Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH2:14][C:15]1[C:16]([CH3:21])=[CH:17][CH:18]=[CH:19][CH:20]=1.C([O-])([O-])=O.[K+].[K+].O>C(OCCO)C>[CH3:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[NH:14][C:2]1[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1ccc(C(=O)O)c(Br)c1
Reactant: Cc1ccccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCCO
Product: Cc1ccccc1Nc1cc(C(=O)O)ccc1C(=O)O
Temperature: 150 °C
Reaction time: 6 h

Procedure:
Bromoterephthalic acid (12.2 g), ortho-toluidine (10.7 ml), anhydrous K2CO3 (13.8 g), catalytic Cu powder (0.2 g) in 2-ethoxy-ethanol (17.5 ml) were stirred together while heating under reflux conditions in an oil bath at 150° C. After 6 hours, water (200 ml) was added and, when all salts had dissolved, the solution was clarified and crude product precipitated by acidification to pH 2. The collected diacid was well washed with boiling water then recrystallised from 50% ethanol, pure product being obtained as yellow needles of mp 318° C. (dec).
Reaction SMILES: C[O:2][C:3](=[O:17])[C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1)([CH3:6])[CH3:5].C(O)(=O)C.S(=O)(=O)(O)O>O>[CH3:6][C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:14])([F:16])[F:15])[CH:8]=1)([CH3:5])[C:3]([OH:17])=[O:2]
Reactant: COC(=O)C(C)(C)c1cccc(C(F)(F)F)c1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C(=O)O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 71.5 %

Procedure:
α,α-Dimethyl-(3-trifluoromethylphenyl)acetic acid methyl ester (24.6 g, 0.1 mol), acetic acid (150 ml), water (75ml) and sulfuric acid (36 g, 0.36 mol) are combined. The reaction is refluxed for 3 hours and stirred at room temperature for 3 days. The reaction is concentrated to half its original volume and added to ethyl acetate and washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give 16.6 g α,α-dimethyl-(3-trifluoromethylphenyl)acetic acid as a white solid. 1H NMR CDCl3 1.63 (6H,s) 7.45-7.65 (4H, m)
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:9]([CH3:10])=[C:8]([S:11][CH2:12][C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[CH:7]=[CH:6][N:5]=1.[SH:18][C:19]1[NH:23][C:22]2[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=2[N:20]=1.[OH-].[Na+]>C(O)C>[CH3:10][C:9]1[C:4]([CH2:3][S:18][C:19]2[NH:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[N:20]=2)=[N:5][CH:6]=[CH:7][C:8]=1[S:11][CH2:12][C:13]1[S:14][CH:15]=[CH:16][CH:17]=1
Reactant: Sc1nc2ccccc2[nH]1
Reactant: Cc1c(SCc2cccs2)ccnc1CCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(SCc2cccs2)ccnc1CSc1nc2ccccc2[nH]1
Yield: 75 %

Procedure:
2-Chloromethyl-3-methyl-4-(2-thienylmethylthio)pyridine hydrochloride, 2-mercapto-1H-benzimidazole and sodium hydroxide are reacted in ethanol at 25° C. for 20 h. After crystallization from toluene/methanol, the title compound is isolated. Yield: 75%, m.p. 131°-133° C.
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[CH3:5][O:6][C:7]1[N:12]=[C:11]([CH3:13])[C:10]([NH2:14])=[C:9]([CH3:15])[N:8]=1>O1CCCC1.C(=O)([O-])O.[Na+]>[N:14]([C:10]1[C:9]([CH3:15])=[N:8][C:7]([O:6][CH3:5])=[N:12][C:11]=1[CH3:13])=[C:1]=[S:2]
Reactant: COc1nc(C)c(N)c(C)n1
Reactant: S=C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1nc(C)c(N=C=S)c(C)n1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 88 %

