Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([C:6]#[N:7])[C:4]#[N:5].[CH3:8][C:9]1[S:10][C:11](S(C)(=O)=O)=[N:12][N:13]=1>C1COCC1>[CH3:8][C:9]1[S:10][C:11]([CH:3]([C:6]#[N:7])[C:4]#[N:5])=[N:12][N:13]=1
Reactant: N#CCC#N
Reactant: Cc1nnc(S(C)(=O)=O)s1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nnc(C(C#N)C#N)s1
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
Under argon, 400 mg (10.0 mmol) of sodium hydride (60% suspension in oil) are suspended at room temperature in 40 ml of THF. A solution of 661 mg (10.0 mmol) of malonodinitrile in 10 ml of THF is added dropwise, and the reaction mixture is stirred for 15 min. A solution of 891 mg (5.0 mmol) of 2-methyl-5-methylsulphonyl-1,3,4-thiadiazole in 10 ml of THF is added dropwise. The reaction mixture is heated to 50° C. and stirred overnight, cooled and concentrated using a rotary evaporator. The residue is dissolved in water and adjusted to pH=3 using HCl. A brown solid precipitates out, and this solid is filtered off and dried under reduced pressure.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1.Cl.[C:31]1([CH:37]2[CH2:42][N:41]3[CH:43]=[C:44]([C:46]([OH:48])=O)[N:45]=[C:40]3[CH2:39][CH2:38]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[F:49][C:50]([F:64])([F:63])[C:51]1[CH:52]=[C:53]([N:57]2[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]2)[CH:54]=[CH:55][CH:56]=1>CN(C=O)C>[C:31]1([CH:37]2[CH2:42][N:41]3[CH:43]=[C:44]([C:46]([N:60]4[CH2:59][CH2:58][N:57]([C:53]5[CH:54]=[CH:55][CH:56]=[C:51]([C:50]([F:63])([F:64])[F:49])[CH:52]=5)[CH2:62][CH2:61]4)=[O:48])[N:45]=[C:40]3[CH2:39][CH2:38]2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: O=C(O)c1cn2c(n1)CCC(c1ccccc1)C2
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(c1cn2c(n1)CCC(c1ccccc1)C2)N1CCN(c2cccc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
TBTU (276 mg; 0.86 mmol) and N-methylmorpholine (237 μl; 218 mg; 2.15 mmol) were added to a solution of 6-phenyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxylic acid hydrochloride (200 mg; 0.72 mmol) in DMF (1 ml). The reaction mixture was stirred vigorously for 30 min at room temperature and then 1-(3-trifluoromethylphenyl)piperazine (162 μl; 198 mg; 0.86 mmol) was added. The reaction mixture was stirred for 4 h at room temperature, then poured onto water and extracted with chloroform. The organic phase was dried over MgSO4, filtered and concentrated to small volume. The raw product was purified by column chromatography on silica gel (chloroform). Yield: 191 mg (59%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].I[CH2:24][CH:25]1[CH2:30][O:29][CH2:28][CH2:27][O:26]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(=O)CC.C(OCC)(=O)C>[O:26]1[CH2:27][CH2:28][O:29][CH2:30][CH:25]1[CH2:24][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22]
Reactant: ICC1COCCO1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCC(C)=O
Solvent: CCOC(C)=O
Product: O=C1N(CC2COCCO2)c2ccccc2C12COc1cc3c(cc12)OCCO3

