Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C@H:10]2[C@@H:16]([OH:17])[C:15](=[O:18])[N:14]([CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])[C:13]3[C:24]([CH3:29])=[C:25]([CH3:28])[CH:26]=[CH:27][C:12]=3[S:11]2)=[CH:6][CH:5]=1.[C:30](OC(=O)C)(=[O:32])[CH3:31]>C(O)(=O)C>[ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([C@H:10]2[C@@H:16]([O:17][C:30](=[O:32])[CH3:31])[C:15](=[O:18])[N:14]([CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])[C:13]3[C:24]([CH3:29])=[C:25]([CH3:28])[CH:26]=[CH:27][C:12]=3[S:11]2)=[CH:8][CH:9]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc([C@@H]2Sc3ccc(C)c(C)c3N(CCN(C)C)C(=O)[C@@H]2O)cc1
Agent: Cl
Solvent: CC(=O)O
Product: COc1ccc([C@@H]2Sc3ccc(C)c(C)c3N(CCN(C)C)C(=O)[C@@H]2OC(C)=O)cc1
Temperature: 105 °C

Procedure:
A mixture of 0.618 g of (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]-6,7-dimethyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride, 6 ml of acetic anhydride and 6 ml of acetic acid is heated at 105° C. for 18 hours. After the reaction is completed, the mixture is evaporated under reduced pressure to remove solvent. Benzene is added to the residue, and the mixture is evaporated under reduced pressure to remove solvent. The residue is recystallized from a mixture of ethanol and ether. 0.44 g of (±)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-(dimethylamino)ethyl]-6,7-dimethyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride 3/2 H2O is obtained.
Reaction SMILES: [CH3:1]COCC.[OH-].[K+].CN(N=O)C(N[N+]([O-])=O)=N.[O:18]([C:25]1[CH:26]=[C:27]([C:31]23[CH2:38][CH2:37][C:34]([CH2:39][CH2:40]/[CH:41]=[CH:42]/[C:43]([O:45][CH3:46])=[O:44])([CH2:35][CH2:36]2)[CH2:33][O:32]3)[CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[O:18]([C:25]1[CH:26]=[C:27]([C:31]23[CH2:36][CH2:35][C:34]([CH2:39][CH2:40][CH:41]4[CH2:1][CH:42]4[C:43]([O:45][CH3:46])=[O:44])([CH2:37][CH2:38]2)[CH2:33][O:32]3)[CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COC(=O)/C=C/CCC12CCC(c3cccc(Oc4ccccc4)c3)(CC1)OC2
Reactant: CCOCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CN(N=O)C(=N)N[N+](=O)[O-]
Solvent: C1CCOC1
Product: COC(=O)C1CC1CCC12CCC(c3cccc(Oc4ccccc4)c3)(CC1)OC2
Temperature: 25 °C
Yield: 63 %

Procedure:
To a vigorously stirred mixed of Et2O (5 mL) and 40% KOH (1 mL) was added N-methyl-N′-nitro-N-nitrosoguanidine (1.00 g, 6.80 mmol) portionwise over 15 min at 0° C. Upon complete addition, stirring was stopped. The organic layer was separated and was dried with KOH pellets. The solution was poured onto a solution of (E)-methyl 5-(1-(3-phenoxyphenyl)-2-oxabicyclo[2.2.2]octan-4-yl)pent-2-enoate (230 mg, 0.586 mmol) in THF (2 mL/mL). Pd(OAc)2 (13.16 mg, 0.059 mmol) was then added and the reaction was allowed to warm to rt and stirred for 1 h. The reaction was concentrated in vacuo and purified by flash chromatography on SiO2 (0 to 30% EtOAc:hexanes) to afford methyl 2-(2-(1-(3-phenoxyphenyl)-2-oxabicyclo[2.2.2]octan-4-yl)ethyl)cyclopropanecarboxylate (149 mg, 63%) as clear oil. A mixture of the above ester (149 mg, 0.367 mmol) and 1 N aqueous NaOH (1.1 mL, 1.10 mmol) in THF (1 mL) was stirred at rt for 18 h and then concentrated in vacuo. The residue was acidified to pH 5 with 1 N aqueous HCl and extracted with EtOAc. The organic layer was washed with brine and concentrated in vacuo. The residue was purified by preparative HPLC (PHENOMENEX® Axia 5μ C18 30×100 mm column; detection at 220 nm; flow rate=40 mL/min; continuous gradient from 30% B to 100% B over 10 min+2 min hold time at 100% B, where A=90:10:0.1 H2O:MeOH:TFA and B=90:10:0.1 MeOH:H2O:TFA) to afford the title compound (110 mg, 73% yield) as a white solid. LCMS, [M−H]+=391.2. 1H NMR (500 MHz, CDCl3) δ 7.36-7.23 (m, 3H), 7.17-7.05 (m, 3H), 6.98 (d, J=7.7 Hz, 2H), 6.83 (dd, J=8.0, 1.7 Hz, 1H), 3.77 (s, 2H), 2.07-1.92 (m, 4H), 1.69-1.55 (m, 4H), 1.44-1.18 (m, 7H), 0.82-0.73 (m, 1H). HPLC-1: RT=12.3 min, purity=100%; HPLC-2: RT=10.2 min, purity=96.3%.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:54]1[CH:59]=[C:58]([N+:60]([O-:62])=[O:61])[CH:57]=[CH:56][C:55]=1[O:63][CH3:64].[CH3:65][C@H:66]1[CH2:71][NH:70][CH2:69][C@@H:68]([CH3:72])[NH:67]1>O1CCCC1.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:65][C@H:66]1[NH:67][C@@H:68]([CH3:72])[CH2:69][N:70]([C:54]2[CH:59]=[C:58]([N+:60]([O-:62])=[O:61])[CH:57]=[CH:56][C:55]=2[O:63][CH3:64])[CH2:71]1
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: COc1ccc([N+](=O)[O-])cc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc([N+](=O)[O-])cc1N1C[C@@H](C)N[C@@H](C)C1
Temperature: 25 °C

