Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:26]4[CH:27]=[C:28](Br)[CH:29]=[CH:30][CH:31]=4)[C:12]4[C:17]([C:18]=3[CH:19]=2)=[CH:16][C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:14][CH:13]=4)C=CC=CC=1.[NH2:33][C:34]1[CH:35]=[C:36]([C:42]#[N:43])[CH:37]=[C:38]([CH:41]=1)[C:39]#[N:40].[C:44](O[Na])([CH3:47])([CH3:46])C>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:42]([C:36]1[CH:35]=[C:34]([N:33]([C:8]2[CH:7]=[CH:19][CH:18]=[C:10]([N:11]3[C:12]4[CH:13]=[CH:14][C:15]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)=[CH:16][C:17]=4[C:27]4[C:26]3=[CH:31][CH:30]=[C:29]([C:46]3[CH:44]=[CH:47][CH:17]=[CH:12][CH:13]=3)[CH:28]=4)[CH:9]=2)[C:7]2[CH:8]=[CH:9][CH:10]=[CH:18][CH:19]=2)[CH:41]=[C:38]([C:39]#[N:40])[CH:37]=1)#[N:43]
Reactant: Brc1cccc(-n2c3ccc(-c4ccccc4)cc3c3cc(-c4ccccc4)ccc32)c1
Reactant: CC(C)(C)O[Na]
Reactant: N#Cc1cc(N)cc(C#N)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: N#Cc1cc(C#N)cc(N(c2ccccc2)c2cccc(-n3c4ccc(-c5ccccc5)cc4c4cc(-c5ccccc5)ccc43)c2)c1
Reaction time: 8 h
Yield: 50 %

Procedure:
9.0 g of carbazole from step (2b) from Example 2 above and 2.7 g 5-aminoisophthalonitrile were mixed in 50 mL toluene in nitrogen filled glove box. 0.2 g Pd2DBA3 and 0.09 g tri-t-butylphosphinewere added followed quickly by 1.81 g t-BuONa. The mixture was heated briefly to reflux then held at 80° C. overnight in the glove box with vigorous stirring. After cooling the reaction was chromatographed on silica using a gradient of DCM:hexanes (1:4 to 4:1) to elute the product which upon concentration and addition of hexanes precipitated the desired product in 50% yield (˜4 g) with structure confirmed by 1-H nmr spectroscopy.
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]([NH:21][C@H:22]([CH2:26][CH3:27])[C:23]([NH2:25])=[O:24])=[N:7][C:8]=1[NH:9][C:10]1[S:14][N:13]=[C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:11]=1)#[N:2].[OH-].[Na+].OO.CC(O)=[O:34]>CCO.CS(C)=O>[NH2:25][C:23](=[O:24])[C@H:22]([NH:21][C:6]1[N:7]=[C:8]([NH:9][C:10]2[S:14][N:13]=[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:11]=2)[C:3]([C:1]([NH2:2])=[O:34])=[N:4][CH:5]=1)[CH2:26][CH3:27]
Reactant: CC(=O)O
Reactant: CC[C@@H](Nc1cnc(C#N)c(Nc2cc(-c3ccccc3)ns2)n1)C(N)=O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CS(C)=O
Product: CC[C@@H](Nc1cnc(C(N)=O)c(Nc2cc(-c3ccccc3)ns2)n1)C(N)=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
The compound (R)-2-(5-cyano-6-(3-phenylisothiazol-5-ylamino)pyrazin-2-ylamino)butanamide (8 mg, 0.021 mmol) was dissolved in EtOH (1 mL) and DMSO (0.5 mL), aq. 1N NaOH (0.5 mL) and aq. H2O2 (30%, 0.5 mL) were added. The mixture was stirred at room temperature for 20 min. HOAc (0.1 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (5 mg). MS found for C18H19N7O2S as (M+H)+ MS 398.2. UV: λ=UV 201.1, 267.7, 321.9 nm.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[O:17](S(C(F)(F)F)(=O)=O)[S:18]([C:21]([F:24])([F:23])[F:22])(=O)=[O:19]>C(Cl)Cl>[C:4]([C:3]1[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:2]=1[NH:1][S:18]([C:21]([F:24])([F:23])[F:22])(=[O:19])=[O:17])(=[O:5])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: O=C(c1ccccc1)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Temperature: 25 °C
Yield: 90.4 %

