Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:6]([CH2:15][C:16]#[CH:17])[C:5](=[O:18])[C:4]=1[CH2:19][C:20]([O:22]C)=O)[CH3:2].[NH4+:24].[OH-]>C1COCC1>[NH2:24][C:20]([CH2:19][C:4]1[C:5](=[O:18])[N:6]([CH2:15][C:16]#[CH:17])[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8][C:3]=1[CH2:1][CH3:2])=[O:22]
Reactant: C#CCn1c(-c2ccccc2)nc(CC)c(CC(=O)OC)c1=O
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C#CCn1c(-c2ccccc2)nc(CC)c(CC(N)=O)c1=O

Procedure:
To a stirred solution of 1.75 g (5.7 mmol) of 6-ethyl-5-methoxycarbonylmethyl-2-phenyl-3-propargyl-4(3H)-pyrimidinone (Compound 105) in 100 mL of THF was added 200 mL of concentrated aqueous NH4OH. The mixture was stirred for 2 weeks and the bulk of the THF was removed on the rotovap. The mixture was shaken with 100 mL of ethyl acetate and filtered. The solid collected was dried in a vacuum oven at 50° C. to afford 0.57 g of 5-aminocarbonylmethyl-6-ethyl-2-phenyl-3-propargyl-4(3H)-pyrimidinone (Compound 275), m.p. 196°-198° C. 1H-NMR (d6 -DMSO) 1.15(3H,t), 2.5(2H,q), 3.2(1H,t), 3.4(2H,s), 4.55(2H,d), 6.9(1H,br s), 7.35(1H,br s), 7.55(3H,m), 7.7(2H,m). The aqueous layer of the filtrate was extracted with two additional 100 mL portions of ethyl acetate. The combined ethyl acetate extracts were dried over MgSO4 and rotovaped to afford a further 0.54 g of Compound 275.
Reaction SMILES: [CH3:1][C:2]([CH3:24])([CH3:23])[CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=3)=[C:12]([F:13])[C:7]=2[N:6]([CH3:21])[C:5]1=[O:22].C(=O)([O-])[O-].[K+].[K+].Cl[C:32]1[CH:37]=[CH:36][N:35]=[CH:34][C:33]=1[C:38]#[N:39]>CS(C)=O>[CH3:1][C:2]([CH3:24])([CH3:23])[CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][C:11]([C:14]3[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=3)[O:20][C:32]3[C:33]([C:38]#[N:39])=[CH:34][N:35]=[CH:36][CH:37]=3)=[C:12]([F:13])[C:7]=2[N:6]([CH3:21])[C:5]1=[O:22]
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc(-c3cccc(O)c3)c(F)c21
Reactant: N#Cc1cnccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cn1c(=O)n(CC(C)(C)C)c2ccc(-c3cccc(Oc4ccncc4C#N)c3)c(F)c21
Reaction time: 0.33 h

