resulting mixture, and stirred at 64° C. for 12 hours. After the reaction mixture was cooled, and diluted with ethyl acetate, a saturated ammonium chloride aqueous solution was added thereto. After the insoluble matter resulting in this stage was removed by filtration, the organic layer was separated. The resulting organic layer was dried over anhydrous sodium sulfate, then filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (developing solvent: ethyl acetate/methanol) to obtain (S)-tert-butyl (4-amino-5-(quinolin-3-yl)-6,7,8,9-tetrahydropyrimido[5,4-b]indolizin-8-yl)carbamate (203 mg) (yield: 80%) as a light-yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[N:10][CH:9]=[C:8](Cl)[N:7]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:13]([Sn](CCCC)(CCCC)C=C)[CH2:14]CC.C(OCC)(=O)C>CN(C)C=O.[Cl-].[Na+].O.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>[C:1]([O:5][C:6]1[CH:11]=[N:10][CH:9]=[C:8]([CH:13]=[CH2:14])[N:7]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CC(C)(C)Oc1cncc(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: C=Cc1cncc(OC(C)(C)C)n1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 84.6 %

Procedure:
After dissolving 5.25 g of 2-tert-butoxy-6-chloropyrazine in 80 ml of N,N-dimethylformamide, 9.66 g of tributyl(vinyl)tin and 0.97 g of dichlorobis(triphenylphosphine)palladium(II) were added and the mixture was stirred for 8 hours and 30 minutes at 80° C. under a nitrogen atmosphere. Saturated brine and ethyl acetate were added to the reaction solution, and the insoluble portion was filtered off. The ethyl acetate layer was washed with water and saturated brine in that order and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain the title compound (4.24 g, 85% yield).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([F:24])([F:23])[F:22])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:25]>O1CCOCC1>[ClH:25].[ClH:25].[NH:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([F:22])([F:23])[F:24])[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccccc2C(F)(F)F)CC1
Agent: Cl
Solvent: C1COCCO1
Product: FC(F)(F)c1ccccc1NC1CCNCC1
Reaction time: 0.25 h
Yield: 41 %

Procedure:
To a stirred solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (0.20 g, 0.0001 mole) in dry 1,2-dichloroethane (7 mL) under an atmosphere of nitrogen for 10 minutes, was added 2-trifluoromethylaniline (0.161 g, 0.0001 mole), acetic acid (0.06 g, 0.0001 mole) and sodium triacetoxyborohydride (1.05 g, 0.0005 mole). The stirring was continued at ambient temperature for 14 hours. The reaction mixture was then quenched in cold aqueous 1N NaOH solution and the product extracted with ether. The ether layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to get the crude product as transparent viscous liquid. Purification by column chromatography using silica gel 60-120 mesh (2% ethyl acetate in hexane) afforded 0.106 g (31%) of 4-(2-trifluoromethyl-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester. 1H NMR (DMSO-d6): δ 7.4 (t, 2H), 7.0 (d, 1H), 6.7 (t, 1H), 3.9 (m, 2H), 2.9 (m, 2H), 1.9 (m, 2H), 1.4 (s, 9H). To a solution of 4-(2-trifluoromethyl-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (0.106 g, 0.000307 mole) in dioxane (0.5 mL) which was cooled to 0° C., was added, dioxane.HCl (2.5 mL) and the mixture was stirred at the same temperature for 10 minutes. The reaction mixture was gradually brought to ambient temperature and stirring was continued for 15 minutes. The reaction mixture was evaporated under reduced pressure and the resulting residue was washed with dry ether to afford 0.04 g (41%) of piperidin-4-yl-(2-trifluoromethyl-phenyl)-amine dihydrochloride. 1H NMR (DMSO-d6): δ 7.41 (t, 2H), 7.0 (d, 2H), 6.75 (t, 1H), 4.8 (d, 1H), 3.7 (bs, 1H), 3.3 (bs, 1H), 3.0 (m, 2H), 2.1 (m, 2H), 1.7 (m, 2H).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[CH3:27][C:28]1[CH:38]=[CH:37][C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:30][C:29]=1[C:39]([F:42])([F:41])[F:40]>C(Cl)(Cl)(Cl)Cl.ClCCl>[Br:1][CH2:27][C:28]1[CH:38]=[CH:37][C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:30][C:29]=1[C:39]([F:41])([F:40])[F:42]
Reactant: CCOC(=O)c1ccc(C)c(C(F)(F)F)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)c1ccc(CBr)c(C(F)(F)F)c1
Temperature: 25 °C
Yield: 42.3 %

