Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:14]=[C:13]([C:15]3[C:20]([Cl:21])=[CH:19][CH:18]=[C:17]([NH:22][CH2:23][CH:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[N:16]=3)[C:12]([Cl:30])=[CH:11][N:10]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.FC(F)(F)S(O[CH2:44][CH2:45][O:46][C:47]([F:50])([F:49])[F:48])(=O)=O>C(Cl)(Cl)Cl>[Cl:21][C:20]1[C:15]([C:13]2[C:12]([Cl:30])=[CH:11][N:10]=[C:9]([NH:8][C@H:5]3[CH2:6][CH2:7][C@H:2]([NH:1][CH2:44][CH2:45][O:46][C:47]([F:50])([F:49])[F:48])[CH2:3][CH2:4]3)[CH:14]=2)=[N:16][C:17]([NH:22][CH2:23][CH:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:18][CH:19]=1
Reactant: N[C@H]1CC[C@H](Nc2cc(-c3nc(NCC4CCOCC4)ccc3Cl)c(Cl)cn2)CC1
Reactant: O=S(=O)(OCCOC(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: FC(F)(F)OCCN[C@H]1CC[C@H](Nc2cc(-c3nc(NCC4CCOCC4)ccc3Cl)c(Cl)cn2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of N2′-(trans-4-aminocyclohexyl)-3,5′-dichloro-N6-((tetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridine-2′,6-diamine (45 mg, 0.10 mmol) and triethylamine (0.028 mL, 0.20 mmol) in chloroform (0.4 ml) was added 2-(trifluoromethoxy)ethyl trifluoromethanesulfonate (39 mg, 0.15 mmol). The mixture was stirred at ambient temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, purified by reverse phase HPLC, and lyophilized to give 29 mg of 3,5′-dichloro-N6-((tetrahydro-2H-pyran-4-yl)methyl)-N2′-(trans-4-(2-(trifluoromethoxy)ethylamino)cyclohexyl)-2,4′-bipyridine-2′,6-diamine as its TFA salt. LCMS (m/z): 562.4 (MH+), retention time=0.67 min.; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.07-1.32 (m, 4 H) 1.36-1.52 (m, 2 H) 1.58 (d, J=12.91 Hz, 2 H) 1.65-1.84 (m, 1 H) 2.07 (d, J=10.56 Hz, 4 H) 2.99-3.17 (m, 3 H) 3.23 (t, J=10.76 Hz, 2 H) 3.35 (br. s., 2 H) 3.64 (br. s., 1 H) 3.72-3.89 (m, 2 H) 4.34 (t, J=4.89 Hz, 2 H) 6.32-6.47 (m, 1 H) 6.49-6.65 (m, 1 H) 6.67-7.10 (m, 2 H) 7.49 (d, J=9.00 Hz, 1 H) 8.03 (s, 1 H) 8.75 (d, J=3.91 Hz, 1 H)
Reaction SMILES: C[O:2][C:3](=[O:40])[C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:13][CH:12]=2)=[C:6]([NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([C:36]([CH3:39])([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)[CH:5]=1.[Li+].[OH-]>C1COCC1.CO>[C:21]([O:20][C:18]([NH:17][C:14]1[CH:13]=[CH:12][C:11]([S:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:40])=[O:2])=[CH:5][C:6]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([C:36]([CH3:39])([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:16][CH:15]=1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: COC(=O)c1ccc(Sc2ccc(NC(=O)OC(C)(C)C)cc2)c(Nc2ncnc3nc(C(C)(C)C)ccc23)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(Sc2ccc(C(=O)O)cc2Nc2ncnc3nc(C(C)(C)C)ccc23)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 971.3 %