Procedure:
A solution of 1-(2,2-dimethylpropyl)-4-fluoro-5-(3-hydroxyphenyl)-3-methyl-1,3-dihydro-2H-benzimidazol-2-one (7-15, 55 mg, 0.17 mmol) in DMSO (1 ml) was charged with Potassium carbonate (46.3 mg, 0.34 mmol, 2.0 eq) and 4-Chloro-3-cyanopyridine (34.8 mg, 0.25 mmol, 1.5 eq). The mixture was irradiated in a microwave at 160 deg C. for 20 min, then purified via reverse-phase HPLC (Acetonitrile/Water gradient with 0.1% TFA present) providing 4-{3-[1-(2,2-dimethylpropyl)-4-fluoro-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl]phenoxy}nicotinonitrile (8-1) as a tan solid-oil. 1H NMR (400 MHz, CDCl3) δ 8.81 (bs, 1H), 7.60-7.53 (m, 2H), 7.35 (s, 1H), 7.27 (s, 1H), 7.17-7.14 (m, 1H), 7.11-7.07 (m, 1H), 6.91 (d, 2H, J=8.24 Hz), 3.69 (s, 2H), 3.66 (s, 3H), 1.10 (s, 9H). LRMS m/z: Calc'd for C25H23FN4O2(M+H) 431.4, found 431.5.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.C([Li])CCC.[CH:22](=[O:24])[CH3:23]>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[S:10][C:9]([CH:22]([OH:24])[CH3:23])=[CH:8][C:6]=2[N:7]=1
Reactant: CC=O
Reactant: Clc1nc(N2CCOCC2)c2sccc2n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(O)c1cc2nc(Cl)nc(N3CCOCC3)c2s1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (500 mg) in THF (20 mL) at −78° C. was added n-butyllithium (0.94 mL of a 2.5 M solution in hexanes) and the reaction stirred at −78° C. for 1 h. Then, acetaldehyde (0.33 mL) was added and the reaction allowed to warm to room temperature over 16 h. The reaction was quenched with water (20 mL) and extracted into dichloromethane (2×20 mL). The combined organics were dried (MgSO4) and reduced in vacuo to give 1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-ethanol as a cream solid.
Reaction SMILES: [SH:1][C:2]1SC=[C:5]([C:7]2C=CC=[CH:9][CH:8]=2)[N:6]=1.F[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[N:6]1[CH:5]=[CH:7][CH:8]=[CH:9][C:2]=1[S:1][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Sc1nc(-c2ccccc2)cs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1ccc(Sc2ccccn2)cc1
Temperature: 65 °C
Yield: 145.7 %

Procedure:
4-(2-(4-Phenyl)thiazolyl)thio-1-nitrobenzene: A solution of 2-mercapto-4-phenylthiazole (4.0 g, 20.7 mmoles) in DMF (40 mL) was treated with 1-fluoro-4-nitrobenzene (2.3 mL, 21.7 mmoles) followed by K2CO3 (3.18 g, 23 mmol), and the mixture was heated at approximately 65° C. overnight. The reaction mixture was then diluted with EtOAc (100 mL), sequentially washed with water (100 mL) and a saturated NaCl solution (100 mL), dried (MgSO4) and concentrated under reduced pressure. The solid residue was triturated with a Et2O/hexane solution to afford the desired product (6.1 g): TLC (25% EtOAc/75% hexane) Rf 0.49; 1H-NMR (CDCl3) δ 7.35-7.47 (m, 3H), 7.58-7.63 (m, 3H), 7.90 (d, J=6.9 Hz, 2H), 8.19 (d, J=9.0 Hz, 2H).
Reaction SMILES: [CH2:1]([OH:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]([CH3:13])[CH3:12].[OH-:15].[Na+]>>[C:1]([OH:15])(=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]([CH3:12])[CH3:13]
Reactant: [OH-]
Reactant: CC(C)CCCCCCCCCCO
Agent: [Na+]
Product: CC(C)CCCCCCCCCC(=O)O
Temperature: 340 °C

Procedure:
180 kg of isotridecyl alcohol and 33.6 kg of NaOH were introduced into the 350 liter reactor and heated to 340° C. under a nitrogen pressure of 6 bar. The process was otherwise carried out as described in Example 1. The product obtained had an acid value of 240 and an OH value of 6.3.
Reaction SMILES: C[O:2][C:3](=[O:26])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:14](=[O:25])[N:15]([CH3:24])[C:16]([CH3:23])=[CH:17][C:18]=2[C:19]([F:22])([F:21])[F:20])=[CH:9][CH:8]=1)[NH2:5].[CH3:27][O:28][CH2:29][CH2:30][C:31]1([C:36](O)=[O:37])[CH2:35][CH2:34][CH2:33][CH2:32]1>>[CH3:27][O:28][CH2:29][CH2:30][C:31]1([C:36]([NH:5][C@H:4]([C:3]([OH:2])=[O:26])[CH2:6][C:7]2[CH:8]=[CH:9][C:10]([C:13]3[C:14](=[O:25])[N:15]([CH3:24])[C:16]([CH3:23])=[CH:17][C:18]=3[C:19]([F:22])([F:20])[F:21])=[CH:11][CH:12]=2)=[O:37])[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2c(C(F)(F)F)cc(C)n(C)c2=O)cc1
Reactant: COCCC1(C(=O)O)CCCC1
Product: COCCC1(C(=O)N[C@@H](Cc2ccc(-c3c(C(F)(F)F)cc(C)n(C)c3=O)cc2)C(=O)O)CCCC1

