Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C(SSC2C=CC([N+]([O-])=[O:16])=C(C(O)=O)C=2)=CC(C(O)=O)=C([N+]([O-])=O)C=1.CCCCCCCC[N:35]1[S:40][CH:39]=[CH:38][C:36]1=O.[P:41]([O-:45])([O-:44])([O-:43])=[O:42]>>[P:41]([O-:45])([O-:44])([O-:43])=[O:42].[S:40]1[CH2:35][C:36](=[O:16])[CH:38]=[N:39]1
Reactant: O=C(O)c1cc(SSc2ccc([N+](=O)[O-])c(C(=O)O)c2)ccc1[N+](=O)[O-]
Reactant: CCCCCCCCn1sccc1=O
Agent: O=P([O-])([O-])[O-]
Product: O=C1C=NSC1
Reaction time: 0.02 h

Procedure:
The spectrum of DTNB added to 10 ppm ITA was analyzed versus time at various pHs to evaluate the color change mechanism. 1.0 M Phosphate buffer was prepared and 30 mL aliquots were adjusted to the following pHs: 3, 7, 10, and 12. 22.2 uL of 1000 ppm KATHON® 886 MW was added to a semi micro cuvette followed by 2.065 mL of one of the above phosphate buffers. The solution was mixed and allowed to stand for one minute. These preparations resulted in a final isothiazolinone concentration 10 ppm.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([OH:20])[C:6]2[CH:7]=[N:8][N:9]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([F:19])[CH:13]=3)[C:10]=2[CH:11]=1)=[CH2:2]>C(O)C.C(OCC)(=O)C.[Pd]>[CH2:1]([C:3]1[CH:4]=[C:5]([OH:20])[C:6]2[CH:7]=[N:8][N:9]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([F:19])[CH:13]=3)[C:10]=2[CH:11]=1)[CH3:2]
Reactant: C=Cc1cc(O)c2cnn(-c3ccc(O)c(F)c3)c2c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCc1cc(O)c2cnn(-c3ccc(O)c(F)c3)c2c1
Yield: 18.9 %

Procedure:
A solution of 6-ethenyl-1-(3-fluoro-4-hydroxyphenyl)-1H-indazol-4-ol (E6) (190 mg, 0.70 mmol) in ethanol (6 mL) and ethyl acetate (6 mL) was hydrogenated over a weekend at room temperature and a pressure of 50 psi over a 10% palladium on charcoal catalyst (20 mg). After filtration to remove the catalyst, the filtrate was concentrated and the crude product purified using MDAP to yield the title compound (E7) (36 mg).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[SH:14].I[CH2:16][C:17]#[N:18]>CN(C)C=O>[NH2:3][C:4]1[CH:9]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:7]=[CH:6][C:5]=1[S:14][CH2:16][C:17]#[N:18]
Reactant: Nc1cc(C(F)(F)F)ccc1S
Reactant: N#CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCSc1ccc(C(F)(F)F)cc1N
Reaction time: 0.25 h

