Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][C:3](O)=O.C(=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.N1CCCCC1.Cl>N1C=CC=CC=1.O>[C:1]([OH:7])(=[O:6])[CH:2]=[CH:3][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1ccccc1
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Solvent: O
Product: O=C(O)C=Cc1ccccc1
Temperature: 80 °C
Reaction time: 17 h

Procedure:
To a solution of malonic acid (10.4 g, 0.1 mol) and the benzaldehyde (0.05 mol) in pyridine (20 mL) was added neat piperidine (0.75 mL, 7.6 mmol). The reaction mixture was stirred at 80° C. for 17 hr, chilled, then added to 200 mL cold water. This mixture was acidified with conc. HCl (25 mL) and the white precipitate collected by filtration, washed with 5×10 mL water, and dried to give pure cinnamic acid in typical yields of >95%.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)[C:3]=1[C:4]#[N:5].O=[C:28]([CH3:35])[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>>[CH2:33]([O:32][C:30]([C:29]1[C:28]([CH3:35])=[N:1][C:2]2[C:3]([C:4]=1[NH2:5])=[C:6]([O:10][CH2:11][CH:12]1[CH2:13][CH2:14][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[CH2:16][CH2:17]1)[CH:7]=[CH:8][CH:9]=2)=[O:31])[CH3:34]
Reactant: COc1ccc(CN2CCC(COc3cccc(N)c3C#N)CC2)cc1
Reactant: CCOC(=O)CC(C)=O
Product: CCOC(=O)c1c(C)nc2cccc(OCC3CCN(Cc4ccc(OC)cc4)CC3)c2c1N

Procedure:
Prepared as in Example 2a from 2-amino-6-((1-(4-methoxybenzyl)piperidin-4-yl)methoxy)benzonitrile (Example 125b) and ethyl 3-oxobutanoate as an off-white solid (30%). 1H NMR (400 MHz, DMSO-d6) δ 1.29-1.33 (m, 5H), 1.74 (m, 2H), 1.92 (m, 3H), 2.54 (s, 3H), 2.83 (m, 2H), 3.38 (s, 2H), 3.71 (s, 3H), 4.04 (d, J=8.0 Hz, 2H), 4.31 (q, J=8.0 Hz, 2H), 6.86 (d, J=8.0 Hz, 2H), 6.90 (d, J=8.0 Hz, 1H), 7.19 (d, J=8.0 Hz, 2H), 7.23 (d, J=8.0 Hz, 1H), 7.50 (t, J=8.0 Hz, 1H), 8.04 (brs, 2H). MS 464 (MH+).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@@H:11]([CH2:13][NH:14][CH:15]([CH3:17])[CH3:16])[C@@H:10]([CH2:18][N:19]([CH:36]([CH3:38])[CH3:37])[C:20](=[O:35])[C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH2:30][CH2:31][CH2:32][O:33][CH3:34])[CH:22]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:46]1([CH2:52][C:53](Cl)=[O:54])[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.[OH-].[Na+]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:1]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:15]([CH3:17])[CH3:16])[C:53](=[O:54])[CH2:52][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C@@H:10]([CH2:18][N:19]([CH:36]([CH3:38])[CH3:37])[C:20](=[O:35])[C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH2:30][CH2:31][CH2:32][O:33][CH3:34])[CH:22]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCCOc1cc(C(=O)N(C[C@H]2CN(Cc3ccccc3)C[C@H]2CNC(C)C)C(C)C)ccc1OC
Reactant: O=C(Cl)Cc1ccccc1
Agent: CN(C)c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCCOc1cc(C(=O)N(C[C@H]2CN(Cc3ccccc3)C[C@H]2CN(C(=O)Cc2ccccc2)C(C)C)C(C)C)ccc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-[(3R*,4R*)-1-benzyl-4-(isopropylamino-methyl)-pyrrolidin-3-ylmethyl]-N-isopropyl-4-methoxy-3-(3-methoxy-propoxy)-benzamide (0.19 g, 0.36 mmol), triethyl-amine (0.15 mL, 1.09 mmol), and DMAP (0.013 g, 0.11 mmol) in CH2Cl2, is added dropwise phenyl-acetyl chloride (0.058 mL, 0.44 mmol) at 0° C. under a nitrogen atmosphere. The solution is stirred overnight at room temperature. The mixture is added an aqueous solution of NaOH 0.1N (50 mL) and CH2Cl2 (50 mL). The organic layer is separated and the aqueous phase extracted twice with CH2Cl2, dried over MgSO4, filtered, and concentrated in vacuo. The crude product is purified by flash chromatography on silica gel (eluent: CH2Cl2/MeOH 90:10) to give the title product. TLC, Rf (CH2Cl2/MeOH 9:1)=0.23. MS (LC-MS): [M+H]+; 644.4 tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/2.5 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 mL/min): 5.95 min.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.C[Sn](C)(C)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1>C1(C)C=CC=CC=1>[N:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1
Reactant: COC(=O)Cc1ccc(Br)cc1
Reactant: C[Sn](C)(C)c1ccccn1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Cc1ccc(-c2ccccn2)cc1

