Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH:16]=[C:17]([CH3:20])[CH:18]=[CH:19][C:12]2=[N:11][C:10]=1[C:21]([NH:23][NH:24][C:25](=O)[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[CH:27]=1)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(Cl)(Cl)Cl.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(OCC)(=O)C.C(#N)C>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH:16]=[C:17]([CH3:20])[CH:18]=[CH:19][C:12]2=[N:11][C:10]=1[C:21]1[O:22][C:25]([C:26]2[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=2)=[N:24][N:23]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(C(=O)NNC(=O)c2nc3ccc(C)cn3c(=O)c2OCc2ccccc2)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cccc(-c2nnc(-c3nc4ccc(C)cn4c(=O)c3OCc3ccccc3)o2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The product from Example 8.3 (202 mg, 0.457 mmol), carbon tetrachloride (0.221 mL, 2.28 mmol) and triethylamine (0.165 mL, 1.19 mmol) were mixed with acetonitrile (10 mL). To this mixture was added triphenylphosphine (291 mg, 1.11 mmol) at room temperature. After being stirred at room temperature overnight, the reaction solution was diluted with ethyl acetate (100 mL), washed with aqueous saturated sodium bicarbonate (50 mL), water (50 mL) and brine (50 mL) successively, and then dried (Na2SO4). The crude product was subjected to flash chromatography (hexane-ethyl acetate 1:1) to give the desired compound
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([OH:8])([C:6]#[CH:7])[CH3:5].Br[CH2:10][C:11]([O:13][CH3:14])=[O:12]>C1COCC1>[CH3:14][O:13][C:11](=[O:12])[CH2:10][O:8][C:4]([CH3:5])([CH3:3])[C:6]#[CH:7]
Reactant: COC(=O)CBr
Reactant: C#CC(C)(C)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C#CC(C)(C)OCC(=O)OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 21.3 %

Procedure:
A mechanically stirred suspension of sodium hydride (10.0 g, 0.25 mol) in THF (170 mL) at 0° C. under N2 gas was treated dropwise with a solution of 2-methyl-3-butyn-2-ol (29.1 mL, 0.30 mol) in THF (70 mL). After stirring at 0° C. for 1 hour, the reaction mixture was treated at 0° C. with a solution of methyl bromoacetate (35.5 mL, 0.38 mol) in THF (100 mL). After stirring at ambient temperature overnight, the reaction mixture was quenched into 1M HCl (300 mL) and extracted with ethyl acetate (3×300 mL). The organic layers were combined, dried over Na2SO4, and concentrated to half the volume. The residue was distilled by vacuum distillation (bp. 118-120° C./20 mmHg) to provide the title compound (10.0 g).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:12]#[N:13])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)=O.[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CO>>[N:14]1([CH2:1][C:3]2[CH:8]=[CH:7][C:6]([C:9]3([C:12]#[N:13])[CH2:11][CH2:10]3)=[CH:5][CH:4]=2)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: C1CCNC1
Reactant: N#CC1(c2ccc(C=O)cc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: N#CC1(c2ccc(CN3CCCC3)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 1-(4-formylphenyl)cyclopropanecarbonitrile (0.30 g, 0.0018 mol), pyrrolidine (0.18 mL, 0.0021 mol) and sodium triacetoxyborohydride (0.74 g, 0.0035 mol) in methanol (5.0 mL, 0.12 mol) was stirred at rt for 1 h. The reaction mixture was adjusted to be basic (pH=12) and extracted with ethyl acetate. The combined organic extract was washed with brine, dried and concentrated to provide the desired product. LC-MS: 227.1 (M+H)+
Reaction SMILES: [O:1]1[CH2:5][C:4](=O)[CH2:3][C:2]1=[O:7].[C:8]([NH:13][C:14]([NH2:16])=[O:15])([CH2:11][CH3:12])([CH3:10])[CH3:9].O>C1C=CC=CC=1>[C:8]([NH:13][C:14]([NH:16][C:4]1[CH2:5][O:1][C:2](=[O:7])[CH:3]=1)=[O:15])([CH2:11][CH3:12])([CH3:10])[CH3:9]
Reactant: O=C1COC(=O)C1
Reactant: CCC(C)(C)NC(N)=O
Solvent: c1ccccc1
Solvent: O
Product: CCC(C)(C)NC(=O)NC1=CC(=O)OC1
Yield: 39.3 %