Procedure:
N-[[1-(2-methoxyethyl)cyclopentyl]carbonyl]-4-[1,6-dimethyl-4-(trifluoromethyl)-2-oxo-3-pyridinyl]-L-phenylalanine (mp 181-183° C.) was prepared from 4-[1,6-dimethyl-4-(trifluoromethyl)-2-oxo-3-pyridinyl]-L-phenylalanine methyl ester and 1-(2-methoxyethyl)cyclopentane carboxylic acid (obtained as described in WO 9910313) using the general procedures described in example 36. ES-HRMS m/e calcd for C26H31F3N2O5 (M+Na) 531.2077. found 531.2084.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][NH:9][C:10]([NH:12][CH:13]([CH3:15])[CH3:14])=O)[CH:3]=1.P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:10]([NH:12][CH:13]([CH3:15])[CH3:14])=[N:9][N:8]=[C:4]2[CH:3]=1
Reactant: CC(C)NC(=O)NNc1cc(Br)ccn1
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)Nc1nnc2cc(Br)ccn12
Temperature: 100 °C

Procedure:
A heterogeneous mixture of 1-(4-bromopyridin-2-yl)-4-isopropylsemicarbazide (0.315 g, 1.15 mmol) in phosphorous oxychloride (1.06 mL, 11.5 mmol) was heated at 100° C. for 2 h. The homogenous solution was allowed to cool to RT. Toluene (10 mL) was added and removed in vacuo (3×). DCM (20 mL) and saturated sodium bicarbonate (aq.) was added to the solid and stirred. The off-white solid was collected by filtration and washed with DCM to give 7-bromo-N-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-3-amine. MS (ESI, pos. ion) m/z: 255.2 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[F:29])[C:10]=3[N:11]=[C:12](S(C)(=O)=O)[N:13]=2)=[C:4]([CH3:30])[CH:3]=1.[NH2:31][C:32]([CH3:37])([CH2:35][OH:36])[CH2:33][OH:34]>C1COCC1>[OH:34][CH2:33][C:32]([NH:31][C:12]1[N:13]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=2[CH3:30])[C:9]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[F:29])[C:10]=2[N:11]=1)([CH3:37])[CH2:35][OH:36]
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1ccccc1F
Reactant: CC(N)(CO)CO
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1-c1nc(NC(C)(CO)CO)nc2c1ccc(=O)n2-c1ccccc1F
Reaction time: 72 h

Procedure:
The product of Example 59 (200 mg, 0.47 mmol) and 2-amino-2-methyl-1,3-propanediol (105 mg, 1 mmol) were combined in THF (10 mL) and stirred under Ar at 50° for 3 days. The solvents were removed in vacuo, and the residue was flash chromatographed with 0-25% EtOAc/CH2Cl2 Recrystallization from CH2Cl2/hexane gave the title compound as a white-crystalline solid. mp 160-162°, LC MS m/z=453 (MH+) Retention time=1.75 min
Reaction SMILES: C([O:3][P:4]([C:9]([C:11]1[S:12][C:13]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH3:25])=[CH:19][CH:18]=2)=[CH:14][CH:15]=1)=[O:10])(=[O:8])[O:5]CC)C.Br[Si](C)(C)C.CO>ClCCl>[CH2:24]([O:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][C:13]2[S:12][C:11]([C:9]([P:4](=[O:3])([OH:8])[OH:5])=[O:10])=[CH:15][CH:14]=2)=[CH:18][CH:19]=1)[CH3:25]
Reactant: CCOc1ccc(Cc2ccc(C(=O)P(=O)(OCC)OCC)s2)cc1
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Solvent: CO
Product: CCOc1ccc(Cc2ccc(C(=O)P(=O)(O)O)s2)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 32.6 %