Procedure:
Thiophosgene (1.8 mL, 23.6 mmol) was added dropwise to a stirred mixture of 2-methoxy-4,6-dimethylpyrimidin-5-amine (2.82 g, 18.4 mmol) in tetrahydrofuran (25 mL) and saturated aqueous sodium hydrogen carbonate (25 mL) at 0° C., and the mixture was stirred at 0° C. for 40 minutes. The mixture was diluted with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was washed with diisopropyl ether/n-hexane to give the title compound as a pale yellow powder (3.16 g, 16.2 mmol, 88%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15]Cl)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[CH:17](=O)[C:18]1[C:19](=[CH:21][CH:22]=[CH:23][CH:24]=1)[OH:20]>>[O:20]1[C:2]([C:3]2[CH:8]=[CH:7][C:6]([C:9]3[CH:14]=[CH:13][C:12]([C:15]4[O:20][C:19]5[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=5[CH:17]=4)=[CH:11][CH:10]=3)=[CH:5][CH:4]=2)=[CH:17][C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]1=2
Reactant: ClCc1ccc(-c2ccc(CCl)cc2)cc1
Reactant: O=Cc1ccccc1O
Product: c1ccc2oc(-c3ccc(-c4ccc(-c5cc6ccccc6o5)cc4)cc3)cc2c1

Procedure:
In accordance with the statements of German Offenlegungsschrift No. 2,238,734, 4,4'-bis-(chloromethyl)biphenyl (42) is reacted with salicylaldehyde to give 4,4'-bis-(benzo[b]furan-2-yl)-biphenyl and this product is reacted further with oleum to give a mixture of the corresponding tri- and tetra-sulphonic acids. This mixture can also be used for the optical brightening of cotton and polyamide.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:11]2[CH:12]=[N:13][C:14]([C:17]3[NH:21][C:20]4[CH:22]=[C:23]([N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)[CH:24]=[CH:25][C:19]=4[N:18]=3)=[CH:15][CH:16]=2)=[N:4][CH:5]=[C:6]([C:8](O)=[O:9])[CH:7]=1.[CH2:32]([NH2:34])[CH3:33]>O1CCCC1.CN(C)C=O>[CH2:32]([NH:34][C:8]([C:6]1[CH:7]=[C:2]([Cl:1])[C:3]([C:11]2[CH:12]=[N:13][C:14]([C:17]3[NH:21][C:20]4[CH:22]=[C:23]([N:26]5[CH2:27][CH2:28][O:29][CH2:30][CH2:31]5)[CH:24]=[CH:25][C:19]=4[N:18]=3)=[CH:15][CH:16]=2)=[N:4][CH:5]=1)=[O:9])[CH3:33]
Reactant: CCN
Reactant: O=C(O)c1cnc(-c2ccc(-c3nc4ccc(N5CCOCC5)cc4[nH]3)nc2)c(Cl)c1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCNC(=O)c1cnc(-c2ccc(-c3nc4ccc(N5CCOCC5)cc4[nH]3)nc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.5 %

Procedure:
0.43 g of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphine (1.12 mmol) was added to 0.49 g of 3-chloro-6′-(6-morpholin-4-yl-1H-benzoimidazol-2-yl)-[2,3]bipyridinyl-5-carboxylic acid (79) (1.12 mmol) prepared in Example 66 dissolved in 1.0 mL of tetrahydrofuran and 1.0 mL of dimethylformamide, and stirred at room temperature for 10 minutes. 0.56 mL of ethylamine (1.12 mmol) in 2.0 M tetrahydrofuran solution was added thereto, and refluxed under heating and stirring for 18 hours. The mixture was cooled to room temperature, and concentrated under reduced pressure. Then, the mixture was dissolved in ethyl acetate, and washed with water. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography (eluting solvent: chloroform/methanol=20/1) to obtain 0.35 g of 3-chloro-6′-(6-morpholin-4-yl-1H-benzoimidazol-2-yl)-[2,3]bipyridinyl-5-carboxylic acid ethyl amide (yield 68%).
Reaction SMILES: C(N1CCN(C2C=CC(N)=CC=2C)CC1)(=O)C.[Br:18][C:19]1[CH:24]=[C:23]([N+:25]([O-])=O)[CH:22]=[CH:21][C:20]=1[N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[Br:18][C:19]1[CH:24]=[C:23]([NH2:25])[CH:22]=[CH:21][C:20]=1[N:28]1[CH2:29][CH2:30][O:31][CH2:32][CH2:33]1
Reactant: O=[N+]([O-])c1ccc(N2CCOCC2)c(Br)c1
Agent: CC(=O)N1CCN(c2ccc(N)cc2C)CC1
Product: Nc1ccc(N2CCOCC2)c(Br)c1
Reaction time: 5 h