Procedure:
N-Bromosuccinimide (1.04 g, 5.83 mmol) and benzoyl peroxide (0.12 g, 0.49 mmol) were added to a solution of ethyl 4-methyl-3-(trifluoromethyl)benzoate (1.06 g, 4.56 mmol) in carbon tetrachloride (25 mL). The reaction mixture was heated at reflux overnight. After it was cooled to room temperature, it was diluted with dichloromethane (50 mL), and washed with water (20 mL). The aqueous layer was extracted with dichloromethane (20 mL). It was dried over Na2SO4 and concentrated. It was purified by prep-TLC (Hexanes:ethyl acetate=10:1) to give the product as an oil (0.60 g, 44%) 1H NMR (400 MHz, DMSO-d6) δ 8.31 (d, J=1.6 Hz, 1H), 8.20 (dd, J=4.8, 1.6 Hz, 1H), 7.68 (d, J=8.0 Hz, 1H), 4.64 (s, 1H), 4.40 (q, J=7.2 Hz, 2H), 1.40 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]([C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:5]O.CCCCCC.C1(C)C=CC=CC=1.O>P(OP(O)(O)=O)(O)(O)=O>[CH3:1][O:2][C:3]([C:4]1[C:7]2[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=2[O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH:5]=1)=[O:21]
Reactant: COC(=O)C(=CO)c1cc(Cl)ccc1Oc1ccccc1
Agent: O=P(O)(O)OP(=O)(O)O
Solvent: O
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: COC(=O)C1=Cc2ccccc2Oc2ccc(Cl)cc21
Temperature: 20 °C
Reaction time: 2 h
Yield: 86.8 %

Procedure:
A slurry of 2-(5-chloro-2-phenoxy-phenyl)-3-hydroxy-acrylic acid methyl ester (210 g, 691 mmol) was heated in pyrophosphoric acid (420 g) to 60° C. After two hours, the reaction was cooled to 20° C. and hexane (250 mL), toluene (500 mL), and water (500 mL) were added to quench the reaction. The organic layer was separated and washed with saturated aqueous sodium bicarbonate (500 mL) and saturated brine (500 mL). The organic fraction was concentrated and the resulting oil was crystallized from n-butanol (500 mL; 20° C. for one hour and −10° C. for two hours), which provided the titled compound as off-white crystals (172 g, 85% yield for steps A and B). 1H NMR (400 MHz, CDCl3) 3.9 (s, 3H), 7.1-7.2 (m, 3H), 7.3 (m, 2H), 7.4 (t, 1H), 7.6 (d, 1H), 8.0 (s, 1H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[CH:9]([CH3:12])[S:8][CH2:7]1.Cl.[S:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[C:16]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[N:15]1.C([O-])([O-])=O.[K+].[K+].[Na+].[I-]>C(#N)C>[S:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[C:16]([N:23]2[CH2:24][CH2:25][N:26]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:10](=[O:11])[CH:9]([CH3:12])[S:8][CH2:7]3)[CH2:27][CH2:28]2)=[N:15]1
Reactant: CC1SCN(CCCCBr)C1=O
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC#N
Product: CC1SCN(CCCCN2CCN(c3nsc4ccccc34)CC2)C1=O
Yield: 58.8 %