Procedure:
To a solution of 3 g of 2,4-furandione in 100 ml of benzene is added 4 g of tert-amylurea. The solution is heated under nitrogen at reflux for three hours with water removal. At the end of that period the solution is cooled and concentrated. The residual material is recrystallized from acetonitrile to give 2.5 g of 1-tert-amyl-3-(2,5-dihydro-5-oxo-3-furyl)urea, m.p. 169°-171° C. The infrared and n.m.r. spectra are consistent with the assigned structure.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10]1[N:15]=[N:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([N:22]=C(C4C=CC=CC=4)C4C=CC=CC=4)=[CH:18][CH:17]=3)=[CH:12][CH:11]=1)[CH2:2]2.Cl>C1COCC1>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10]1[N:15]=[N:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=3)=[CH:12][CH:11]=1)[CH2:2]2
Reactant: c1ccc(C(=Nc2ccc(-c3ccc(O[C@H]4CN5CCC4CC5)nn3)cc2)c2ccccc2)cc1
Agent: Cl
Solvent: C1CCOC1
Product: Nc1ccc(-c2ccc(O[C@H]3CN4CCC3CC4)nn2)cc1

Procedure:
The product of Example 24E (360 mg, 0.78 mmol) was treated with HCl (aq. 10%, 5 mL) in THF (5 mL) at ambient temperature for 4 h. It was then concentrated and the title compound was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3.H2O, 90:10:1, Rf. 0.1) as solid (210 mg, yield, 90%). 1H NMR (300 MHz, CD3OD) δ 1.44-1.66 (m, 1H), 1.65-1.94 (m, 2H), 1.95-2.16 (m, 1H), 2.20-2.40 (m, 1H), 2.68-3.06 (m, 5H), 3.37-3.57 (m, 1H), 5.15-5.37 (m, 1H), 6.65-6.89 (m, 2H), 7.18 (d, J=9.5 Hz, 1H), 7.55-7.81 (m, 2H), 7.93 (d, J=9.2 Hz, 1H) ppm. MS (DCI/NH3): 297 (M+H)+.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1([CH3:22])[CH2:17][CH2:16][C:15]2[C:10](=[C:11]([CH3:21])[C:12]([CH3:20])=[C:13]([OH:19])[C:14]=2[CH3:18])[O:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:23]=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>>[C:1]([NH:5][C:6](=[O:7])[C:8]([OH:23])([CH3:22])[CH2:17][CH2:16][C:15]1[C:10](=[O:9])[C:11]([CH3:21])=[C:12]([CH3:20])[C:13](=[O:19])[C:14]=1[CH3:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)NC(C)(C)C)O2
Agent: [Ce+4]
Agent: [NH4+]
Product: CC1=C(C)C(=O)C(CCC(C)(O)C(=O)NC(C)(C)C)=C(C)C1=O
Yield: 92.2 %

Procedure:
Oxidation as described in protocol B, using 95 mg (0.311 mmol) of N-tert-butyl-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide and 358 mg CAN (0.653 mmol) yielded 92.2 mg of N-tert-butyl-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:22])=[N:4][S:5][C:6]=1[NH:7][C:8](=[O:21])[CH:9]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([N+:18]([O-])=O)[CH:12]=1)[CH3:10]>[Pt].CN(C)C=O>[Cl:1][C:2]1[C:3]([CH3:22])=[N:4][S:5][C:6]=1[NH:7][C:8](=[O:21])[CH:9]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([NH2:18])[CH:12]=1)[CH3:10]
Reactant: Cc1nsc(NC(=O)C(C)c2ccc(O)c([N+](=O)[O-])c2)c1Cl
Agent: [Pt]
Solvent: CN(C)C=O
Product: Cc1nsc(NC(=O)C(C)c2ccc(O)c(N)c2)c1Cl
Reaction time: 6 h
Yield: 89.6 %