Procedure:
To a solution of 4-(4-tert-butoxycarbonylamino-phenylsulfanyl)-3-(7-tert-butyl-pyrido[2,3-d]pyrimidin-4-ylamino)-benzoic acid methyl ester (0.53 g, 0.1 mmol) in a mixture of THF (9 mL) and MeOH (3 mL) was added aqueous LiOH [prepared from LiOH monohydrate (0.21 g, 5.0 mmol) and H2O (3 mL)] dropwise at room temperature. The mixture was stirred at 50° C. for 4 hours, and then evaporated. The aqueous mixture was diluted with H2O, washed with AcOEt, and then carefully acidified to pH 4-5 with 10% HCl at 5° C. under stirring. The resulting solid was collected by filtration, washed with H2O, and dried at 60° C. overnight under reduced pressure to give the title compound as yellow powder (0.53 g, 99%).
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:11](=O)[NH:10][C:9](=[O:14])[N:8]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:7]=2[N:6]=[CH:5]1)[CH:2]=[CH2:3].P(Cl)(Cl)([Cl:22])=O>>[CH2:1]([N:4]1[C:12]2[C:11]([Cl:22])=[N:10][C:9](=[O:14])[N:8]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:7]=2[N:6]=[CH:5]1)[CH:2]=[CH2:3]
Reactant: O=P(Cl)(Cl)Cl
Reactant: C=CCn1cnc2c1c(=O)[nH]c(=O)n2CCCCC
Product: C=CCn1cnc2c1c(Cl)nc(=O)n2CCCCC
Yield: 71.2 %

Procedure:
A mixture of 7-allyl-3-pentyl-3,7-dihydro-1H-purine-2,6-dione (0.80 g, 3.0 mmol) and phosphoryl chloride (10.0 mL, 100 mmol) was refluxed for 2 h. The excess phosphoryl chloride was removed by vacuum distillation. The residue was diluted with ice-water, neutralized with solid K2CO3, and then extracted with DCM three times. The combined organic layers were dried, filtered and concentrated to provide the crude product (0.60 g), which was used for next step without further purification. LCMS calculated for C13H18ClN4O (M+H): 281.1. found: 281.1.
Reaction SMILES: [OH:1][C@@H:2]1[C@H:10]2[C@@:6]([CH3:15])([C@@H:7]([C@H:11]([CH3:14])C=O)[CH2:8][CH2:9]2)[CH2:5][CH2:4][CH2:3]1.O.O.P([O-])(O)(O)=O.[Na+].ClC1C=CC=C([C:31]([O:33]O)=[O:32])C=1>C(Cl)Cl>[CH:31]([O:33][C@H:11]([C@@H:7]1[C@:6]2([CH3:15])[C@H:10]([C@@H:2]([OH:1])[CH2:3][CH2:4][CH2:5]2)[CH2:9][CH2:8]1)[CH3:14])=[O:32]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C[C@H](C=O)[C@H]1CC[C@H]2[C@@H](O)CCC[C@]12C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: C[C@H](OC=O)[C@H]1CC[C@H]2[C@@H](O)CCC[C@]12C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 90.4 %

Procedure:
Under a nitrogen atmosphere, a solution of (S)-2-{(3R,3aR,7S,7aR)-octahydro-7-hydroxy-3a-methyl-1H-indene-3-yl}propanal (Compound 15: 1.85 g, 8.797 mmol) in methylene chloride (30 ml) was cooled in an ice bath, and sodium dihydrogen phosphate dihydrate (6.86 g, 43.99 mmol) was added thereto. Meta-chloroperbenzoic acid (3.50 g, 13.2 mmol, calculated as 65%) was added thereto over 10 minutes. The reaction solution was stirred in the ice bath for 30 minutes, and at 17° C. to 21° C. for 12.5 hours. The reaction mixture was transferred to a separatory funnel such that insoluble matters were not included therein (the reaction vessel was washed with ethyl acetate), and water (40 ml) and ethyl acetate were added thereto. The aqueous layer was extracted twice with ethyl acetate. The combined organic layer was washed with saturated aqueous sodium thiosulfate solution (45 ml), saturated aqueous sodium hydrogen carbonate solution (25 ml) and with saturated brine (50 ml), and dried over sodium sulfate, followed by evaporation under reduced pressure. The crude product (2.41 g) was purified by flash column chromatography to obtain (S)-1-{(3S,3aS,7S,7aR)-octahydro-7-hydroxy-3a-methyl-1H-indene-3-yl}ethyl formate (1.80 g).
Reaction SMILES: [Br-].[Br:2][C:3]1[CH:4]=[C:5]([CH2:9][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].O=[C:32]1[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]1>CN(C=O)C.CCOCC>[Br:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:32]2[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]2)[CH:6]=[CH:7][CH:8]=1
Reactant: Brc1cccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(Br)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.6 %

