Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:21]2[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:28])=[CH:4][C:5]2[CH:10]=[N:9][C:8]([NH:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[N:7][C:6]=2[N:20]=1.[CH:29]([N:32]=[C:33]=[O:34])([CH3:31])[CH3:30]>>[Cl:28][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]([Cl:27])[C:21]=1[C:3]1[C:2]([NH:1][C:33]([NH:32][CH:29]([CH3:31])[CH3:30])=[O:34])=[N:20][C:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[N:9]=[CH:10][C:5]=2[CH:4]=1
Reactant: CC(C)N=C=O
Reactant: CCN(CC)CCCNc1ncc2cc(-c3c(Cl)cccc3Cl)c(N)nc2n1
Product: CCN(CC)CCCNc1ncc2cc(-c3c(Cl)cccc3Cl)c(NC(=O)NC(C)C)nc2n1

Procedure:
The procedure of Example 21 was followed to react 0.30 g of 7-amino-6-(2,6-dichlorophenyl)-2-(3-diethylamino-propylamino)-pyrido[2,3-d]pyrimidine from Example 20 and 0.077 mL of isopropyl isocyanate. The product was purified by medium pressure chromatography on silica gel eluting with 90:10:1 EtOAc:MeOH:TEA to afford the title compound, mp 88-100° C.; CIMS (1% ammonia in methane): m/z (relative intensity) 504 (MH+, 3), 506 (MH+ +2, 2), 86 (100)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[C:10]2[C:15]([N:16]=1)=[C:14]([NH:17][C@H:18]1[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]1)[N:13]=[CH:12][N:11]=2.[CH3:31][S:32](Cl)(=[O:34])=[O:33].C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:24]2[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=2)[C:10]2[C:15]([N:16]=1)=[C:14]([NH:17][C@H:18]1[CH2:23][CH2:22][CH2:21][N:20]([S:32]([CH3:31])(=[O:34])=[O:33])[CH2:19]1)[N:13]=[CH:12][N:11]=2
Reactant: CS(=O)(=O)Cl
Reactant: Clc1ccc(-n2c(-c3ccccc3Cl)nc3c(N[C@H]4CCCNC4)ncnc32)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCC[C@H](Nc2ncnc3c2nc(-c2ccccc2Cl)n3-c2ccc(Cl)cc2)C1
Reaction time: 16 h
Yield: 88.3 %

Procedure:
To a solution of 8-(2-chlorophenyl)-9-(4-chlorophenyl)-N-[(3S)-piperidin-3-yl]-9H-purin-6-amine (15.3 mg, 0.035 mmol, 1 eq.) in 2 mL of THF was added methanesulfonyl chloride (0.005 mL, 0.07 mmol, 2 eq.) and triethylamine (0.015 mL, 0.11 mmol, 3 eq.). The mixture was stirred for 16 h. The reaction was concentrated in vacuo. The crude material was purified by silica gel column chromatography using 0-100% ethyl acetate/hexanes to yield 16 mg (89%) of 8-(2-chlorophenyl)-9-(4-chlorophenyl)-N-[(3S)-1-methanesulfonylpiperidin-3-yl]-9H-purin-6-amine. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.63-2.02 (m, 4 H) 2.77 (s, 3 H) 2.98-3.19 (m, 2 H) 3.31 (br. s., 1 H) 3.71 (d, J=10.55 Hz, 1 H) 4.56 (br. s., 1 H) 6.01 (d, J=7.54 Hz, 1 H) 6.97-7.56 (m, 8 H) 8.37 (s, 1 H), [M+H]+ 517.4.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:19]=[CH:18][CH:17]=[CH:16][C:4]=1[CH2:5][S:6][C:7]1[NH:8][C:9]2[C:10]([N:15]=1)=[N:11][CH:12]=[CH:13][CH:14]=2.[Cl-].[Na+].ClC1C=CC=C(C(OO)=[O:30])C=1.C([O-])(O)=O.[Na+]>CO.C(Cl)(Cl)Cl>[CH3:1][NH:2][C:3]1[CH:19]=[CH:18][CH:17]=[CH:16][C:4]=1[CH2:5][S:6]([C:7]1[NH:8][C:9]2[C:10]([N:15]=1)=[N:11][CH:12]=[CH:13][CH:14]=2)=[O:30]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CNc1ccccc1CSc1nc2ncccc2[nH]1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CNc1ccccc1CS(=O)c1nc2ncccc2[nH]1
Reaction time: 0.25 h

