Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[Br:32][C:33]1[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=1>>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:39]([C:36]4[CH:37]=[CH:38][C:33]([Br:32])=[CH:34][CH:35]=4)(=[O:41])=[O:40])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4ccc(Br)cc4)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and 4-bromo-benzenesulfonyl chloride. Purity (ELSD, based on MW=640.5)=100%.
Reaction SMILES: [N+:1]([C:4]1[NH:5][CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2].[CH:9]12[O:14][CH:10]1[CH2:11][CH2:12][CH2:13]2.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[OH:14][CH:10]1[CH2:11][CH2:12][CH2:13][CH:9]1[N:5]1[CH:6]=[CH:7][N:8]=[C:4]1[N+:1]([O-:3])=[O:2]
Reactant: C1CC2OC2C1
Reactant: O=[N+]([O-])c1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=[N+]([O-])c1nccn1C1CCCC1O
Reaction time: 20 h
Yield: 47.3 %

Procedure:
A suspension of 0.339 g (3 mmol) of 2-nitroimidazole, 30 ml of ethanol, 3.5 ml of cyclopentene oxide and 0.15 g of potassium carbonate was refluxed with stirring under nitrogen for 20 hr. A clear yellow solution resulted; this was evaporated and the residue dissolved in 50 ml of chloroform and filtered. The filtrate was evaporated to yield 0.28 g (47.3%) of the title compound. It was recrystallized from ethyl acetate, mp 109° C.
Reaction SMILES: BrC[C:3]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[Ca+2]>O1CCOCC1.O>[F:13][C:10]1[CH:9]=[C:4]2[C:3]([CH2:8][O:7][C:5]2=[O:6])=[CH:12][CH:11]=1
Reactant: COC(=O)c1cc(F)ccc1CBr
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: C1COCCO1
Solvent: O
Product: O=C1OCc2ccc(F)cc21
Yield: 91.4 %

Procedure:
A mixture of methyl 2-(bromomethyl)-5-fluorobenzoate (0.750 g, 3.04 mmol) and calcium carbonate (1.823 g, 18.21 mmol) in 1,4-dioxane (30 mL) and water (30.0 mL) was heated at reflux for 2.5 hr. The insoluble material was removed by filtration. The filtrate was concentrated under vacuum and then extracted with CH2Cl2 (4×30 mL). The combined extract was dried over anhydrous MgSO4. Removal of solvent under vacuum provided the desired product (0.423 g, 2.78 mmol, 92% yield) as a white solid.
Reaction SMILES: C([O:6][CH2:7][CH:8]1[O:12][N:11]=[C:10]([C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][N:14]=2)[CH2:9]1)(=O)CCC>CO>[Br:19][C:16]1[CH:17]=[CH:18][C:13]([C:10]2[CH2:9][C@H:8]([CH2:7][OH:6])[O:12][N:11]=2)=[N:14][CH:15]=1
Reactant: CCCC(=O)OCC1CC(c2ccc(Br)cn2)=NO1
Solvent: CO
Product: OC[C@H]1CC(c2ccc(Br)cn2)=NO1

Procedure:
(R,S)-[3-(5-Bromopyridin-2-yl)-4,5-dihydroisoxazol-5-yl]methanol (prepared by hydrolysis of Intermediate 9, 3.1 g) was dissolved in hot methanol (25 ml), it was then separated by chiral column (Chiral Pak AS) eluting with 30%, isopropanol in hexanes. The title compound [(−) isomer, 1.5 g)] which eluted first from the column was collected along with the (+) isomer (second peak, 1.18 g). Chiral HPLC analysis indicated <2% of the (+) isomer was present. [α]D=−125° (c=0.0076 g/ml in methanol).
Reaction SMILES: CCN=C=NCCCN(C)C.OC(C(F)(F)F)=O.[NH2:19][CH2:20][C:21]([NH:23][CH:24]1[CH2:27][N:26]([CH:28]2[CH2:33][CH2:32][CH:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:30][CH2:29]2)[CH2:25]1)=[O:22].[OH:40][C:41]1[CH:42]=[C:43]([C:50]([F:53])([F:52])[F:51])[CH:44]=[C:45]([CH:49]=1)[C:46](O)=[O:47]>>[OH:40][C:41]1[CH:49]=[C:45]([CH:44]=[C:43]([C:50]([F:51])([F:52])[F:53])[CH:42]=1)[C:46]([NH:19][CH2:20][C:21](=[O:22])[NH:23][CH:24]1[CH2:27][N:26]([CH:28]2[CH2:33][CH2:32][CH:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:30][CH2:29]2)[CH2:25]1)=[O:47]
Reactant: O=C(O)c1cc(O)cc(C(F)(F)F)c1
Reactant: NCC(=O)NC1CN(C2CCC(c3ccccc3)CC2)C1
Agent: CCN=C=NCCCN(C)C
Solvent: O=C(O)C(F)(F)F
Product: O=C(CNC(=O)c1cc(O)cc(C(F)(F)F)c1)NC1CN(C2CCC(c3ccccc3)CC2)C1