Procedure:
To [(3-bromophenyl)methyl](triphenyl)phosphonium bromide (1.13 mg, 2.2 mmol) in DMF (4 mL) was added NaH (52.8 mg, 2.2 mmol) after which the mixture was stirred at RT for 5 min before 1,1-dimethylethyl 4-oxo-1-piperidinecarboxylate (400 mg, 2.0 mmol) was added. This mixture was stirred at RT for 1 h. The resultant mixture was diluted with Et2O (25 mL), washed with H2O (12+2×8 mL), brine (8 mL), dried over NaSO4, and filtered. The filtrate was concentrated and purified with CombiFlash chromatograph to afford the title compound (0.2014 g, 28%). LC-MS m/z 352 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)=[CH2:2].[CH3:9][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C(O)(=O)C.[OH-].[Na+]>C(O)C>[CH3:9][N:10]1[CH2:15][CH2:14][N:13]([CH2:2][CH2:1][C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)[CH2:12][CH2:11]1
Reactant: C=Cc1ccncc1
Reactant: CN1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: CN1CCN(CCc2ccncc2)CC1
Temperature: 160 °C
Yield: 86 %

Procedure:
In a tube, 2 ml (19 mM) of 4-vinylpyridine, 3.16 ml (28.5 mM) of N-methylpiperazine, and 200 μl of acetic acid are mixed in 12 ml of ethanol. The tube is closed and heated for 10 minutes at 160° C. in a microwave oven. After cooling, 20 ml of 0.5N sodium hydroxide are added slowly and the mixture is extracted with dichloromethane. The separated organic phase is dried over magnesium sulphate and concentrated under reduced pressure. The product sought after is thus obtained as a yellow oil (yield=86%).
Reaction SMILES: C1C2C(CO[C:16]([NH:18][C@H:19]([C:43]([NH:45][CH2:46][CH2:47][C:48]3[CH:55]=[CH:54][C:52]([OH:53])=[C:50]([OH:51])[CH:49]=3)=[O:44])[CH2:20][C:21](=[O:42])[NH:22][C:23]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:17])C3C(=CC=CC=3)C=2C=CC=1.[OH:56][C:57]1[CH:58]=[C:59]([CH:63]=[CH:64][C:65]=1[OH:66])C(O)=O>>[OH:56][C:57]1[CH:58]=[C:59]([CH:63]=[CH:64][C:65]=1[OH:66])[C:16]([NH:18][C@H:19]([C:43]([NH:45][CH2:46][CH2:47][C:48]1[CH:55]=[CH:54][C:52]([OH:53])=[C:50]([OH:51])[CH:49]=1)=[O:44])[CH2:20][C:21](=[O:42])[NH:22][C:23]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)=[O:17]
Reactant: O=C(O)c1ccc(O)c(O)c1
Reactant: O=C(C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCCc1ccc(O)c(O)c1)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Product: O=C(C[C@H](NC(=O)c1ccc(O)c(O)c1)C(=O)NCCc1ccc(O)c(O)c1)NC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
The title compound was prepared from N-[Nα-(9-fluorenylmethoxycarbonyl)-Nγ-trityl-L-asparagyl]dopamine (1.3 g, 1.7 mmol, example 7, step A) as described for example 7 (step B) using 3,4-dihydroxybenzoic acid (402 mg, 2.6 mmol) instead of caffeic acid. The crude material was purified by flash chromatography using a solvent gradient from 30% to 60% EtOAc/CH2Cl2 containing 1% AcOH. The title compound was obtained as white crystals (579 mg, 52%).
Reaction SMILES: CC[C:3](C1C=CC=CC=1)=[S:4].Cl[CH2:12][C:13]([C:15]1[CH:16]=[C:17]([OH:22])[C:18](=[CH:20][CH:21]=1)[OH:19])=[O:14].C[S-].[Na+]>CO>[CH3:3][S:4][CH2:12][C:13]([C:15]1[CH:16]=[C:17]([OH:22])[C:18](=[CH:20][CH:21]=1)[OH:19])=[O:14]
Reactant: O=C(CCl)c1ccc(O)c(O)c1
Reactant: CCC(=S)c1ccccc1
Agent: C[S-]
Agent: [Na+]
Solvent: CO
Product: CSCC(=O)c1ccc(O)c(O)c1
Reaction time: 3 h