Procedure:
In a mixture of 1 ml of methanol and 30 ml of chloroform was dissolved 1.5 g of 2-[2-(methylamino)benzylthio]imidazo[4,5-b]pyridine. To the resulting solution was portionwise added under chilling with ice and aqueous sodium chloride solution to -5° C. 1.08 g of m-chloroperbenzoic acid (purity: 80%) over a period of 20 min., maintaining the temperature of the solution at -5° C.±3° C. The reaction mixture was stirred for additional 15 min. at the same temperature, and to the mixture was added a saturated NaHCO3 solution. The resulting mixture was then stirred. The organic phase was separated and extracted with two portions of 14 ml of 0.1N NaOH. The alkaline extracts were combined and neutralized by NH4Cl, and the deposited oil was extracted with chloroform. The chloroform extract was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and placed under reduced pressure to distill of the solvent. The residue was crystallized by addition of acetonitrile to give 2-[2-(methylamino)benzylsulfinyl]imidazo[4,5-b]-pyridine. m.p.: 120° C. (decompn.)
Reaction SMILES: [O:1]1[CH:3]([CH2:4][CH2:5][CH2:6][CH3:7])[CH2:2]1.Cl.[C:9]1([CH3:16])[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=1>>[CH3:16][C:9]1[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][C:14]=1[CH:3]([CH2:4][CH2:5][CH2:6][CH3:7])[CH2:2][OH:1]
Reactant: Cc1cccc(C)c1
Reactant: CCCCC1CO1
Agent: Cl
Product: CCCCC(CO)c1ccc(C)cc1C
Temperature: 3 °C
Reaction time: 0.5 h

Procedure:
To a stirred, 0° C mixture of m-xylene 173g (1.63 mole) and anhydrous stannic chloride 78.0g (0.30 mole) which is constantly swept with nitrogen, is added dropwise, 1,2-epoxyhexane, 30.0 g (0.30 mole) in 50 g m-xylene. The exothermic temperature is maintained at 3° C by the rate of addition. After the addition is completed, the reaction which now contains 223 g (2.0 mole) m-xylene is stirred for 30 minutes at 0° C then poured into iced concentrated hydrochloric acid. The aqueous and organic layers are separated. After extracting the aqueous portion with ethyl ether, this organic layer is combined with the previous organic fraction. This combined organic material is washed successively with water, sodium bicarbonate and again water. The dried organic solvent mixture of ethyl ether and excess unreacted m-xylene is then removed on rotory evaporator. The concentrated residue is fractionally distilled in vacuo. The third fraction, 112° C/.5 mm, is shown to be the desired product by spectral and analytical data. The yield is 35.6g (57.6% theory).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[C:14]([Zn]C#N)#[N:15]>CC(N(C)C)=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[OH:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:14]#[N:15])=[C:3]([C:10]([F:13])([F:12])[F:11])[CH:4]=1
Reactant: OCc1ccc(Cl)c(C(F)(F)F)c1
Reactant: N#C[Zn]C#N
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)N(C)C
Product: N#Cc1ccc(CO)cc1C(F)(F)F
Temperature: 150 °C
Yield: 36.6 %