Procedure:
7.85 g (34.3 mmol) of methyl 4-bromophenylacetate are introduced under argon into 95 ml of toluene and, at room temperature, 7.97 g (61.7 mmol) of diisopropylethylamine, 9.50 g (37.7 mmol) of 2-trimethylstannylpyridine and 0.4 g (0.3 mmol) of tetrakis(triphenylphosphane)palladium(0) are added. The mixture is then heated under reflux for 18 h. Cooling is followed by washing with 100 ml each of 1N hydrochloric acid and saturated sodium bicarbonate solution. The organic phase was discarded. The acidic and the basic aqueous phase were neutralized and each extracted with 100 ml of dichloromethane, and the combined organic phases were dried over magnesium sulfate and freed of solvent in vacuo. Example VII is obtained after silica gel chromatography (toluene/ethyl acetate gradient 5: 1-1:1) as a colorless oil.
Reaction SMILES: [CH2:1]([N:3]1[C:7](=[O:8])[C:6]([CH3:10])([CH3:9])[N:5](CO)[C:4]1=[O:13])[OH:2].C(N1C(C)(C)C(=O)NC1=O)O>>[CH2:1]=[O:2].[CH3:9][C:6]1([CH3:10])[NH:5][C:4](=[O:13])[NH:3][C:7]1=[O:8]
Reactant: CC1(C)C(=O)N(CO)C(=O)N1CO
Agent: CC1(C)C(=O)NC(=O)N1CO
Product: C=O
Product: CC1(C)NC(=O)NC1=O

Procedure:
In a further embodiment (the post addition method), an aqueous solution of dimethyloldimethylhydantoin, monomethyloldimethylhydantoin, and dimethylhydantoin is produced by admixing (a) from about 80 to about 90% by weight of an aqueous solution of methylolated dimethylhydantoins having greater than 0.1% by weight of free formaldehyde with (b) about 20 to about 10% by weight of dimethylhydantoin based upon 100% by weight of aqueous solution of methylolated dimethylhydantoins and dimethylhydantoin combined.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([N:16]4[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]4)=[N:12][N:11]3[CH:23]=2)=[CH:4][CH:3]=1.[I:24]Cl.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([N:16]4[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]4)=[N:12][N:11]3[C:23]=2[I:24])=[CH:4][CH:3]=1
Reactant: CN1CCN(c2ccc3nc(-c4ccc(F)cc4)cn3n2)CC1
Reactant: ClI
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CN1CCN(c2ccc3nc(-c4ccc(F)cc4)c(I)n3n2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.8 %