Procedure:
Sodium hydride (2.93 g, 60% dispersion in mineral oil) was added at 5-10° C. under nitrogen in small portions to a stirred and cooled solution of 2-amino-4-trifluoromethyl-benzenethiol (8.00 g) dissolved in dry dimethylformamide (125 ml). After stirring for 45 min iodoacetonitrile (2.65 ml) was added. Stirring was continued at ˜0° C. for 15 min and then at room temperature for 1 h. The mixture was concentrated in vacuo at 55° C. and the oily residue was extracted with petroleum ether (3×50 ml) in order to remove the mineral oil. The residue was partitioned between water (50 ml) and ethyl acetate (100 ml). The organic phase was washed with water (2×50 ml) and then with brine (30 ml), dried over sodium sulfate, filtered and concentrated in vacuo to give a yellow oil. The crude product was purified by flash chromatography on silica gel eluted with ethyl acetate-heptane 3:7 giving the title compound as a yellow oil. Yield 6.1 g (75%); 1H-NMR (DMSO-d6) δ (ppm): 7.54 (d, J=8.3 Hz, 1H), 7.09 (d, J=1.8 Hz, 1H), 6.86 (dd, 1H), 5.97 (br, 2H), 4.02 (s, 2H); 13C-NMR (DMSO-d6) δ (ppm): 150.0, 135.7, 130.8 (q, J=31 Hz), 124.2 (q, J=272 Hz), 117.7, 117.1, 112.1 (q, J=3.8 Hz), 110.6 (q, J=3.9 Hz), 18.1.
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N+:7]([O-])=[CH:6][CH:5]=1)([O-])=O>C(O)(=O)C.[Fe]>[NH2:1][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1cc[n+]([O-])c2ccccc12
Agent: [Fe]
Solvent: CC(=O)O
Product: Nc1ccnc2ccccc12
Temperature: 110 °C
Yield: 79.3 %

Procedure:
A suspension of 4-nitroquinoline N-oxide (10 g, 52.5 mmol) and metal iron (26.4 g, 0.47 mol) in acetic acid (500 ml) was stirred under heating at 110° C. for 3 hr. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. To the residue was added an aqueous sodium hydroxide solution to make the solution alkaline, which was followed by extraction with chloroform (5 ml×6). The orgariic layer was washed with water and saturated brine, dried over sodium sulfate and concentrated under reduced pressure to give 4-aminoquinoline (6.0 g, 79%, brown crystals).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1.C(N(CC)CC)C.Cl[C:22]1[N:27]([CH3:28])[C:26](=[O:29])[C:25]([C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=2)=[C:24]([C:40]2[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=2)[N:23]=1>ClCCl>[OH:13][CH:3]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)[CH2:2][NH:1][C:22]1[N:27]([CH3:28])[C:26](=[O:29])[C:25]([C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=2)=[C:24]([C:40]2[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=2)[N:23]=1
Reactant: Cn1c(Cl)nc(-c2ccncc2)c(-c2ccc3ccccc3c2)c1=O
Reactant: COc1ccc(CC(O)CN)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CC(O)CNc2nc(-c3ccncc3)c(-c3ccc4ccccc4c3)c(=O)n2C)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirring solution of 1-amino-3-(4-methoxy-phenyl)-propan-2-ol (1.1 g, 6.1 mmol) and triethylamine in 25 mL dichloromethane was added 2-chloro-3-methyl-5-naphthalen-2-yl-6-pyridin-4-yl-3H-pyrimidin-4-one. The solution was stirred at room temperature for 72 h. The organic layer was washed twice with 5% sodium bicarbonate, once with brine, then dried over magnesium sulfate. The product was purified on 90 g of silica eluting with 1 to 5% methanol/dichloromethane to give a yellow foam. M+1=493.2.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:19]([CH2:20][CH2:21][C@:4]12[CH3:5])[C@:17]1([CH3:18])[C@H:12]([CH2:13][C:14](=[O:22])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3.[CH2:23]([O:25][CH:26](OCC)[O:27][CH2:28][CH3:29])[CH3:24].B(F)(F)F.CCOCC>>[CH2:23]([O:25][CH:26]([O:27][CH2:28][CH3:29])[C@@H:15]1[CH2:16][C@@:17]2([CH3:18])[C@@H:12]([CH2:11][CH2:10][C@@H:9]3[C@@H:19]2[CH2:20][CH2:21][C@@:4]2([CH3:5])[C@H:6]3[CH2:7][CH2:8][C@@H:3]2[O:2][CH3:1])[CH2:13][C:14]1=[O:22])[CH3:24]
Reactant: CCOC(OCC)OCC
Reactant: CO[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: FB(F)F
Solvent: CCOCC
Product: CCOC(OCC)[C@@H]1C[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](OC)CC[C@@H]32)CC1=O
Yield: 117.7 %