Procedure:
To a solution of (4-chloro-3-(trifluoromethyl)phenyl)methanol (0.300 g, 1.425 mmol) in DMA was added dicyanozinc (0.335 g, 2.85 mmol) and tetrakis(triphenylphosphine) palladium (0) (0.165 g, 0.142 mmol). The reaction flask was degassed and charged with nitrogen, then heated at 150° C. for 6 h under microwave irradiation. The reaction mixture was poured into water and extracted with EtOAc. The EtOAc extract was washed with brine, dried over MgSO4 and purified by silica gel column chromatography to give the title compound as a white solid (0.105 g). LCMS m/z=202.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ ppm 1.98 (bs, 1H), 4.87 (s, 2H), 7.69 (d, J=0.88 Hz, 1H), 7.77-7.88 (m, 2H)
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][O:3][CH2:4][CH2:5][OH:6].[H-].[Na+].Cl[C:11]1[C:16]([C:17]#[C:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[CH:15][N:14]=[C:13]([NH:26]C=O)[N:12]=1>O1CCCC1>[NH2:26][C:13]1[N:14]=[C:15]([O:7][CH2:1][CH2:2][O:3][CH2:4][CH2:5][OH:6])[C:16]([C:17]#[C:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[CH:11][N:12]=1
Reactant: OCCOCCO
Reactant: O=CNc1ncc(C#Cc2ccc(Cl)cc2)c(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1ncc(C#Cc2ccc(Cl)cc2)c(OCCOCCO)n1
Temperature: 25 °C
Reaction time: 40 h
Yield: 50.5 %

Procedure:
11 g of Diethylene glycol and 0.78 g of a 60% suspension of sodium hydride in mineral oil were stirred in 200 ml of tetrahydrofuran (dried over sieves) for 15 minutes then 1.3 g of 4-chloro-5-(4-chlorophenylethynyl)-2-formamido-pyrimidine was added and the mixture was stirred at 25° C. in a dry atmosphere (drying tube) for 40 hours. The reaction mixture was then evaporated under reduced pressure at 55° C. The resulting syrup was stirred with 250 ml of ethyl acetate, 125 ml of saturated aqueous sodium bicarbonate and 125 ml of water for 15 minutes. The organic phase was washed with 250 ml of water and then 100 ml of brine. After drying over sodium sulfate, the filtered solution was combined with 16 g of Silica gel 60 (230–400 mesh) and evaporated under reduced pressure. The solids were applied to column of silica gel 60 (2.5×9.5 cm). The final height of the column was 16 cm. After eluting the column with increasing concentrations of ethyl acetate in dichloromethane, the product-rich fractions were combined and the solvent evaporated under reduced pressure. The product was recrystallized twice from ethyl acetate to give 0.75 g of the desired product, m.p. 142–143° C.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:35]=[CH:36][CH:37]=1)[CH2:6][N:7]([C@@H:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][CH2:26]1)[C:8]([C:10]1[CH:15]=[C:14]([C:16]([OH:18])=[O:17])[C:13]([C:19]([OH:21])=[O:20])=[CH:12][C:11]=1[C:22]([OH:24])=[O:23])=[O:9])=O.[F:38][C:39]1[C:47]([F:48])=[C:46]([F:49])[C:45]([F:50])=[C:44]([F:51])[C:40]=1[CH2:41][O:42][NH2:43]>>[F:38][C:39]1[C:47]([F:48])=[C:46]([F:49])[C:45]([F:50])=[C:44]([F:51])[C:40]=1[CH2:41][O:42][N:43]=[CH:1][C:3]1[CH:4]=[C:5]([CH:35]=[CH:36][CH:37]=1)[CH2:6][N:7]([C@@H:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][CH2:26]1)[C:8]([C:10]1[CH:15]=[C:14]([C:16]([OH:18])=[O:17])[C:13]([C:19]([OH:21])=[O:20])=[CH:12][C:11]=1[C:22]([OH:24])=[O:23])=[O:9]
Reactant: NOCc1c(F)c(F)c(F)c(F)c1F
Reactant: O=Cc1cccc(CN(C(=O)c2cc(C(=O)O)c(C(=O)O)cc2C(=O)O)[C@H]2CCCc3ccccc32)c1
Product: O=C(O)c1cc(C(=O)O)c(C(=O)N(Cc2cccc(C=NOCc3c(F)c(F)c(F)c(F)c3F)c2)[C@H]2CCCc3ccccc32)cc1C(=O)O

Procedure:
The product from Example 76E and O-(2,3,4,5,6-pentafluorobenzyl)hydroxylamine were processed as described in Example 76F to provide the title compound.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[CH2:3][CH2:4][S:5][CH2:6][CH2:7][C:8](O)=[O:9].S(Cl)([Cl:15])=O>ClCCl>[F:1][C:2]([F:12])([F:11])[CH2:3][CH2:4][S:5][CH2:6][CH2:7][C:8]([Cl:15])=[O:9]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CCSCCC(F)(F)F
Solvent: ClCCl
Product: O=C(Cl)CCSCCC(F)(F)F
Temperature: 36 °C
Yield: 86 %