Procedure:
To a solution of 2-amino-5-chlorobenzophenone (500 mg, 2.16 mmol) in anhydrous CH2Cl2 (30 mL) at 0° C. was added dropwise (CF3SO2)2O (545 μL, 3.24 mmol) in anhydrous CH2Cl2 (10 mL) over 10 min and the reaction allowed to warm to RT over 15 hours. The reaction mixture was washed with water, dried over MgSO4 and concentrated under vacuum. The residue was filtered through a pad of silica (eluting with CH2Cl2/PE, 7:3) to afford N-(2-benzoyl-4-chlorophenyl)trifluoromethanesulfonamide 25 (710 mg, 90%), as a pale yellow solid. 1H n.m.r. (200 MHz, CDCl3) δ 7.80-7.69, m, 3H; 7.66-7.51, m, 5H. HRMS (M+) 362.9928.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:26])[C:4](=[O:25])[C:5]([C:17]2[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=2)[CH:20]=O)([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH:14]([F:16])[F:15])=[CH:9][CH:8]=2)[N:6]=1.[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl.C(O)(=O)C>[NH2:1][C:2]1[N:3]([CH3:26])[C:4](=[O:25])[C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH:14]([F:15])[F:16])=[CH:9][CH:8]=2)([C:17]2[CH:24]=[CH:23][CH:22]=[C:19]([CH2:20][N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH:18]=2)[N:6]=1
Reactant: CN1C(=O)C(c2ccc(OC(F)F)cc2)(c2cccc(C=O)c2)N=C1N
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CN1C(=O)C(c2ccc(OC(F)F)cc2)(c2cccc(CN3CCCC3)c2)N=C1N
Yield: 82.9 %

Procedure:
A small vial (10 ml) was charged with 3-[2-Amino-4-(4-difluoromethoxy-phenyl)-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl]-benzaldehyde (69 mg, 192 μmol) and 1,2-dichloroethane (DCE, 1 ml). To this was added one-third of a solution of pyrrolidine (41 mg, 0.576 mmol) in 1,2-dichloroethane (3.00 ml). After stirring overnight at room temperature sodium triacetoxyborohydride (58 mg, 270 μmol) was added followed by 1 drop of glacial acetic acid (˜12 mg), then after another 20 hours 1N sodium hydroxide (1 ml) was added and the mixture extracted with diethyl ether. The ethereal layer was concentrated by rotary evaporation, diluted with methanol and re-concentrated (repeated three times). Finally the oily residue was redissolved in diethylether/hexanes and concentrated, twice then placed under vacuum to give a white foam 66 mg (82%) 1H NMR (400 MHz, DMSO-d6) δ ppm 1.61 (t, J=3.4 Hz, 4H) 2.32 (t, J=6.5 Hz, 4H) 2.93 (s, 3H) 3.44 (s, 2H) 6.62 (br. s., 3H) 7.05 (d, J=8.8 Hz, 2H) 7.08-7.11 (m, 1H) 7.12 (t, J=74.18 Hz, 1H) 7.17 (t, J=7.6 Hz, 1H) 7.25 (t, J=4.6 Hz, 1H) 7.34 (s, 1H) 7.40 (d, J=8.8 Hz, 2H); MS (ES) m/z 413.3 [M−H]−
Reaction SMILES: CO[N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]1[C:12]([O:14]C)=O.[ClH:16].[NH2:17][C:18]([NH2:20])=[NH:19].[CH3:21][O-:22].[Na+]>CO>[ClH:16].[CH3:21][O:22][NH:19][C:18]([NH2:20])=[N:17][C:12]([C:4]1[NH:3][C:11]2[C:6]([CH:5]=1)=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:14]
Reactant: C[O-]
Reactant: N=C(N)N
Reactant: COC(=O)c1cc2ccccc2n1OC
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CONC(N)=NC(=O)c1cc2ccccc2[nH]1
Yield: 24.9 %