Procedure:
A mixture of 3-(4-bromobutyl)-5-methyl-4-thiazolidinone (4.00 g), 1-(1,2-benzisothiazol-3-yl)piperazine hydrochoride (4.46 g), K2CO3 (8.00 g) and NaI (300 mg) in acetonitrile (210 ml) was heated at 40°-45° C. for 64 hours and the product was processed in substantially the same manner as in Example 10 to afford 3.64 g of crystals, m.p. 113°-115° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[C:9]([C:11]1[CH:12]=[CH:13][C:14]([O:24][CH3:25])=[C:15]([NH:17][C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH:16]=1)#[CH:10]>C1COCC1.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.[Cu]I>[Cl:1][C:2]1[N:7]=[C:6]([C:10]#[C:9][C:11]2[CH:12]=[CH:13][C:14]([O:24][CH3:25])=[C:15]([NH:17][C:18](=[O:23])[C:19]([F:20])([F:21])[F:22])[CH:16]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: C#Cc1ccc(OC)c(NC(=O)C(F)(F)F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Product: COc1ccc(C#Cc2ccnc(Cl)n2)cc1NC(=O)C(F)(F)F
Yield: 83.1 %

Procedure:
To an oven-dried flask under N2 was added 2,4-dichloropyrimidine (860 mg, 5.76 mmol), anhydrous degassed THF (100 mL), dichlorobis(triphenylphosphine)-palladium(II) (81 mg, 0.12 mmol), copper(I) iodide (13 mg, 0.07 mmol), and TEA (1.26 g, 0.013 mol). After heating the reaction at 60° C. for 30 min, N-[5-ethynyl-2-(methyloxy)phenyl]-2,2,2-trifluoroacetamide (560 mg, 2.30 mmol) was added dropwise as a solution in THF (10 mL) and the resulting mixture was allowed to heat overnight. The crude reaction mixture was adsorbed to silica gel and purified by column chromatography (0-10% EtOAc in hexanes) to afford the desired product (0.68 g, 42%) as an off white solid. ES-LC/MS m/z=356 [M+H]+.
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[N+:9]([C:12]1[C:20]([O:21][CH3:22])=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=[O:15])([O-])=O.[OH-].[NH4+]>O>[NH2:9][C:12]1[C:20]([O:21][CH3:22])=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=[O:15]
Reactant: COc1cccc(C(=O)O)c1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Product: COc1cccc(C(=O)O)c1N
Reaction time: 3 h

Procedure:
Sodium dithionite (84 g, 0.48 m) in water (100 ml) was added to 2-nitro-3-methoxybenzoic acid (20 g, 0.10 m) in water (100 ml)/concentrated ammonium hydroxide solution (6 ml). After stirring 3 hours the product was filtered. Acidification of the filtrate, saturation with sodium chloride and extraction with ether provided a small second crop of product.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[S:9]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][OH:16])=[CH:10]1.C(Cl)Cl.O>CC(O)=O>[Br:8][C:10]1[S:9][CH:13]=[CH:12][C:11]=1[CH2:14][CH2:15][OH:16]
Reactant: OCCc1ccsc1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: ClCCl
Solvent: CC(=O)O
Product: OCCc1ccsc1Br
Temperature: 40 °C
Reaction time: 1 h

Procedure:
NBS (9.53 g, 53.6 mmol) was added portionwise to a solution of 3-thiopheneethanol 6.87 g, 53.6 mmol) in AcOH (30 ml). The temperature was raised to 40° C. and mixture was stirred for 1 h. DCM (400 ml) and water was added. The organic layer was washed with water and sat. NaHCO3. The organic layer evaporated and residue purified by flash chromatography using 25-33% EtOAc in iso-hexane. Yield: 5.39 g (49%); colourless oil. 1H NMR (400 MHz, CDCl3): δ 2.89 (t, J 6.4 Hz, 2H), 3.85 (t, J 6.4 Hz, 2H), 6.89 (d, J 5.6 Hz, 1H), 7.26 (d, J 5.6 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[F:9].[CH3:10][NH:11][CH2:12][CH2:13][NH:14][CH3:15].O(C(C)(C)C)[Na]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[F:9][C:3]1[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[N:11]([CH3:10])[CH2:12][CH2:13][NH:14][CH3:15]
Reactant: Fc1ccc(Br)c(F)c1
Reactant: CNCCNC
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CNCCN(C)c1ccc(F)cc1F