Procedure:
A dry 5 L round bottom flask equipped with magnetic stirrer, nitrogen inlet, reflux condenser, and thermometer, was charged with 3-((3,3,3-trifluoropropyl)thio)propanoic acid ((188 g, 883 mmol) in dichloromethane (3 L). Thionyl chloride (525 g, 321 mL, 4.42 mol) was then added dropwise over 50 minutes. The reaction mixture was heated to reflux (about 36° C.) for two hours, then cooled to room temperature. Concentration under vacuum on a rotary evaporator, followed by distillation (40 Torr, product collected from 123-127° C.) gave the title compound as a clear colorless liquid (177.3 g, 86%): 1H NMR (400 MHz, CDCl3) δ 3.20 (t, J=7.1 Hz, 2H), 2.86 (t, J=7.1 Hz, 2H), 2.78-2.67 (m, 2H), 2.48-2.31 (m, 2H); 19F NMR (376 MHz, CDCl3) δ −66.42, −66.43, −66.44, −66.44.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:24])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:20]([CH3:21])=[N:19][N:18]=[C:17]1[CH2:22]O.P(Br)(Br)[Br:26]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:24])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:20]([CH3:21])=[N:19][N:18]=[C:17]1[CH2:22][Br:26]
Reactant: Cc1nnc(CO)n1-c1ccc(Cl)cc1C(=O)c1ccccc1Cl
Reactant: BrP(Br)Br
Product: Cc1nnc(CBr)n1-c1ccc(Cl)cc1C(=O)c1ccccc1Cl

Procedure:
In the manner given in Example 5, 2',5-dichloro-2-[3-(hydroxymethyl)-5-methyl-4H-1,2,4-triazol-4-yl]benzophenone is treated with phosphorus tribromide to give 2',5-dichloro-2-[3-(bromomethyl)-5-methyl-4H-1,2,4-triazol-4-yl]benzophenone.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[NH:16][C@@H:15]([C@H:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH3:18])[CH2:14][S:13]1.[CH2:24](Br)[CH:25]([CH3:27])[CH3:26]>>[C:20]([O:19][C@@H:17]([C@H:15]1[CH2:14][S:13][C:12](=[N:11][C:3]2[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=2[CH3:1])[N:16]1[CH2:24][CH:25]([CH3:27])[CH3:26])[CH3:18])([CH3:22])([CH3:21])[CH3:23]
Reactant: CC(C)CBr
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C1N[C@@H]([C@@H](C)OC(C)(C)C)CS1
Product: Cc1cc([N+](=O)[O-])ccc1N=C1SC[C@H]([C@@H](C)OC(C)(C)C)N1CC(C)C
Yield: 56 %

Procedure:
(1R,2R)-1-(Methanesulfonyloxymethyl)-2-(tert-butoxy)propanammonium chloride (Method B8a; 1.5 g, 5.5 mmol) was reacted with 2-methyl-4-nitrophenyl isothiocyanate in a manner analogous to that described in Method C1a to afford 4(S)-(1(R)-tert-butoxyethyl)-2-(2-methyl-4-nitrophenylimino)-1,3-thiazolidine (1.2 g, 67%). The (4S)-2-(2-methyl-4-nitrophenylimino)-4-(1(R)-tert-butoxyethyl)-1,3-thiazolidine was reacted with isobutyl bromide in a manner analogous to Method D2a to yield (4S)-4-(1(R)-tert-butoxyethyl)-3-isobutyl-2-(2-methyl-4-nitrophenylimino)-1,3-thiazolidine (0.26 g, 56%): TLC (25% EtOAc/hex) Rf0.67.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]([CH2:15][C:16](O)=[O:17])[C:13](=[O:19])[N:12]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)[C:11]([CH3:30])=[C:10]2[C:31]([C:33]2[O:34][CH:35]=[CH:36][CH:37]=2)=[O:32])=[CH:5][CH:4]=1)#[N:2].[F:38][C:39]([F:46])([F:45])[CH2:40][S:41]([NH2:44])(=[O:43])=[O:42].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClCCl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]([CH2:15][C:16]([NH:44][S:41]([CH2:40][C:39]([F:46])([F:45])[F:38])(=[O:43])=[O:42])=[O:17])[C:13](=[O:19])[N:12]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:27])[F:28])[CH:21]=3)[C:11]([CH3:30])=[C:10]2[C:31]([C:33]2[O:34][CH:35]=[CH:36][CH:37]=2)=[O:32])=[CH:5][CH:4]=1)#[N:2]
Reactant: CC1=C(C(=O)c2ccco2)C(c2ccc(C#N)cc2)N(CC(=O)O)C(=O)N1c1cccc(C(F)(F)F)c1
Reactant: NS(=O)(=O)CC(F)(F)F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC1=C(C(=O)c2ccco2)C(c2ccc(C#N)cc2)N(CC(=O)NS(=O)(=O)CC(F)(F)F)C(=O)N1c1cccc(C(F)(F)F)c1