Procedure:
A mixture of 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.30 g, 1.03 mmol), 2-(iodomethyl)-1,4-dioxane (0.31 g, 1.35 mmol) and cesium carbonate (0.52 g, 1.58 mmol) in 2-butanone (7 mL) was stirred at reflux under nitrogen for 4 h. Once cooled, the reaction was diluted with ethyl acetate and the suspension was filtered through Celite. The filtrate was concentrated under reduced pressure and the residue was purified by flash column chromatography with dichloromethane/diethyl ether (14:1) to afford 1′-(1,4-dioxan-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one as an inseparable mixture with unreacted lactam (0.36 g). A mixture of this material, benzyl bromide (0.12 mL, 1.00 mmol) and cesium carbonate (0.50 g, 1.55 mmol) in 2-butanone (7 mL) was then stirred at reflux under nitrogen for 15 h. Work-up as described above and purified by flash column chromatography with (hexanes/ethyl acetate) (2:1, increased to 1:1) afforded 1′-(1,4-dioxan-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.24 g, 58%) as a colorless solid, along with 1′-benzyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.09 g, 24%) as a colorless solid. Characterization for 1-(1,4-dioxan-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one: mp 160-165° C. (hexanes); 1H NMR (300 MHz, CDCl3) (diastereomers) δ7.26-7.34 (m, 1H), 7.16 (d, J=7.5 Hz, 1H), 7.01-7.09 (m, 2H), 6.49 (s, 1H), 6.24 (s, 0.5H), 6.21 (s, 0.5H), 4.88 (d, J=8.9 Hz, 0.5 Hz), 4.87 (d, J=8.9 Hz, 0.5H), 4.64 (d, J=8.9 Hz, 0.5H), 4.63 (d, J=8.9 Hz, 0.5H), 4.22-4.16 (m, 2H), 4.15-4.09 (m, 2H), 3.99-3.78 (m, 4H), 3.76-3.55 (m, 4H), 3.47-3.37 (m, 1H); 13C NMR (75 MHz, CDCl3) (diastereomers) δ177.9, 177.8, 156.3, 155.3, 144.71, 144.69, 142.72, 142.66, 138.42, 138.39, 132.4, 132.3, 128.91, 128.85, 123.9, 123.8, 123.5, 121.3, 121.1, 111.7, 111.6, 109.6, 109.4, 99.49, 99.46, 80.2, 80.0, 73.32, 73.29, 69.4, 69.2, 66.8, 66.7, 66.52, 66.48, 64.6, 64.0, 58.1, 58.0, 41.85, 41.76; MS (ES+) m/z 396.2 (M+1).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH2:5]([O:12][C:13]([N:15]1[C@H:22]([CH3:23])[CH2:21][CH2:20][C@H:19]2[C@H:17]([O:18]2)[CH2:16]1)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cl-].[NH4+]>CO.O>[CH2:5]([O:12][C:13]([N:15]1[CH2:16][C@@H:17]([OH:18])[C@H:19]([N:1]=[N+:2]=[N-:3])[CH2:20][CH2:21][C@H:22]1[CH3:23])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C[C@@H]1CC[C@@H]2O[C@@H]2CN1C(=O)OCc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C[C@@H]1CC[C@@H](N=[N+]=[N-])[C@H](O)CN1C(=O)OCc1ccccc1
Yield: 62.9 %

Procedure:
Sodium azide (1.8 g, 27.7 mmol) was added to a (1R,4R,7S)-4-Methyl-8-oxa-3-aza-bicyclo[5.1.0]octane-3-carboxylic acid benzyl ester (2.4 g, 9.2 mmol, Example 1e) and ammonium chloride (1.48 g, 27.7 mmol) in MeOH (16 ml) and H2O (1.6 ml), then was refluxed overnight. The reaction mixture was concentrated in vacuo by rotary evaporation, then was diluted with water (5 ml) and extracted with EtOAc (10 ml). The organic layer was then extracted with water, brine, dried with MgSO4, filtered, concentrated in vacuo by rotary evaporation, and chromatographed (silica gel, 25% EtOAc/hexanes) to yield the title compound (1.76 g, 63%); Liquid chromatgraphy/Electrospray mass spec: M+H+=305.2.
Reaction SMILES: N#[C:2][Br:3].C(N(CC)C[C:8]#[C:9][CH2:10][N:11]1[CH:15]=[CH:14][N:13]([CH3:16])[C:12]1=[O:17])C>O1CCOCC1>[Br:3][CH2:2][C:8]#[C:9][CH2:10][N:11]1[CH:15]=[CH:14][N:13]([CH3:16])[C:12]1=[O:17]
Reactant: N#CBr
Reactant: CCN(CC)CC#CCn1ccn(C)c1=O
Solvent: C1COCCO1
Product: Cn1ccn(CC#CCBr)c1=O