Procedure:
Combine 1-bromo-2,4-difluorobenzene (1.00 g, 5.18 mmol), N,N′-dimethyl-ethylenediamine (2.74 g, 31.1 mmol), NaO-t-Bu (0.70 g, 7.2 mmol), Pd(dba)2 (0.060 g, 0.10 mmol) and (±)-BINAP (0.19 g, 0.31 mmol) in toluene (10 ml). Heat at 110° for 18 h, allow to cool, and extract with 1N HCl. Basify the aqueous solution with NaOH and extract with CH2Cl2. Dry, concentrate, and purify by PLC to give N-(2,4-difluoro-phenyl)-N,N′-dimethylethylenediamine.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[NH2:14][CH2:15][CH2:16][OH:17]>CO>[OH:17][CH2:16][CH2:15][NH:14][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: NC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: NCCO
Solvent: CO
Product: NC(=O)c1ccc(NCCO)c([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
Add 6.0 g (0.03 moles) 4-chloro-3-nitrobenzamide to 60 ml 2-aminoethanol and stir at ambient temperature. When TLC (silica support; 9:1 CHCL3 :MeOH eluent) shows no starting material, ca. 3 hrs., pour onto ice. Filter, wash (3×15 ml) with cold H2O, and recrystallize from MeOH/IPA. Yield is 4.5 g (66%) of orange crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1B(O)O>>[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: OB(O)c1ccccc1F
Reactant: Brc1cccnc1
Product: Fc1ccccc1-c1cccnc1

Procedure:
3-Bromopyridine and 2-fluorobenzeneboronic acid were coupled using the procedure described in Example 31 to afford 3-(2-fluorophenyl)pyridine as a pale yellow oil which crystallised on standing: δH (360 MHz, DMSO) 7.33-7.40 (2H, m), 7.46-7.55 (2H, m), 7.61 (1H, ddd, J 8, 8 and 2), 7.96-8.01 (1H, m), 8.61 (1H, dd, J 5 and 2), 8.77 (1H, s).
Reaction SMILES: [Sn](Cl)Cl.[Cl:4][C:5]1[N:10]=[C:9]([N+:11]([O-])=O)[C:8]([NH2:14])=[CH:7][CH:6]=1.[OH-].[Na+]>Cl>[Cl:4][C:5]1[N:10]=[C:9]([NH2:11])[C:8]([NH2:14])=[CH:7][CH:6]=1
Reactant: Nc1ccc(Cl)nc1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Product: Nc1ccc(Cl)nc1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.5 %

Procedure:
A solution of tin (II) chloride (21.8 g) in concentrated hydrochloric acid (30 ml) was added, with cooling, to 6-chloro-3-amino-2-nitropyridine (5 g) and the suspension stirred for 3 hours at room temperature. The pH was adjusted to pH12 (40% NaOH) and the solvent removed in vacuo. The residue was purified by flash column chromatography, eluting with System C (100:8:1), to afford the title compound as a yellow solid (3.29 g).
Reaction SMILES: [CH2:1]([C:4]1[C:17]2[CH2:16][C:15]3[C:10](=[C:11]([CH2:27][CH2:28][CH3:29])[C:12]([CH2:24][CH2:25][CH3:26])=[C:13]([CH2:21][CH2:22][CH3:23])[C:14]=3[CH2:18][CH2:19][CH3:20])[CH2:9][C:8]=2[C:7]([CH2:30][CH2:31][CH3:32])=[C:6]([CH2:33][CH2:34][CH3:35])[C:5]=1[CH2:36][CH2:37][CH3:38])[CH2:2][CH3:3]>C1C=CC=CC=1>[CH2:30]([C:7]1[C:8]2[C:17](=[CH:16][C:15]3[C:10]([CH:9]=2)=[C:11]([CH2:27][CH2:28][CH3:29])[C:12]([CH2:24][CH2:25][CH3:26])=[C:13]([CH2:21][CH2:22][CH3:23])[C:14]=3[CH2:18][CH2:19][CH3:20])[C:4]([CH2:1][CH2:2][CH3:3])=[C:5]([CH2:36][CH2:37][CH3:38])[C:6]=1[CH2:33][CH2:34][CH3:35])[CH2:31][CH3:32]
Reactant: CCCc1c(CCC)c(CCC)c2c(c1CCC)Cc1c(CCC)c(CCC)c(CCC)c(CCC)c1C2
Solvent: c1ccccc1
Product: CCCc1c(CCC)c(CCC)c2cc3c(CCC)c(CCC)c(CCC)c(CCC)c3cc2c1CCC
Yield: 79.6 %