Procedure:
Cesium carbonate (9.77 g, 30 mmol), palladium (II) acetate (448 mg, 2 mmol) and rac-2,2′-bis(diphenylphosphino)-1,1′-binapthyl (1.87 g, 3 mmol) were stirred under an inert atmosphere in tetrahydrofuran (40 ml) for 30 minutes. 2-Bromo-4-nitroanisole (4.64 g, 20 mmol) and cis-2,6-dimethylpiperazine (6.85 g, 60 mmol) in tetrahydrofuran (20 ml) was added and the mixture heated at reflux for 24 hours. After cooling to room temperature the reaction mixture was diluted with ethyl acetate and extracted with 2N hydrochloric acid (×3). The aqueous extract was stirred with ethyl acetate and activated charcoal, filtered through celite. The aqueous component of the filtrate was separated and the pH of the solution was adjusted to pH 7 with 50% potassium hydroxide solution and the solution evaporated in vacuo to a small volume. The residue was basified to pH 10 with 50% potassium hydroxide solution and extracted with dichloromethane (×3). The combined organic extracts were washed with saturated brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford the title product (D1). MS (ES+) m/e 266 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].N1C=CC=CC=1.Cl[C:16]([O:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1)=[O:17].Cl>O1CCCC1.C(OCC)(=O)C>[OH:1][C:2]1[CH:3]=[C:4]([NH:5][C:16](=[O:17])[O:18][C:19]2[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(O)c1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(Nc1cccc(O)c1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Yield: 11 %