Procedure:
Cyanogen bromide (6.0 g, 0.057 mol) was added to a stirred solution of 1-[4-(diethylamino)-2-butynyl]-1,3-dihydro-3-methyl-2H-imidazol-2-one in dioxane (130 mL). After evaporation of the dioxane, the residual oil was chromatographed on silica gel using chloroform:1% methanol as the eluant to give 10.8 g of 1-(4-bromo-2-butynyl)-1,3-dihydro-3-methyl-2H-imidazol-2-one as an oil.
Reaction SMILES: N1([C:6]2[NH:11][C:10]3[CH:12]=[CH:13][C:14]([C:16]([F:19])([F:18])[F:17])=[CH:15][C:9]=3[S:8](=[O:21])(=[O:20])[N:7]=2)C=CN=C1.[CH:22]([NH2:26])([CH2:24][CH3:25])[CH3:23]>>[CH:22]([NH:26][C:6]1[NH:11][C:10]2[CH:12]=[CH:13][C:14]([C:16]([F:18])([F:17])[F:19])=[CH:15][C:9]=2[S:8](=[O:21])(=[O:20])[N:7]=1)([CH2:24][CH3:25])[CH3:23]
Reactant: CCC(C)N
Reactant: O=S1(=O)N=C(n2ccnc2)Nc2ccc(C(F)(F)F)cc21
Product: CCC(C)NC1=NS(=O)(=O)c2cc(C(F)(F)F)ccc2N1

Procedure:
3-(Imidazol-1-yl)-7-trifluoromethyl-4H-1,2,4-benzothiadiazine 1,1-dioxide was treated with sec-butylamine according to the general procedure Method A to give the title compound; m.p. 234-236° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([OH:14])=O)[CH:9]=2)[NH:4][CH:3]1[C:15]1[CH:20]=[C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH:18]=[C:17]([O:27][CH3:28])[CH:16]=1.Cl.C(N=C=N)C.[CH3:36][S:37]([NH2:40])(=[O:39])=[O:38]>CN(C)C1C=CN=CC=1.ClCCl>[CH3:29][C:2]1([CH3:1])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([NH:40][S:37]([CH3:36])(=[O:39])=[O:38])=[O:14])[CH:9]=2)[NH:4][CH:3]1[C:15]1[CH:20]=[C:19]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)[CH:18]=[C:17]([O:27][CH3:28])[CH:16]=1
Reactant: COc1cc(C2Nc3ccc(C(=O)O)cc3CC2(C)C)cc(N2CCOCC2)c1
Reactant: CS(N)(=O)=O
Agent: CCN=C=N
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1cc(C2Nc3ccc(C(=O)NS(C)(=O)=O)cc3CC2(C)C)cc(N2CCOCC2)c1
Temperature: 65 °C
Yield: 40.1 %

Procedure:
A mixture of 3,3-dimethyl-2-(3-methoxy-5-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (120 mg, 0.3 mmol), 1-3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (87 mg, 0.45 mmol), 4-dimethylaminopyridine (55 mg, 0.45 mmol), methane sulfonamide (86 mg, 0.9 mmol) in dichloromethane (10 mL) was heated for at 65° C. for 12 hours. Removal of the solvent afforded an oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded N-[3,3-dimethyl-2-(3-methoxy-5-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-methanesulfonamide (57 mg, 40%) as a light yellow solid: LC/MS m/e calcd for C24H31N3O5S (M+H)+: 474.6, observed: 474.0.
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].[C:6]1(C2C=CC=CC=2)[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:23][C:24]([N:26]([CH:32]([CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:33][S:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])=[O:25])[C:14](OC2C=CC=CC=2)=[O:15])=[CH:8][CH:7]=1>O1CCCC1>[C:6]1([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:7]=[CH:8][C:9]([CH2:12][C@H:13]([NH:23][C:24]([N:26]([CH:32]([CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:33][S:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:27][CH2:28][CH:29]([CH3:30])[CH3:31])=[O:25])[C:14]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])=[O:15])=[CH:10][CH:11]=1
Reactant: CCCCN
Reactant: CCOC(=O)CC(CSc1ccccc1)N(CCC(C)C)C(=O)N[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)Oc1ccccc1
Solvent: C1CCOC1
Product: CCCCNC(=O)[C@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)N(CCC(C)C)C(CSc1ccccc1)CC(=O)OCC
Yield: 90 %