Procedure:
The title compound was prepared as a white solid from the EDCI coupling of 2-amino-N-[1-(4-phenyl-cyclohexyl)-azetidin-3-yl]-acetamide TFA salt (as prepared in Step D of Example 66) and 5-hydroxy-3-trifluoromethyl-benzoic acid (Alfa Aesar) using the procedure described in Step F of Example 1.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.[C:11]([O:16][CH2:17][CH3:18])(=[O:15])[C:12]([CH3:14])=O.C(O)(=O)C>C(O)C>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][N:10]=[C:12]([CH3:14])[C:11]([O:16][CH2:17][CH3:18])=[O:15])=[CH:5][CH:4]=1
Reactant: NNc1ccc(Br)cc1
Reactant: CCOC(=O)C(C)=O
Agent: Cl
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C(C)=NNc1ccc(Br)cc1
Temperature: 25 °C
Yield: 71 %

Procedure:
4-Bromophenylhydrazine hydrochloride (15 g), ethyl pyruvate (11 ml) and acetic acid (1 ml) were dissolved in ethanol and heated to reflux for 2 hours, then cooled to room temperature, resulting in precipitation of a yellow solid, which was filtered off and dried in vacuo to give the ethyl pyruvate 4-bromophenylhydrazone (16.3 g, 71%), mp 153-154°; NMR δ(CD3SOCD3) 1.23 (t, 3H), 2.03 (s, 3H), 4.18 (q, 2H), 7.19 (d, 2H), 7.40 (d, 2H), 9.88 (brs, 1H); M/z (−) 285 (M+), 283, 171, 169, 113.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C@H:12]2[CH2:17][CH2:16][C@@H:15]([OH:18])[CH2:14][CH2:13]2)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[O:19]1[CH:23]=[N:22][N:21]=[C:20]1[C:24]1[CH:29]=[CH:28][C:27](O)=[CH:26][CH:25]=1>>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C@H:12]2[CH2:13][CH2:14][C@H:15]([O:18][C:27]3[CH:26]=[CH:25][C:24]([C:20]4[O:19][CH:23]=[N:22][N:21]=4)=[CH:29][CH:28]=3)[CH2:16][CH2:17]2)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCN(C(=O)[C@H]2CC[C@@H](O)CC2)CC1
Reactant: Oc1ccc(-c2nnco2)cc1
Product: CC(C)N1CCN(C(=O)[C@H]2CC[C@H](Oc3ccc(-c4nnco4)cc3)CC2)CC1

Procedure:
According to the procedure described for example 1, the title compound had been synthesized from cis-(4-isopropyl-piperazin-1-yl)-(4-hydroxy-cyclohexyl)-methanone and 4-(1,3,4-oxadiazole-2-yl)-phenol. MS (m/e): 399.1 (MH+).
Reaction SMILES: [CH3:1][C:2]([CH2:10][CH3:11])([CH2:6][CH2:7][CH2:8][CH3:9])[C:3](O)=[O:4].S(Cl)([Cl:14])=O>>[CH3:1][C:2]([CH2:10][CH3:11])([CH2:6][CH2:7][CH2:8][CH3:9])[C:3]([Cl:14])=[O:4]
Reactant: O=S(Cl)Cl
Reactant: CCCCC(C)(CC)C(=O)O
Product: CCCCC(C)(CC)C(=O)Cl
Yield: 90.6 %

