Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][NH2:4].[CH:12]1([C:19]2[CH:28]=[CH:27][C:22]3[NH:23][C:24](=[O:26])[O:25][C:21]=3[CH:20]=2)[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1>>[CH3:1][CH:2]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][NH:4][C@H:15]1[CH2:16][CH2:17][C@H:12]([C:19]2[CH:28]=[CH:27][C:22]3[NH:23][C:24](=[O:26])[O:25][C:21]=3[CH:20]=2)[CH2:13][CH2:14]1
Reactant: CC(CN)Cc1ccccc1
Reactant: O=C1CCC(c2ccc3[nH]c(=O)oc3c2)CC1
Product: CC(CN[C@H]1CC[C@H](c2ccc3[nH]c(=O)oc3c2)CC1)Cc1ccccc1

Procedure:
Condensation of 2-methyl-3-phenylpropylamine (830 mg, 3.97 mmol) and ketone 5 (918 mg, 3.97 mmol), following the procedure described in Example 1, gave compound 6-{trans-[4-(2-methyl-3-phenylpropylamino)-cyclohexyl]}-3H-benzoxazol-2-one (400 mg, 48%): 1H NMR (500 MHz, DMSO-d6): δ 7.32-7.21 (m, 2H), 7.19-7.17 (m, 4H), 7.03-6.98 (m, 2H), 2.77 (dd, J=13, 6 Hz, 1H), 2.55-2.34 (m, 7H), 1.99-1.97 (m, 2H), 1.84-1.80 (m, 2H), 1.50-1.47 (m, 2H), 1.18-1.05 (m, 2H), 0.88 (d, J=6 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8](=[O:12])[NH:7][C:6]=2[N:5]=[C:4](S(CC2C=CC=CC=2)(=O)=O)[N:3]=1.[Cl:23][C:24]1[CH:25]=[C:26]([CH2:32][SH:33])[CH:27]=[CH:28][C:29]=1[O:30][CH3:31]>>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8](=[O:12])[NH:7][C:6]=2[N:5]=[C:4]([S:33][CH2:32][C:26]2[CH:27]=[CH:28][C:29]([O:30][CH3:31])=[C:24]([Cl:23])[CH:25]=2)[N:3]=1
Reactant: COc1ccc(CS)cc1Cl
Reactant: Nc1nc(S(=O)(=O)Cc2ccccc2)nc2[nH]c(=O)cnc12
Product: COc1ccc(CSc2nc(N)c3ncc(=O)[nH]c3n2)cc1Cl
Yield: 102 %

Procedure:
The subtitled compound (1.36 g) was prepared by the method of Example 6, step (d) using the product from Example 6, step (b) (1.21 g) and 3-chloro-4-methoxy-benzenemethanethiol (0.72 g).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:23][C:24]1[C:32]([OH:33])=[CH:31][CH:30]=[C:29]2[C:25]=1[CH:26]=[C:27]([CH3:34])[NH:28]2>>[F:23][C:24]1[C:32]([O:33][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][N:3]=2)=[CH:31][CH:30]=[C:29]2[C:25]=1[CH:26]=[C:27]([CH3:34])[NH:28]2
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCCC1
Reactant: Cc1cc2c(F)c(O)ccc2[nH]1
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCCCN1CCCC1
Yield: 50.3 %

Procedure:
Using a procedure identical to that described in Example 237, 4-chloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (2 g, 6.22 mmol), (prepared as described for the starting material in Example 9), was reacted with 4-fluoro-5-hydroxy-2-methylindole (1.23 g, 7.46 mmol), (prepared as described for the starting material in Example 237), to give 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (1.41 g, 50%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][N:5]([C:7]2[CH:8]=[CH:9][C:10]3[O:11][CH2:12][C:13](=[O:17])[NH:14][C:15]=3[N:16]=2)[C:4](=[O:18])[CH2:3]1.[CH3:19][O:20][C:21]1[CH:30]=[C:29]2[C:24]([N:25]=[CH:26][C:27](=[O:36])[N:28]2[CH2:31][CH2:32][CH2:33][CH:34]=O)=[CH:23][CH:22]=1.S([O-])([O-])(=O)=O.[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>CN(C)C=O.ClCCl>[CH3:19][O:20][C:21]1[CH:30]=[C:29]2[C:24]([N:25]=[CH:26][C:27](=[O:36])[N:28]2[CH2:31][CH2:32][CH2:33][CH2:34][NH:1][CH:2]2[CH2:6][N:5]([C:7]3[CH:8]=[CH:9][C:10]4[O:11][CH2:12][C:13](=[O:17])[NH:14][C:15]=4[N:16]=3)[C:4](=[O:18])[CH2:3]2)=[CH:23][CH:22]=1
Reactant: COc1ccc2ncc(=O)n(CCCC=O)c2c1
Reactant: NC1CC(=O)N(c2ccc3c(n2)NC(=O)CO3)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc2ncc(=O)n(CCCCNC3CC(=O)N(c4ccc5c(n4)NC(=O)CO5)C3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.7 %