Procedure:
To a solution of [5-(4-ethoxybenzyl)thiophen-2-carbonyl]phosphonic acid diethylester (0.54 g) in dichloromethane (14.0 mL) was added bromotrimethylsilane (0.9 mL) at 0° C., and the reaction mixture was stirred for 22 hr at room temperature. Methanol (1.0 mL) was added to the reaction mixture, and the mixture was stirred for 10 min at room temperature. After evaporation, the residue was crystallized from ethyl acetate to give the title compound (0.15 g) as a colorless crystal.
Reaction SMILES: I[CH:2]([CH3:4])[CH3:3].[NH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12]>>[CH:2]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12])([CH3:4])[CH3:3]
Reactant: Nc1ccccc1O
Reactant: CC(C)I
Product: CC(C)Nc1ccccc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The same procedure as in Example 1 was repeated except that the molar ratio of 2-iodopropane to o-aminophenol was changed to 1.0, the 2-iodopropane was dropped over 3 h, and then the reaction mixture was stirred at room temperature for 2 h.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:9]2)=[N:6][CH:7]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:26]=[CH:27][C:28]([C:31]#[CH:32])=[N:29][CH:30]=2)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH:26]=[CH:27][C:28]([C:31]#[C:32][C:2]3[CH:3]=[CH:4][C:5]([N:8]4[CH2:12][CH2:11][CH:10]([N:13]5[CH2:17][CH2:16][CH2:15][CH2:14]5)[CH2:9]4)=[N:6][CH:7]=3)=[N:29][CH:30]=2)=[CH:23][CH:24]=1
Reactant: Ic1ccc(N2CCC(N3CCCC3)C2)nc1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Product: Clc1ccc(-c2ccc(C#Cc3ccc(N4CCC(N5CCCC5)C4)nc3)nc2)cc1

Procedure:
Prepared according to general working method I from 1′-(5-iodo-pyridin-2-yl)-[1,3′]bipyrrolidinyl (172 mg, 0.50 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (107 mg, 0.50 mmol).
Reaction SMILES: N1C=CC=CC=1.[O:7]([C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17][OH:18])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(Cl)Cl.[O-2].[O-2].[O-2].[Cr+6]>[O:7]([C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=[O:18])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: OCc1cccc(Oc2ccccc2)c1
Agent: [Cr+6]
Agent: [O-2]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=Cc1cccc(Oc2ccccc2)c1
Reaction time: 0.25 h

Procedure:
Chromium trioxide (3.00 g.) was added to a stirred solution of pyridine (4.75 g.) in dry methylene chloride (75 ml.), and stirring was continued for a further 15 minutes. 3-Phenoxybenzyl alcohol (1 g.) in methylene chloride (5 ml.) was added, the mixture stirred for a further 15 minutes, decanted and the residue washed with diethyl ether (100 ml.). The filtrate was washed with 5% sodium hydroxide solution (3×50 ml), 2.5 NHCl (50 ml.) and 5% sodium carbonate solution (50 ml.) and dried over Na2SO4 to give 3-phenoxy-benzaldehyde. Alternatively the alcohol can be oxidized using Jones' reagent, a similar yield of aldehyde being obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]([CH3:18])[C:12]=1[C:13]1[N:14]=[CH:15][NH:16][CH:17]=1.Cl[C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][N:21]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]([CH3:18])[C:12]=1[C:13]1[N:14]=[CH:15][N:16]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][N:21]=2)[CH:17]=1
Reactant: Cn1nnc(-c2ccccc2F)c1-c1c[nH]cn1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nnc(-c2ccccc2F)c1-c1cn(-c2ccc(C(F)(F)F)cn2)cn1
Temperature: 120 °C
Yield: 76 %