Procedure:
A mixture of 3-hydroxyaniline (2.0 g) and pyridine (3.3 ml) in tetrahydrofuran was stirred at 0° C. and then p-nitrophenyl chloroformate (3.88 g) was added, stirred at the same temperature for 5 hours. Ethyl acetate and 1N HCl were added to the reaction mixture, and the organic layer was separated, washed with water, dried over magnesium sulfate, and evaporated in vacuo. The yellow powder was washed with ethyl acetate to afford 4-nitro-phenyl N-(3-hydroxyphenyl)carbamate (554 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[C:18]([OH:20])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.F[B-](F)(F)F.C[N+](C)=C(N(C)C)O.C(N(C(C)C)C(C)C)C.[NH2:43][CH:44]([C:47]1[CH:52]=[CH:51][CH:50]=[C:49]([OH:53])[CH:48]=1)[C:45]#[N:46]>CC#N>[C:45]([CH:44]([NH:43][C:18]([C@@H:13]1[CH2:14][CH2:15][CH2:16][CH2:17][C@H:12]1[NH:11][S:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)(=[O:9])=[O:10])=[O:20])[C:47]1[CH:52]=[CH:51][CH:50]=[C:49]([OH:53])[CH:48]=1)#[N:46]
Reactant: N#CC(N)c1cccc(O)c1
Reactant: O=C(O)[C@@H]1CCCC[C@H]1NS(=O)(=O)c1ccc(Cl)cc1
Agent: CN(C)C(O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: N#CC(NC(=O)[C@@H]1CCCC[C@H]1NS(=O)(=O)c1ccc(Cl)cc1)c1cccc(O)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Trans-2-(4-Chloro-benzenesulfonylamino)-cyclohexanecarboxylic acid (0.095 g, 0.3 mmol) is dissolved in CH3CN. O-1,2-Dihydro-2-oxo-1-pyridyl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TPTU, 90.2 mg, 0.3 mmol), N-Ethyldiisopropylamine (DIPEA, 0.208 ml, 1.21 mmol) are added. The amino-(3-hydroxy-phenyl)-acetonitrile in CH3CN (1.5 ml) is added. The mixture is stirred at RT for 16 hours. The solution is filtered and concentrated. The residue is dissolved in CH2Cl2 (15 mL) and extracted with NH4Cl (2×10 ml). The H2O layers are extracted with CH2Cl2 (2×15 ml). The collected CH2Cl2 layers are dried over MgSO4 and evaporated. The solid is purified by preparative HPLC.
Reaction SMILES: [C:1](Cl)(=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[NH2:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][N:23]=1>ClCCl.N1C=CC=CC=1>[N:25]1[CH:26]=[CH:27][C:22]([NH:21][C:1](=[O:19])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][S:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([NH:21][C:22]2[CH:27]=[CH:26][N:25]=[CH:24][N:23]=2)=[O:13])=[N:23][CH:24]=1
Reactant: O=C(Cl)c1ccccc1SSc1ccccc1C(=O)Cl
Reactant: Nc1ccncn1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccncn1)c1ccccc1SSc1ccccc1C(=O)Nc1ccncn1
Yield: 2 %

Procedure:
This compound was prepared according to the general method of Example 90 using 2,2'-dithiobisbenzoyl chloride (3.00 g, 8.74 mmol) in 75 mL of dichloromethane and 4-aminopyrimidine (1.66 g, 17.5 mmol) in 14 mL of pyridine. The crude product was triturated with a hot mixture of acetonitrile and DMF, filtered, and recrystallized from water-DMF to yield 0.08 g of the title compound, mp 234°-235° C.
Reaction SMILES: [CH:1]([NH:3][CH:4]1[C:38](=[O:39])[N:6]2[C:7]([C:22]([O:24][CH:25]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])=[C:8]([CH2:12][O:13][C:14]([N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[CH2:9][S:10](=O)[C@H:5]12)=[O:2].C(OCC)(=O)C.O>CN(C)C=O.P(Cl)(Cl)Cl>[CH:1]([NH:3][CH:4]1[C:38](=[O:39])[N:6]2[C:7]([C:22]([O:24][CH:25]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])=[C:8]([CH2:12][O:13][C:14]([N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[CH2:9][S:10][C@H:5]12)=[O:2]
Reactant: O=CNC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(COC(=O)N3CCCCC3)CS(=O)[C@H]12
Solvent: CN(C)C=O
Solvent: ClP(Cl)Cl
Solvent: CCOC(C)=O
Product: O=CNC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(COC(=O)N3CCCCC3)CS[C@H]12
Temperature: -60 °C
Reaction time: 0.58 h
Yield: 93 %

Procedure:
To a solution of benzhydryl 7-formamido-3-(1-piperidinyl)carbonyloxymethyl-3-cephem-4-carboxylate-1-oxide (2.07 g) in N,N-dimethylformamide (25 ml), phosphorus trichloride (1 ml) was added under cooling in a dry ice-ethanol bath (-60° C.), followed by stirring for 35 minutes. The reaction mixture was successively added with ethyl acetate and water under cooling in a dry ice-ethanol bath and then, the resulting mixture was increased to room temperature. The ethyl acetate layer was collected and the water layer was extracted further with ethyl acetate. Both ethyl acetate layers were combined together, successively washed with water and a saturated aqueous sodium chloride solution, and then dried over magnesium sulfate. Then, the solvent was distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column, whereby benzhydryl 7-formamido-3-(1-piperidinyl)carbonyloxymethyl-3-cephem-4-carboxylate (1.87 g, 93.0%) was obtained.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[C:18](=[NH:25])[N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH2:9]1)=O)(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[NH:25]=[C:18]([N:19]1[CH2:20][CH2:21][O:22][CH2:23][CH2:24]1)[C:14]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:15]=1[CH2:16][CH2:17][NH:8][CH2:9]2
Reactant: CC(C)(C)OC(=O)N1CCc2c(cccc2C(=N)N2CCOCC2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N=C(c1cccc2c1CCNC2)N1CCOCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 105.7 %