Procedure:
A mixture of N-(chloro-3-methylisothiazol-5-yl)-2-(4-hydroxy-3-nitrophenyl)propionamide (11.0 g, 0.0322 mol) and 3% platinum on carbon in N,N-dimethylformamide (100 ml) was hydrogenated at 15 bar (15×105 Nm−2) for 6 hours at room temperature. The catalyst was removed by filtration and the filtrate evaporated in vacuo to give N-(4-chloro-3-methylisothiazol-5-yl)-2-(3-amino-4-hydroxyphenyl)propionamide (9.0 g) as an off-white solid, m.p.222-223° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:13]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1)([CH3:16])([CH3:15])[CH3:14]>C(O)C.C(OCC)(=O)C>[CH3:16][C:13]([C:17]1[CH:18]=[CH:19][C:20]([CH2:21][NH:22][C:2]2[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:23][CH:24]=1)([CH3:14])[CH3:15]
Reactant: CCOC(=O)c1cccnc1Cl
Reactant: CC(C)(C)c1ccc(CN)cc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)c1cccnc1NCc1ccc(C(C)(C)C)cc1
Temperature: 160 °C

Procedure:
A solution of ethyl 2-chloro-3-pyridinecarboxylate (0.610 g, 3.29 mmol) in ethanol (10.0 mL) was treated with 4-tert-butylbenzylamine (0.580 mL, 3.29 mmol). The mixture was heated to 160° C. for 1 h in a Biotage Initiator microwave synthesizer. The solution was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate. The organic portion was dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification via flash column chromatography (20-60% ethyl acetate in hexanes) afforded the title compound clear yellow oil (0.461 g, 45%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.34 (dd, J=4.8, 1.8 Hz, 1H), 8.18 (dd, J=7.8, 2.0 Hz, 1H), 7.30-7.42 (m, 4H), 6.58 (dd, J=7.6, 4.8 Hz, 1H), 4.75 (d, J=5.6 Hz, 2H), 4.34 (q, J=7.1 Hz, 2H), 1.39 (t, J=7.2 Hz, 3H), 1.34 (s, 9H). MS(ES+) m/e 313 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][O:8][C:9]1[C:10]([CH3:16])=[CH:11][C:12]([NH2:15])=[CH:13][CH:14]=1.[ClH:17].[Cl:18][C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=2)[N:22]=[CH:21][N:20]=1>>[ClH:18].[ClH:17].[CH3:30][O:29][C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][C:25]=1[O:31][CH3:32])[N:22]=[CH:21][N:20]=[C:19]2[NH:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[C:10]([CH3:16])[CH:11]=1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: Cc1cc(N)ccc1OCc1ccccn1
Agent: Cl
Product: COc1cc2ncnc(Nc3ccc(OCc4ccccn4)c(C)c3)c2cc1OC
Yield: 60 %

Procedure:
Using an analogous procedure to that described in Example 1, 5-amino-2-tolyl 2-pyridylmethyl ether was reacted with 4-chloro-6,7-dimethoxyquinazoline hydrochloride to give 6,7-dimethoxy-4-[3-methyl-4-(2-pyridylmethoxy)anilino]quinazoline dihydrochloride salt in 60% yield, m.p. 239°-241° C.;
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]([F:21])([F:20])[F:19])=[CH:15][CH:16]=2)[N:11]=[CH:10][CH:9]=1.[CH3:22][O:23][C:24]([C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][CH:27]=1)=[O:25]>CN(C)C=O.C(OCC)(=O)C.O>[CH3:22][O:23][C:24]([C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([C:18]([F:21])([F:20])[F:19])=[CH:15][CH:16]=3)[N:11]=[CH:10][CH:9]=2)[CH:27]=1)=[O:25]
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2c1
Reactant: COC(=O)c1c[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1cn(-c2ccnc3cc(C(F)(F)F)ccc23)c2ccccc12
Temperature: 100 °C
Reaction time: 20 h
Yield: 86.4 %