Procedure:
A mixture of 4-(2-fluorophenyl)-5-(1H-imidazol-4-yl)-1-methyl-1H-1,2,3-triazole (70 mg, 0.288 mmol), 2-chloro-5-(trifluoromethyl)pyridine (53 mg, 0.288 mmol) and potassium carbonate (80 mg, 0.576 mmol) in DMF (2.0 mL) was stirred under Ar in a sealed flask and heated at 120° C. for 3 h. After cooling to room temperature the mixture was poured into water and extracted with ethyl acetate and the combined extracts washed with water, brine, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, 0 to 5% methanol in dichloromethane) afforded the title compound (85 mg, 76%) as an off white solid. MS: m/e=389.2 [M+H]+.
Reaction SMILES: [C:1]([O:7][C:8]1[C:9]([CH3:18])=[C:10]2[N:15]([CH:16]=1)[N:14]=[CH:13][N:12]=[C:11]2Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[F:19][C:20]1[CH:21]=[C:22]([NH:27][C:28]([NH:30][C:31](=[O:39])[CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[S:29])[CH:23]=[CH:24][C:25]=1[OH:26].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:1]([O:7][C:8]1[C:9]([CH3:18])=[C:10]2[N:15]([CH:16]=1)[N:14]=[CH:13][N:12]=[C:11]2[O:26][C:25]1[CH:24]=[CH:23][C:22]([NH:27][C:28]([NH:30][C:31](=[O:39])[CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[S:29])=[CH:21][C:20]=1[F:19])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: O=C(Cc1ccccc1)NC(=S)Nc1ccc(O)c(F)c1
Reactant: Cc1c(OC(=O)C(C)(C)C)cn2ncnc(Cl)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1c(OC(=O)C(C)(C)C)cn2ncnc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)c12
Temperature: 100 °C
Yield: 23.2 %

Procedure:
A vial was charged with 4-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl pivalate (13.3 mg, 0.19 mmol, Compound D of Example 1), 1-(3-fluoro-4-hydroxyphenyl)-3-(2-phenylacetyl)thiourea (16 mg, 0.05 mmol), cesium carbonate (spatula tip) and DMF (2 mL) and warmed to 100° C. for 26 h. The mixture was concentrated in vacuo. The residue was purified by flash chromatography to give the title compound (6.2 mg, 25%) as a white solid. 1H NMR (CDCl3) 12.46 (s, 1H), 8.50 (s, 1H), 7.88 (m, 3H), 7.40 (m, 4H), 7.31 (m, 2H), 3.75 (s, 3H), 2.44 (s, 3H), 1.40 (s, 9H); MS(ESI+) m/z 536 (M+H)+.
Reaction SMILES: N[C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([Br:10])=[CH:4][N:3]=1.N([O-])=O.[Na+].[ClH:15]>O>[Br:10][C:5]1[CH:6]=[C:7]([C:8]#[N:9])[C:2]([Cl:15])=[N:3][CH:4]=1
Reactant: N#Cc1cc(Br)cnc1N
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: N#Cc1cc(Br)cnc1Cl
Yield: 70 %

Procedure:
Compound 2 was dissolved in conc. HCl at 0° C., to which 1.1 equivalent of NaNO2 in H2O was added dropwise. Precipitation was formed. The white solid was filtered off, which gave the title compound 3. Overall yield was 70%.
Reaction SMILES: [CH:1](=O)[CH3:2].[C:4]1([CH3:11])[C:5]([CH3:10])=[CH:6][CH:7]=[CH:8][CH:9]=1>>[CH3:11][C:4]1[CH:9]=[C:8]([CH:4]([C:5]2[CH:6]=[CH:7][C:8]([CH3:9])=[C:1]([CH3:2])[CH:10]=2)[CH3:11])[CH:7]=[CH:6][C:5]=1[CH3:10]
Reactant: CC=O
Reactant: Cc1ccccc1C
Product: Cc1ccc(C(C)c2ccc(C)c(C)c2)cc1C