Procedure:
Following the general procedure of Intermediate 36 but using 4-(2-bromo-4-nitrophenyl)morpholine as starting material and allowing 5 h for hydrogenation and subsequently purifying by chromatography eluting with EtOAc/isohexane there was thus obtained the title compound (Intermediate 75) in 24% yield; 1H NMR δ 6.90 (1H, d), 6.80 (1H, s), 6.50 (1H, dd), 5.00 (2H, s), 5.40 (1H, d), 3.70-3.60 (4H, m), 2.80-2.70 (4H, m); MS m/e MH+ 258.
Reaction SMILES: FC(F)(F)S([O-])(=O)=O.[Sn+2].FC(F)(F)S([O-])(=O)=O.[C:18]([S:22][CH3:23])(=[S:21])[CH2:19][CH3:20].C(O[C@H:28]1[NH:31][C:30](=[O:32])[C@@H:29]1[C@H:33]([O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])[CH3:34])(=O)C.C(O)(=O)C(O)=O>ClCCl.C(N(CC)CC)C>[C:39]([Si:36]([CH3:37])([CH3:38])[O:35][C@@H:33]([C@@H:29]1[C@@H:28]([S:21][C:18]([S:22][CH3:23])=[CH:19][CH3:20])[NH:31][C:30]1=[O:32])[CH3:34])([CH3:40])([CH3:41])[CH3:42]
Reactant: CC(=O)O[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Reactant: CCC(=S)SC
Agent: O=C(O)C(=O)O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Sn+2]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC=C(SC)S[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Temperature: -25 °C
Reaction time: 2 h
Yield: 47.1 %

Procedure:
To a suspension of Tin(II) trifluoromethanesulfonate (5.58 g) in dichloromethane (27 ml) cooled to -25° C. were added triethylamine (1.62 g) and methyl dithiopropionate (1.20 g) successively. The mixture was stirred for 2 hours at -20° C. and (3R,4R)-4-acetoxy-3-[(1R)-1-(tertbutyldimethylsilyloxy)ethyl]-2-oxoazetidine (2.0 g) was added thereto. After stirring for 2 hours at 0° C., the mixture was poured into 20% aqueous solution of oxalic acid (100 ml) and the precipitates were filtered off. The organic layer of the filtrate was separated, dried, and concentrated under reduced pressure. The residue was purified by silica gel (50 g) column chromatography (20% ethyl acetate-hexane) to afford (3S,4R)-3-[(1R)-1-(tertbutyldimethylsilyloxy)ethyl]-4-[(1-methylthio-1-propenyl)thio]-2-oxoazetidine (mixture of E and Z isomers) (1.14 g).
Reaction SMILES: Cl[C:2]1[N:34]=[C:5]2[C:6]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)=[C:7]([CH3:23])[C:8]([C:10]3[N:14]([C:15]4[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=4)[N:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1.[CH3:35][N:36]([CH3:41])[CH2:37][CH2:38][CH2:39][NH2:40].C(N(CC)CC)C>CN1C(=O)CCC1>[CH3:35][N:36]([CH3:41])[CH2:37][CH2:38][CH2:39][NH:40][C:2]1[N:34]=[C:5]2[C:6]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)=[C:7]([CH3:23])[C:8]([C:10]3[N:14]([C:15]4[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=4)[N:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(Cl)nc2c1-c1cccc(C(F)(F)F)c1
Reactant: CN(C)CCCN
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(NCCCN(C)C)nc2c1-c1cccc(C(F)(F)F)c1
Temperature: 220 °C
Yield: 69.5 %