Procedure:
n-Butylamine (0.35 ml) is added to a solution of phenyl (2S)-3-(4-biphenylyl)-2-[3-[(1RS)-1-(ethoxycarbonylmethyl)-2-(phenylthio)ethyl]-3-isoamylureido]propionate (Compound No. 1-80, 464 mg) in tetrahydrofuran (7 ml), and the mixture is stirred at room temperature for 1.5 hours. The reaction mixture is concentrated under reduced pressure, water is added to the concentrate, and the whole is extracted with ethyl acetate. The organic layer is washed with water and saturated brine successively, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting oily matter is purified by silica gel column chromatography to give 402 mg (90%) of the titled compound (Compound No. 38-1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]#[N:10])=[C:4]([Cl:11])[N:3]=1.[CH2:12]([NH2:14])[CH3:13]>CC(C)=O>[Cl:11][C:4]1[C:5]([C:9]#[N:10])=[C:6]([Cl:8])[N:7]=[C:2]([NH:14][CH2:12][CH3:13])[N:3]=1
Reactant: N#Cc1c(Cl)nc(Cl)nc1Cl
Reactant: CCN
Solvent: CC(C)=O
Product: CCNc1nc(Cl)c(C#N)c(Cl)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A stirred solution of 12.9 grams of 2,4,6-trichloro-5-pyrimidinecarbonitrile in 150 ml of acetone was cooled to -10°, and 7.7 grams of an aqueous 70% ethylamine solution was added dropwise during 2 hours. The temperature of the reaction mixture was maintained at -10° throughout the addition. Following complete addition, the reaction mixture was allowed to warm to room temperature, where it stood for 16 hours. Then most of the acetone was removed by evaporation under reduced pressure. The residue was extracted with a mixture of water and diethyl ether. The ether layer was separated and dried over magnesium sulfate. The dried ether layer was filtered, and the ether was removed under reduced pressure. The residue was recrystallized from a mixture of methylcyclohexane and benzene, then from carbon tetrachloride, to give 4.2 grams of 4,6-dichloro-2-ethylamino-5-pyrimidinecarbonitrile; mp, 145-150°.
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9]C2)=[CH:4][CH:3]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]2[CH2:32][CH2:31][C@H:30]([C:33](O)=[O:34])[CH2:29]2)[N:23]=1.C(OC(N1CC(C(O)=O)C1)=O)C1C=CC=CC=1>>[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]2[CH2:32][CH2:31][C@H:30]([C:33]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([O:6][C@@H:7]4[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:9]4)=[CH:20][CH:21]=3)=[O:34])[CH2:29]2)[N:23]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N)cc2)CC1
Reactant: O=C(O)[C@H]1CCN(c2cccnn2)C1
Agent: O=C(O)C1CN(C(=O)OCc2ccccc2)C1
Product: CC(C)(C)OC(=O)N1CC[C@@H](Oc2ccc(NC(=O)[C@H]3CCN(c4cccnn4)C3)cc2)C1

Procedure:
The title compound was prepared as described in Example 1A, substituting (R)-tert-butyl 3-(4-aminophenoxy)pyrrolidine-1-carboxylate for tert-butyl 4-(4-aminophenoxy)piperidine-1-carboxylate and (S)-1-(pyridazin-3-yl)pyrrolidine-3-carboxylic acid for 1-(benzyloxycarbonyl)azetidine-3-carboxylic acid.
Reaction SMILES: Cl[C:2]1[CH:9]=[C:8]([C:10]2[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][NH:12][N:11]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[F:19][C:20]([F:24])([F:23])[CH2:21][SH:22].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:19][C:20]([F:24])([F:23])[CH2:21][S:22][C:2]1[CH:9]=[C:8]([C:10]2[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][NH:12][N:11]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: FC(F)(F)CS
Reactant: N#Cc1ccc(-c2n[nH]cc2C(F)(F)F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(-c2n[nH]cc2C(F)(F)F)cc1SCC(F)(F)F
Yield: 56.9 %