Procedure:
To a solution, cooled to about 5° C., of 31.0 g (99.6 mmol) of 2-(4-fluorophenyl)-6-(4-methylpiperazin-1-yl)imidazo[1,2-b]pyridazine in chloroform is rapidly added dropwise a solution of 64.7 g (398 mmol) of iodine monochloride in 150 mL of methanol. Mild exothermicity and the formation of a precipitate during the addition are observed. After cooling to room temperature and stirring for 30 minutes, the mixture is poured into 2 L of aqueous 5% sodium thiosulfate solution saturated with sodium bicarbonate. After vigorous stirring until the mixture has decolorized, the product is extracted with chloroform. The organic phase is separated out, dried over sodium sulfate, filtered and concentrated under reduced pressure to give a brown solid. This solid is triturated in a mixture of 400 mL of diisopropyl ether and 50 mL of isopropanol at reflux. After cooling, 40 g of a beige-colored powder are isolated by filtration through a sinter funnel and drying under vacuum.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=O)=[CH:6][CH:5]=[C:4]([Cl:10])[N:3]=1.[NH2:11][NH2:12]>C1COCC1>[Cl:10][C:4]1[N:3]=[C:2]2[NH:11][N:12]=[CH:8][C:7]2=[CH:6][CH:5]=1
Reactant: O=Cc1ccc(Cl)nc1Cl
Reactant: NN
Solvent: C1CCOC1
Product: Clc1ccc2cn[nH]c2n1
Yield: 21.6 %

Procedure:
To a solution of 2,6-dichloro-3-formylpyridine (0.89 mmol, 1 eq.) in 3 ml THF was added hydrazine (1.06 mmol, 1.2 eq.) at rt. The resultant solution was heated at 120° C. in sealed tube for overnight. The solvent was removed in vacuo, and the residue was dry loaded on silica gel column. Purification by silica gel chromatography provide 29.5 mg final product: HPLC retention time=2.17 minutes (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C.) using 1 ml/min flow rate, a 2.5 minute gradient of 0% to 100% B with a 1.1 minute wash at 100% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.1% formic acid/5% water/94.9% acetonitrile); MS (ES) M+H expect=154.0. found=154.0.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[NH2:19][CH2:20][CH2:21][C:22]1[N:30]=[C:29]2[C:25]([N:26]=[CH:27][N:28]2[C@H:31]2[C@H:35]([OH:36])[C@H:34]([OH:37])[C@@H:33]([CH2:38][O:39][CH3:40])[O:32]2)=[C:24]([NH:41][CH2:42][CH:43]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[N:23]=1.[C:56]1(=O)[CH2:61][CH2:60][CH2:59][CH2:58][CH2:57]1>ClCCl>[CH:56]1([NH:19][CH2:20][CH2:21][C:22]2[N:30]=[C:29]3[C:25]([N:26]=[CH:27][N:28]3[C@H:31]3[C@H:35]([OH:36])[C@H:34]([OH:37])[C@@H:33]([CH2:38][O:39][CH3:40])[O:32]3)=[C:24]([NH:41][CH2:42][CH:43]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)[N:23]=2)[CH2:61][CH2:60][CH2:59][CH2:58][CH2:57]1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CCN)nc32)[C@H](O)[C@@H]1O
Reactant: O=C1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CCNC4CCCCC4)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 56.6 %

Procedure:
Sodium triacetoxyborohydride (75 mg, 0.35 mmol) and acetic acid (16 mg, 0.27 mmol) were added sequentially to a stirred solution of (2R,3R,4S,5R)-2-{2-(2-aminoethyl)-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl}-5-(methoxymethyl)tetrahydro-3,4-furandiol (example 11) (120 mg, 0.24 mmol) and cyclohexanone (23 mg, 0.235 mmol) in dichloromethane (15 ml). The resulting mixture was stirred at room temperature for 24 hr, diluted with dichloromethane and washed sequentially with a saturated aqueous solution of sodium hydrogen carbonate, water and brine. The organic phase was dried with anhydrous sodium sulfate, the solvent removed under reduced pressure and the residue purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:methanol:ammonia (95:5:0.5) changing to dichloromethane:methanol:ammonia (90:10:1) to afford the title compound as a solid (78 mg). MS: 587 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[C:9]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][C@H:17]1[CH3:22])([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].C(N(CC)C(C)C)(C)C>C(OCC)(=O)C>[Cl:1][C:2]1[N:3]=[N:4][C:5]([N:19]2[CH2:20][CH2:21][N:16]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:17]([CH3:22])[CH2:18]2)=[CH:6][CH:7]=1
Reactant: C[C@@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: Clc1ccc(Cl)nn1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CN(c2ccc(Cl)nn2)CCN1C(=O)OC(C)(C)C
Temperature: 120 °C
Reaction time: 5 h
Yield: 81.7 %