Procedure:
The reaction was carried out in a manner similar to Example 1 except for using 0.46 g (2.24 mmol) of methyl 1-methoxy-2-indolecarboxylate, 2.14 g (22.4 mmol) of guanidine hydrochloride and 15 ml of a methanol solution of 1.21 g (22.4 mmol) of sodium methoxide. Thus 0.15 g (24.9%) of 1-methoxy-2-indoloylguanidine hydrochloride was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl[C:14](Cl)([O:16]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.[C:32]1([CH3:61])[C:33]([C:38]([CH2:40][N:41]2[C:47]3[CH:48]=[C:49]([CH3:52])[CH:50]=[CH:51][C:46]=3[N:45]([C:53](=[O:58])[CH:54]=[C:55]([CH3:57])[CH3:56])[CH2:44][CH:43]([NH2:59])[C:42]2=[O:60])=[O:39])=[CH:34][CH:35]=[CH:36][CH:37]=1>O1CCCC1>[C:32]1([CH3:61])[C:33]([C:38]([CH2:40][N:41]2[C:47]3[CH:48]=[C:49]([CH3:52])[CH:50]=[CH:51][C:46]=3[N:45]([C:53](=[O:58])[CH:54]=[C:55]([CH3:57])[CH3:56])[CH2:44][CH:43]([NH:59][C:14]([NH:1][C:2]3[CH:12]=[CH:11][CH:10]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:3]=3)=[O:16])[C:42]2=[O:60])=[O:39])=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CCOC(=O)c1cccc(N)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)=CC(=O)N1CC(N)C(=O)N(CC(=O)c2ccccc2C)c2cc(C)ccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cccc(NC(=O)NC2CN(C(=O)C=C(C)C)c3ccc(C)cc3N(CC(=O)c3ccccc3C)C2=O)c1
Reaction time: 0.67 h
Yield: 106 %

Procedure:
Ethyl 3-aminobenzoate (290 mg) was dissolved in tetrahydrofuran (60 m), under ice-cooling triphosgene (175 mg) was added, triethylamine (151 μl) was added thereto five times every 3 minutes,a solution of 1-(2-toluoylmethyl)-2-oxo-3-amino-5-(3-methyl-2-butenoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (647 mg) in tetrahydrofuran (5 ml) was subsequently added, and the mixture was allowed to come to room temperature and stirred for 2 hours and 40 minutes. The reaction mixture was concentrated under reduced pressure, water was added, and extracted with methylene chloride. The organic layer was successively washed with 1N hydrochloric acid and saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography(chloroform:ethyl acetate=5:1), to thereby obtain 373 mg of the titled compound.
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10].[N+:16]([O-])([OH:18])=[O:17].[NH4+].[OH-]>>[N+:16]([NH:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])([O-:18])=[O:17]
Reactant: O=[N+]([O-])O
Reactant: Nc1ccccc1C(=O)O
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: O=C(O)c1ccccc1N[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.4 %

Procedure:
To a solution of concentrated sulfuric acid (2 mL) was slowly added 2-aminobenzoic acid (CXXIV) (1.0 g, 7.24 mmol). A mixture of concentrated sulfuric acid (1.5 mL) and fuming nitric acid (1.5 mL) was then slowly added and the reaction was stirred at room temperature overnight. The reaction mixture was poured into crushed ice and treated with aqueous NH4OH until pH 3.0. The yellow-orange solid was washed with cold water and dried to produce 2-(nitroamino)benzoic acid (CXXV) as a yellow solid (1.0 g, 5.46 mmol, 75.4% yield). The crude product was used for the next step without further purification. ESIMS found for C7H6N2O4 m/z 183.9 (M+H).
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:10](Cl)(=[O:17])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>>[CH2:1]([NH:9][C:10]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCN
Reactant: CCCCCCC(=O)Cl
Product: CCCCCCCCNC(=O)CCCCCC