Procedure:
To a solution of 4-{5-[2-chloro-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl]-pyrazol-1-yl}-benzonitrile (Int. 19, 68 mg, 0.14 mmol) in NMP (2.5 mL) was added N,N-dimethyl-propane-1,3-diamine (54 μL, 0.43 mmol) followed by triethylamine (39 μL, 0.28 mmol). The reaction mixture was heated to 220° C. for 5 hrs using microwave irradiation. The cooled reaction mixture was concentrated in vacuo then loaded onto a SCX-2 cartridge (2 g) in MeOH. After washing with DCM/MeOH, the crude product was eluted with 2 M NH3 in MeOH and following concentration in vacuo gave a brown oil (53 mg). The oil thus obtained was purified using preparative TLC (20×20 cm×1 mm) eluting with 20% MeOH in DCM to give the title compound as a pale yellow oil, which solidified on standing (14 mg).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[N:6][C:7]([C@@H:17]([NH2:19])[CH3:18])=[C:8]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[CH:9]=2)[CH:4]=[CH:3]1.[Cl:20][C:21]1[C:22]([NH2:29])=[N:23][C:24]([NH2:28])=[N:25][C:26]=1Cl.CCN(CC)CC>CN(C=O)C>[Cl:20][C:21]1[C:26]([NH:19][C@H:17]([C:7]2[N:6]=[C:5]3[CH:4]=[CH:3][N:2]([CH3:1])[C:10]3=[CH:9][C:8]=2[N:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)[CH3:18])=[N:25][C:24]([NH2:28])=[N:23][C:22]=1[NH2:29]
Reactant: Nc1nc(N)c(Cl)c(Cl)n1
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1N1CCOCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@H](Nc1nc(N)nc(N)c1Cl)c1nc2ccn(C)c2cc1N1CCOCC1
Temperature: 90 °C
Reaction time: 8 h
Yield: 14.2 %

Procedure:
To a 10 mL vial were added (S)-1-(1-methyl-6-morpholino-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine (100 mg, 0.384 mmol), 5,6-dichloropyrimidine-2,4-diamine (68.8 mg, 0.384 mmol) and Et3N (0.11 mL, 0.77 mmol) in DMF (3 mL). The resulting yellow solution was heated to 90° C. and stirred overnight. The reaction mixture was purified by preparative HPLC eluting with 20-40% ACN in water (with 0.05% ammonium formate). The fractions containing the desired product were combined and lyophilized to give the title compound as a white solid (22 mg, 14%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.31-1.41 (m, 3 H), 2.70-2.82 (m, 2 H), 3.00-3.15 (m, 3 H), 3.69-3.93 (m, 10 H), 5.55-5.67 (m, 2H), 5.79-5.89 (m, 1 H), 5.89-5.96 (m, 2 H), 6.11-6.22 (m, 1 H), 6.47-6.57 (m, 1 H), 7.49-7.59 (m, 1 H), 7.75-7.84 (m, 1 H); ESI-MS m/z [M+H]+ calc'd for C18H23ClN8O, 403. found 403.
Reaction SMILES: ClCCCCO[C:7]1[C:12]2[C:13]([CH3:19])([CH3:18])[O:14][C:15](=[O:17])[NH:16][C:11]=2[C:10]([CH3:20])=[CH:9][CH:8]=1.[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([SH:28])=[CH:24][CH:23]=1>>[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([S:28][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:8]2[CH:9]=[C:10]([CH3:20])[C:11]3[NH:16][C:15](=[O:17])[O:14][C:13]([CH3:18])([CH3:19])[C:12]=3[CH:7]=2)=[CH:24][CH:23]=1
Reactant: Cc1ccc(OCCCCCl)c2c1NC(=O)OC2(C)C
Reactant: Cc1ccc(S)cc1
Product: Cc1ccc(SCCCCOc2cc(C)c3c(c2)C(C)(C)OC(=O)N3)cc1

Procedure:
Prepared analogously to Example 1 from 6-(4-chlorobutoxy-4,4,8-trimethyl-4H-3,1-benzoxazin-2-one and 4-methyl-thiophenol.
Reaction SMILES: [C:1]1([CH2:11][CH:12]([CH2:16][C:17]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[O:18])[C:13](O)=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.Cl.[CH3:27][O:28][C:29](=[O:38])[C@H:30]([CH2:32][C:33]1[N:37]=[CH:36][NH:35][CH:34]=1)[NH2:31].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O>[CH3:27][O:28][C:29](=[O:38])[C@H:30]([CH2:32][C:33]1[N:37]=[CH:36][NH:35][CH:34]=1)[NH:31][C:13](=[O:14])[CH:12]([CH2:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[CH2:16][C:17]([N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)=[O:18]
Reactant: COC(=O)[C@@H](N)Cc1c[nH]cn1
Reactant: O=C(O)C(CC(=O)N1CCOCC1)Cc1cccc2ccccc12
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1c[nH]cn1)NC(=O)C(CC(=O)N1CCOCC1)Cc1cccc2ccccc12
Yield: 19.2 %