Procedure:
A mixture of 3,6-dichloropyridazine (298 mg, 2 mmol) and (R)-1-N-Boc-2-methyl piperazine (401 mg, 2.0 mmol) in N,N-diisopropylethylamine (0.7 mL, 4 mmol) was stirred at 120° C. for 5 h. The reaction mixture was diluted with ethyl acetate and washed with brine (2×), then dried over MgSO4. The salts were removed by filtration and the filtrate was concentrated and the residue was purified by chromatography on silica gel eluting with 20% to 80% ethyl acetate in hexane to give compound 11as a light yellow solid (511 mg, 82%). 1H NMR (500 MHz, CD3OD) δ 7.24 (1H, d, J=10 Hz), 6.88 (1H, d, J=10 Hz), 4.38 (1H, br s), 4.17 (1H, d, J=10 Hz), 4.05-3.97 (2H, m), 3.39 (1H, dd, J=15 Hz, J=5 Hz), 3.29 (1H, ddd, J=15 Hz, J=10 Hz, J=5 Hz), 1.51 (9H, s), 1.21 (3H, d, J=10 Hz) ppm; LCMS-ESI (POS), M/Z, M+1: Found 313.1, Calculated 313.1.
Reaction SMILES: F[C:2]1[CH:9]=[C:8](C=C)[CH:7]=[C:6]([O:12][CH3:13])[C:3]=1[C:4]#[N:5].C1C=C(Cl)C=[C:16]([C:21]([O:23]O)=O)C=1.[F:25]C1C(C2CO2)=CC(OC)=C(C=1)C#N>>[F:25][C:8]1[C:9]([CH:16]2[CH2:21][O:23]2)=[CH:2][C:3]([C:4]#[N:5])=[C:6]([O:12][CH3:13])[CH:7]=1
Reactant: C=Cc1cc(F)c(C#N)c(OC)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1cc(C2CO2)c(F)cc1C#N
Product: COc1cc(F)c(C2CO2)cc1C#N

Procedure:
4-Fluoro-2-methoxy-5-(oxiran-2-yl)benzonitrile was prepared from 2-fluoro-6-methoxy-4-vinylbenzonitrile using m-CPBA in an analagous fashion to that described for 5-fluoro-2-methoxy-4-(oxiran-2-yl)benzonitrile (Step H) above: LC/MS: [(M+1)]+=194
Reaction SMILES: [OH:1][C@@H:2]1[CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][CH2:5][N:4]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N:22]3[C:30]4[CH:29]=[C:28]([C:31]5[CH:32]=[N:33][N:34]([CH2:36][C:37]([F:40])([F:39])[F:38])[CH:35]=5)[N:27]=[CH:26][C:25]=4[CH:24]=[N:23]3)[N:17]=2)[CH2:3]1>Cl.CO>[F:40][C:37]([F:38])([F:39])[CH2:36][N:34]1[CH:35]=[C:31]([C:28]2[N:27]=[CH:26][C:25]3[CH:24]=[N:23][N:22]([C:18]4[N:17]=[C:16]([N:4]5[CH2:3][C@H:2]([OH:1])[CH2:8][NH:7][CH2:6][CH2:5]5)[CH:21]=[CH:20][CH:19]=4)[C:30]=3[CH:29]=2)[CH:32]=[N:33]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(-n3ncc4cnc(-c5cnn(CC(F)(F)F)c5)cc43)n2)C[C@H](O)C1
Agent: Cl
Solvent: CO
Product: O[C@@H]1CNCCN(c2cccc(-n3ncc4cnc(-c5cnn(CC(F)(F)F)c5)cc43)n2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.3 %