Procedure:
6-(4-Amino-2-oxopyrrolidin-1-yl)-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one (Reference Examples 19; 67 mg, 0.250 mmol) and 4-(7-methoxy-2-oxoquinoxalin-1(2H)-yl)butanal (Reference Examples 3; 58 mg, 0.250 mmol) were dissolved in N,N-dimethylformamide (4 ml). Sodium sulfate (800 mg) was added to this solution and the mixture was stirred at room temperature for 8 hours. Sodium triacetoxyborohydride (80 mg, 0.375 mmol) was added to the reaction solution and the mixture was stirred overnight at room temperature. After completion of the reaction, the reaction solution was diluted with dichloromethane, a saturated sodium hydrogen carbonate aqueous solution was added thereto and the mixture was stirred for 10 minutes. The organic layer was separated, washed sequentially with water (3×) and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform/methanol) to yield 93 mg (76%) of the title compound in the form of a yellow solid.
Reaction SMILES: C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:34]([O:38][C:39]([NH:41][C:42]1[S:46][C:45]([C:47]2[C:52]([F:53])=[CH:51][CH:50]=[CH:49][C:48]=2[F:54])=[N:44][C:43]=1[C:55]([OH:57])=O)=[O:40])([CH3:37])([CH3:36])[CH3:35].FC1C(N)CCCN(C2NN=CC=2[N+]([O-])=O)C1.[NH2:75][C:76]1[CH:77]=[N:78][N:79]([CH2:96][CH:97]([F:99])[F:98])[C:80]=1[N:81]1[CH2:87][CH2:86][CH:85]([F:88])[CH:84]([NH:89][C:90](=[O:95])[C:91]([F:94])([F:93])[F:92])[CH2:83][CH2:82]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:99][CH:97]([F:98])[CH2:96][N:79]1[C:80]([N:81]2[CH2:82][CH2:83][CH:84]([NH:89][C:90](=[O:95])[C:91]([F:94])([F:93])[F:92])[CH:85]([F:88])[CH2:86][CH2:87]2)=[C:76]([NH:75][C:55]([C:43]2[N:44]=[C:45]([C:47]3[C:52]([F:53])=[CH:51][CH:50]=[CH:49][C:48]=3[F:54])[S:46][C:42]=2[NH:41][C:39](=[O:40])[O:38][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:57])[CH:77]=[N:78]1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Reactant: Nc1cnn(CC(F)F)c1N1CCC(F)C(NC(=O)C(F)(F)F)CC1
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CCCN(c2[nH]ncc2[N+](=O)[O-])CC1F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)Nc1cnn(CC(F)F)c1N1CCC(F)C(NC(=O)C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.4 %