Procedure:
0.65 g (2.4 mmol) of 2-chloro-4-(4-trifluoromethylpyrazolyl)benzonitrile, 0.33 g (2.9 mmol) of 2,2,2-trifluoroethanthiol and 0.40 g (2.9 mmol) of potassium carbonate were stirred in 5 ml of N,N-dimethylformamide at room temperature overnight. The resulting reaction mixture was poured into 50 ml of water, and the organic matters were extracted with 20 ml of ethyl acetate twice. The ethyl acetate layers were combined, washed with 30 ml of water twice and dried over anhydrous magnesium sulfate, and the ethyl acetate was distilled off under reduced pressure. Purification of the residue by silica gel column chromatography afforded 0.48 g of 2-(2,2,2-trifluoroethylthio)-4-(4-trifluoromethylpyrazolyl)benzonitrile (yield 57.1%) as a milk-white powder (m.p. 90-91° C.).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1[N:8]=[CH:9][C:10]([O:13][C:14]2[CH:31]=[CH:30][C:17]3[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH2:22][C:16]=3[CH:15]=2)=[N:11][CH:12]=1)=[O:6].Cl.O>CC(C)=O>[CH3:29][C:26]([O:25][C:23]([N:20]1[CH2:19][CH2:18][C:17]2[CH:30]=[CH:31][C:14]([O:13][C:10]3[N:11]=[CH:12][C:7]([C:5]([OH:6])=[O:4])=[N:8][CH:9]=3)=[CH:15][C:16]=2[CH2:22][CH2:21]1)=[O:24])([CH3:27])[CH3:28]
Reactant: COC(=O)c1cnc(Oc2ccc3c(c2)CCN(C(=O)OC(C)(C)C)CC3)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCc2ccc(Oc3cnc(C(=O)O)cn3)cc2CC1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 96.2 %

Procedure:
2M Sodium hydroxide solution (110 ml) was added to a solution of 1,1-dimethylethyl 7-({5-[(methyloxy)carbonyl]-2-pyrazinyl}oxy)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (D49, Step 1) (29.38 g, 73.6 mmol) in acetone (480 ml) and the resulting mixture was stirred at room temperature for 25 minutes. The mixture was acidified with 2M hydrochloric acid and then poured into water (2 L). The resulting white solid was collected by filtration, washed with water and dissolved in ethyl acetate (1 L). This solution was dried under sodium sulfate and evaporated in vacuo to give the title compound (27.3 g); MS (ES+) m/e 384 [M−H]+.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1O)([CH3:3])[CH3:2].[P:11](Cl)([Cl:14])([Cl:13])=[S:12].N1C=CC=CC=1>ClC=C(Cl)Cl>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[P:11]([Cl:14])([Cl:13])=[S:12])([CH3:3])[CH3:2]
Reactant: CC(C)c1ccccc1O
Reactant: S=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClC=C(Cl)Cl
Product: CC(C)c1ccccc1P(=S)(Cl)Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-iso-propylphenol (10.0 g, 73.4 mmol) in trichloroethylene (600 mL) is added dropwise to a 0°-4° C. mixture of thiophosphoryl chloride (18.63 g, 110 mmol) and anhydrous pyridine (8.70 g, 110 mmol) in trichloroethylene (250 mL) over a 1 hour period under a nitrogen atmosphere. The resultant reaction mixture is stirred at 0°-4° C. for 2 hours, is warmed to room temperature and then is stirred at room temperature for 12 hours. A white solid gradually precipitates. The white solid is filtered from the reaction mixture. The resultant reaction mixture is concentrated in vacuo to a residue. Successive aliquots of toluene (200 mL) are added to the residue and then separately evaporated in vacuo to give (2-iso-propylphenyl)-thiophosphoryl dichloride which can be used directly without further purification as the starting material for Example 27.
Reaction SMILES: [NH:1](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:2]([C:5]([NH:7][C@H:8]([C:13]([OH:15])=[O:14])[CH2:9][CH:10]([CH3:12])[CH3:11])=[O:6])[CH2:3][OH:4].[CH3:33][C:34]([NH:45][CH2:46][CH:47]([OH:63])[CH2:48][O:49][C:50]1[C:55]2[C:56]3[C:61]([NH:62][C:54]=2[CH:53]=[CH:52][CH:51]=1)=[CH:60][CH:59]=[CH:58][CH:57]=3)([C:36]1[CH:41]=[CH:40][C:39]([N:42]=[N+:43]=[N-:44])=[CH:38][CH:37]=1)[CH3:35].[CH3:64][C:65]1[C@@H:82]([O:83][C:84]([C@H:86]([OH:103])[C@@H:87]([NH:94][C:95]([C:97]2[CH:98]=[CH:99][CH:100]=[CH:101][CH:102]=2)=[O:96])[C:88]2[CH:89]=[CH:90][CH:91]=[CH:92][CH:93]=2)=[O:85])[CH2:81][C@:77]2([OH:104])[C:78]([CH3:80])([CH3:79])[C:66]=1[C@@H:67]([O:122][C:123]([CH3:125])=[O:124])[C:68]([C@@:70]1([CH3:121])[C@H:75]([C@@H:76]2[O:105][C:106]([C:108]2[CH:109]=[CH:110][CH:111]=[CH:112][CH:113]=2)=[O:107])[C@:74]2([O:116][C:117]([CH3:119])=[O:118])[CH2:114][O:115][C@@H:73]2[CH2:72][C@@H:71]1[OH:120])=[O:69].C1CCN2C(=NCCC2)CC1>C1COCC1>[NH2:1][C@H:2]([C:5]([NH:7][C@H:8]([C:13]([OH:15])=[O:14])[CH2:9][CH:10]([CH3:11])[CH3:12])=[O:6])[CH2:3][OH:4].[CH3:35][C:34]([NH:45][CH2:46][CH:47]([OH:63])[CH2:48][O:49][C:50]1[C:55]2[C:56]3[C:61]([NH:62][C:54]=2[CH:53]=[CH:52][CH:51]=1)=[CH:60][CH:59]=[CH:58][CH:57]=3)([C:36]1[CH:41]=[CH:40][C:39]([N:42]=[N+:43]=[N-:44])=[CH:38][CH:37]=1)[CH3:33].[CH3:64][C:65]1[C@@H:82]([O:83][C:84]([C@H:86]([OH:103])[C@@H:87]([NH:94][C:95]([C:97]2[CH:102]=[CH:101][CH:100]=[CH:99][CH:98]=2)=[O:96])[C:88]2[CH:89]=[CH:90][CH:91]=[CH:92][CH:93]=2)=[O:85])[CH2:81][C@:77]2([OH:104])[C:78]([CH3:79])([CH3:80])[C:66]=1[C@@H:67]([O:122][C:123]([CH3:125])=[O:124])[C:68]([C@@:70]1([CH3:121])[C@H:75]([C@@H:76]2[O:105][C:106]([C:108]2[CH:113]=[CH:112][CH:111]=[CH:110][CH:109]=2)=[O:107])[C@:74]2([O:116][C:117]([CH3:119])=[O:118])[CH2:114][O:115][C@@H:73]2[CH2:72][C@@H:71]1[OH:120])=[O:69]
Reactant: CC(C)C[C@H](NC(=O)[C@H](CO)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: CC(=O)O[C@H]1C(=O)[C@@]2(C)[C@H]([C@H](OC(=O)c3ccccc3)[C@]3(O)C[C@H](OC(=O)[C@H](O)[C@@H](NC(=O)c4ccccc4)c4ccccc4)C(C)=C1C3(C)C)[C@]1(OC(C)=O)CO[C@@H]1C[C@@H]2O
Agent: CC(C)(NCC(O)COc1cccc2[nH]c3ccccc3c12)c1ccc(N=[N+]=[N-])cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CC(C)C[C@H](NC(=O)[C@@H](N)CO)C(=O)O