Procedure:
1.04 g (7.5 mmol) of potassium carbonate and 0.695 g (3 mmol) of 4-chloro-7-(trifluoromethyl)quinoline are added to 0.525 g (3 mmol) of 3-methoxycarbonyl-1H-indole in 10 cm3 of dimethylformamide under an argon atmosphere. After stirring at a temperature in the region of 100° C. for 20 hours, the reaction mixture is cooled and diluted with 100 cm3 of ethyl acetate and 100 cm3 of water. The organic phase is separated off by settling and washed with twice 100 cm3 of water and 100 cm3 of saturated aqueous sodium chloride solution and then it is dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa), resulting in an orange-coloured oil. This oil is triturated in 20 cm3 of isopropyl ether and the resulting precipitate is filtered off, giving 0.96 g of 3-methoxycarbonyl-1-(7-(trifluoromethyl)quinol-4-yl)-1H-indole in the form of a yellow powder. Mass spectrum (EI): m/e 370 (M+•), m/e 339.
Reaction SMILES: [OH:1][CH2:2][C@@:3]12[C@@H:20]3[C@H:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C@@H:15]([O:21][Si:22]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:14][CH2:13]4)[CH2:10][CH2:9][C:8]1=[C:7]([CH3:41])[C:6](=[O:42])[CH2:5][CH2:4]2.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[CH3:41][C:7]1[C:6](=[O:42])[CH2:5][CH2:4][C@@:3]2([CH:2]=[O:1])[C:8]=1[CH2:9][CH2:10][C@@H:11]1[C@@H:20]2[CH2:19][CH2:18][C@@:16]2([CH3:17])[C@H:12]1[CH2:13][CH2:14][C@@H:15]2[O:21][Si:22]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CC1=C2CC[C@@H]3[C@H](CC[C@]4(C)[C@@H](O[Si](c5ccccc5)(c5ccccc5)c5ccccc5)CC[C@@H]34)[C@@]2(CO)CCC1=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: CC1=C2CC[C@H]3[C@@H]4CC[C@H](O[Si](c5ccccc5)(c5ccccc5)c5ccccc5)[C@@]4(C)CC[C@@H]3[C@@]2(C=O)CCC1=O
Reaction time: 0.5 h

Procedure:
To a solution of 19-hydroxy-4-methyl-17β-triphenylsiloxy-androst-4-en-3-one in acetone chilled to 10° C. is added one equivalent of Jones Reagent. After 30 minutes, the acetone layer is decanted and poured onto water with vigorous stirring. The solid is filtered, dried in a vacuum oven and crystallized from hexane to yield 4-methyl-17β-triphenylsiloxy-4-androstene-3,19-dione.
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:8]=[N:9][C:10]([O:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[C:17]([F:22])[CH:16]=2)=[C:11]([F:13])[CH:12]=1)(=O)=O.[F-].[CH2:24]([N+:28](CCCC)(CCCC)CCCC)CCC.C[Si](C#N)(C)C>C(#N)C>[F:22][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][C:18]=1[F:21])[O:14][C:10]1[N:9]=[CH:8][C:7]([CH2:6][C:24]#[N:28])=[CH:12][C:11]=1[F:13]
Reactant: CS(=O)(=O)OCc1cnc(Oc2ccc(F)c(F)c2)c(F)c1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[Si](C)(C)C#N
Agent: [F-]
Solvent: CC#N
Product: N#CCc1cnc(Oc2ccc(F)c(F)c2)c(F)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 100.7 %