Procedure:
A solution of PyBOP (692 mg, 1.33 mmol) and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid from Example 25 (372 mg, 1.05 mmol) in DCM (40 mL) was stirred at room temperature for 30 min. A solution of Intermediate 51, N-(1-(4-amino-1-(2,2-difluoroethyl)-1H-pyrazol-5-yl)-5-fluoroazepan-4-yl)-2,2,2-trifluoroacetamide (354 mg, 0.95 mmol) and DIPEA (0.28 mL, 1.62 mmol) in DCM (40 mL) was added and the mixture stirred at room temperature for 16 hr. The mixture was diluted with DCM (50 mL) and washed with water (20 mL). The organic layer was separated, passed through a phase separation cartridge and concentrated under reduced pressure. Purification via silica gel column chromatography (0-5% MeOH/DCM) gave tert-butyl 4-(1-(2,2-difluoroethyl)-5-(4-fluoro-5-(2,2,2-trifluoroacetamido)azepan-1-yl)-1H-pyrazol-4-ylcarbamoyl)-2-(2,6-difluorophenyl)thiazol-5-ylcarbamate as an off-white solid (600 mg, 0.84 mmol) which was dissolved in HCl in 1,4-dioxane (4 M, 10 mL, 40.0 mmol) and MeOH (10 mL) and heated in a sealed pressure vessel behind a blast shield at 60° C. for 16 hr. The solvents were removed under reduced pressure and the residue re-dissolved in MeOH and loaded onto an SCX column. The column was washed with MeOH and eluted with 0-10% 7 N ammonia in MeOH/DCM to give 203 as an off-white solid (197 mg, 40% over two steps). 1H NMR (400 MHz, CDCl3) δ 8.75 (s, 1H), 8.00 (s, 1H), 7.37-7.29 (m, 1H), 7.09-6.99 (m, 2H), 6.31-6.01 (m, 3H), 4.56-4.28 (m, 3H), 3.39-3.13 (m, 5H), 2.32-2.17 (m, 1H), 2.14-1.94 (m, 2H), 1.77-1.64 (m, 1H). Alkyl NH2 not observed. LCMS (ES+) m/z 516 (M+1).
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:5]([OH:6])[CH:4]=1.C[C:13]1[CH:18]=[CH:17][C:16](S(OCCC#CCC)(=O)=O)=[CH:15][CH:14]=1>>[CH2:17]([O:6][C:5]1[CH:4]=[C:3]([CH:11]=[CH:10][C:7]=1[O:8][CH3:9])[CH:2]=[O:1])[CH2:18][C:13]#[C:14][CH2:15][CH3:16]
Reactant: COc1ccc(C=O)cc1O
Reactant: CCC#CCCOS(=O)(=O)c1ccc(C)cc1
Product: CCC#CCCOc1cc(C=O)ccc1OC
Yield: 49.9 %

Procedure:
Isovanillin (0.76 g, 5.0 mmol) was alkylated with hex-3-ynyl 4-methylbenzenesulfonate (1.9 g, 7.53 mmol) according to Procedure 4. The crude product was recrystallised from EtOAc/petrol to provide 3-(hex-3-ynyloxy)-4-methoxybenzaldehyde (0.58 g, 50%) as a colourless crystalline solid; mp 86.5-87.5° C.; δH (400 MHz, CDCl3) 1.13 (t, J=7.6 Hz, 3H, CH3), 2.17 (tq, J=7.6, 2.4 Hz, 2H, CH3CH2), 2.72 (tt, J=7.6, 2.4 Hz, 2H, OCH2CH2C), 3.95 (s, 3H, OCH3), 4.17 (t, J=7.6 Hz, 2H, OCH2), 6.98 (d, J5,6=8.0 Hz, 1H, H5), 7.44 (d, J2,6=1.6 Hz, 1H, H2), 7.47 (dd, J5,6=8.0, J2,6=1.6 Hz, 1H, H6), 9.85 (s, 1H, CHO); δC (100 MHz, CDCl3) 12.4, 14.1, 19.6, 56.2, 67.6, 74.5, 83.9, 110.8, 111.0, 126.9, 130.1, 148.6, 154.8, 190.8; vmax 1019, 1134, 1265, 1586, 1683, 2841, 2977 cm−1.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].CCOCC.[C:12]([C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:21])#[N:13].C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>O>[Cl:20][C:19]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:21])[C:14]=1[CH2:12][NH2:13]
Reactant: Cc1cccc(Cl)c1C#N
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Product: Cc1cccc(Cl)c1CN
Reaction time: 1 h