Procedure:
The procedure is as in Example 4 for the preparation of α-methylthioacetophenone, starting with a stirred solution of 4-(2-chloroacetyl)pyrocatechol (18.6 g) in methanol (200 cc). Sodium methanethiolate (7 g) is added in the course of 15 minutes at a temperature in the region of 20° C., and the mixture is left with stirring for 3 hours at the same temperature. 4-[2-(Methylthio)acetyl]pyrocatechol (14.5 g), m.p. 107° C., is thereby obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10](OS(C)(=O)=O)[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17]([OH:20])(=[S:19])[CH3:18].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([S:19][C:17](=[O:20])[CH3:18])[CH3:11])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(CNC(=O)OC(C)(C)C)OS(C)(=O)=O
Reactant: CC(O)=S
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)SC(C)CNC(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A solution of 11.9 g (47.0 mmol) crude methanesulfonic acid 2-tert-butoxycarbonylamino-1-methyl-ethyl ester in 100 ml DMF was added to a mixture of 5.0 g (1.4 equiv.) thioacetic acid and 15.3 g (1.0 equiv.) Cs2CO3 in 150 ml DMF. The reaction mixture was stirred for 4 h at 80° C. under argon and light protection. The mixture was poured into 300 ml water and extracted twice with 300 ml ethyl acetate each. The combined organic layers were washed with brine, dried over anhydrous MgSO4 and concentrated under reduced pressure. Purification by flash chromatography on silica gel (eluent: CH2Cl2) gave pure thioacetic acid S-(2-tert-butoxycarbonylamino-1-methyl-ethyl) ester as brown oil.
Reaction SMILES: ClC1C(F)=CC(F)=C(C=1)C(NS(C)(=O)=O)=O.[Cl:17][C:18]1[C:19](F)=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24].C12(CO)CC3CC(CC(C3)C1)C2.[CH3:47][C:48]1([CH3:57])[C@H:53]2[CH2:54][C@@H:49]1[CH2:50][CH2:51][C@H:52]2[CH2:55][OH:56]>>[Cl:17][C:18]1[C:19]([O:56][CH2:55][C@@H:52]2[CH2:51][CH2:50][C@H:49]3[CH2:54][C@@H:53]2[C:48]3([CH3:57])[CH3:47])=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24]
Reactant: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Reactant: CC1(C)[C@H]2CC[C@@H](CO)[C@@H]1C2
Agent: CS(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Agent: OCC12CC3CC(CC(C3)C1)C2
Product: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(OC[C@@H]2CC[C@H]3C[C@@H]2C3(C)C)cc1F

Procedure:
Following the procedure as described in Example 8 and making variations as required to replace 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide with 5-chloro-N—(N,N-dimethylsulfamoyl)-2,4-difluorobenzamide and adamantan-1-ylmethanol with ((1S,2R,5S)-6,6-dimethylbicyclo[3.1.1]-heptan-2-yl)methanol, the title compound was obtained as a colorless solid (0.12 g, 29%): 1H NMR (300 MHz, DMSO-d6) δ 11.76 (s, 1H), 7.72 (d, J=6.1 Hz, 1H), 7.26 (d, J=13.2 Hz, 1H), 4.12-4.05 (m, 2H), 2.87 (s, 6H), 2.38-2.37 (m, 1H), 2.13-1.90 (m, 6H), 1.56 (m, 1H), 1.18 (s, 3H), 1.00-0.92 (m, 4H); MS (ES−) m/z 431.1, 433.1 (M−1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[CH:36][C:4]=1[CH2:5][N:6]1[C:11]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17]([CH3:21])[C:16]([CH2:22][CH2:23]OS(C)(=O)=O)=[CH:15]3)=[C:10]([CH2:29][CH3:30])[CH:9]=[C:8]([C:31]([O:33][CH3:34])=[O:32])[C:7]1=[O:35].[N-:42]=[N+:43]=[N-:44].[Na+]>CS(C)=O.O>[N:42]([CH2:23][CH2:22][C:16]1[N:17]([CH3:21])[C:18]2[C:14]([CH:15]=1)=[CH:13][C:12]([C:11]1[N:6]([CH2:5][C:4]3[CH:36]=[CH:37][C:38]([O:40][CH3:41])=[CH:39][C:3]=3[O:2][CH3:1])[C:7](=[O:35])[C:8]([C:31]([O:33][CH3:34])=[O:32])=[CH:9][C:10]=1[CH2:29][CH3:30])=[CH:20][CH:19]=2)=[N+:43]=[N-:44]
Reactant: CCc1cc(C(=O)OC)c(=O)n(Cc2ccc(OC)cc2OC)c1-c1ccc2c(c1)cc(CCOS(C)(=O)=O)n2C
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCc1cc(C(=O)OC)c(=O)n(Cc2ccc(OC)cc2OC)c1-c1ccc2c(c1)cc(CCN=[N+]=[N-])n2C
Temperature: 80 °C
Yield: 72.7 %