Procedure:
A process for preparing 3,4,3',4'-benzophenonetetracarboxylic dianhydride which comprises condensing an impure ortho-xylene mixture with acetaldehyde in contact with an acid catalyst to obtain an impure 1,1-bis(3,4-dimethylphenyl)ethane mixture, oxidizing the 1,1-bis(3,4-dimethylphenyl)ethane mixture with nitric acid to obtain a mixture of carboxylic acids, from which by crystallization and dehydration substantially pure 3,4,3',4'-benzophenonetetracarboxylic dianhydride is recovered.
Reaction SMILES: Br[C:2]([F:9])([F:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C1COCC1.[CH2:15]([C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=1)[CH2:16][CH3:17].Cl>[Zn].C(OCC)(=O)C>[F:8][C:2]([F:9])([CH:22]([OH:23])[C:21]1[CH:24]=[CH:25][C:18]([CH2:15][CH2:16][CH3:17])=[CH:19][CH:20]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCCc1ccc(C=O)cc1
Reactant: CCOC(=O)C(F)(F)Br
Agent: Cl
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCc1ccc(C(O)C(F)(F)C(=O)OCC)cc1
Reaction time: 1 h
Yield: 98 %

Procedure:
To a reaction vessel under a nitrogen atmosphere, 4.4 g of well-dried zinc, 10.3 g of ethyl bromodifluoroacetate (e-14) and 25 ml of THF were added, and the resultant mixture was cooled to 0° C. and stirred for 1 hour. The solution was slowly added dropwise in a temperature range of 20° C. to 25° C. to another reaction vessel under a nitrogen atmosphere in which 5.0 g of 4-propylbenzaldehyde (e-23) and 50 ml of THF were put, and the resultant mixture was further subjected to heating reflux for 4 hours. After cooling the resultant reaction mixture to 25° C., 200 ml of 1 N HCl aqueous solution and 200 ml of ethyl acetate were added to separate the mixture into an organic layer and an aqueous layer, and an extraction operation was performed. The resultant organic layer was isolated, and washed with water, a saturated aqueous solution of sodium hydrogencarbonate and water, and then the resultant solution was dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, the resultant residue was purified by a preparative isolation operation by means of column chromatography using a mixed solvent of heptane and ethyl acetate (heptane:ethyl acetate=20:1 in a volume ratio) as an eluent and silica gel as a filler, the resultant product was dried, and thus 9.0 g of ethyl 2,2-difluoro-3-hydroxy-3-(4-propylphenyl)propanoate (e-24) was obtained. A yield based on compound (e-23) was 97.8%.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH2:11]([NH2:14])[CH2:12][NH2:13]>>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:13][CH2:12][CH2:11][NH2:14])=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: NCCN
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Product: NCCNc1ccc([N+](=O)[O-])cc1
Reaction time: 24 h
Yield: 95.3 %

Procedure:
23.63 g (150 mmol) of 4-chloronitrobenzene are dissolved in 92.1 ml (1.38 mol) of ethylenediamine and heated to the boil under a nitrogen atmosphere. After 24 hours, the mixture is evaporated to dryness, and the crude product is suspended in 100 ml of 1 N sodium hydroxide solution and filtered off. Washing with water and drying under reduced pressure gives 25.9 g of N1-(4-nitrophenyl)ethane-1,2-diamine in the form of yellow crystals (ESI 182).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16](O)([CH3:17])[C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:9]2=[O:19])=[C:4]([F:20])[CH:3]=1.S(=O)(=O)(O)[O-].[K+]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16](=[CH2:17])[C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:9]2=[O:19])=[C:4]([F:20])[CH:3]=1
Reactant: CC1(O)C2=C(CCCC2)C(=O)N1c1ccc(Cl)cc1F
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: C=C1C2=C(CCCC2)C(=O)N1c1ccc(Cl)cc1F
Reaction time: 0.25 h