Procedure:
A solution of [6-(4-cyanophenyl)-5-(2-furoyl)-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidin-1(2H)-yl]acetic acid (Example 29A) (75 mg, 0.15 mmol), 2,2,2-trifluoroethane-sulfonamide (23 mg, 0.16 mmol), 1,3-dicyclohexylcarbodiimide (33 mg, 0.16 mmol) and 4-dimethylaminopyridine (20 mg, 0.16 mmol) in dichloromethane (4 ml) is stirred at room temperature for 4 days. The product is extracted with dichloromethane (100 ml), washed with 2 N hydrochloric acid and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by preparative HPLC (RP18 column; eluent: acetonitrile/0.1% aq. formic acid 30:70→90:10). The title compound is isolated as a colourless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=1.[Mg].[C:14](=[O:16])=[O:15].Cl>CCOCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:14]([OH:16])=[O:15])=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=1
Reactant: FC(F)(F)c1cc(Cl)ccc1I
Reactant: O=C=O
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Product: O=C(O)c1ccc(Cl)cc1C(F)(F)F
Temperature: 0 °C

Procedure:
A solution of 4-chloro-2-trifluoromethyliodobenzene (100 g) in ether was added to a suspension of magnesium (8 g) in ether at a such a rate as to maintain the mixture at reflux. The mixture was stirred at reflux for 1 hour and then cooled to 0° C. Carbon dioxide was then passed into the stirred mixture for 3 hours. Hydrochloric acid (2M) was added and the resulting layers separated. The organic layer was washed with water and then extracted into aqueous sodium carbonate solution and this aqueous extract was acidified to pH 1 and extracted with ether. The ether layer was washed with saturated sodium chloride solution, dried (anhydrous magnesium sulphate) and the solvent evaporated to give 4-chloro-2-trifluoromethylbenzoic acid (57.1 g) as a brown solid, m.p. 106.5°-108° C.
Reaction SMILES: B(Br)(Br)Br.[NH2:5][C:6]1[N:11]=[C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:9]([CH2:17][C:18]2[CH:19]=[C:20]([CH2:26][C:27]([OH:29])=[O:28])[CH:21]=[CH:22][C:23]=2[O:24]C)=[C:8]([CH3:30])[N:7]=1.[CH3:31]O.Cl>C(Cl)Cl.O1CCOCC1>[NH2:5][C:6]1[N:11]=[C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:9]([CH2:17][C:18]2[CH:19]=[C:20]([CH2:26][C:27]([O:29][CH3:31])=[O:28])[CH:21]=[CH:22][C:23]=2[OH:24])=[C:8]([CH3:30])[N:7]=1
Reactant: CO
Reactant: CCCCNc1nc(N)nc(C)c1Cc1cc(CC(=O)O)ccc1OC
Agent: BrB(Br)Br
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCCCNc1nc(N)nc(C)c1Cc1cc(CC(=O)OC)ccc1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of boron tribromide (2.51 ml, 1M in DCM) was added portionwise over 30 min to a stirred suspension of the product from example 83 step (iv) (300 mg) in DCM (5 mL) at 0° C. The suspension was allowed to warm to rt and stirred for 3 h. A further portion of boron tribromide (1.674 ml, 1M in DCM) was added and the mixture stirred at rt for a further 2 h. MeOH (2 mL) and 4M HCl in dioxane (2 mL) were added and the mixture stirred for 1 h. The solvent was evaporated under reduced pressure and the residue purified by RPHPLC, to give the title compound as a white solid, 27 mg.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].C(O[CH2:13][C:14]1[CH:19]([C:20]([OH:22])=[O:21])[N:18]2[C:23](=[O:35])[CH:24]([NH:25][C:26](=[O:34])[CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C@H:17]2[S:16][CH:15]=1)(=O)C>FC(F)(F)C(O)=O.C1(C)C=CC=CC=1>[OH:2][C:1]1[CH:3]=[C:4]([OH:5])[CH:6]=[CH:7][C:8]=1[CH2:13][C:14]1[CH:19]([C:20]([OH:22])=[O:21])[N:18]2[C:23](=[O:35])[CH:24]([NH:25][C:26](=[O:34])[CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C@H:17]2[S:16][CH:15]=1
Reactant: CC(=O)OCC1=CS[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)O
Reactant: Oc1cccc(O)c1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)O)C(Cc3ccc(O)cc3O)=CS[C@H]12
Reaction time: 0.25 h