Procedure:
To solution of methyl 1-(2,4-dimethoxybenzyl)-5-ethyl-6-(1-methyl-2-(2-(methylsulfonyloxy)ethyl)-1H-indol-5-yl)-2-oxo-1,2-dihydropyridine-3-carboxylate (309.6 mg, 0.53 mmol), prepared according to procedure described in Example 159 Step 10, in DMSO (2 mL) was added NaN3 (100 mg, 1.54 mmol). The reaction mixture was heated at 80° C. for 1.5 h until complete consumption of starting material was observed. The reaction mixture was then diluted with H2O and the product was extracted with DCM (3×10 mL). The combined organics were washed with NaCl (aqueous saturated, 5 mL) and dried over Na2SO4. Upon solvent removal, the residue was purified by column chromatography using EtOAc/hexanes (gradient 0-80%) to afford methyl 6-(2-(2-azidoethyl)-1-methyl-1H-indol-5-yl)-1-(2,4-dimethoxybenzyl)-5-ethyl-2-oxo-1,2-dihydropyridine-3-carboxylate (204.0 mg) in 73% yield. The product could not be completely separated from mesylate elimination by-product.
Reaction SMILES: N1C=CC=CC=1.P(Cl)(Cl)(Cl)(Cl)[Cl:8].[C:13]([CH:15]1[CH2:20][CH:19]2[CH2:21][CH2:22][CH:16]1[CH:17]=[CH:18]2)#[N:14]>C(Cl)(Cl)Cl>[Cl:8][C:15]1([C:13]#[N:14])[CH2:20][CH:19]2[CH2:21][CH2:22][CH:16]1[CH:17]=[CH:18]2
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: N#CC1CC2C=CC1CC2
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: N#CC1(Cl)CC2C=CC1CC2
Yield: 94.8 %

Procedure:
To a refluxing mixture of pyridine (14.2 g, 0.180 mol), phosphorus pentachloride (28.0 g, 0.135 mol), and chloroform (100 mL) was added drop-wise a solution of 5-cyanobicyclo[2,2,2]oct-2-ene (12 g, 90 mmol) in chloroform (50 mL). The resulting mixture was heated at reflux for 15 h, cooled, and poured onto ice. The organic layer was concentrated, and the residue was purified by chromatography on silica gel, eluting with mixtures of ethyl acetate (0.5% to 1%) in petroleum ether, to give 5-chloro-5-cyanobicyclo[2,2,2]oct-2-ene (14.3 g, 95% yield) as a white semisolid, 1H NMR (300 MHz, CDCl3) δ 1.3-1.5 (m, 3H), 2.02-2.18 (m, 2H), 2.51 (m, 1H), 2.72 (m, 1H), 3.12 (m, 1H), 6.22 (m, 1H), 6.41 (m, 1H); GCMS (m/z); 167.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:22][O:23][C:24]1[CH:31]=[C:30]([O:32][CH3:33])[C:29]([C:34]2[N:35]([CH3:43])[C:36]3[C:41]([CH:42]=2)=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:28][C:25]=1[CH:26]=O>CO.C(Cl)Cl>[CH3:22][O:23][C:24]1[CH:31]=[C:30]([O:32][CH3:33])[C:29]([C:34]2[N:35]([CH3:43])[C:36]3[C:41]([CH:42]=2)=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:28][C:25]=1/[CH:26]=[CH:2]/[C:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])(=[O:11])=[O:12])=[CH:8][CH:9]=1)=[O:3]
Reactant: COc1cc(OC)c(-c2cc3ccccc3n2C)cc1C=O
Reactant: CC(=O)c1ccc(S(=O)(=O)NO[Si](C)(C)C(C)(C)C)cc1
Solvent: CO
Solvent: ClCCl
Product: COc1cc(OC)c(-c2cc3ccccc3n2C)cc1/C=C/C(=O)c1ccc(S(=O)(=O)NO[Si](C)(C)C(C)(C)C)cc1
Yield: 19 %