Procedure:
Octylamine was acrylated with one equivalent of heptanoyl chloride to provide N-octylhexanecarboxamide. The amide was reduced by reaction with diborane in tetrahydrofuran to provide N-heptyloctylamine. To a cold stirred solution of 19.79 g. of N-heptyloctylamine and 23.4 g. of sodium carbonate in 82 ml. of acetone and 82 ml. of water was added dropwise over thirty minutes a solution of 13.7 ml. of acetyl chloride in 164 ml. of acetone. The reaction mixture was stirred for twelve hours following complete addition, after which time the solvent was removed by evaporation under reduced pressure. The residual oil was dissolved in diethyl ether and washed with water and with 2 N hydrochloric acid. The ethereal solution then was dried and the solvent was removed by evaporation to provide 22.48 g. of N-heptyl-N-octylacetamide.
Reaction SMILES: [CH:1]([CH:4]1[N:9]([C:10]2[N:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[C:13]([C:20](O)=[O:21])=[CH:12][N:11]=2)[CH2:8][CH2:7][N:6]2[C:23]3[CH:29]=[C:28]([S:30]([CH3:33])(=[O:32])=[O:31])[CH:27]=[CH:26][C:24]=3[N:25]=[C:5]12)([CH3:3])[CH3:2].C[N:35](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>CN(C=O)C.O>[CH:1]([CH:4]1[N:9]([C:10]2[N:15]=[C:14]([C:16]([F:17])([F:19])[F:18])[C:13]([C:20]([NH2:35])=[O:21])=[CH:12][N:11]=2)[CH2:8][CH2:7][N:6]2[C:23]3[CH:29]=[C:28]([S:30]([CH3:33])(=[O:32])=[O:31])[CH:27]=[CH:26][C:24]=3[N:25]=[C:5]12)([CH3:2])[CH3:3]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)C1c2nc3ccc(S(C)(=O)=O)cc3n2CCN1c1ncc(C(=O)O)c(C(F)(F)F)n1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)C1c2nc3ccc(S(C)(=O)=O)cc3n2CCN1c1ncc(C(N)=O)c(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.8 %

Procedure:
To a solution of 2-(1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidine-5-carboxylic acid (50 mg, 0.10 mmol) in DMF (10 mL) was added HATU (59 mg, 0.16 mmol), NH4CI (100 mg, 1.97 mmol), Et3N (30 mg, 0.31 mmol) under N2. The mixture was stirred at rt for 2 h. The mixture was diluted with water (15 mL) and extracted with EtOAc (3×15 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na2SO4, filtered, concentrated and purified by basic preparative HPLC to afford a racemic mixture of 2-(1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidine-5-carboxamide (13.4 mg, 27% yield) as a white solid. LC-MS m/z 483.1 [M+H]+. 1H NMR (CDCl3 400 MHz): δ 8.77 (s, 1H), 8.02 (s, 1H), 7.92-7.83 (m, 2H), 6.12 (d, J=8.4 Hz, 1H), 8.78 (brs, 2H), 5.48-5.38 (m, 1H), 4.41-4.34 (m, 1H), 4.25-4.12 (m, 1H), 3.87-3.77 (m, 1H), 3.10 (s, 3H), 2.52 (brs, 1H), 1.34 (d, J=6.8 Hz, 3H), 1.10 (d, J=6.8 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[O:16][CH3:17])[N:3]=1.B(O)(O)[C:19]1[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)[CH:5]=[C:4]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[O:16][CH3:17])[N:3]=1
Reactant: COc1ccc(Cl)cc1-c1cc(N)cc(Cl)n1
Reactant: Cc1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(Cl)cc1-c1cc(Nc2ccc(C)cc2)cc(Cl)n1
Reaction time: 60 h
Yield: 71.4 %