Procedure:
By the method of part A of Example 20 (5α,17β)-17-methoxyandrostan-3-one (45.67 g., 0.15 mole) was diethoxymethylated using triethylorthoformate (55.0 ml., 49.0 g., 0.33 mole) and boron trifluoride etherate (50.0 ml., 57.7 g., 0.407 mole), affording (2α,5α,17β)-2-(diethoxymethyl)-17-methoxyandrostan-3-one (71.81 g.).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][C@H:16]([OH:18])[CH3:17])=[CH:9][CH:10]=2)[N:5]=1.[CH3:19]I>CN(C=O)C>[CH3:19][O:18][C@H:16]([CH3:17])[CH2:15][O:14][C:8]1[CH:7]=[C:6]2[C:11]([CH:12]=[CH:13][C:4]([CH3:3])=[N:5]2)=[CH:10][CH:9]=1
Reactant: Cc1ccc2ccc(OC[C@@H](C)O)cc2n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CO[C@H](C)COc1ccc2ccc(C)nc2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 50.6 %

Procedure:
To a stirred suspension of NaH (60% dispersion in oil, 95 mg, 2.4 mmol) in DMF (8 mL) was added dropwise a solution of (R)-1-(2-methylquinolin-7-yloxy)propan-2-ol (344 mg, 1.58 mmol) in DMF (4 mL) at 0° C. under nitrogen. The reaction mixture was stirred at 0° C. for 30 minutes. MeI (0.198 mL, 3.17 mmol) was added dropwise. The reaction was stirred at ambient temperature overnight. The reaction mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with water and brine, dried and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (5:1 hexanes/EtOAc) to give (R)-7-(2-methoxypropoxy)-2-methylquinoline (185 mg, 51%).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:9][C:7](=O)[CH2:6][C:4](=[O:5])[CH2:3]1.P(Cl)(Cl)(Cl)(Cl)[Cl:12]>C(Cl)(Cl)Cl>[Cl:12][C:7]1[CH2:9][C:2]([CH3:10])([CH3:1])[CH2:3][C:4](=[O:5])[CH:6]=1
Reactant: CC1(C)CC(=O)CC(=O)C1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CC1(C)CC(=O)C=C(Cl)C1
Reaction time: 18 h

Procedure:
A mixture of dimedone (50.0 g), phosphorus pentachloride (34.25 g) and dry chloroform (400 ml) was heated at the reflux temperature for a period of 2.5 hours, after which it was kept at the ambient temperature for 18 hours. After removal of the chloroform by evaporation under reduced pressure, the residue was mixed with water and ice and extracted with diethyl ether (3 × 100 ml). The combined ethereal extracts were washed with dilute potassium hydroxide and with water. The combined washings were extracted with fresh ether and these extracts combined with the washed ethereal extracts, and the whole dried over anhydrous magnesium sulphate. The ethereal extract was concentrated by evaporation under reduced pressure, and the residual oil purified by distillation to yield 3-chloro-5,5-dimethylcyclohex-2-enone, b.p. 94° C./15 mm Hg. The infra-red spectrum (liquid film) showed main absorption bands at 3000, 1700, 1620, 1360, 1310, 1160, 1010, 910 and 850 cm-1.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].[Cl:19][CH2:20][C:21](Cl)=[O:22]>CC(C)=O.O>[CH3:1][N:2]([C:21](=[O:22])[CH2:20][Cl:19])[C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=C(Cl)CCl
Reactant: CNc1ccccc1C(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)c1ccccc1N(C)C(=O)CCl
Reaction time: 1 h