Procedure:
The title compound was prepared in an analogous manner as Ex-1 using 4-acetyl-N-(tert-butyldimethylsiloxy)benzenesulfonamide (Ex-33A) and 2,4-dimethoxy-5-(1-methyl-1H-indol-2-yl)benzaldehyde (Ex-15A), 19% yield after preparative TLC (MeOH/CH2Cl2, 1:10), yellow solid, mp 129–131° C. 1H-NMR (300 MHz, CDCl3) δ 8.18 (d, J=15 Hz, 1H), 8.12 (d, J=8 Hz, 2H), 8.02 (d, J=8 Hz, 2H), 7.69 (s, 1H), 7.64 (d, J=8 Hz, 1H), 7.47 (d, J=15 Hz, 1H), 7.36 (d, J=7 Hz, 1H), 7.22–7.26 (m, 1H), 7.11–7.16 (m, 1H), 6.58 (s, 1H), 6.50–6.51 (m, 2H), 4.03 (s, 3H), 3.90 (s, 3H), 3.59 (s, 3H), 0.90 (s, 9H), 0.20 (s, 6H). HRMS (ESI) Calcd. for C32H39N2O6SSi: 607.2298 (M+H)+; Found: 607.2306.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC=CC=1.[CH2:15]([NH2:18])[CH:16]=C.C=O>C(O)C>[O:7]1[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=2[CH:16]=[CH:15][NH:18]1
Reactant: C=CCN
Reactant: Oc1ccccc1
Agent: C=O
Solvent: Cc1ccccc1
Solvent: CCO
Product: C1=Cc2ccccc2ON1
Yield: 75.5 %

Procedure:
At room temperature, phenol was dissolved in anhydrous ethanol; the pH was adjusted to 8-10; toluene, allyl amine and paraformaldehyde were added according to the molar ratio of phenolic hydroxyl group:amine group:aldehyde group of 1:0.8:1.5. After being homogeneously stirred, the mixture was heated and refluxed, reacted for 4 h to vacuum distill off ethanol, toluene, and placed in a cooling unit. Butanone was added to obtain a yellowish, translucent viscous body. The viscous body was washed, purified and dried to obtain a benzoxazine intermediate having the following structural formula, wherein the yield is 75.5%.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([NH2:7])[C:4]([NH2:8])=[N:3][CH:2]=1.[CH:9](O)=O>C(OC(OCC)OCC)C>[N:1]1[CH:6]=[C:5]2[C:4]([NH:8][CH:9]=[N:7]2)=[N:3][CH:2]=1
Reactant: O=CO
Reactant: Nc1cncnc1N
Solvent: CCOC(OCC)OCC
Product: c1ncc2nc[nH]c2n1
Yield: 100 %

Procedure:
A solution of pyrimidine-4,5-diamine (718 mg, 6.53 mmol) and HCOOH (0.36 mL) in triethoxymethane (19 mL) was stirred at 90° C. for 3.5 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 40:1 DCM/MeOH to give 9H-purine as a brown solid (784 mg, 100%). 1H NMR (300 MHz, DMSO-d6) δ 13.40 (br s, 1H), 9.12 (s, 1H), 8.92 (s, 1H), 8.60 (s, 1H). LCMS (ESI) m/z 121 (M+H)+.
Reaction SMILES: [CH:1]1([C:4]2[NH:5][CH:6]=[CH:7][N:8]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:16][N:17]([CH3:22])[S:18](Cl)(=[O:20])=[O:19]>ClCCl>[CH:1]1([C:4]2[N:5]([S:18]([N:17]([CH3:22])[CH3:16])(=[O:20])=[O:19])[CH:6]=[CH:7][N:8]=2)[CH2:3][CH2:2]1
Reactant: CN(C)S(=O)(=O)Cl
Reactant: c1c[nH]c(C2CC2)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)S(=O)(=O)n1ccnc1C1CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 67 %