Procedure:
A solution of 0.055 g of resorcinol in 0.3 ml of trifluoracetic acid is mixed with 0.04 g of 3-acetoxymethyl-7-(N-phenylacetyl-amino)-ceph-2-em-4ξ-carboxylic acid and the solution is left to stand for 15 minutes at room temperature. It is diluted with an equal quantity of toluene and then evaporated to dryness under reduced pressure. 3-(2,4-Dihydroxybenzyl)-7-(N-phenylacetyl-amino)-ceph-2-em-4ξ-carboxylic acid is obtained by working up the residue in accordance with the process indicated in example 6; this acid shows the following Rf values in a thin layer chromatogram (silica gel): 0.66 (system n-butanol/acetic acid/water, 75:7.5:21), 0.70 (system n-butanol/acetic acid/water, 67:10:23) and 0.52 (system n-butanol/ethanol/water, 40:10:50).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([NH:14][CH2:15][CH2:16][OH:17])[N:3]=1.[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)#[N:19].C(N(C(C)C)C(C)C)C>O1CCOCC1>[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][N:29]([C:2]2[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([NH:14][CH2:15][CH2:16][OH:17])[N:3]=2)[CH2:28][CH2:27]1)#[N:19]
Reactant: N#Cc1c(Cl)nc(NCCO)nc1NCCO
Reactant: N#Cc1ccccc1N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: N#Cc1ccccc1N1CCN(c2nc(NCCO)nc(NCCO)c2C#N)CC1

Procedure:
In analogy to the procedure described in example 20b, 4-chloro-2,6-bis-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile was treated with 1-(2-cyanophenyl)-piperazine in dioxane in the presence of N-ethyl-diisopropylamine at 50° C. to yield 4-[4-(2-cyano-phenyl)-piperazin-1-yl]-2,6-bis-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile as an amorphous, light brown solid; MS: [M]+=408.
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[NH:13]1[CH:17]=[CH:16][CH:15]=[N:14]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[N:13]1([C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=2)[CH:17]=[CH:16][CH:15]=[N:14]1
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1ccc(-n2cccn2)cc1
Temperature: 130 °C
Reaction time: 16 h
Yield: 68.2 %

Procedure:
To a solution of ethyl 4-fluorobenzoate (105 g) in DMSO (250 mL) were added pyrazole (34.0 g) and potassium carbonate (138 g), and the mixture was heated with stirring at 130° C. for 16 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (73.7 g).
Reaction SMILES: [CH:1]1([N:5]2[C:14]3[N:13]=[C:12]([N:15]4[CH:19]=[CH:18][N:17]=[CH:16]4)[N:11]=[CH:10][C:9]=3[N:8]([CH3:20])[C:7](=[O:21])[C@H:6]2[CH2:22][CH3:23])[CH2:4][CH2:3][CH2:2]1.[CH2:24]1[C:29](=[O:30])[N:28](I)[C:26](=[O:27])[CH2:25]1>C1COCC1>[CH:1]1([N:5]2[C:14]3[N:13]=[C:12]([N:15]4[CH:19]=[CH:18][N:17]=[C:16]4[N:28]4[C:29](=[O:30])[CH2:24][CH2:25][C:26]4=[O:27])[N:11]=[CH:10][C:9]=3[N:8]([CH3:20])[C:7](=[O:21])[C@H:6]2[CH2:22][CH3:23])[CH2:2][CH2:3][CH2:4]1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(-n3ccnc3)nc2N1C1CCC1
Reactant: O=C1CCC(=O)N1I
Solvent: C1CCOC1
Product: CC[C@@H]1C(=O)N(C)c2cnc(-n3ccnc3N3C(=O)CCC3=O)nc2N1C1CCC1
Temperature: 80 °C
Reaction time: 6 h
Yield: 150.5 %