Procedure:
To a stirred mixture of 5.7 parts of lithium aluminum hydride in 20 parts of ether is added dropwise a solution of 15 parts of 2-cyano3-chlorotoluene in 140 parts of ether ar relfux temperature. After the addition is complete, stirring at reflux temperature is continued for one hour. The reaction mixture is cooled in an ice-bath and decomposed with 25 parts of water and with a 20% solution of potassium-sodium tartrate (450 parts). The aqueous phase is separated and extracted with ether. The combined ether layers are washed with water, dried, filtered and evaporated. The oily residue is distilled in vacuo, yielding 12 parts of 2-chloro-6-methylbenzylamine; bp. 113°-118° C at 18 mm. pressure.
Reaction SMILES: [N-:1]=[N+]=[N-].[Na+].C(OC([N:12]1[CH2:17][C@@H:16]([CH2:18]OS(C2C=CC(C)=CC=2)(=O)=O)[C@H:15]([C:30]2[CH:35]=[CH:34][C:33]([CH2:36][O:37][CH2:38][C@H:39]([O:41][CH2:42][CH3:43])[CH3:40])=[CH:32][CH:31]=2)[C@@H:14]([O:44][CH2:45][C:46]2[CH:47]=[CH:48][C:49]3[O:54][CH2:53][CH2:52][N:51]([CH2:55][CH2:56][CH2:57][O:58][CH3:59])[C:50]=3[CH:60]=2)[CH2:13]1)=O)(C)(C)C>CN1CCCN(C)C1=O.CC(OC)(C)C>[CH2:42]([O:41][C@H:39]([CH3:40])[CH2:38][O:37][CH2:36][C:33]1[CH:34]=[CH:35][C:30]([C@@H:15]2[C@@H:14]([O:44][CH2:45][C:46]3[CH:47]=[CH:48][C:49]4[O:54][CH2:53][CH2:52][N:51]([CH2:55][CH2:56][CH2:57][O:58][CH3:59])[C:50]=4[CH:60]=3)[CH2:13][NH:12][CH2:17][C@H:16]2[CH2:18][NH2:1])=[CH:31][CH:32]=1)[CH3:43]
Reactant: CCO[C@H](C)COCc1ccc([C@H]2[C@H](COS(=O)(=O)c3ccc(C)cc3)CN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)N(CCCOC)CCO3)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CN1CCCN(C)C1=O
Product: CCO[C@H](C)COCc1ccc([C@H]2[C@H](CN)CNC[C@@H]2OCc2ccc3c(c2)N(CCCOC)CCO3)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4.57 mmol of sodium azide are added to a solution of 0.91 mmol of (3R,4R,5S)-4-[4-((R)-2-ethoxy-propoxymethyl)-phenyl]-3-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-5-(toluene-4-sulfonyloxymethyl)-piperidine-1-carboxylic acid tert-butyl ester (example 5d) in 5 ml of 1,3-dimethyl-tetrahydro-pyrimidin-2-one (DMPU) under argon at 50° C. After 2 h, the reaction mixture is cooled to RT, diluted with TBME, washed successively with H2O (2×) and brine, dried over Na2SO4 and concentrated by evaporation. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F) as a pale yellow oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.27 (EtOAc/heptane 1:1); Rt=5.98 (gradient I).
Reaction SMILES: Br[C:2](Br)=[CH:3][CH2:4][CH:5]([N:8]1[CH:12]=[C:11]([C:13]2[C:14]3[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:15]=3[N:16]=[CH:17][N:18]=2)[CH:10]=[N:9]1)[CH2:6][CH3:7].C1COCC1.C([Li])CCC.O.Cl>CCCCCC>[CH2:6]([CH:5]([N:8]1[CH:12]=[C:11]([C:13]2[C:14]3[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:28])([CH3:29])[CH3:27])[C:15]=3[N:16]=[CH:17][N:18]=2)[CH:10]=[N:9]1)[CH2:4][C:3]#[CH:2])[CH3:7]
Reactant: CCC(CC=C(Br)Br)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: C#CCC(CC)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Temperature: -78 °C
Reaction time: 1 h
Yield: 75.8 %