Procedure:
316 gm (2moles) of 2-methyl-2-ethyl-hexanoic acid were heated to boiling with 357 gm (3 moles) of thionyl chloride under agitation until the evolution of gas had ended. The surplus thionyl chloride was distilled off and the residue was fractionated in vacuo. 320 gm (90% of theory) of 2-methyl-2-ethyl-hexanoyl chloride of b.p. 78° C. at 13 mmHg were obtained.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[C@@H:9]([OH:14])[C@H:8]([N:15]3[CH2:19][C:18]([O:20][CH3:21])=[CH:17][C:16]3=[O:22])[C:7]=2[CH:23]=1)#[N:2].C(O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CS(O)(=O)=O>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[C@@H:9]([OH:14])[C@H:8]([N:15]3[CH2:19][C:18]([O:20][CH2:21][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:17][C:16]3=[O:22])[C:7]=2[CH:23]=1)#[N:2]
Reactant: OCc1ccccc1
Reactant: COC1=CC(=O)N([C@@H]2c3cc(C#N)ccc3OC(C)(C)[C@H]2O)C1
Agent: CS(=O)(=O)O
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](N2CC(OCc3ccccc3)=CC2=O)[C@@H]1O

Procedure:
Alternatively, a mixture of 6-cyano-3,4-dihydro-2,2-dimethyl-trans-3-hydroxy-4-(4-methoxy-2-oxo-3-pyrrolin-1-yl)-2H-1-benzopyran (0.7 g), benzyl alcohol (0.92 ml) and methanesulfonic acid (0.01 g) was refluxed for 2 hours in the presence of 3A molecular sieves. After cooling the molecular sieves were filtered off, the filtrate stirred with diethylether, the insoluble product filtered off and washed twice with diethylether, to give 6-cyano-3,4-dihydro-2,2-dimethyl-trans-3-hydroxy-4-(4-benzyloxy-2-oxo-3-pyrrolin-1-yl)-2H-1-benzopyran, m.p. 248° C.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([N:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[CH2:14][CH:13]([C:27](O)=[O:28])[CH2:12]2)=[O:10])[CH2:5][CH2:4]1)#[N:2].O[N:31]=[C:32]([NH2:38])[CH2:33][S:34]([CH3:37])(=[O:36])=[O:35]>>[CH3:37][S:34]([CH2:33][C:32]1[N:38]=[C:27]([CH:13]2[CH2:14][CH:15]([C:17]3[CH:18]=[CH:19][C:20]([C:23]([F:25])([F:24])[F:26])=[CH:21][CH:22]=3)[CH2:16][N:11]([C:9]([N:6]3[CH2:7][CH2:8][CH:3]([C:1]#[N:2])[CH2:4][CH2:5]3)=[O:10])[CH2:12]2)[O:28][N:31]=1)(=[O:36])=[O:35]
Reactant: N#CC1CCN(C(=O)N2CC(C(=O)O)CC(c3ccc(C(F)(F)F)cc3)C2)CC1
Reactant: CS(=O)(=O)CC(N)=NO
Product: CS(=O)(=O)Cc1noc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCC(C#N)CC3)C2)n1

Procedure:
100 mg (0.244 mmol) of 1-[(4-cyanopiperidin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 100A) and 40.9 mg (0.269 mmol) of N′-hydroxy-2-(methylsulphonyl)ethanimidamide were reacted according to the General Method 1. Yield: 31.2 mg (24% of theory).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:18])[NH:10][C@@H:11]([C@@H:14]([F:17])[CH2:15][CH3:16])[CH2:12]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N:21](CC)CC)C.CS(Cl)(=O)=O.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9](=[O:18])[NH:10][C@@H:11]([C@@H:14]([F:17])[CH2:15][CH3:16])[CH2:12][NH2:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC[C@H](F)[C@@H](CO)NC(=O)OCc1ccccc1
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC[C@H](F)[C@@H](CN)NC(=O)OCc1ccccc1
Reaction time: 0.5 h