Procedure:
25 Grams of methyl o-methylaminobenzoate was dissolved in 125 ml of acetone, to this solution was added a solution prepared by dissolving 20.92 g of potassium carbonate in 60 ml of water. Under an ice-cooled condition, 17.95 g of chloroacetyl chloride was added dropwise thereto, then the reaction mixture was stired at a room temperature for 1 hour. Acetone was removed by distillation, the residue obtained was extracted with chloroform, then the chloroform layer was washed with water, dried and the solvent was removed by distillation. The residue thus obtained was purified by a silica gel column chromatography to obtain 16.80 g of N-methyl-o-methoxycarbonyl-α-chloroacetanilide in the form of colorless oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].Cl[C:12]1[C:13]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[S:24][C:14]=2[N:15]=[C:16]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[N:17]=1>>[N:21]1[CH:22]=[CH:23][C:18]([C:16]2[N:17]=[C:12]([NH:6][CH2:5][C:4]3[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=3)[C:13]3[CH:26]=[C:25]([C:27]([F:29])([F:28])[F:30])[S:24][C:14]=3[N:15]=2)=[CH:19][CH:20]=1
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: FC(F)(F)c1cc2c(Cl)nc(-c3ccncc3)nc2s1
Product: FC(F)(F)c1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(-c3ccncc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-dichlorobenzylamine with 4-chloro-2-(pyridin-4-yl)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-(3,4-dichlorobenzylamino)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([CH3:13])[C:10]([OH:12])=O)=[CH:4][CH:3]=1.CN(C(O[N:22]1N=N[C:24]2C=CC=C[C:23]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.C(N)C>CN(C=O)C>[CH2:23]([NH:22][C:10](=[O:12])[CH:9]([CH3:13])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([I:1])=[CH:7][CH:6]=1)[CH3:24]
Reactant: CC(Cc1ccc(I)cc1)C(=O)O
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CCN
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)C(C)Cc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To 0.17 mg (0.59 mmol) 3-(4-iodo-phenyl)-2-methyl-propionic acid (XI.5) in 1 mL DMF, 0.28 mg (0.88 mmol) TBTU and 0.50 mL (2.9 mmol) DIPEA are added. The mixture is stirred for 15 min at rt. After that time, 106 mg (2.34 mmol) ethylamine are added and the mixture is stirred for 12 h at rt. After that time, the solvent is evaporated and the residue is purified by HPLC (Waters Xbridge 5 μm; eluent A: water+0.3% NH4OH, eluent B: MeOH) to yield the desired product.
Reaction SMILES: N(C(N(C)C)=O)=NC(N(C)C)=O.C(P(CCCC)CCCC)CCC.[O:26]1[CH2:30][CH2:29][CH:28]([OH:31])[CH2:27]1.[C:32]([O:36][C:37]([NH:39][C:40]1[N:45]=[CH:44][C:43]([CH2:46][CH:47]([CH:55]([S:65][CH2:66][C:67]2[CH:72]=[CH:71][C:70]([O:73][CH3:74])=[CH:69][CH:68]=2)[CH2:56][CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[C:60](O)[CH:59]=2)[C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])=[CH:42][CH:41]=1)=[O:38])([CH3:35])([CH3:34])[CH3:33]>C1(C)C=CC=CC=1>[C:32]([O:36][C:37]([NH:39][C:40]1[N:45]=[CH:44][C:43]([CH2:46][CH:47]([CH:55]([S:65][CH2:66][C:67]2[CH:72]=[CH:71][C:70]([O:73][CH3:74])=[CH:69][CH:68]=2)[CH2:56][CH2:57][C:58]2[CH:59]=[CH:60][CH:61]=[C:62]([O:31][CH:28]3[CH2:29][CH2:30][O:26][CH2:27]3)[CH:63]=2)[C:48]([O:50][C:51]([CH3:52])([CH3:53])[CH3:54])=[O:49])=[CH:42][CH:41]=1)=[O:38])([CH3:33])([CH3:34])[CH3:35]
Reactant: OC1CCOC1
Reactant: COc1ccc(CSC(CCc2cccc(O)c2)C(Cc2ccc(NC(=O)OC(C)(C)C)nc2)C(=O)OC(C)(C)C)cc1
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Solvent: Cc1ccccc1
Product: COc1ccc(CSC(CCc2cccc(OC3CCOC3)c2)C(Cc2ccc(NC(=O)OC(C)(C)C)nc2)C(=O)OC(C)(C)C)cc1
Temperature: 80 °C
Reaction time: 12 h
Yield: 44.2 %