Procedure:
A solution of 4-[1-(4,4-dibromo-1-ethylbut-3-en-1-yl)-1H-pyrazol-4-yl]-7-[2-(trimethylsilyl)-ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (20 mg, 0.00004 mol) (from Example 503 Step 1) in THF (1 mL, 0.01 mol) at −78° C. was treated with 2.5 M n-butyllithium in hexane (0.032 mL). The mixture was stirred at −78° C. for 1 h and then at room temperature for 1 h. The reaction was quenched with water (1 mL, 0.06 mol) and 1N HCl. The reaction was partitioned between water and ethyl acetate. The organic extract was washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to give 4-[1-(1-ethylbut-3-yn-1-yl)-1H-pyrazol-4-yl]-7-[2-(tri-methylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine as a semisolid (12 mg, 80%). LC/MS (M+H)+: m/z=396.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[O:29][C:30]1[CH:31]=[N:32][C:33]([F:36])=[CH:34][CH:35]=1)[CH2:5][O:6][C:7]1[CH:8]=[C:9]2[N:16](C(OC(C)(C)C)=O)[C:15]([CH3:25])([CH3:24])[CH2:14][N:10]2[C:11](=[O:13])[N:12]=1.C(O)(C(F)(F)F)=O>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[O:29][C:30]1[CH:31]=[N:32][C:33]([F:36])=[CH:34][CH:35]=1)[CH2:5][O:6][C:7]1[CH:8]=[C:9]2[NH:16][C:15]([CH3:25])([CH3:24])[CH2:14][N:10]2[C:11](=[O:13])[N:12]=1
Reactant: CC(C)(C)OC(=O)N1c2cc(OCc3ccc(Oc4ccc(F)nc4)c(F)c3)nc(=O)n2CC1(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)Cn2c(cc(OCc3ccc(Oc4ccc(F)nc4)c(F)c3)nc2=O)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 7-((3-fluoro-4-((6-fluoropyridin-3-yl)oxy)benzyl)oxy)-2,2-dimethyl-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate (130 mg, 0.260 mmol) in dichloromethane (DCM) (4 mL) was added TFA (1.00 mL, 13.0 mmol) at 25° C. The reaction mixture was stirred at 25° C. overnight, concentrated and diluted with ethyl acetate/saturated sodium bicarbonate solution. Organic layer was separated, washed with water then saturated brine, dried over sodium sulphate. Purification via preparative TLC (DCM/MeOH=10/1) afforded the desired product as a white solid.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[CH:5][C:6]([N:17]2[CH:21]=[CH:20][N:19]=[C:18]2[CH2:22]O)=[C:7]([CH:16]=1)[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9].[C:26]1(=[O:36])[NH:30][C:29](=[O:31])[C:28]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:27]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[F:25][C:2]([F:1])([F:24])[C:3]1[CH:4]=[CH:5][C:6]([N:17]2[CH:21]=[CH:20][N:19]=[C:18]2[CH2:22][N:30]2[C:26](=[O:36])[C:27]3=[CH:35][CH:34]=[CH:33][CH:32]=[C:28]3[C:29]2=[O:31])=[C:7]([CH:16]=1)[C:8]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:9]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=C(c1ccccc1)c1cc(C(F)(F)F)ccc1-n1ccnc1CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=C(c1ccccc1)c1cc(C(F)(F)F)ccc1-n1ccnc1CN1C(=O)c2ccccc2C1=O

Procedure:
In the manner given in Example 17, 5-(trifluoromethyl)-2-[2-(hydroxymethyl)imidazol-1-yl]benzophenone is treated with phthalimide and triphenylphosphine and finally with diethyl azocarboxylate to give 5-(trifluoromethyl)-2-[2-(phthalimidomethyl)imidazol-1-yl]benzophenone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8](Br)=[CH:7][C:4]=1[CH:5]=[O:6].[F:12][C:13]([F:25])([F:24])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1OB(O)O.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[C:13]([F:25])([F:24])[F:12])=[CH:7][C:4]=1[CH:5]=[O:6]
Reactant: COc1ccc(Br)cc1C=O
Reactant: OB(O)Oc1ccccc1C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(-c2ccccc2C(F)(F)F)cc1C=O
Temperature: 70 °C
Reaction time: 16 h
Yield: 71.5 %