Procedure:
Twenty-one parts of 2-(4-chloro-2-fluorophenyl)-2,-3,4,5,6,7-hexahydro-3-hydroxy-3-methyl-1H-isoindol-1-one and one part of potassium bisulfate were heated with occasional stirring in an oil bath at 160°-170° for 15 minutes. The melt was poured into 200 parts of chloroform and washed successively with 100 parts of water, 50 parts of 10% aqueous sodium hydroxide and 100 parts of saturated aqueous sodium chloride solution. After drying the organic phase with anhydrous sodium sulfate, the solvent was evaporated at 300 mm. Hg at 50°. The residue was crystallized from 100 parts of absolute ethanol to yield 10.1 parts of 2-(4-chloro-2-fluorophenyl)-2,3,4,5,6,7-hexahydro-3-methylene-1H-isoindol-1-one melting at 84.0°-85.5°.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[C:7](=[O:18])[C@@H:6]([CH3:19])[N:5]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:4]=2[N:3]=1.C1C=C(Cl)C=C(C(OO)=[O:34])C=1>ClCCl>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([C:12]3[CH:13]=[N+:14]([O-:34])[CH:15]=[CH:16][CH:17]=3)[C:7](=[O:18])[C@@H:6]([CH3:19])[N:5]([CH:20]3[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]3)[C:4]=2[N:3]=1
Reactant: C[C@@H]1C(=O)N(c2cccnc2)c2cnc(Cl)nc2N1C1CCCCC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: C[C@@H]1C(=O)N(c2ccc[n+]([O-])c2)c2cnc(Cl)nc2N1C1CCCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.1 %

Procedure:
To a stirred solution of (7R)-2-chloro-8-cyclohexyl-7-methyl-5-(pyridin-3-yl)-7,8-dihydropteridin-6(5H)-one (51.2 mg, 0.143 mmol) in dichloromethane (2.5 mL) was added mCPBA (77% max, 33.7 mg, 0.150 mmol) at rt, and the solution was stirred at rt. More mCPBA (77% max, 10.2 mg, 0.0455 mmol) was added after 2.5 h, and stirring at rt was continued for additional 4 h. The reaction solution was diluted with dichloromethane (15 mL), washed with aq. NaHCO3 solution (20 mL×2), dried over Na2SO4, and concentrated in vacuo to give a crude residue, which was then purified by silica gel column chromatography (eluent: 5% methanol in dichloromethane) to give the desired product (0.116 mmol, 81% yield). 1H NMR (CDCl3, 400 MHz): δ 8.30 (d, J=6.8 Hz, 1H), 8.17 (s, 1H), 7.45 (dd, J=8.4, 6.8 Hz, 1H), 7.33 (s, 1H), 7.16 (d, J=8.4 Hz, 1H), 4.49 (q, J=6.8 Hz, 1H), 4.49-4.39 (me, 1H), 2.17-2.10 (m, 1H), 1.96-1.87 (m, 2H), 1.83-1.64 (m, 3H), 1.55-1.43 (m, 3H), 1.47 (d, J=6.8 Hz, 3H), 1.25-1.14 (m, 1H). MS(ES+): m/z=374.13/376.21 [MH+].
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.CCN(C(C)C)C(C)C.[CH:21]1([C:24]2[NH:28][N:27]=[C:26]([NH2:29])[CH:25]=2)[CH2:23][CH2:22]1>CCO>[Cl:11][C:4]1[N:3]=[C:2]([NH:29][C:26]2[CH:25]=[C:24]([CH:21]3[CH2:23][CH2:22]3)[NH:28][N:27]=2)[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: Nc1cc(C2CC2)[nH]n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: O=[N+]([O-])c1ccc(Cl)nc1Nc1cc(C2CC2)[nH]n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 97.8 %

Procedure:
To a solution of 2,6-dichloro-3-nitropyridine (0.67 g, 3.2 mmol) and DIEA (0.46 ml, 2.65 mmol) in EtOH (20 ml) was added a 5-cyclopropyl-1H-pyrazol-3-amine (0.26 g, 2.12 mmol) solution in EtOH (5 ml) dropwise at 0° C. After addition, the reaction mixture was stirred at 25° C. for 24 hours. The solvent was removed under reduced pressure and the resulted residue was purified by column chromatography (hexane:EtOAc=5:1) to give the title compound as a yellow solid (0.58 g, 98%). NMR (400 MHz) 12.36 (s, 1H), 10.20 (s, 1H), 8.54 (d, J=8.4 Hz, 1H), 7.01 (d, J=8.4 Hz, 1H), 6.39 (d, J=1.6 Hz, 1H), 1.94 (m, 1H), 0.96 (m, 2H), 0.71 (m, 2H). MS: Calcd.: 279; Found: [M+H]+ 280.