Procedure:
5-(Imino-morpholin-4-yl-methyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester 27a (0.24 g, 0.69 mmol) was dissolved to room temperature in 10 mL of 10% trifluoroacetic acid in dichloromethane and stirred to room temperature for 18 h. The volatiles were evaporated, the residue was suspended in toluene and evaporated again. The residue was purified by flash chromatography eluting with 7% methanol in dichloromethane containing 0.7% of ammonium hydroxide to yield 0.179 g of 5-(imino-morpholin-4-yl-methyl)-3,4-dihydro-1H-isoquinoline 28a.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([S:14][C:15]([F:18])([F:17])[F:16])=[CH:9][C:8]=2[Cl:19])[N:5]=[C:4]([C:20]#[N:21])[C:3]=1I.C(N(CC)CC)C.[CH3:30][Si:31]([C:34]#[CH:35])([CH3:33])[CH3:32]>CN(C)C=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>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([S:14][C:15]([F:18])([F:17])[F:16])=[CH:9][C:8]=2[Cl:19])[N:5]=[C:4]([C:20]#[N:21])[C:3]=1[C:35]#[C:34][Si:31]([CH3:33])([CH3:32])[CH3:30]
Reactant: C#C[Si](C)(C)C
Reactant: N#Cc1nn(-c2c(Cl)cc(SC(F)(F)F)cc2Cl)c(N)c1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1c(C#N)nn(-c2c(Cl)cc(SC(F)(F)F)cc2Cl)c1N
Temperature: 75 °C

Procedure:
To a stirred solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylsulphenylphenyl)4-iodopyrazole (10 g) in dimethylformamide (45 ml) at room temperature was added triethylamine (34 ml), trimethylsilylacetylene (6 ml), cuprous iodide (0.4 g), and bis(triphenylphosphine)palladium(II) chloride (0.4 g). The mixture was heated at 75° C. for 6 hours. The cooled reaction mixture was evaporated to dryness and the residue partitioned between water and dichloromethane. The organic layer was separated and washed with water, then brine, and then dried (Na2SO4) and evaporated to give the crude product which was purified by column chromatography on silica gel (400 g) eluting with dichloromethane. Combination and evaporation of suitable fractions provided an oily solid which was further purified by column chromatography on silica gel (400 g) eluting with dichloromethane/hexane. Combination and evaporation of suitable fractions followed by recrystallisation of their residue from dichloromethane/hexane provided the title compound as a buff solid m.p. 165-169° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH3:18][N:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:24](O)=[O:25]>>[CH3:18][N:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:24]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:25]
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: Cn1cccc1C(=O)O
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4cccn4C)cc23)CC1

Procedure:
Beginning with 12.0 mg (0.05 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 19.0 mg (0.15 mMol) N-methylpyrrole-2-carboxylic acid, 18.0 mg (100+%) of the title compound were recovered.
Reaction SMILES: N[C:2]1[CH:26]=[CH:25][C:5]([O:6][C:7]2[C:8]([Cl:24])=[CH:9][C:10]([Cl:23])=[C:11]([N:13]3[C:17](=[O:18])[N:16]([CH:19]([F:21])[F:20])[C:15]([CH3:22])=[N:14]3)[CH:12]=2)=[C:4]([Cl:27])[CH:3]=1.N([O-])=[O:29].[Na+]>S(=O)(=O)(O)O.O.C1(C)C(C)=CC=CC=1.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[Cl:23][C:10]1[CH:9]=[C:8]([Cl:24])[C:7]([O:6][C:5]2[CH:25]=[CH:26][C:2]([OH:29])=[CH:3][C:4]=2[Cl:27])=[CH:12][C:11]=1[N:13]1[C:17](=[O:18])[N:16]([CH:19]([F:20])[F:21])[C:15]([CH3:22])=[N:14]1
Reactant: Cc1nn(-c2cc(Oc3ccc(N)cc3Cl)c(Cl)cc2Cl)c(=O)n1C(F)F
Reactant: O=N[O-]
Agent: [Cu+2]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Solvent: Cc1ccccc1C
Solvent: O
Product: Cc1nn(-c2cc(Oc3ccc(O)cc3Cl)c(Cl)cc2Cl)c(=O)n1C(F)F
Yield: 32 %