Procedure:
11 (0.1 g, 0.070 mmol) was treated with 1% DBU in THF (3 mL) for 45 seconds at room temperature and the product was precipitated by 1 M HCl in diethyl ether (200 mL) then it was purified on a silica gel column using chloroform/methanol (7:1) to afford 12 (75 mg, 89%) as a white powder. ESI-MS (5 kV, MeOH): m/z (%)=1225.1 (100) [M+Na]+; HPLC (230 nm): >95%.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:3]=1[CH2:4][N:5]=[N+:6]=[N-:7].Cl[C:14](=[CH2:17])[C:15]#[N:16]>O>[C:15]([C:14]1[N:7]=[N:6][N:5]([CH2:4][C:3]2[C:2]([F:1])=[CH:11][CH:10]=[CH:9][C:8]=2[F:12])[CH:17]=1)#[N:16]
Reactant: [N-]=[N+]=NCc1c(F)cccc1F
Reactant: C=C(Cl)C#N
Solvent: O
Product: N#Cc1cn(Cc2c(F)cccc2F)nn1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
A mixture of 2,6-difluorobenzyl azide (34.2 g), 2-chloroacrylonitrile (26.6 g) and water (125 ml) is stirred at about 80° C. for 24 hours. Excess 2-chloroacrylonitrile is distilled off by raising the external temperature to about 130° C. The mixture is cooled to about 95° C. and the product is crystallized by seeding. After cooling to about 40° C., the suspension is treated with cyclohexane (50 -ml) and brought to about 20° C., and stirred for about 2 hours. The product is isolated by filtration, washed with cyclohexane (75 ml) and then with water and dried in vacuo at about 60° C. Yield: 43.13 g=98%.
Reaction SMILES: Cl[C:2]1[N:3]([CH2:24][CH:25]2[CH2:29][CH2:28][O:27][CH2:26]2)[C:4]2[C:9]([N:10]=1)=[C:8]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)[N:7]=[C:6]([C:17]1[CH:18]=[N:19][C:20]([NH2:23])=[N:21][CH:22]=1)[N:5]=2.[S:30]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)([CH3:33])(=[O:32])=[O:31]>CS(C)=O>[CH3:33][S:30]([N:34]1[CH2:39][CH2:38][N:37]([C:2]2[N:3]([CH2:24][CH:25]3[CH2:29][CH2:28][O:27][CH2:26]3)[C:4]3[C:9]([N:10]=2)=[C:8]([N:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)[N:7]=[C:6]([C:17]2[CH:22]=[N:21][C:20]([NH2:23])=[N:19][CH:18]=2)[N:5]=3)[CH2:36][CH2:35]1)(=[O:32])=[O:31]
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: Nc1ncc(-c2nc(N3CCOCC3)c3nc(Cl)n(CC4CCOC4)c3n2)cn1
Solvent: CS(C)=O
Product: CS(=O)(=O)N1CCN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC2CCOC2)CC1
Temperature: 150 °C
Reaction time: 3 h
Yield: 38.3 %