Procedure:
A mixture of tert-butyl(S)-6-hydroxy-4-(6-(6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate (70 mg, 0.13 mmol) in HCl/MeOH (4.0 M, 10 mL) was stirred at room temperature for 3 hours, which was monitored by LCMS. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The crude material was purified by reverse phase prep-HPLC to afford (R)-1-(6-(6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine-1-yl)pyridin-2-yl)-1,4-diazepan-6-ol 188 as a white solid (30 mg, 52.6%). 1H NMR (500 MHz, DMSO-d6) δ (ppm) 9.16 (s, 1H), 8.74 (s, 1H), 8.55 (s, 1H), 8.49 (s, 1H), 8.21 (s, 1H), 7.69 (t, J=16 Hz, 1H), 7.17 (d, J=7.5 Hz, 1H), 6.66 (d, J=8 Hz, 1H), 5.18-5.24 (m, 2H), 4.93 (d, J=5.5 Hz, 1H), 3.96 (t, J=8.5 Hz, 1H), 3.88 (m, 2H), 3.56-3.64 (m, 2H), 2.98 (t, J=10.5 Hz, 2H), 2.80-2.84 (m, 1H), 2.64-2.72 (m, 1H); MS (ESI) m/z: 459 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[CH:10]=[C:9]([C:11]([OH:14])([CH3:13])[CH3:12])[S:8][C:6]=2[N:7]=1.[CH3:21][C:22]1[N:39](COCC[Si](C)(C)C)[C:25]2=[N:26][CH:27]=[C:28](C3OC(C)(C)C(C)(C)O3)[CH:29]=[C:24]2[N:23]=1.C[Si](C)(C)CCOCN1C2C=C(C3N=C(N4CCOCC4)C4C=C(C(O)(C)C)SC=4N=3)C=CC=2N=C1C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH3:21][C:22]1[NH:39][C:25]2=[N:26][CH:27]=[C:28]([C:2]3[N:3]=[C:4]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)[C:5]4[CH:10]=[C:9]([C:11]([OH:14])([CH3:13])[CH3:12])[S:8][C:6]=4[N:7]=3)[CH:29]=[C:24]2[N:23]=1
Reactant: Cc1nc2cc(C3OC(C)(C)C(C)(C)O3)cnc2n1COCC[Si](C)(C)C
Reactant: CC(C)(O)c1cc2c(N3CCOCC3)nc(Cl)nc2s1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cc1nc2ccc(-c3nc(N4CCOCC4)c4cc(C(C)(C)O)sc4n3)cc2n1COCC[Si](C)(C)C
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1nc2cc(-c3nc(N4CCOCC4)c4cc(C(C)(C)O)sc4n3)cnc2[nH]1

Procedure:
2-(2-Chloro-4-morpholinothieno[2,3-d]pyrimidin-6-yl)propan-2-ol (100 mg) was reacted with 161 mg of 3-(2-(trimethylsilyl)ethoxy)methyl)-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3H-imidazo[4,5-b]pyridine 54 via Example 6b and General Procedure A. Crude 2-(2-(1-((2-(trimethylsilyl)ethoxy)methyl)-2-methyl-1H-benzo[d]imidazol-6-yl)-4-morpholinothieno[2,3-d]pyrimidin-6-yl)propan-2-ol was then refluxed overnight with 2 equivalents of tetrabutylammoniumfloride in THF to remove the SEM protecting group. The crude material was then extracted with water and ethyl acetate. The organic layer was concentrated to dryness and then purified via reverse phase HPLC to give 5.1 mg of 414. MS (Q1) 411.2 (M)+
Reaction SMILES: Cl.[C:2]([CH2:4][NH:5][C:6]([C@@H:8]1[CH2:12][C@@H:11]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([F:25])([F:24])[F:23])(=[O:15])=[O:14])[CH2:10][NH:9]1)=[O:7])#[N:3].[C:26](O)(=[O:33])[C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1>>[C:2]([CH2:4][NH:5][C:6]([C@@H:8]1[CH2:12][C@@H:11]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([F:25])([F:23])[F:24])(=[O:15])=[O:14])[CH2:10][N:9]1[C:26]([C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1)=[O:33])=[O:7])#[N:3]
Reactant: O=C(O)c1ccncc1
Reactant: N#CCNC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1
Agent: Cl
Product: N#CCNC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1C(=O)c1ccncc1