Procedure:
In a manner similar to Step C of Example 1, 8.10 g (0.0186 mole) of 1-[5-(4-amino-2-chlorophenoxy)-2,4-dichlorophenyl]-4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one in 60 ml of concentrated sulfuric acid was reacted with a solution of 1.30 g (0.019 mole) of sodium nitrite in 10 ml of water. Subsequent reaction of this mixture with a refluxing solution of 150.0 g (0.60 mole) of copper (II) sulfate pentahydrate in 150 ml of water and 1.50 ml of xylene yielded 2.6 g of 1-[2,4-dichloro-5-(2-chloro-4-hydroxyphenoxy)phenyl]-4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one, compound 181 of Table 1.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[C@H:9]([O:10][Si:11]([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][CH2:7][N:6]1[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=O.[Li+].[B-](CC)(CC)CC>C1COCC1>[C:31]([O:30][C:28]([N:6]1[CH2:7][CH2:8][C@@H:9]([O:10][Si:11]([C:24]([CH3:27])([CH3:26])[CH3:25])([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@H:5]1[CH2:3][OH:2])=[O:29])([CH3:34])([CH3:33])[CH3:32]
Reactant: COC(=O)[C@@H]1[C@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CCN1C(=O)OC(C)(C)C
Agent: CC[B-](CC)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@H]1CO
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.6 %

Procedure:
To a solution of compound 1E (538 mg, 1.11 mmol) in THF (10 mL) at −78° C. was added a 1 M solution of Super-Hydride® in THF (5.50 mL, 5.50 mmol). The cold bath was removed and the reaction was allowed to warm to rt. After 3 h, the reaction was poured into a 1-L Erlenmeyer flask and was carefully quenched with ice while stirring and then diluted with EtOAc. The layers were separated and the organic layer was washed with 1 M H3PO4, saturated aqueous NaHCO3 and brine, dried (MgSO4), filtered and concentrated. The residue was purified via flash chromatography (silica gel, 0-40% EtOAc in hexane) to provided the title compound (332 mg).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[N:4][C:5]([NH:17][C@H:18]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH3:19])=[N:6][C:7]=1[NH:8][C:9]1[CH:13]=[C:12]([CH:14]2[CH2:16][CH2:15]2)[NH:11][N:10]=1.[C:32](O)(=O)C.C(N)=N>CCO>[CH:14]1([C:12]2[NH:11][N:10]=[C:9]([N:8]3[CH:32]=[N:1][C:2]4[C:7]3=[N:6][C:5]([NH:17][C@H:18]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH3:19])=[N:4][C:3]=4[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:13]=2)[CH2:16][CH2:15]1
Reactant: CCOC(=O)c1nc(N[C@@H](C)c2ccc(F)cc2)nc(Nc2cc(C3CC3)[nH]n2)c1N
Reactant: CC(=O)O
Agent: N=CN
Solvent: CCO
Product: CCOC(=O)c1nc(N[C@@H](C)c2ccc(F)cc2)nc2c1ncn2-c1cc(C2CC2)[nH]n1
Yield: 9.5 %

Procedure:
A mixture of (S)-ethyl 5-amino-6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-2-[1-(4-fluorophenyl)ethylamino]pyrimidine-4-carboxylate (Method 47; 0.6 g, 1.4 mmol) and formamidine acetate (0.32 g, 3.1 mmol) in EtOH (20 ml) was heated to reflux for 12 hours. The reaction was then concentrated, and the resulting residue was dissolved in EtOAc (50 ml) and washed with saturated NaHCO3 solution (50 ml). The organic layer was dried, filtered, and concentrated. The resulting solid was purified by column chromatography (DCM:MeOH=20:1) to give the title compound (0.058 g, 8%). NMR (400 MHz, CD3OD) 8.48 (s, 1H), 7.45-7.41 (m, 2H), 7.03-6.99 (m, 2H), 6.25 (s, 1H), 5.12-5.03 (m, 1H), 4.50 (q, J=7.2 Hz, 2H), 2.00-1.96 (m, 1H), 1.54 (d, J=7.0 Hz, 3H), 1.44 (t, J=7.2 Hz, 3H), 1.10-1.08 (m, 2H), 0.81-0.74 (m, 2H). MS: Calcd.: 435; Found: [M+H]+ 436.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12]([C:25]3[CH:30]=[CH:29][C:28](Cl)=[CH:27][CH:26]=3)[N:13]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:14]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:13]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:14]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2nn(Cc3ccccc3)c(-c3ccc(Cl)cc3)c2CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2nn(Cc3ccccc3)c(-c3ccccc3)c2CC1