Procedure:
1,1′-azobis(N,N-dimethylformamide)(134 mg, 0.78 mmol) was added to a solution of tri-n-butylphosphine (221 μL, 0.89 mmol) in toluene (2 mL). Tetrahydrofuran-3-ol (36 μL, 44 mmol) and tert-butyl 2-({6-[(tert-butoxycarbonyl)amino]pyridin-3-yl}methyl)-5-(3-hydroxyphenyl)-3-[(4-methoxybenzyl)thio]pentanoate (154 mg, 0.25 mmol) was added sequentially. The reaction mixture was stirred for 12 h at 80° C. Toluene (100 mL) was added and the mixture was washed with brine, dried and concentrated. Flash chromatography (toluene/EtOAc, 100:0 to 70:30) gave tert-butyl 2-({6-[(tert-butoxycarbonyl)amino]pyridin-3-yl}methyl)-3-[(4-methoxybenzyl)thio]-5-[3-(tetrahydrofuran-3-yloxy)phenyl]pentanoate (75 mg, 35%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]([OH:14])([CH2:12][CH3:13])[CH2:10][CH3:11].[Li]CCCC.[B:20](OC)(OC)[O:21]C.CC(=O)OCC>C1COCC1>[CH2:10]([C:9]1([CH2:12][CH3:13])[O:14][B:20]([OH:21])[C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]1=2)[CH3:11]
Reactant: CCC(O)(CC)c1cc(C)ccc1Br
Reactant: COB(OC)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC1(CC)OB(O)c2ccc(C)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.9 %

Procedure:
To a solution of 3-(2-bromo-5-methylphenyl)pentan-3-ol (6.5 g, 25.2 mmol) in THF (150 ml) at −78° C. was slowly added n-BuLi (30.24 ml, 75.6 mmol). The reaction mixture was warmed to rt and stirred for 2 h. After being cooled to −78° C., trimethyl borate (5.23 g, 50.4 mmol) was added dropwise and the reaction mixture was warmed to rt, stirred for 10 h under nitrogen and quenched with 2N HCl (50 ml). The mixture was extracted with EA (40 ml×3). The combined organic layers were washed with water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel eluted with PE:EA (10:1 to 1:1) to give the product (2.0 g, yield 38.9%) as a white solid. 1H NMR (300 MHz, DMSO-d6): δ 8.87 (s, 1H), 7.52-7.47 (d, 1H), 7.11-7.06 (m, 2H), 2.35 (s, 3H), 1.88-1.68 (m, 4H), 0.60-0.45 (m, 6H). MS: m/z=205 [M+1]+.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)=[C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][CH3:14])=[CH:7][C:6]=1[F:28].[CH3:29][NH2:30]>CO>[F:28][C:6]1[CH:7]=[C:8]([C:11]([C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)=[C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][CH3:14])[CH:9]=[CH:10][C:5]=1[O:4][CH2:3][CH2:2][NH:30][CH3:29]
Reactant: CCC(=C(c1ccc(O)cc1)c1ccc(OCCBr)c(F)c1)c1ccccc1
Reactant: CN
Solvent: CO
Product: CCC(=C(c1ccc(O)cc1)c1ccc(OCCNC)c(F)c1)c1ccccc1
Temperature: 85 °C
Yield: 57 %