Procedure:
A solution of benzyl[(2R,3S)-3-fluoro-1-hydroxypentan-2-yl]carbamate (2.4 g) in chloroform (40 mL) was cooled in ice, triethylamine (2 mL) and methanesulfonyl chloride (0.8 mL) were added thereto, and the mixture was stirred for 30 min. Saturated sodium hydrogen carbonate was added thereto, followed by extraction with chloroform and drying over anhydrous magnesium sulfate. After the desiccant was filterred off, the solvent was distilled off under reduced pressure, and the residue was dissolved in DMF (40 mL). Sodium azide (3.06 g) was added thereto, and the mixture was stirred at 60° C. for 2 hr. Water was added thereto, the resulting mixture was extracted with ethyl acetate, and the organic layer was washed with water and brine. After drying over anhydrous magnesium sulfate, the desiccant was filtered off, and the solvent was distilled off under reduced pressure. The residue was dissolved in THF (50 mL), triphenylphosphine (3.59 g) and water (10 mL) were added thereto, and the resulting mixture was stirred at room temperature overnight. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (silica gel cartridge, chloroform/methanol=98:2-80:20) to afford benzyl[(2R,3S)-1-amino-3-fluoropentan-2-yl]carbamate (2.34 g).
Reaction SMILES: CN(C)C[CH2:4][NH:5][C:6]([C@@H:8]([NH:20][C:21]([C:23]1[CH:42]=[CH:41][C:26]2[N:27]([CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)[C:28]([C:30]3[CH:34]=[CH:33][O:32][CH:31]=3)=[N:29][C:25]=2[CH:24]=1)=[O:22])[CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([OH:19])[CH:17]=2)[NH:12][CH:11]=1)=[O:7].[CH3:44][N:45]([CH2:47][CH2:48]CN)[CH3:46]>>[CH3:44][N:45]([CH3:46])[CH2:47][CH2:48][CH2:4][NH:5][C:6]([C@@H:8]([NH:20][C:21]([C:23]1[CH:42]=[CH:41][C:26]2[N:27]([CH:35]3[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]3)[C:28]([C:30]3[CH:34]=[CH:33][O:32][CH:31]=3)=[N:29][C:25]=2[CH:24]=1)=[O:22])[CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([OH:19])[CH:17]=2)[NH:12][CH:11]=1)=[O:7]
Reactant: CN(C)CCCN
Reactant: CN(C)CCNC(=O)[C@H](Cc1c[nH]c2ccc(O)cc12)NC(=O)c1ccc2c(c1)nc(-c1ccoc1)n2C1CCCCC1
Product: CN(C)CCCNC(=O)[C@H](Cc1c[nH]c2ccc(O)cc12)NC(=O)c1ccc2c(c1)nc(-c1ccoc1)n2C1CCCCC1

Procedure:
The carboxylic acid of example 133 was coupled to dimethylaminopropylamine under standard TBTU conditions to yield the title compound of example 136.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:4]=1[NH2:5].C(N(CC)CC)C.[C:20](Cl)(=[O:23])[CH2:21][CH3:22]>ClCCl>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:4]=1[NH:5][C:20](=[O:23])[CH2:21][CH3:22]
Reactant: COc1ccc([N+](=O)[O-])cc1N
Reactant: CCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)Nc1cc([N+](=O)[O-])ccc1OC
Yield: 98.1 %