Procedure:
To a solution of 2-benzyl-3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (0.1 mmol) (Example 59, Step D) in THF (25 mL) was added lithium aluminum hydride (100 mg). The mixture was heated at reflux for 4 h. Water (1 mL) was added, the mixture was filtered, and the filtrate was concentrated. After purification (SiO2, EtOAc/hexanes), 2-benzyl-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester was obtained. The intermediate was diluted with CH2Cl2 (5 mL) and TFA (1 mL) was added. The reaction mixture was stirred at RT for 4 h. The reaction mixture was concentrated to obtain the title compound (0.018 g). MS (ESI): exact mass calculated for C20H21N3, 303.17. found, m/z 304.3 [M+H]+. 1H NMR (400 MHz, CD3OD): 7.38-7.35 (m, 3H), 7.19-7.18 (m, 3H), 7.12-7.10 (m, 2H), 5.13 (s, 2H), 3.35-3.21 (br m, 6H), 3.34-3.30 (br m, 2H), 2.81-2.79 (br m, 2H).
Reaction SMILES: FC1C=C([N+]([O-])=O)C(OC)=CC=1C(O)=O.[F:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([O:29][CH3:30])[C:25]=1[N+:26]([O-:28])=[O:27])[C:20](O)=[O:21]>>[F:16][C:17]1[CH:18]=[C:19]([CH2:20][OH:21])[CH:23]=[C:24]([O:29][CH3:30])[C:25]=1[N+:26]([O-:28])=[O:27]
Reactant: COc1cc(C(=O)O)cc(F)c1[N+](=O)[O-]
Agent: COc1cc(C(=O)O)c(F)cc1[N+](=O)[O-]
Product: COc1cc(CO)cc(F)c1[N+](=O)[O-]

Procedure:
The title compound was prepared using the procedure from Compound 130E (2-fluoro-5-methoxy-4-nitrobenzoic acid) with 3-fluoro-5-methoxy-4-nitrobenzoic acid (Compound 146E). 1H NMR (CDCl3, 400 MHz): δ=3.95 (s, 3H), 4.76 (s, 2H), 6.81-6.86 (m, 1H), 6.88 (s, 1H). MS (ES+): m/z 202.05 [MH+] (TOF, polar).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[N:12]=[C:11]2[C:7]([NH:8][CH:9]=[N:10]2)=[C:6]([SH:13])[N:5]=1.Cl[CH2:15][CH:16]([OH:39])[CH2:17][N:18]1[CH2:23][CH2:22][N:21]([CH:24]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH2:20][CH2:19]1.CO>CN(C=O)C.C(Cl)Cl>[CH3:3][C:4]1[N:12]=[C:11]2[C:7]([NH:8][CH:9]=[N:10]2)=[C:6]([S:13][CH2:15][CH:16]([OH:39])[CH2:17][N:18]2[CH2:19][CH2:20][N:21]([CH:24]([C:32]3[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=3)[C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[CH2:22][CH2:23]2)[N:5]=1
Reactant: OC(CCl)CN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Reactant: Cc1nc(S)c2[nH]cnc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1nc(SCC(O)CN2CCN(C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)c2[nH]cnc2n1
Reaction time: 72 h
Yield: 23.7 %

Procedure:
To NaH (2.4 mmol, 115 mg, 50% in oil, pentane washed and decanted), in DMF (5 mL) was added 2-methyl-6-mercaptopurine (400 mg, 2.4 mmol) in portions, at 0° After stirring 2 h 1-(1-chloro-2-hydroxy-3-propanyl)-4-(4,4'- difluorobenzhydryl)piperazine (2.4 mmol, 0.914 g) was added in DMF (5 mL) dropwise over 15 min, at 0° C., under nitrogen. After three days, the solution was filtered and the DMF removed from the filtrate in vacuo (vacuum oven, 1 mm Hg, 60° C.) to give the crude product. Silica gel flash column chromatography using 10% MeOH:CH2Cl2 gave the product with DMF. This product was dried 72 h in vacuo (room temperature, 1 mm Hg) to give pure product (290 mg, 23.2%). mp 83°-86° C. (dec.) DCI/MS (M+1)=511. (300 MHz) 1H NMR (CDCl3)δ: 8.1 (s, 1H), 7.3 (m, 4H), 6.95 (m, 4H), 4.2 (s, 1H), 4.15 (m, 1H), 3.4 and 3.6 (d of d, 2H), 2.65 (s, 3H), 2.6 (M, 6H), 2.4 (m, 4H).