Procedure:
To a stirred solution of 4-(1-(4-(2-bromoethoxy)-3-fluorophenyl)-2-phenyl but-1-enyl)phenol (111 mg, 0.25 mmol) in 5 mL MeOH was added 1 mL CH3NH2 (30% aq) and the mixture was heated at 85° C. for 18 h. The mixture was extracted with EtOAc. The extract was washed with water and brine, dried over Na2SO4, filtered, concentrated, and purified by column chromatography (CH2Cl2/MeOH (NH3 gas)=10/1) to give the desired product (56 mg, 57% yield, Z/E=1/1) as a beige solid. 1H NMR (400 MHz, CDCl3) δ 7.08-7.11 (m, 5H), 7.03 & 6.77 (d, J=8.6 Hz, 2H), 6.91-6.96 (m, 1H), 6.76 & 6.44 (d, J=8.4 Hz, 2H), 6.51-6.58 (m, 2H), 4.17 & 4.01 (t, J=5.0 Hz, 2H), 3.03 & 2.93 (t, J=5.0 Hz, 2H), 2.55 & 2.48 (s, 3H), 2.47 (q, J=7.6 Hz, 2H), 0.91 (t, J=7.6 Hz, 3H); m/z=392[M+1]+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([N+:12]([O-])=O)[C:8]([CH3:11])=[N:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([C:5]1[CH:6]=[C:7]([NH2:12])[C:8]([CH3:11])=[N:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ncc(C(C)(C)C)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Cc1ncc(C(C)(C)C)cc1N
Temperature: 25 °C
Reaction time: 18 h
Yield: 104 %

Procedure:
The above pyridine (388 mg, 1.99 mmol) was dissolved in ethanol (6 mL) and placed in a Parr hydrogenation vessel. Pd (10% on carbon, 20 mg) was added and the reaction was placed under a hydrogen atmosphere (50 psi) and shaken at room temperature for 18 h. The solution was then filtered through diatomaceous earth, concentrated in vacuo to provide 5-tert-butyl-2-methyl-pyridin-3-ylamine (340 mg, 99%) as a pale orange solid: ESI MS m/z 164 [C10H16N2+H]+.
Reaction SMILES: [CH2:1]([C:3]1([O:13][CH2:12]1)[CH2:4][CH2:5][C:6]1[O:11][CH2:10][CH2:9][CH2:8][CH:7]=1)[CH3:2].Cl.C([O:17]CC)C>O1CCCC1>[CH2:1]([C:3]1([CH2:12][OH:17])[CH2:4][CH2:5][C:6]2([CH2:7][CH2:8][CH2:9][CH2:10][O:11]2)[O:13]1)[CH3:2]
Reactant: CCC1(CCC2=CCCCO2)CO1
Reactant: CCOCC
Agent: Cl
Solvent: C1CCOC1
Product: CCC1(CO)CCC2(CCCCO2)O1
Reaction time: 120 h

Procedure:
To 5.5 g of 6-(3-ethyl-(3,4-epoxybutyl))-3,4-dihydro-2H-pyran was added a solution of 2 ml of 10% hydrochloric acid in 25 ml of tetrahydrofuran. The reaction mixture was stirred under nitrogen for five days and then poured into 150 ml of diethyl ether. The resulting solution was washed twice with 50 ml of saturated sodium bicarbonate solution, and dried, and the solvent was removed under high vacuum to yield 6 g of the desired product as a dark brown oil.
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:6](=[O:12])[NH:7][C:8](=[O:11])[NH:9][CH:10]=1)=[N+]=[N-].O.[H][H]>C(O)C.[Pd]>[NH2:1][CH2:4][C:5]1[C:6](=[O:12])[NH:7][C:8](=[O:11])[NH:9][CH:10]=1
Reactant: [H][H]
Reactant: [N-]=[N+]=NCc1c[nH]c(=O)[nH]c1=O
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: NCc1c[nH]c(=O)[nH]c1=O
Reaction time: 2 h
Yield: 86.4 %