Procedure:
(2S,4R)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid cyanomethyl-amide hydrochloride from experiment K2 was coupled with isonicotinic acid in analogy to experiment A1 to give (2S,4R)-1-(pyridine-4-carbonyl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid cyanomethyl-amide as a colorless oil. MS: 467.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[Cl:9]N1C(=O)CCC1=O.O>ClCCl>[Cl:9][C:8]1[CH:7]=[CH:6][C:4]([NH2:5])=[CH:3][C:2]=1[F:1]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Nc1cccc(F)c1
Solvent: O
Solvent: ClCCl
Product: Nc1ccc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Into a solution of 96 ml of 3-fluoroaniline in 1000 ml of dichloromethane, 147 g of N-chlorosuccinimide was added at 0° C., and stirred for 12 hours at room temperature. After addition of water to the reaction solution, the system was extracted with chloroform. The chloroform layer was washed with saturated brine, dried on anhydrous magnesium sulfate and the solvent was distilled off. The resulting residue was separated and purified on silica gel column chromatography (hexane/ethyl acetate=5/1) to provide 21 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:20]1(=[O:26])[O:25][C:23](=[O:24])[CH2:22][CH2:21]1>CN(C=O)C>[O:26]=[C:20]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1)[CH2:21][CH2:22][C:23]([OH:25])=[O:24]
Reactant: O=C1CCC(=O)O1
Reactant: Nc1ccc(N2CCN(c3ccncc3)CC2)cc1
Solvent: CN(C)C=O
Product: O=C(O)CCC(=O)Nc1ccc(N2CCN(c3ccncc3)CC2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 76.1 %

Procedure:
To a solution of 1-(4-aminophenyl)-4-(4-pyridyl)piperazine (100 mg) in DMF (8 ml) was added succinic anhydride (79 mg). The reaction mixture was stirred at room temperature for 2.5 hr and a precipitate was collected, washed with DMF and ethanol, then dried to give the title compound (106 mg) as a beige-coloured solid: m.p. 263°-264° C.; NMR (d6 -DMSO+CF3CO2H) δ2.68 (4H, m), 3.80 (4H, m), 4.19 (4H, m), 7.20 (2H, d), 7.56 (2H, d), 7.82 (2H, d), 8.21 (2H, d), 9.62 (1H, s); m/Z 355 (M+H)+ ; calculated for C19H22N4O3. 0.4 H2O: C, 63.1%; H, 6.36%; N, 15.5%; found: C, 63.1%; H, 6.4%; N, 15.7%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([NH2:23])[S:11][C:12]=2[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.[C:24]([C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1)#[N:25]>>[C:24]([C:26]1[CH:34]=[CH:33][C:29]([C:30]([NH:23][C:10]2[S:11][C:12]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[N:9]=2)=[O:31])=[CH:28][CH:27]=1)#[N:25]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: Nc1nc(-c2ccc(F)cc2)c(Cc2ccc([N+](=O)[O-])cc2)s1
Product: N#Cc1ccc(C(=O)Nc2nc(-c3ccc(F)cc3)c(Cc3ccc([N+](=O)[O-])cc3)s2)cc1
Yield: 62.9 %