Procedure:
To a solution of (6-(3,4-difluorophenoxy)-5-fluoropyridin-3-yl)methyl methanesulfonate (8 g, 11.28 mmol) and tetrabutylammonium fluoride (5.90 g, 22.56 mmol) in acetonitrile (100 mL) was added trimethylsilyl cyanide (3.02 mL, 22.56 mmol). The reaction mixture was stirred at 80° C. for 2 hr., and then concentrated under reduced pressure. The crude product was purified bysilica gel chromatography eluting with Hex/EtOAc (5:1) to give get 2-(6-(3,4-difluorophenoxy)-5-fluoropyridin-3-yl)acetonitrile (3 g, 89%).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15](O)=[O:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.N1C=CN=C1.[H-].[Na+].[NH2:39][C:40]1[S:41][S:42][C:43](=[S:45])[N:44]=1>O1CCCC1.O>[F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([NH:39][C:40]3[S:41][S:42][C:43](=[S:45])[N:44]=3)=[O:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1ccc(OCc2ccc(F)cc2)cc1
Reactant: Nc1nc(=S)ss1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(Cc1ccc(OCc2ccc(F)cc2)cc1)Nc1nc(=S)ss1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 33.6 %

Procedure:
2-{4-[(4-Fluorobenzyl)oxy]phenyl}acetic acid (1.00 g, 3.84 mmol) was dissolved in tetrahydrofuran (10 ml), and 1,1′-carbonyldiimidazole (0.748 g, 4.61 mmol) was added thereto. The imidazole mixture was stirred for 1 hour at room temperature. Sodium hydride (60% oil suspension 0.131 g, 3.27 mmol) was suspended in tetrahydrofuran (8 ml), and 3-amino-1,2,4-dithiazole-5-thione (0.491 g, 3.27 mmol) was added thereto. After being stirred for 30 minutes at 0° C., the reaction mixture, with the imidazole mixture added thereto, was stirred for 3 hours at room temperature. The mixture, with water added thereto, was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over MgSO4, and then concentrated. The obtained residue was purified by silica gel column chromatography (chloroform), to give 2-{4-[(4-fluorobenzyl)oxy]phenyl}-N-(3-thioxo-3H-1,2,4-dithiazol-5-yl)acetoamide (Compound 5) (0.431 g, 29%).
Reaction SMILES: [Br:1][CH2:2][C:3]1[C:4]([O:25]C)=[C:5]([CH2:11][CH2:12][C:13]2[CH:18]=[C:17]([O:19]C)[CH:16]=[C:15]([CH2:21][Br:22])[C:14]=2[O:23]C)[CH:6]=[C:7]([O:9]C)[CH:8]=1.C(#N)C.C(OCC)(=O)C>O>[CH2:12]([C:13]1[C:14](=[O:23])[C:15]([CH2:21][Br:22])=[CH:16][C:17](=[O:19])[CH:18]=1)[CH2:11][C:5]1[C:4](=[O:25])[C:3]([CH2:2][Br:1])=[CH:8][C:7](=[O:9])[CH:6]=1
Reactant: COc1cc(CBr)c(OC)c(CCc2cc(OC)cc(CBr)c2OC)c1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C1C=C(CBr)C(=O)C(CCC2=CC(=O)C=C(CBr)C2=O)=C1