Procedure:
To a suspension of 0.89 g of 2-(1-naphthylmethyl)3-(morpholinocarbonyl)propionic acid and 0.79 g of L-histidine methyl ester dihydrochloride in 23 ml of N,N-dimethylformamide were added 0.70 ml of diphenylphosphoryl azide and 1.50 ml of triethylamine with stirring under ice-cooling, and then the mixture was additionaly stirred for 16 hours. The reaction mixture was evaporated under reduced pressure, and to the residue was added a 5% aqueous sodium bicarbonate solution. The mixture was extracted with ethyl acetate, and the ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol=20/1, by volume) to obtain 0.25 g of N-[2-(1-Naphthylmethyl)-3-(morpholinocarbonyl)propionyl]-L-histidine methyl ester having an Rf2 value of 0.56 as a white powder.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:26])[O:19][C:20]4[CH:25]=CC=CC=4)=[C:13]([O:27][CH3:28])[CH:12]=3)=[CH:9][N:8]([CH:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[O:35]1[CH2:40][CH2:39][N:38](CCO)[CH2:37][CH2:36]1>N1C=CC=CC=1>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:26])[O:19][CH2:20][CH2:25][N:38]4[CH2:39][CH2:40][O:35][CH2:36][CH2:37]4)=[C:13]([O:27][CH3:28])[CH:12]=3)=[CH:9][N:8]([CH:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: OCCN1CCOCC1
Reactant: COc1cc(-c2cn(C3CCOCC3)c3ncnc(N)c23)ccc1NC(=O)Oc1ccccc1
Solvent: c1ccncc1
Product: COc1cc(-c2cn(C3CCOCC3)c3ncnc(N)c23)ccc1NC(=O)OCCN1CCOCC1
Temperature: 100 °C

Procedure:
Phenyl N-[4-(4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]carbamate (25 mg, 0.054 mmol) was mixed with 2-morpholino-1-ethanol (0.1 mL) in pyridine (0.7 mL). The reaction mixture was heated at 100° C. overnight. The solvent was removed and the residue was purified by preparative reverse phase HPLC to give 2-morpholinoethyl N-[4-(4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]carbamate (24 mg, 0.048 mmol). The solid was dissolved in ethyl acetate (2 mL) and 1.0N HCl in ether (0.2 mL) was added slowly. The precipitate was collected through filtration under nitrogen to give 2-morpholinoethyl N-[4-(4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]carbamate hydrochloride (24 mg, 0.045 mmol). 1H NMR (DMSO-d6) δ 1.88(m, 2H), 2.16(m, 2H), 3.55(m, 8H), 3.90(s, 3H), 4.03 (m, 4H), 4.49(m, 2H), 4.92(m, 1H), 7.07(m, 1H), 7.15(s, 1H), 7.65(bs, 2H), 7.84(s, 1H), 8.45(s, 1H), 8.75(s, 1H) 10.95(bs, 1H). LC/MS MH+=497.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:16])[C@@H:10]([CH2:12][CH:13]([CH3:15])[CH3:14])[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]1[CH2:23][S:20](=[O:22])(=[O:21])[O:19][CH2:18]1>C(#N)C.CO>[CH2:1]([O:8][C:9]([C@H:10]([NH:11][CH2:18][CH2:17][CH2:23][S:20]([OH:22])(=[O:21])=[O:19])[CH2:12][CH:13]([CH3:14])[CH3:15])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S1(=O)CCCO1
Reactant: CC(C)C[C@@H](N)C(=O)OCc1ccccc1
Solvent: CO
Solvent: CC#N
Product: CC(C)C[C@@H](NCCCS(=O)(=O)O)C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 49 %