Procedure:
(R)-8-cyclobutyl-7-ethyl-2-(1H-imidazol-1-yl)-5-methyl-7,8-dihydropteridin-6(5H)-one (Example 111, 0.14 g, 0.448 mmol) was dissolved in 2 mL of THF and NIS (0.20 g, 0.896 mmol) was added. The solution was stirred at 80° C. for 6 hours after which the solution was concentrated and purified by preparative HPLC to give the title compound (276 mg). LCMS: 410.2 m/z (M+H)+; ret. Time: 3.81 (Analytical Method A).
Reaction SMILES: [CH3:1][N:2]([CH2:27][C:28]([OH:30])=O)[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[N:13]=[C:14]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:15][C:16]=2[C:17]([F:20])([F:19])[F:18])=[O:11])=[CH:5][N:4]=1.[CH3:31][NH2:32]>>[CH3:1][N:2]([CH2:27][C:28](=[O:30])[NH:32][CH3:31])[C:3]1[N:4]=[CH:5][C:6]([NH:9][C:10]([C:12]2[N:13]=[C:14]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[O:15][C:16]=2[C:17]([F:18])([F:20])[F:19])=[O:11])=[CH:7][CH:8]=1
Reactant: CN
Reactant: CN(CC(=O)O)c1ccc(NC(=O)c2nc(-c3ccccc3)oc2C(F)(F)F)cn1
Product: CNC(=O)CN(C)c1ccc(NC(=O)c2nc(-c3ccccc3)oc2C(F)(F)F)cn1

Procedure:
With a procedure similar to example 1 above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(methyl-methylcarbamoylmethyl-amino)-pyridin-3-yl]-amide was prepared from (methyl-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-amino)-acetic acid and methyl amine. LCMS calcd for C20H18F3N5O3 (m/e) 433, obsd 434 (M+H).
Reaction SMILES: [C:1]([O-:4])(=O)[CH3:2].[Na+].Cl.Cl.[CH2:8]([NH:15][NH2:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O>C1(C)C(C)=CC=CC=1>[CH2:8]([N:15]1[C:8]2[C:9](=[CH:10][CH:11]=[C:1]([OH:4])[CH:2]=2)[C:14]([CH2:13][CH3:12])=[N:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NNCc1ccccc1
Reactant: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1C
Product: CCc1nn(Cc2ccccc2)c2cc(O)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.9 %

Procedure:
1-(2-Fluoro-4-hydroxyphenyl)propan-1-one (5.37 g) that can be produced by the method described in Reference Example 9 or the like, sodium acetate (12.75 g; manufactured by Wako Pure Chemical Industries, Ltd.) and benzylhydrazine dihydrochioride (9.452 g; manufactured by Sigma-Aldrich Co.) were suspended in xylene (76 mL). The suspension was stirred overnight at reflux using a Dean-Stark apparatus. The reaction solution was cooled to room temperature, subsequently water was added thereto, and the mixture was extracted two times with ethyl acetate. The organic layer was washed two times with water and with brine, and was dried over anhydrous sodium sulfate. Subsequently, the solvent was evaporated under reduced pressure. Before completely evaporating the solvent, precipitates were filtered, and the solids were washed with n-hexane. Thus, the title compound (4.76 g) was obtained. Furthermore, the filtrate was concentrated under reduced pressure, and the solids precipitating in the middle of the concentrating process were also filtered. Thus, the title compound (3.44 g) was obtained.