Procedure:
After 2,3-dichloro-5,6-dicyanoquinone (0.100 g, 0.440 mmol) was added to a solution of 1,2,3,4,5,6,7,8-octapropyl-9,10-dihydroanthracene (0.208 g, 0.400 mmol) in benzene (5 ml), the mixture was refluxed for an hour with heating. The reaction mixture was filtered to remove hydroquinone and purified by silica gel column chromatography (ethyl acetate/hexane, 99/1) to give the title compound (0.164 g) as a white solid. The isolation yield was 79%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19]([CH3:23])[N:18]=[CH:17]4)(O)[CH3:12])=[CH:9][N:10]=2)[N:7]=1.II.O[PH2]=O.ClC1C=CC2N(C(CC3C=C4C(=CC=3)N(C)N=C4)=CN=2)N=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19]([CH3:23])[N:18]=[CH:17]4)[CH3:12])=[CH:9][N:10]=2)[N:7]=1
Reactant: Cn1ncc2cc(C(C)(O)c3cnc4ccc(Cl)nn34)ccc21
Agent: Cn1ncc2cc(Cc3cnc4ccc(Cl)nn34)ccc21
Agent: II
Agent: O=[PH2]O
Product: CC(c1ccc2c(cnn2C)c1)c1cnc2ccc(Cl)nn12
Yield: 95.5 %

Procedure:
The title compound (390.0 mg, 91%) was synthesized from 1-(6-chloro-imidazo[1,2-b]pyridazin-3-yl)-1-(1-methyl-1H-indazol-5-yl)-ethanol (430.0 mg, 1.31 mmol), I2(832.0 mg, 3.28 mmol) and H3PO2(0.72 mL, 6.56 mmol) using the same procedure as described in the synthesis of compound 13.2. 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.18 (d, 1H), 7.95 (s, 1H), 7.83 (s, 1H), 7.55 (m, 2H), 7.36 (d, 1H), 7.28 (d, 1H), 4.70 (q, 1H), 3.99 (s, 3H), 1.74 (d, 3H). LCMS (method A): [MH]+=312, tR=5.49 min.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.CN(C)C=O.[NH:17]1[CH2:22][CH2:21][CH2:20][C@@H:19]([C:23]([OH:25])=[O:24])[CH2:18]1.C(N(C(C)C)CC)(C)C>>[NH2:8][C:6]1[N:7]=[C:2]([N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([C:23]([OH:25])=[O:24])[CH2:18]2)[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: O=C(O)[C@@H]1CCCNC1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(N2CCC[C@@H](C(=O)O)C2)ccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A solution of 6-chloro-3-nitropyridin-2-amine in N,N-dimethylformamide (70 mL, 12.25 mmol, 0.175M) was added to (R)-piperidine-3-carboxylic acid (12.25 mmol) followed by diisopropylethylamine (4.55 mL, 24.5 mmol). The reaction mixture was stirred at 80° C. for 16 h. The solvent was removed under reduced pressure to afford (R)-1-(6-amino-5-nitropyridin-2-yl)piperidine-3-carboxylic acid which was used without further purification.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:21][CH:20]=3)=[C:14]([CH2:33][CH2:34][CH3:35])[N:13]3[N:36]=[CH:37][N:38]=[C:12]23)[CH2:7][CH2:6]1.C(N(CC)CC)C.Cl>CS(C)=O>[O:17]=[C:16]1[C:15]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:21][CH:20]=2)=[C:14]([CH2:33][CH2:34][CH3:35])[N:13]2[N:36]=[CH:37][N:38]=[C:12]2[N:11]1[C@H:8]1[CH2:7][CH2:6][C@H:5]([O:4][CH2:3][CH:2]=[O:1])[CH2:10][CH2:9]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCCO)CC2)c2ncnn12
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC=O)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a mixture of 4′-({4-[trans-4-(2-hydroxyethoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (1.3 g), triethylamine (1.8 mL) and dimethyl sulfoxide (8 mL) was added dropwise a solution of sulfur trioxide-pyridine complex (1.2 g) in dimethyl sulfoxide (7 mL), and the mixture was stirred at room temperature for 1.5 hr. A solution of triethylamine (1.8 mL) and sulfur trioxide-pyridine complex (1.2 g) in dimethyl sulfoxide (5 mL) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was added to 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.31 g, 23%).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:17][NH2:18]>C1(C)C=CC=CC=1>[CH3:17][NH:18][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: CN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CNc1ncccc1[N+](=O)[O-]