Procedure:
Dimethyl sulfoxide (1 ml) was added to a mixture of 5-[8-chloro-6-morpholin-4-yl-9-(tetrahydrofuran-3-ylmethyl)-9H-purin-2-yl]pyrimidin-2-amine (100 mg, 0.24 mmol) and N-mesylpiperazine (118 mg, 0.72 mmol) and the resulting mixture was stirred at 150° C. for 3 hours. The reaction mixture was cooled and then partitioned with chloroform and water, and the organic layer was washed with water again and then dried over magnesium sulfate. The solvent was evaporated under reduced pressure and then the residue was purified by silica gel chromatography (chloroform:methanol=10:0 to 25:1 to 20:1) to give the title compound (50 mg, 45%) as a pale yellow solid.
Reaction SMILES: C([N:3]1[CH2:8][CH2:7][C:6]2([CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])[CH2:5][CH2:4]1)C>C(O)C.[OH-].[K+]>[O:18]=[C:9]1[C:6]2([CH2:7][CH2:8][NH:3][CH2:4][CH2:5]2)[CH2:17][CH2:16][C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2
Reactant: CCN1CCC2(CCc3ccccc3C2=O)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C1c2ccccc2CCC12CCNCC2
Yield: 77.7 %

Procedure:
A solution of 1.84 g (6.4 mmoles) ethyl 3,4-dihydro-1-oxospiro[naphthalene-2(1H), 4'piperidine] in 32 ml ethanol and 16 ml of 50% potassium hydroxide solution was heated at reflux for 18 hours. The solution was concentrated in vacuo to remove ethanol and the aqueous residue was extracted with 3×40 ml ether. The combined organic extracts were extracted with 2×40 ml 3N hydrochloric acid. The combined aqueous extracts were made basic with 10N sodium hydroxide and extracted with 3×75 ml ether. The combined organic extracts were washed with 20 ml water and brine, dried, and the solvent was removed in vacuo to give 1.07 g (78%) product as an oil;
Reaction SMILES: C([O:5][C:6](=[O:17])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=1)(C)(C)C.[CH3:18]I>>[N+:14]([C:10]1[CH:9]=[C:8]([CH:7]([CH3:18])[C:6]([OH:5])=[O:17])[CH:13]=[CH:12][CH:11]=1)([O-:16])=[O:15]
Reactant: CC(C)(C)OC(=O)Cc1cccc([N+](=O)[O-])c1
Reactant: CI
Product: CC(C(=O)O)c1cccc([N+](=O)[O-])c1

Procedure:
Using 3-nitrophenylacetic acid t-butyl ester as a starting material and methyl iodide (1 eq.) as a reagent, the same procedures of Examples 1a and 1b gave 2-(3-nitrophenyl)propionic acid.