Procedure:
To a solution of D-Leucine benzylester (6.3 mmol) in acetonitrile (9 mL) and MeOH (3 mL) was added 1,3-propane sultone (691 mg, 5.7 mmol). The solution was stirred at reflux for 2.5 hours. The reaction mixture was cooled to room temperature. The solid material was filtered and washed with aconitrile (2×20 mL). The solid was dissolved in 20% water/EtOH (75 mL). Dowex Marathon C ion exchange resin (strongly acidic) was added to the solution. The suspension was stirred for 15 minutes before the resin was removed by filtration. The filtrate was evaporated under reduced pressure and dried in vacuo, affording the title compound (960 mg, 49%). 1H NMR (D2O, 500 MHz) δ ppm 7.52 (m, 5H), 5.41 (d, 1H, J=12.2 Hz), 5.35 (d, 1H, J=12.2 Hz), 4.16 (m, 1H), 3.22 (m, 2H), 2.97 (t, 2H, J=6.8 Hz), 2.16 (m, 2H), 1.88 (m, 1H), 1.79 (m, 1H), 1.76 (m, 1H), 0.94 (d, 6H, J=3.9 Hz). 13C (DMSO, 125 MHz) δ ppm 169.60, 135.62, 129.24, 129.21, 129.11, 68.08, 58.09, 49.87, 46.48, 24.77, 23.50, 22.50, 22.04. [α]D=−2.1° (c=0.00095 in water), ES-MS 344 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:3]=1.[Li]CCCC.C(OC([N:27]1[CH2:31][CH2:30][CH2:29][C:28]1=O)=O)(C)(C)C>C1COCC1>[O:8]([C:4]1[CH:3]=[C:2]([C:28]2[CH2:29][CH2:30][CH2:31][N:27]=2)[CH:7]=[CH:6][CH:5]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Brc1cccc(Oc2ccccc2)c1
Reactant: CC(C)(C)OC(=O)N1CCCC1=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: c1ccc(Oc2cccc(C3=NCCC3)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
To a cold solution (−78° C.) of 1-bromo-3-phenoxy-benzene (10.13 g, 40.6 mmol) in anhydrous THF (100 mL) and under nitrogen is added n-BuLi (1.6M, 44.7 mmol, 27 mL). The mixture is allowed to stir for 30 minutes before being added to a cold solution (−78° C.) of 1-(tert-Butoxycarbonyl)-2-pyrrolidinone in anhydrous THF (50 mL) under nitrogen via cannula. The resulting mixture is allowed to warm to room temperature overnight before being quenched with water (200 mL) and extracted with EtOAc (3×100 mL). The organics were collected, dried over Na2SO4, filtered and concentrated under reduced pressures. The residue is dissolved in CH2Cl2 (20 mL) and TFA (10 mL) is added with stirring. The mixture is stirred for 30 minutes and quenched over ice cold sat. NaHCO3, extracted with CH2Cl2 (3×100 mL) and the organics were combined, dried over Na2SO4, filtered and concentrated under reduced pressures. The residue is purified by silica gel column chromatography (20% EtOAc/Hexanes) to give 5-(3-phenoxy-phenyl)-3,4-dihydro-2H-pyrrole as light yellow oil (6.1 g, 63%). LCMS m/z 238 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:13]=[CH:12][C:6]([NH:7][S:8]([CH3:11])(=[O:10])=[O:9])=[C:5]([O:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH:4]=1)#[N:2].Cl.[NH2:24][OH:25].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O>[F:22][C:16]1[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:15]=1[O:14][C:5]1[CH:4]=[C:3]([CH:13]=[CH:12][C:6]=1[NH:7][S:8]([CH3:11])(=[O:10])=[O:9])[C:1](=[N:24][OH:25])[NH2:2]
Reactant: NO
Reactant: CS(=O)(=O)Nc1ccc(C#N)cc1Oc1ccc(F)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)Nc1ccc(C(N)=NO)cc1Oc1ccc(F)cc1F
Yield: 60.5 %