Procedure:
In 70 ml of toluene were suspended 320 mg of 2-methoxy-5-bromobenzaldehyde, 570 mg of 2-trifluoromethylphenylboric acid, 45 mg of palladium acetate and 136 mg of tri-o-tollylphosphine under nitrogen atmosphere, and then, 3.3 ml of 2M aqueous sodium carbonate solution was added to the suspension, and a small amount of ethanol was further added thereto. The obtained solution was heated up to 70° C., and stirred for 16 hours. The reaction mixture was cooled to room temperature, and the formed black precipitates were removed by filtration. The filtrate was washed with an aqueous sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=10/1) and crystallized from diisopropyl ether and n-hexane to give 298 mg of 2-methoxy-5-(2-trifluoromethylphenyl)benzaldehyde.
Reaction SMILES: O1[C:5]2([CH2:15][CH2:14][C:8]3([CH2:12][C:11](=[O:13])[NH:10][CH2:9]3)[CH2:7][CH2:6]2)[O:4]CC1.O.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CC(C)=O>[CH2:9]1[C:8]2([CH2:7][CH2:6][C:5](=[O:4])[CH2:15][CH2:14]2)[CH2:12][C:11](=[O:13])[NH:10]1
Reactant: O=C1CC2(CCC3(CC2)OCCO3)CN1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CC(C)=O
Product: O=C1CCC2(CC1)CNC(=O)C2
Yield: 57.6 %

Procedure:
To a solution of 1,4-dioxa-10-aza-dispiro[4.2.4.2]tetradecan-11-one (3.95 g, 18.7 mmol) in 160 mL of acetone was added 16 mL of water and pyridinium p-toluenesulfonate (1.41 g, 5.61 mmol). The resulting mixture was stirred at reflux for 20 h. Then, it was cooled and concentrated. The crude was purified by silica gel column chromatography using a 5% MeOH:EtOAc mixture as eluent to afford 2-aza-spiro[4.5]decane-3,8-dione (1.80 g, 58%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[CH:6]=1.[H-].[Na+].Br[CH2:16][CH2:17][O:18][CH2:19][CH2:20]Br>CN(C=O)C>[CH3:1][O:2][C:3]([C:4]1([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[CH:6]=2)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:12]
Reactant: BrCCOCCBr
Reactant: COC(=O)Cc1cccc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C1(c2cccc(Br)c2)CCOCC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 77.8 %

Procedure:
A solution of (3-bromo-phenyl)-acetic acid methyl ester (0.6 g, 2.62 mmol) in dry N,N′-dimethylformamide is added to a stirred suspension of sodium hydride (60% in mineral oil, 0.26 g, 6.55 mmol) in dry N,N′-dimethylformamide at 0° C. and stirring is continued for 20 minutes. A solution of bis(2-bromoethyl)ether (0.39 mL, 3.14 mmol) in N,N-dimethylformamide is added drop-wise and the reaction mixture is stirred overnight, while warming to room temperature. The reaction is quenched with water, extracted twice with ethyl acetate, the combined extracts is washed with brine and water, dried over sodium sulfate, filtered and concentrated in vacuo to afford 4-(3-bromo-phenyl)-tetrahydro-pyran-4-carboxylic acid methyl ester (610 mg) used in the next step without further purification. LCMS: RT=2.81 minutes; MS: 299, 301 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[SH:9].Cl[CH2:11][C:12]1[N:13]=[CH:14][N:15]([CH2:17][CH2:18][CH3:19])[CH:16]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([S:9][CH2:11][C:12]2[N:13]=[CH:14][N:15]([CH2:17][CH2:18][CH3:19])[CH:16]=2)=[C:2]([CH:7]=1)[NH2:1]
Reactant: CCCn1cnc(CCl)c1
Reactant: Nc1cc(Cl)ccc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCn1cnc(CSc2ccc(Cl)cc2N)c1
Yield: 67 %

Procedure:
(1-propyl-1H-imidazol-4-yl)methanol (535 mg, 3.11 mmol) was first treated with SOCl2 (3 ml) in CH2Cl2 (5 ml) at 35° C. for 2 hrs. The solvent was removed to get a crude 4-(chloromethyl)-1-propyl-1H-imidazole. Then following General Procedure A, the title compound (587 mg, 67%) was prepared from 2-amino-4-chlorobenzenethiol (744 mg, 4.66 mmol), 4-(chloromethyl)-1-propyl-1H-imidazole, K2CO3 (2.1 g, 15.54 mmol) in DMF (10 ml).
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][C:8]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)=[N:9][C:10](N)=[C:5]2[C:4]([CH3:18])=[N:3]1.N([O-])=[O:20].[Na+]>S(=O)(=O)(O)O.O>[CH3:1][N:2]1[C:6]2=[N:7][C:8]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)=[N:9][C:10](=[O:20])[C:5]2=[C:4]([CH3:18])[NH:3]1
Reactant: O=N[O-]
Reactant: Cc1nn(C)c2nc(-c3ccncc3)nc(N)c12
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Cc1[nH]n(C)c2nc(-c3ccncc3)nc(=O)c1-2
Temperature: 25 °C
Reaction time: 24 h
Yield: 74.9 %