Procedure:
A procedure similar to that in Example 4 was used. 4-(4-fluoro-phenyl)-5-(4-nitro-benzyl)-thiazol-2-ylamine prepared in Example 9 and p-cyanobenzoyl chloride prepared in the step 1 of Example 13 were used as starting materials, allowed to react at room temperature overnight, followed by post-treatment to obtain a crude product, which was recrystallized with a solvent mixture of ethyl acetate and petroleum ether to obtain a product as a off-white solid in a yield of 62.9%, mp: 244-245└. 1H-NMR (CDCl3, 400 MHz) δ: 4.33 (2H, s, CH2), 7.07 (2H, t, 3JFH=3JHH=8.44 Hz, ArH), 7.38 (2H, d, J=8.40 Hz, ArH), 7.43 (2H, dd, 3JHH=8.72, 4JFH=5.32 Hz, ArH), 7.75 (2H, d, J=7.84 Hz, ArH), 7.98 (2H, d, J=8.12 Hz, ArH), 8.20 (2H, d, J=8.40 Hz, ArH); EI-MS m/e (%): 458.3 (M+, 79), 129.9 (100); HREI-MS Calcd. for C24H15FN4O3S: 458.0849. found: 458.0850. Anal. Calcd. for C24H15FN4O3S: C, 62.88; H, 3.30; N, 12.22. found: C, 62.52; H, 2.96; N, 12.04.
Reaction SMILES: [CH3:1][C:2]([N:13]=[C:14]=[O:15])([CH3:12])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([CH3:11])=[CH2:10])[CH:4]=1.[C:16]([OH:20])([CH3:19])([CH3:18])[CH3:17]>CC(C)([O-])C.[K+].CCCCCC>[CH3:17][C:16]([O:20][C:14](=[O:15])[NH:13][C:2]([CH3:1])([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([CH3:11])=[CH2:10])[CH:4]=1)[CH3:12])([CH3:19])[CH3:18]
Reactant: CC(C)(C)O
Reactant: C=C(C)c1cccc(C(C)(C)N=C=O)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCCCCC
Product: C=C(C)c1cccc(C(C)(C)NC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Yield: 80.5 %

Procedure:
Into a 3-neck, 10 L round bottom flask equipped with a mechanical stirrer, condenser, and a nitrogen inlet was placed α,α-dimethyl-m-isopropenylbenzyl isocyanate (1083 g, 5.38 mol), hexane (6L), and t-butyl alcohol (398.8 g, 5.38 mol). While the mixture was stirred at room temperature, potassium t-butoxide (18.0 g, 160 mmol) was added in portions. Throughout the addition the reaction temperature increased to 50° C. The reaction was complete within an hour. The reaction mixture was washed with water (5L), and thereafter, the organics were separated from the aqueous layer. The organics were dried over magnesium sulfate, filtered, and evaporated to yield a yellow-brown semi-solid. Recrystallization from hexane afforded essentially pure {1-methyl-1-[3-(1-methylethenyl)phenyl]ethyl}carbamic acid 1,1-dimethylethyl ester (1193 g, 81% isolated yield), as shown by proton and carbon-13 NMR spectroscopy.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][CH3:3].Cl[P:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.N>>[C:13]1([P:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[O:4][CH2:1][CH2:2][CH3:3])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCCO
Reactant: ClP(c1ccccc1)c1ccccc1
Agent: N
Product: CCCOP(c1ccccc1)c1ccccc1
Yield: 62.8 %

Procedure:
915 g (15.25 mol) of n-propanol are cooled to -15° C. with stirring under a nitrogen atmosphere. 330 g (1.5 mol) of chloro(diphenyl)phosphine are then added dropwise at this temperature with vigorous stirring in one hour and 15 minutes. 38 g (2.24 mol) of ammonia gas are then introduced at this temperature with further vigorous stirring. The mixture is then stirred for a further ten hours without cooling. After filtering off the ammonium chloride by suction, the filtrate is freed from propanol and excess ammonia in vacuo. The remaining residue is distilled (boiling point 122° C. at 0.4m bar). 230 g of propyl diphenylphosphinite are obtained. This corresponds to a yield of 63% of theory.