Procedure:
A mixture of 4'-cyano-2'-(2,4-difluorophenoxy)methanesulfonanilide (1.5 g), hydroxylamine hydrochloride (0.8 g), and sodium carbonate (1.2 g) in ethanol (21 ml) and water (32 ml) was refluxed for 13 hours. The mixture was concentrated and the residue was dissolved in water, acidified with diluted hydrochloric acid, and extracted with ethyl acetate. The extract was washed with water, dried, and concentrated. The residue was purified by column chromatography on silica gel (40 g) eluting with a mixture of toluene and ethyl acetate (1:1) to give colorless crystals of 3-(2,4-difluorophenoxy)-4-(methanesulfonamido)benzamidoxime (1.0 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[C:5]([CH2:7][C:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=1)=O.[CH3:20][NH:21][C:22]([NH2:24])=[O:23].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)(=O)C>[CH3:20][N:21]1[C:5]([C:4]2[CH:17]=[CH:18][CH:19]=[C:2]([Cl:1])[CH:3]=2)=[CH:7][C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)=[N:24][C:22]1=[O:23]
Reactant: CNC(N)=O
Reactant: O=C(CC(=O)c1cccc(Cl)c1)c1cccc(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)O
Product: Cn1c(-c2cccc(Cl)c2)cc(-c2cccc(Cl)c2)nc1=O

Procedure:
To a solution of 38 g. di(m-chlorobenzoyl)methane in 400 ml. glacial acetic acid is added 23 g. N-methylurea and 57 g. p-toluene sulfonic acid. This mixture is refluxed for 24 hours and acetic acid removed by evaporation in vacuo. The residue is treated with 2N. sodium hydroxide till basic, extracted several times with methylene chloride. The combined methylene chloride extracts are then exhaustively extracted with water, dried and evaporated in vacuo to dryness. The residue is crystallized from methylene chloride/diethyl ether and then twice from benzene to obtain 1-methyl-4,6-di(m-chlorophenyl)-pyrimidine-2(1H)-one, m.p. 178°-181°C.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([CH:7]=O)[CH:3]=1.Cl.[NH2:10][N:11]1[CH2:15][CH2:14][NH:13][C:12]1=[O:16]>O>[CH3:1][C:2]1[O:6][N:5]=[C:4]([CH:7]=[N:10][N:11]2[CH2:15][CH2:14][NH:13][C:12]2=[O:16])[CH:3]=1
Reactant: Cc1cc(C=O)no1
Reactant: NN1CCNC1=O
Agent: Cl
Solvent: O
Product: Cc1cc(C=NN2CCNC2=O)no1
Reaction time: 1.5 h

Procedure:
14.0 pts. by wt. of 5-methyl-3-formyl-isoxazole are reacted with 25.6 pts. by wt. of 1-amino-2-oxo-imidazolidine hydrochloride in 100 pts. by vol. of water as in Example 25.1. After 90 minutes, the precipitate is filtered off, washed with water, dried and recrystallised from absolute acetonitrile. 12.5 pts. by wt. of 1-(5-methyl-isoxazol-3-yl-methyleneamino)-2-oxo-imidazolidine of melting point 195°-7° C. are obtained.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][CH:13]=[C:14]([C:17]([CH3:19])=O)[C:15]=2[OH:16])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:20][C:21]1[CH:30]=[C:29]([C:31]([NH:33][NH2:34])=[O:32])[CH:28]=[CH:27][C:22]=1[C:23]([O:25][CH3:26])=[O:24].O.S(C1C=CC(C)=CC=1)(O)(=O)=O>>[F:20][C:21]1[CH:30]=[C:29]([C:31]([NH:33][N:34]=[C:17]([C:14]2[C:15]([OH:16])=[C:11]([C:8]3[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=3)[S:12][CH:13]=2)[CH3:19])=[O:32])[CH:28]=[CH:27][C:22]=1[C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)c1ccc(C(=O)NN)cc1F
Reactant: CC(=O)c1csc(-c2ccc(C(C)(C)C)cc2)c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: COC(=O)c1ccc(C(=O)NN=C(C)c2csc(-c3ccc(C(C)(C)C)cc3)c2O)cc1F
Yield: 94.2 %

Procedure:
From 2-(4-t-butylphenyl)-3-hydroxy-4-methylcarbonylthiophene (59.0 mg, 0.215 mmol), methyl 2-fluoro-4-hydrazinocarbonylbenzoate (45.6 mg, 0.215 mmol) and tosylic acid monohydrate (12.3 mg, 0.0645 mmol), 94.9 mg of the desired product was obtained in the same manner as in Synthetic Example 65 as a pale yellow solid (yield 94%).