Procedure:
2-methoxy-5-nitroaniline (1) (10.1 g, 60.0 mmol) in 250 mL dichloromethane at 0°-5° C. was treated with triethylamine (10.0 g, 100.0 mmol) and propionyl chloride (6.7 g, 6.3 mL, 72.0 mmol) for 1 hour and 0.5 h at room temperature (RT). Normal aqueous workup and removal of solvent gave a light yellow solid which was washed with hexane/EtOAc (9:1) to yield solid N-(2-Methoxy-5-nitro-phenyl)-propionamide (2) (13.2 g, 98%).
Reaction SMILES: CS([O:5][CH2:6][C@@H:7]([O:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][O:11]1)[CH3:8])(=O)=O.CC(C)([O-])C.[K+].[CH3:22][N:23]1[CH:27]=[CH:26][C:25]([NH:28][C:29]2[C:38]3[C:33](=[CH:34][CH:35]=[C:36]([O:39][C:40]4[N:45]=[CH:44][C:43](O)=[CH:42][CH:41]=4)[CH:37]=3)[N:32]=[CH:31][N:30]=2)=[N:24]1.Cl>O.CS(C)=O>[CH3:22][N:23]1[CH:27]=[CH:26][C:25]([NH:28][C:29]2[C:38]3[C:33](=[CH:34][CH:35]=[C:36]([O:39][C:40]4[CH:41]=[CH:42][C:43]([O:5][CH2:6][C@H:7]([O:9][CH:10]5[CH2:15][CH2:14][CH2:13][CH2:12][O:11]5)[CH3:8])=[CH:44][N:45]=4)[CH:37]=3)[N:32]=[CH:31][N:30]=2)=[N:24]1
Reactant: Cn1ccc(Nc2ncnc3ccc(Oc4ccc(O)cn4)cc23)n1
Reactant: C[C@@H](COS(C)(=O)=O)OC1CCCCO1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: C[C@H](COc1ccc(Oc2ccc3ncnc(Nc4ccn(C)n4)c3c2)nc1)OC1CCCCO1
Temperature: 100 °C
Reaction time: 24 h
Yield: 75.1 %

Procedure:
(2S)-2-(tetrahydro-2H-pyran-2-yloxy)propyl methanesulfonate (214 mg, 0.90 mmol) and potassium tert-butoxide (200 mg, 1.8 mmol) were added to a dimethyl sulfoxide solution (5 ml) of 6-({4-[(1-methyl-1H-pyrazol-3-yl)amino]quinazolin-6-yl}oxy)pyridin-3-ol (300 mg, 0.90 mmol) obtained in Example 6-3), and the reaction solution was stirred for 24 hours at 100° C. The reaction solution was cooled to room temperature, then water and aqueous 1 N hydrochloric acid solution (0.9 ml, 0.9 mmol) were added, and extracted with ethyl acetate. The organic layer was washed with saturated saline water, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=99:1) to obtain N-(1-methyl-1H-pyrazol-3-yl)-6-[(5-{[(2R)-2-(tetrahydro-2H-pyran-2-yloxy)propyl]oxy}pyridin-2-yl)oxy]quinazoline-4-amine (322 mg, yield: 75%) as a pale brown solid.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([SH:7])=[N:4][N:3]=1.[H-].[Na+].Cl[C:11]1[C:12]([C:17]#[N:18])=[N:13][CH:14]=[CH:15][N:16]=1>CN(C=O)C.C1C=CC=CC=1>[CH3:1][C:2]1[S:6][C:5]([S:7][C:11]2[C:12]([C:17]#[N:18])=[N:13][CH:14]=[CH:15][N:16]=2)=[N:4][N:3]=1
Reactant: Cc1nnc(S)s1
Reactant: N#Cc1nccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: Cc1nnc(Sc2nccnc2C#N)s1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
The title compound was prepared according to Example 1 by using 5-methyl-1,3,4-thiadiazole-2-thiol (264 mg, 2.00 mmol), NaH (60% dispersion in mineral oil, 88 mg, 2.20 mmol), and 3-chloropyrazine-2-carbonitrile (280 mg, 2.00 mmol) in DMF and benzene (6 ml, 1/1) by stirring at room temperature under nitrogen atmosphere for 6 hr.
Reaction SMILES: [F-:1].[K+].[C:3]([S:22][CH2:23][CH2:24][NH:25][C:26]([C:28]1[CH:39]=[CH:38][C:31]([CH2:32]OS(C)(=O)=O)=[CH:30][CH:29]=1)=[O:27])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O>C(#N)C>[F:1][CH2:32][C:31]1[CH:38]=[CH:39][C:28]([C:26]([NH:25][CH2:24][CH2:23][S:22][C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[O:27])=[CH:29][CH:30]=1
Reactant: [F-]
Reactant: CS(=O)(=O)OCc1ccc(C(=O)NCCSC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=C(NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccc(CF)cc1
Temperature: 65 °C
Reaction time: 0.08 h
Yield: 24.7 %