Procedure:
0.85 g. (1.7 mmole) of 1,2-bis[3-(bromomethyl)-2,5-dimethoxyphenyl]ethane, prepared as described in Example IX above, was dissolved in 50 ml. of hot acetonitrile. This solution was cooled to a temperature just above the point at which it became cloudy and then there was added dropwise thereto a solution of 6.37 g. (11.6 mmole) of ceric ammonium nitrate in 8 ml. of water. Stirring of the mixed solution was continued for ten minutes after the addition of the ceric ammonium nitrate was complete, then the reaction mixture was diluted with water and extracted with methylene chloride. The organic extract was washed with water, dried over sodium sulfate and the solvent removed in vacuo to yield 0.75 g. of a dark brown solid. Trituration of this dark brown solid with a small quantity of ethyl acetate afforded 2,2'-ethylenebis[6-(bromomethyl)-p-benzoquinone] as a yellow-brown solid, the yield being 0.62 g. (83 percent of theoretical). Recrystallization from a mixture of ethyl acetate and hexane gave yellow-brown needles, melting point 146°-147° C. The infrared spectrum of the recrystallized material showed peaks at 1650, 1635 and 1615 cm-1, while the PNMR spectrum in deuterochloroform showed peaks at delta=2.72 (singlet, 4 protons, attributed to methylene protons), 4.25 (doublet, 4 protons, J=1.0 Hz., attributed to bromomethyl protons), 6.59 (doublet, 2 protons, J=2.2 Hz., attributed to protons on the quinone rings) and 6.85 (multiplet, 2 protons, attributed to protons on the quinone rings) ppm. The mass spectrum of the compound showed a peak at m/e 348 (M-80 for the formula C16H12O4Br2).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([O:17][CH2:18][C:19]([OH:21])=[O:20])=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.[C:22](O)([CH3:25])([CH3:24])[CH3:23].C(OCC)(=O)C>CCCCCC>[C:22]([O:20][C:19](=[O:21])[CH2:18][O:17][C:14]1[N:13]=[CH:12][C:11]([C:9](=[O:10])[NH:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[CH:16][N:15]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)O
Reactant: O=C(O)COc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)COc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Yield: 8 %

Procedure:
The titled compound was prepared from [5-(4-fluorophenylcarbamoyl)pyrimidin-2-yloxy]acetic acid using tert-butyl alcohol (9.6 mg, 0.13 mmol) as the source alcohol. Chromatography (1:1 ethyl acetate:hexane) through SiO2 yielded 5 mg (8%) of the titled compound. ESI-MS m/z 348 (MH+), 346 (M−H−).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])=[CH:4][CH:3]=1.[CH3:15][C:16]1[NH:20][CH:19]=[N:18][C:17]=1[CH:21]=[O:22].C([O-])([O-])=O.[K+].[K+].OC1C=CC=C2C=1N=CC=C2>CS(C)=O.C(#N)C.[Cu]I>[CH3:15][C:16]1[N:20]([C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]3=[O:14])=[CH:4][CH:3]=2)[CH:19]=[N:18][C:17]=1[CH:21]=[O:22]
Reactant: Cc1[nH]cnc1C=O
Reactant: O=c1ccccn1-c1ccc(I)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Solvent: CC#N
Product: Cc1c(C=O)ncn1-c1ccc(-n2ccccc2=O)cc1
Temperature: 130 °C
Reaction time: 16 h

Procedure:
1-(4-Iodophenyl)pyridin-2(1H)-one 6-1 (200 mg, 0.67 mmol) was dissolved in 4 mL DMSO in a sealed tube. To it were added 5-methyl-1H-imidazole-4-carbaldehyde (300 mg, 2.7 mmol), K2CO3 (470 mg, 3.4 mmol), CuI (65 mg, 0.34 mmol) and 8-hydroxyquinoline (50 mg, 0.34 mol). The mixture was stirred at 130° C. for 16 hrs. The mixture was diluted with 100 mL acetonitrile, well stirred, and filtered through a celite layer. The filtrate was concentrated and subjected to prep HPLC to isolate 5-methyl-1-(4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazole-4-carbaldehyde 6-2. MS found for C16H13N3O2 (M+H)+280.1.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[N:9][C:10]3[N:11]([N:13]=[CH:14][C:15]=3[C:16]3[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][CH:17]=3)[CH:12]=2)[CH:4]=[N:3]1.C1N=CN(C(N2C=NC=C2)=O)C=1.C1C=C[C:40]2N(O)N=[N:43][C:41]=2[CH:42]=1.C1(N)CC1>CN(C=O)C>[CH:41]1([NH:43][C:20](=[O:22])[C:19]2[CH:23]=[CH:24][C:16]([C:15]3[CH:14]=[N:13][N:11]4[CH:12]=[C:7]([C:5]5[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=5)[CH:8]=[N:9][C:10]=34)=[CH:17][CH:18]=2)[CH2:42][CH2:40]1
Reactant: On1nnc2ccccc21
Reactant: Cn1cc(-c2cnc3c(-c4ccc(C(=O)O)cc4)cnn3c2)cn1
Agent: NC1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: Cn1cc(-c2cnc3c(-c4ccc(C(=O)NC5CC5)cc4)cnn3c2)cn1
Temperature: 120 °C