Procedure:
A procedure similar to that described in Preparation 66 was repeated, except that 24.9 g of 2-chloro-3-nitropyridine, 41.7 g of sodium carbonate, 22.7 ml of a 30% ethanolic solution of methylamine were reacted in 250 ml of toluene. After working up the product as described in preparation 66, the resulting crude product was crystallized by trituration with isopropanol, to give 24.0 g of the title compound, melting at 52°-53° C.
Reaction SMILES: ClP([N:5]=[C:6]=[O:7])(Cl)=O.[O:8]1[CH:12]=[CH:11][CH:10]=[C:9]1/[C:13](=[N:31]/[O:32][CH3:33])/[C:14]([NH:16][C@@H:17]1[C:29](=[O:30])[N:19]2[C:20]([C:26]([OH:28])=[O:27])=[C:21]([CH2:24][OH:25])[CH2:22][S:23][C@H:18]12)=[O:15]>CC(C)=O>[CH3:33][O:32]/[N:31]=[C:13](\[C:14]([NH:16][C@@H:17]1[C:29](=[O:30])[N:19]2[C:20]([C:26]([OH:28])=[O:27])=[C:21]([CH2:24][O:25][C:6]([NH2:5])=[O:7])[CH2:22][S:23][C@H:18]12)=[O:15])/[C:9]1[O:8][CH:12]=[CH:11][CH:10]=1
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CO)CS[C@H]12)c1ccco1
Reactant: O=C=NP(=O)(Cl)Cl
Solvent: CC(C)=O
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(N)=O)CS[C@H]12)c1ccco1
Reaction time: 8 h
Yield: 56.7 %

Procedure:
The process of Example 3 was repeated, using dichlorophosphinyl isocyanate (1.46 ml) and a solution of (6R,7R)-7-[Z-2-(fur-2-yl)-2-methoxyiminoacetamido]-3hydroxymethylceph-3-em-4-carboxylic acid (3.81 g) in acetone (50 ml) cooled to 4°, but the reaction mixture was heated at 45° for 2 hours and then kept at 20° overnight, to give the title compound (2.40 g, 56.7%); purity by HPLC 95.6% and by TLC 94.5%.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][C@@H:13]1[CH2:17][C:16](=[O:18])[CH2:15][C@H:14]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CCN(C(C)C)C(C)C.Cl>C(Cl)Cl>[O:18]=[C:16]1[CH2:17][C@@H:13]([CH:12]=[O:11])[C@H:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:15]1
Reactant: O=C1C[C@@H](CO)[C@H](c2ccccc2)C1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C[C@@H]1CC(=O)C[C@H]1c1ccccc1
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 90.9 %

Procedure:
To a solution of oxalyl chloride (1.15 mL, 13.1 mmol) in methylene chloride (30 mL) at −70° C. was added dropwise DMSO (1.87 mL, 26.3 mmol). After 15 min, a solution of (+−)-trans-1-hydroxymethyl-4oxo-2-phenylcyclopentane from Step C (1.0 g, 5.26 mmol) in methylene chloride (10 mL) was added. The reaction was stirred at −70° C. for 1.5 h and then DIPEA (9.25 mL, 53 mmol) in methylene chloride (10 mL) was added dropwise over 5 min. After a further 10 min, the mixture was allowed to warm to rt for 1 h and then diluted with methylene chloride and poured into dilute aq. HCl. The layers were separated. The aq. layer was reextracted with a second portion of methylene chloride and the organic layers were each washed with brine, dried over sodium sulfate, combined and concentrated in vacuo. The residue was purified by FC (30% ethyl acetate in hexanes) to give the title product (0.9 g) after vacuum drying.