Procedure:
A solution of 1,3-dimethyl-6-(4-pyridyl)-pyrazolo[3,4-d]-pyrimidin-4-amine (1.99 g, 8.3 mmol) in 50% aqueous sulfuric acid (50 ml) at 0° C. was stirred for 20 minutes and sodium nitrite (5.7 g, 83.0 mmol) in water (25 ml) was added dropwise over 1 hour. The reaction mixture was allowed to warm to room temperature and was stirred for 24 hours. The mixture was poured into ice-water (500 ml) and a white solid was collected by filtration and washed with water, ethanol and finally ether. The solid residue was stirred in 15% KHCO3 (150 ml) for 20 minutes and the product was collected by filtration and washed with water, then ethanol and finally ether. The product was recrystallized from DMF to afford 1.5 g (76%) of 1,3-dimethyl-6-(4-pyridyl)-pyrazolo[3,4-d]-pyrimidin-4-one as a white solid, m.p. >301° C. when dried for 18 hours at 115° C. in high vacuum.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[CH:3]=1.O.[NH2:14][NH2:15]>C(O)C>[NH:14]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[CH:3]=1)[NH2:15]
Reactant: NN
Reactant: Cc1cc(Cl)c2ccccc2n1
Solvent: O
Solvent: CCO
Product: Cc1cc(NN)c2ccccc2n1
Temperature: 25 °C

Procedure:
A solution of 4-chloro-2-methylquinoline (5.01 g, 28.2 mmol) and 80% hydrazine hydrate (8 ml) solution was refluxed in ethanol (30 mL) for 8 h. The resulting solution was cooled to room temperature and the solid formed was collected by filtration, washed with ethanol, and dried to yield known 4-hydrazino-2-methylquinoline,54,55 4.712 g (79.70%); mp 195-197° C.; 1H NMR (DMSO-d6) δ 2.64 (3H, s, Me), 5.15 (2H, brs, exchangeable, NH2), 6.99 (1H, s, ArH), 7.58 (1H, t, J=7.6 Hz, ArH), 7.86 (1H, t, J=7.6 Hz, ArH), 7.85 (1H, d, J=8.4 Hz, ArH), 8.42 (1H, d, J=8.2 Hz, ArH), 10.64 (1H, s, exchangeable, NH), Anal. Calcd. for (C10H12N3.HCl): C, 57.28; H, 5.77; N, 20.04. Found: C, 57.28; H, 5.77; N, 20.04.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[C:12]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([Cl:29])[CH:22]=2)=[N:13][C:14]([S:17][CH3:18])=[N:15][CH:16]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:38])C=1>ClCCl>[CH2:1]([NH:8][C:9]([C:11]1[C:12]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([Cl:29])[CH:22]=2)=[N:13][C:14]([S:17]([CH3:18])=[O:38])=[N:15][CH:16]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(COc2nc(SC)ncc2C(=O)NCc2ccccc2)cc1Cl
Solvent: ClCCl
Product: COc1ccc(COc2nc(S(C)=O)ncc2C(=O)NCc2ccccc2)cc1Cl

Procedure:
N-benzyl-4-(3-chloro-4-methoxybenzyloxy)-2-(methylmercapto)pyrimidine-5-carboxamide (100 mg, 0.23 mmol) was dissolved in 10 mL of dichloromethane, m-CPBA (m-chloroperbenzoic acid, 40 mg, 0.23 mmol) was added and reacted at room temperature for 3 h, washed with water after the reaction is complete, extracted with dichloromethane, the organic layer was dried and dried by rotation to obtain yellow solid, and this product was directly used in the next reaction without purification.