Procedure:
A solution of Kryptofix (Fluka, 15 mg, 40 μmol) in dry acetonitrile (200 μl) was added to solid potassium fluoride (2.3 mg, 80 μmol). The mixture was shaken for 5 min. The Kryptofix/KF-solution was added to a solution of methanesulphonic acid 4-[2-(tritylsulphanyl)ethylcarbamoyl]benzyl ester (21 mg, 40 μmol) in acetonitrile (400 μl). The mixture was heated at 65° C. for 10 min. An aliquot was analysed by HPLC (column Phenomenex Luna 3 μm C18(2) 50×4.60 mm; solvents: A=water/0.1% TFA and B=acetonitrile/0.1% TWA; gradient 40-80% B over 10 min; flow 2.0 ml/min, UV detection at 214 and 254 nm), showing complete conversion of starting material (tR 5.6 min) to a new product (tR 6.3 min). Purification by reverse phase preparative HPLC (column: Phenomenex Luna C18(2) 5 μm 250×21.2 mm, solvents: A=water/0.1% TFA and B=acetonitrile/0.1% TFA; gradient 40-80% B over 60 min; flow 10.0 ml/min, UV detection at 214 nm) gave 4.5 mg of white solid. The structure was confirmed by NMR spectroscopy.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([NH2:13])[CH:7]=1.C([O:17][C:18](=O)[CH:19]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)[C:20](=O)[CH2:21][CH3:22])C>>[CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:7]=1[C:18](=[O:17])[C:19]([CH2:24][C:25]1[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=1)=[C:20]([CH2:21][CH3:22])[NH:13]2
Reactant: CCOC(=O)C(Cc1ccc(OC)cc1)C(=O)CC
Reactant: COC(=O)COc1ccc(F)c(N)c1
Product: CCc1[nH]c2c(F)ccc(OCC(=O)OC)c2c(=O)c1Cc1ccc(OC)cc1

Procedure:
The title compound was prepared by the method of Preparation 1c using (3-amino-4-fluorophenoxy)acetic acid methyl ester and 2-(4-methoxybenzyl)-3-oxopentanoic acid ethyl ester.
Reaction SMILES: CN(C=O)C.[CH3:6][Si:7]([C:10]#[CH:11])([CH3:9])[CH3:8].Br[C:13]1[C:17]2[CH:18]=[CH:19][C:20]([N+:22]([O-:24])=[O:23])=[CH:21][C:16]=2[S:15][C:14]=1[C:25]([O:27][CH2:28][CH3:29])=[O:26]>C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C(N(CC)CC)C>[N+:22]([C:20]1[CH:19]=[CH:18][C:17]2[C:13]([C:11]#[C:10][Si:7]([CH3:9])([CH3:8])[CH3:6])=[C:14]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[S:15][C:16]=2[CH:21]=1)([O-:24])=[O:23]
Reactant: CCOC(=O)c1sc2cc([N+](=O)[O-])ccc2c1Br
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1sc2cc([N+](=O)[O-])ccc2c1C#C[Si](C)(C)C
Temperature: 80 °C
Reaction time: 1 h