Procedure:
A mixture of 2-chloro-6-(5-chloro-2-methoxy-phenyl)-pyridin-4-yl-amine (715 mg, 2.65 mmol), p-tolylboronic acid (722 mg, 5.3 mmol), copper (II) acetate (962 mg, 5.3 mmol), triethylamine (1.5 ml, 10.6 mmol) and molecular sieves (4 angstrom) in dichloromethane (40 ml) was stirred under oxygen atmosphere for 60 hours. The mixture was filtered through a pad of celite under suction. The filtrate was purified by flash chromatography eluting with ethyl acetate-hexane (1:3 followed by 2:5) to provide the title compound (680 mg, 72% yield). 1H NMR (DMSO-d6) δ 2.32 (s, 3H, CH3), 3.91 (s, 3H, CH3), 6.73 (d, 1H, J=1.9 Hz, Ar), 7.14 (d, 2H, J=8.4 Hz, Ar), 7.18 (d, 1H, J=8.9 Hz, Ar), 7.22 (d, 2H, J=8.2 Hz, Ar), 7.44-7.48 (m, 2H, Ar), 7.75 (d, 1H, J=2.8 Hz, Ar), 9.1 (s, 1H, NH).
Reaction SMILES: Br[CH2:2][C:3]([CH2:5][O:6][C:7]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[CH2:4].C[Si]([C:30]#[N:31])(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>CC#N>[C:8]1([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:6][CH2:5][C:3](=[CH2:4])[CH2:2][C:30]#[N:31])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C[Si](C)(C)C#N
Reactant: C=C(CBr)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC#N
Product: C=C(CC#N)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.33 h
Yield: 80.6 %

Procedure:
To a solution of 11 (1.45 g; 3.69 mmol) and in dry CH3CN (37 mL) was added trimethylsilyl cyanide (0.49 mL; 3.69 mmol). Then 1 M tetrabutylammonium fluoride (TBAF) in THF solution (3.69 mL, 3.69 mmol) was added slowly at room temperature and the reaction was stirred for 20 min. Most solvents were evaporated and ethyl acetate (100 mL) and saturated aqueous NaHCO3 (30 mL) were added. The organic layer was washed by saturated aqueous NaCl and dried over anhydrous Na2SO4. After evaporation of the solvent, the residue was purified by flash column chromatography over silica gel using acetate-hexane (1:10) as the eluent to afford 12 as white solid (1.01 g; 64% yield): 1H NMR (400 MHz, CDCl3) δ 7.39-7.45 (m, 6H, six of ArH), 7.21-7.34 (m, 9H, nine of ArH), 5.31 (s, 2H, C═CH2), 3.64 (s, 2H, Ph3COCH2), 3.11 (s, 2H, CH2CN); 13C NMR (100 MHz, CDCl3) δ 143.3, 135.5, 128.2, 127.7, 126.9, 116.8, 114.7, 87.0, 65.7, 21.9, (10).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([CH2:41][CH2:42][O:43]S(C)(=O)=O)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:48][N:49]1[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1.CN(C=[O:59])C>>[CH:42]([OH:43])=[O:59].[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([CH2:41][CH2:42][N:52]2[CH2:53][CH2:54][N:49]([CH3:48])[CH2:50][CH2:51]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1CCNCC1
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4CCOS(C)(=O)=O)c4ccccc43)cn12
Reactant: CN(C)C=O
Product: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4CCN4CCN(C)CC4)c4ccccc43)cn12
Product: O=CO
Yield: 17 %