Procedure:
Into a 500-mL round-bottom flask, was placed a solution of 2-cyclopropyl-1H-imidazole (compound 238.1, 12 g, 110.9 mmol) in dichloromethane (60 mL). Triethylamine (31.4 mL, 225.3 mmol), N,N-dimethylsulfamoyl chloride (13.2 mL, 121.87 mmol, 1.10 equiv) were added to the reaction. The reaction mixture was stirred for 4 h at room temperature, then quenched with 20 mL of water. The aqueous phase was extracted with 3×100 mL of dichloromethane. The combined organic layers were washed with 2×20 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:4) as eluent to furnish 16 g (67%) of the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[F:11].S(Cl)(Cl)=O.[CH:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Cl-].[Cl-].[Cl-].[Al+3].Cl>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:8])=[CH:4][C:3]=1[F:11]
Reactant: O=C(O)c1ccc(Br)c(F)c1
Reactant: c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: O=C(c1ccccc1)c1ccc(Br)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In an oven dried flask was added 4-bromo-3-fluorobenzoic acid (1.0 g, 0.0046 mol), thionyl chloride (0.65 mL, 0.0089 mol) and a drop of DMF and the reaction was refluxed for 2 h. The thionyl chloride was then distilled off and benzene (20 mL, 0.2 mol) and aluminum trichloride (0.576 g, 0.00432 mol) was added to the reaction mixture and the reaction was stirred at room temp for 1 h. The crude reaction mixture was poured onto ice and conc. HCl (15 mL). The organic layer was separated and the aqueous layer extracted with EtOAc. The combined organic phases were washed with 5% aq NaOH solution, water and dried (Na2SO4). The organic phase was concentrated in vacuo to give a residue which was purified by silica gel chromatography, eluting with 2% EtOAc in hexane. 1H NMR (400 MHz, CDCl3): δ=7.45-7.55 (m, 3H), 7.58 (dd, J=8.84, 1.77 Hz, 1H), 7.60-7.66 (m, 1H), 7.70 (dd, J=8.21, 6.69 Hz, 1H), 7.75-7.82 (m, 2H).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:8]2[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]2=[N:6][C:5]=1[C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1.[F:21][C:22]1[CH:27]=[C:26]([F:28])[N:25]=[C:24]([NH2:29])[N:23]=1>>[F:21][C:22]1[CH:27]=[C:26]([F:28])[N:25]=[C:24]([NH:29][CH2:3][C:4]2[N:8]3[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]3=[N:6][C:5]=2[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[N:23]=1
Reactant: Nc1nc(F)cc(F)n1
Reactant: Fc1ccc(-c2nc3ccc(F)cn3c2CCl)cc1
Agent: Cl
Product: Fc1ccc(-c2nc3ccc(F)cn3c2CNc2nc(F)cc(F)n2)cc1
Yield: 39 %

Procedure:
The title compound was prepared according to Method A and the experimentals described for compound 139 from 3-(chloromethyl)-6-fluoro-2-(4-fluorophenyl)imidazo[1,2-a]pyridine hydrochloride and 4,6-difluoropyrimidin-2-amine. (0.35 g, 39% yield). M/e+ 374.2 for C18H11F4N5 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([NH2:16])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[CH:4][CH:3]=1.Cl[C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([C:30]3[O:31][C:32]([C:35]([F:38])([F:37])[F:36])=[N:33][N:34]=3)[CH:28]=2)[N:23]=[CH:22][N:21]=1>>[F:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([NH:16][C:20]4[C:29]5[C:24](=[CH:25][CH:26]=[C:27]([C:30]6[O:31][C:32]([C:35]([F:38])([F:36])[F:37])=[N:33][N:34]=6)[CH:28]=5)[N:23]=[CH:22][N:21]=4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1nnc(-c2ccc3ncnc(Cl)c3c2)o1
Reactant: Nc1ccc2c(cnn2Cc2ccc(F)cc2)c1
Product: Fc1ccc(Cn2ncc3cc(Nc4ncnc5ccc(-c6nnc(C(F)(F)F)o6)cc45)ccc32)cc1

Procedure:
The title compound was prepared according to Procedure A from 1-(4-fluoro-benzyl)-1H-indazol-5-ylamine and 4-chloro-6-(5-trifluoromethyl-1,3,4-oxadiazol-2-yl)-quinazoline; δH [2H6]DMSO 11.91(1H, bs), 9.55(1H, s), 8.91(1H, s), 8.69(1H, dd), 8.23(1H, s), 8.14(2H, m), 7.88(1H, d), 7.69(1H, dd), 7.36(2H, m), 7.18 (2H, dd), 5.71(2H, s); m/z (M+1+) 506