Procedure:
4-[6-(1-Methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-3-yl]benzoic acid (50 mg, 0.16 mmol) was dissolved in DMF (2 mL). Resin bound CDI (288 mg, 0.4 mmol), HOBT (26 mg, 0.17 mmol), and cyclopropylamine (20 mg, 0.32 mmol) was added. The reaction was sealed and heated in the microwave at 120° C. for 20 minutes. The reaction was cooled to ambient temperature, filtered and purified by reverse phase chromatography to give N-cyclopropyl-4-[6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-3-yl]benzamide as a yellow solid: LC/MS [M+H]=359.0.
Reaction SMILES: N1CCCC1.C(NNC1(N=C=S)C=CC=CC1)=O.[CH:19]([NH:21][NH:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([N:32]([CH2:40][C:41]2[CH:46]=[CH:45]C=CC=2)CC2C=CC=CC=2)=[S:31])=[CH:25][CH:24]=1)=[O:20]>>[CH:19]([NH:21][NH:22][C:23]1[CH:24]=[CH:25][C:26]([NH:29][C:30]([N:32]2[CH2:40][CH2:41][CH2:46][CH2:45]2)=[S:31])=[CH:27][CH:28]=1)=[O:20]
Reactant: O=CNNc1ccc(NC(=S)N(Cc2ccccc2)Cc2ccccc2)cc1
Agent: O=CNNC1(N=C=S)C=CC=CC1
Solvent: C1CCNC1
Product: O=CNNc1ccc(NC(=S)N2CCCC2)cc1

Procedure:
Pyrrolidine (0.071 g, 0.001 mole) and 1-(2-formylhydrazino)phenyl isothiocyanate (0.19 g, 0.001 mole) were reacted according to the procedure described for NA-11 in Example 3. Yield 0.15 g (58 percent), m.p. 199°-201° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[N:17]=[CH:16][C:15]2[N:14]([CH3:18])[C:13](=[O:19])[C@@H:12]([CH2:20][CH3:21])[N:11]([CH:22]([CH3:24])[CH3:23])[C:10]=2[N:9]=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27].C(O)(C(F)(F)F)=O>>[CH2:20]([C@H:12]1[N:11]([CH:22]([CH3:23])[CH3:24])[C:10]2[N:9]=[C:8]([C:7]3[CH:6]=[CH:5][N:4]=[CH:3][C:2]=3[NH:1][S:26]([CH3:25])(=[O:28])=[O:27])[N:17]=[CH:16][C:15]=2[N:14]([CH3:18])[C:13]1=[O:19])[CH3:21]
Reactant: CS(=O)(=O)Cl
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(-c3ccncc3N)nc2N1C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC[C@@H]1C(=O)N(C)c2cnc(-c3ccncc3NS(C)(=O)=O)nc2N1C(C)C

Procedure:
The title compound was prepared similarly to the methods described in Example 114, with (R)-2-(3-aminopyridin-4-yl)-7-ethyl-8-isopropyl-5-methyl-7,8-dihydropteridin-6(5H)-one (Example 93) instead of (R)-2-(3-aminopyridin-4-yl)-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropteridin-6(5H)-one (Example 91) and with methane sulfonylchloride instead of chloromethylcarbonate. LCMS (0.05% TFA): 405.2 m/z (M+H)+; 1H-NMR (DMSO-d6, 500 MHz): δ: 12.77 (bs, 1H), 8.89 (bs, 1H), 8.50 (bs, 1H), 8.41 (s, 1H), 8.23 (s, 1H), 4.55 (m, 1H), 4.49 (m, 1H), 3.34 (s, 3H), 3.26 (s, 3H), 1.87 (m, 1H), 1.77 (m, 1H), 1.44 (bs, 6H), 0.75 (bs, 3H).