Procedure:
A yellow solution of Intermediate 127a (0.100 mmol) and N-methyl piperazine (0.056 mL, 0.50 mmol) in dry DMF (2 mL) was stirred at 75° C. for 2.5 h. The cooled solution was concentrated in vacuo, redissolved in MeOH (2 mL), applied to an SCX-2 cartridge (5 g) and washed with MeOH (20 mL). The product was eluted with 2M NH3 in MeOH (15 mL); concentration in vacuo left an orange solid. MDAP (Method 7) gave the title compound as an off-white solid (12 mg, 17%). LCMS (Method 5): Rt 3.36 min, m/z 669.5 [MH+]. 1H NMR (400 MHz, d6-DMSO): 0.91 (3H, d, J=6.3 Hz), 1.20 (9H, s), 1.49-1.56 (2H, m), 1.63-1.72 (2H, m), 1.75-1.85 (2H, m), 1.91-2.02 (2H, m), 2.04-2.10 (1H, m), 2.12 (3H, s), 2.14-2.21 (1H, m), 2.29 (4H, br s), 2.40 (4H, br s), 2.60 (2H, t, J=7.1 Hz), 2.91 (1H, ddd, J=12.2, 9.0, 4.0 Hz), 3.17 (1H, dt, J=12.0, 4.3 Hz), 3.28-3.36 (1H, m), 3.97 (2H, t, J=7.1 Hz), 4.87 (1H, td, J=8.5, 5.7 Hz), 5.54 (1H, t, J=4.3 Hz), 6.04 (1H, s), 6.95 (1H, d, J=8.6 Hz), 7.22 (1H, dd, J=9.8, 2.1 Hz), 7.29 (1H, td, J=7.2, 1.7 Hz), 7.34-7.41 (3H, m), 7.65 (1H, dd, J=9.8, 0.8 Hz), 7.71 (1H, d, J=2.1 Hz), 8.20 (1H, s), 8.27 (1H, s).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:22]3[C:17](=[N:18][CH:19]=[N:20][CH:21]=3)[NH:16][C:15]2=[O:23])[CH2:10][CH2:9]1)C1C=CC=CC=1.[ClH:24]>O1CCOCC1>[ClH:24].[NH:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:22]3[C:17](=[N:18][CH:19]=[N:20][CH:21]=3)[NH:16][C:15]2=[O:23])[CH2:10][CH2:9]1
Reactant: O=c1[nH]c2ncncc2n1C1CCN(Cc2ccccc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=c1[nH]c2ncncc2n1C1CCNCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 7-(1-benzylpiperidin-4-yl)-7,9-dihydro-8H-purin-8-one (1.2 g, 3.7 mmol) in 4N hydrogen chloride in dioxane (50 mL), was stirred vigorously at room temperature for 3 h. The reaction was concentrated in vacuo to give the title compound as a white solid. MS 220 (M+1)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:13][CH2:12][CH2:11][NH:10]1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:13][CH2:12][CH2:11][N:10]1[S:21]([C:18]1[CH:19]=[CH:20][C:15]([F:14])=[CH:16][CH:17]=1)(=[O:23])=[O:22]
Reactant: Cc1ccc(C2CCCN2)c(C)c1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Product: Cc1ccc(C2CCCN2S(=O)(=O)c2ccc(F)cc2)c(C)c1

Procedure:
The title compound, white solid, m.p. 134° C. and MS: m/e=333 (M+) was prepared in accordance with the general method of example 1e from (RS)-2-(2,4-dimethyl-phenyl)-pyrrolidine and 4-fluoro-benzenesulfonyl chloride.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22](O)=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][CH2:26][C:27]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:28]=1[C:29]([O:31][CH3:32])=[O:30]>>[CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:20])([CH3:21])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22]([NH:25][CH2:26][C:27]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:28]=1[C:29]([O:31][CH3:32])=[O:30])=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(F)ccc1CN
Reactant: CC1(C)OCCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Product: COC(=O)c1cc(F)ccc1CNC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCOC2(C)C