Procedure:
DMF (20 ml), (trimethylsilyl)acetylene (5 ml), triethylamine (10 ml) and bis(triphenylphosphine)palladium (II) dichloride (420 mg, 0.6 mmol) were added to ethyl 3-bromo-6-nitro-1-benzothiophene-2-carboxylate obtained in Example (183b) (794 mg, 2.41 mmol) and copper (I) iodide (12 mg, 0.63 mmol), and the mixture was stirred at 80° C. for one hour. The reaction solution was concentrated under reduced pressure, diluted with ethyl acetate, washed with dilute hydrochloric acid and brine, and dried over anhydrous sodium sulfate. Following concentration under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/10) and recrystallized from an ethyl acetate/hexane solvent, to obtain 110 mg of the title compound as crystals.
Reaction SMILES: [H-].[Na+].[C:3]([O:10][CH3:11])(=[O:9])[CH2:4][C:5]([O:7][CH3:8])=[O:6].Br[CH:13]([CH2:22][CH2:23][CH2:24][CH3:25])[C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:15]>CS(C)=O>[CH3:8][O:7][C:5](=[O:6])[CH:4]([CH:13]([C:14](=[O:15])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:22][CH2:23][CH2:24][CH3:25])[C:3]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)CC(=O)OC
Reactant: CCCCC(Br)C(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCCC(C(=O)c1ccccc1)C(C(=O)OC)C(=O)OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Small portions of NaH (60%, 7.92 g, 198 mmol) are added to a solution of dimethyl malonate (22.6 ml, 198 mmol) in DMSO (100 mL) at 0° C. The ice bath is removed and the mixture stirred at room temperature for 2 hours. The solution is rechilled to 0° C. and a solution of 2-bromo-1-phenyl-hexan-1-one (2-1) (16.8 g, 66 mmol) in DMSO (50 mL) is added slowly. The ice bath is removed and the mixture stirred overnight. Water (500 mL) is added and the mixture is extracted with EtOAc (4×150 mL). The combined extracts are washed with brine (300 mL), dried (Na2SO4), and evaporated, to provide the product as a light yellow oil. LC-MS (M+1) 307. 1H NMR (δ, CDCl3) 7.98-8.02 (m, 2H), 7.46-7.60 (m,3H), 4.18-4.28 (m, 1H), 4.03-4.12 (m, 1H), 3.80 (s, 3H), 3.6.1 (s, 3H), 1.55-1.63 (m, 2H), 1.02-1.20 (m, 4H), 0.76 (t, J=0.72 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]([CH2:19][N:20]3C(=O)C4C(=CC=CC=4)C3=O)=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.O.NN>CO>[NH2:20][CH2:19][C:12]1[C:13]([C:15]([F:18])([F:17])[F:16])=[N:14][C:9]([NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[N:10][CH:11]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1cnc(Nc2cccc(Cl)c2)nc1C(F)(F)F
Agent: NN
Solvent: O
Solvent: CO
Product: NCc1cnc(Nc2cccc(Cl)c2)nc1C(F)(F)F
Temperature: 60 °C
Reaction time: 4.5 h

Procedure:
To the crude 2-({2-[(3-chlorophenyl)amino]-4-(trifluoromethyl)pyrimidin-5-yl}methyl)-1H-isoindole-1,3(2H)-dione obtained in Preparative Example 13 were added methanol (15 mL) and hydrazine monohydrate (0.125 mL) at room temperature, followed by stirring at 60° C. for 4.5 hours. The resulting precipitate was removed by filtration and the filtrate was concentrated, and then, the obtained residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to obtain 5-(aminomethyl)-N-(3-chlorophenyl)-4-(trifluoromethyl)pyrimidin-2-amine (105 mg) as a pale yellow powder.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)[CH:6]=[N:5]1.C1COCC1.[I-].[K+].[CH3:25][NH:26][CH3:27]>O>[CH3:25][N:26]([CH3:27])[CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)[CH:6]=[N:5]1
Reactant: CC1(C)OB(c2cnn(CCCl)c2)OC1(C)C
Reactant: CNC
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 25 °C
Reaction time: 48 h
Yield: 76 %

Procedure:
1-(2-Chloro-ethyl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (664 mg, 2.59 mmol) was dissolved in a 2M solution of dimethyl amine in THF (15.32 mL, 30.6 mmol) and stirred for 48 hrs at room temperature. A scoop of potassium iodide was added to the reaction flask and the mixture stirred at 75° C. for 48 hrs. The mixture was cooled, diluted with water and extracted with ethyl acetate. The organics were washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated to afford the title compound (519 mg, 76%). 1H NMR (300 MHz, CDCl3): δ 7.79 (d, 2H), 4.35 (t, 2H), 2.95 (t, 2H), 2.37 (s, 6H), 1.32 (s, 12H).