Procedure:
The title compound can be prepared from intermediate 27, 3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylic acid and intermediate 38, methyl 2-(aminomethyl)-5-fluorobenzoate. 1H NMR (CDCl3, 500 MHz) δ ppm: 1.61 (6H, s, gem-Me), 3.88 (3H, s, OMe), 3.97 (2H, t, J=5.5 Hz, CH2), 4.02 (2H, t, J=5.5 Hz, CH2), 4.73 (2H, d, J=6.7 Hz, NCH2), 5.25 (2H, s, OCH2), 7.19 (1H, dt, J=3, 8.5 Hz, Ar—H), 7.27-7.31 (3H, m, Ar—Hs), 7.48-7.50 (2H, m, Ar—Hs), 7.61 (1H, dd, J=5.5, 8.5 Hz, Ar—H), 7.66 (1H, dd, J=3, 9.5 Hz, Ar—H). LC/MS m/z 496 (M+H).
Reaction SMILES: [ClH:1].[CH2:2]=[CH:3][CH2:4][CH:5]([NH2:9])[C:6]([OH:8])=[O:7].[CH3:10]O>>[ClH:1].[CH3:10][O:7][C:6](=[O:8])[CH:5]([NH2:9])[CH2:4][CH:3]=[CH2:2]
Reactant: C=CCC(N)C(=O)O
Reactant: CO
Agent: Cl
Product: C=CCC(N)C(=O)OC
Reaction time: 8 h
Yield: 100 %

Procedure:
HCl (g) was bubbled through a solution of DL-allylglycine (2.0 g, 17.4 mmol) in methanol (50 mL) at room temperature. The reaction was stirred overnight, concentrated in vacuo, taken up in acetonitrile (50 mL), and re-concentrated to give 2-amino-pent-4-enoic acid methyl ester hydrochloride salt (2.8 g, 100%) as an oil. MS found: (M+CH3CN)+=171.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:10]1[C:14]2=[N:15][CH:16]=[CH:17][C:18](Cl)=[C:13]2[C:12]([CH:20]([CH3:22])[CH3:21])=[N:11]1)[C:5]#[N:6].C(=O)([O-])[O-:24].[K+].[K+].Cl.[CH3:30][N:31]1[CH:35]=[C:34]([C:36]2[N:37]=[CH:38][NH:39][CH:40]=2)[CH:33]=[N:32]1>CS(C)=O.C(Cl)(Cl)Cl.[Cu]=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:10]1[C:14]2=[N:15][CH:16]=[CH:17][C:18]([N:39]3[CH:40]=[C:36]([C:34]4[CH:33]=[N:32][N:31]([CH3:30])[CH:35]=4)[N:37]=[CH:38]3)=[C:13]2[C:12]([CH:20]([CH3:22])[CH3:21])=[N:11]1)[C:5]([NH2:6])=[O:24]
Reactant: Cn1cc(-c2c[nH]cn2)cn1
Reactant: O=C([O-])[O-]
Reactant: CC(C)c1nn(-c2ccc(C#N)cc2Cl)c2nccc(Cl)c12
Agent: O=[Cu]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClC(Cl)Cl
Product: CC(C)c1nn(-c2ccc(C(N)=O)cc2Cl)c2nccc(-n3cnc(-c4cnn(C)c4)c3)c12
Temperature: 120 °C
Reaction time: 48 h
Yield: 18 %

Procedure:
Compound (99a) (0.18 g) was dissolved in DMSO (2.1 mL), and potassium carbonate (0.3 g), copper(II) oxide (nanopowder) (0.086 g), and 4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazole hydrochloride (0.13 g) were added to the resulting solution, followed by stirring at 120° C. for 48 hr. The reaction solution was diluted with chloroform, and insoluble matters were filtered by celite. The solvent was distilled away, and the residue was purified by neutral silica gel column chromatography (chloroform/methanol) to obtain compound (99) (0.045 g, 18%) as a white solid.
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8]O)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C(Cl)Cl.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][S:18]([CH3:17])(=[O:20])=[O:19])=[CH:6][N:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCc1ccc(F)nc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Cc1ccc(F)nc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
(6-Fluoropyridin-3-yl)methanol (215 mg, 1.69 mmol) in CH2Cl2 (10 mL) containing triethylamine (354 μL, 2.54 mmol) was treated with methanesulfonyl chloride (291 mg, 2.54 mmol) dropwise at 0° C., stirred at 0° C. for 30 min, diluted with water, and extracted with CH2Cl2 (2×10 mL). The combined organic extract was dried (MgSO4), filtered, and concentrated to afford a crude oil.