Procedure:
The solution of 5-(azidomethyl)-2,4(1H,3H)-pyrimidinedione (0.275 g, 1.64 mmol) in ethanol: water (25:5 ml) was degassed with nitrogen, palladium on carbon (5%) was added, reaction was charged with hydrogen (55 PSI) and shaken for 2 h. The reaction was filtered and concentrated to give the 5-(aminomethyl)-2,4(1H,3H)-pyrimidinedione (0.20 g, 85%) as a solid. MS found: (M+H)+=142.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:6][C@H:5]([N:7]2[C:11]3[N:12]=[CH:13][N:14]=[C:15]([NH2:16])[C:10]=3[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:18]=3)=[CH:8]2)[CH2:4]1.[CH3:31][N:32]=[C:33]=[O:34]>>[NH2:16][C:15]1[C:10]2[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:18]=3)=[CH:8][N:7]([C@@H:5]3[CH2:4][C@H:3]([CH2:2][NH:1][C:33]([NH:32][CH3:31])=[O:34])[CH2:6]3)[C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: NC[C@H]1C[C@@H](n2cc(-c3cccc(OCc4ccccc4)c3)c3c(N)ncnc32)C1
Reactant: CN=C=O
Product: CNC(=O)NC[C@H]1C[C@@H](n2cc(-c3cccc(OCc4ccccc4)c3)c3c(N)ncnc32)C1

Procedure:
cis-1-{3-[4-Amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-3-methyl-urea is prepared as described in Example 26 starting with cis-7-(3-aminomethyl-cyclobutyl)-5-(3-benzyloxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine and methyl isocyanate (ChemService Inc., West Chester, Pa., U.S.A.). Analytical HPLC: tR=6.49 min (Grad 2); ES-MS: m/eo=456.9.
Reaction SMILES: [C:1](/[CH:9]=[CH:10]/[C:11]([OH:13])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:14](O)[CH3:15].S(=O)(=O)(O)O.C(Cl)(Cl)Cl>O>[C:1](/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)/C=C/C(=O)c1ccccc1
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)/C=C/C(=O)c1ccccc1
Yield: 92.9 %

Procedure:
A mixture of 7.50 g of trans-β-benzoylacrylic acid, 2.36 g of ethanol, 0.50 g of sulfuric acid and 30 ml of chloroform was refluxed for 5 hours while azeotropically removing water produced from the reaction system. After cooling, the reaction mixture was washed with a saturated solution of NaHCO and then with water. The solvent was distilled away to give 8.08 g of ethyl trans-β-benzoylacrylate.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH2:10][CH2:11][CH3:12].[CH2:13]([O:15][C:16](=[O:32])[CH2:17][C@H:18]1[C:26]2[C:21](=[CH:22][C:23]([O:27][CH2:28][CH2:29][CH2:30]Br)=[CH:24][CH:25]=2)[CH2:20][CH2:19]1)[CH3:14].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][CH2:30][CH2:29][CH2:28][O:27][C:23]2[CH:22]=[C:21]3[C:26](=[CH:25][CH:24]=2)[C@H:18]([CH2:17][C:16]([O:15][CH2:13][CH3:14])=[O:32])[CH2:19][CH2:20]3)=[C:3]([CH2:10][CH2:11][CH3:12])[CH:4]=1)#[N:7]
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCBr)ccc21
Reactant: CCCc1cc(C#N)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1cc(C#N)ccc1OCCCOc1ccc2c(c1)CC[C@H]2CC(=O)OCC
Temperature: 40 °C
Reaction time: 16 h
Yield: 65.8 %

Procedure:
To a mixture of 4-hydroxy-3-propylbenzonitrile (Example 29, 0.5 g, 3.1 mmol), ethyl [(1S-5-(3-bromopropoxy)-2,3-dihydro-1H-inden-1-yl]acetate (Example 45, 1.1 g, 3.1 mmol) and Cs2CO3 (1.2 g, 3.7 mmol) in DMF (10 mL) was added water (6 drops). The reaction mixture was stirred at 40° C. for 16 h and then concentrated under reduced pressure. The residue was taken up in water and extracted with EtOAc (2×). The combined organic phases were dried over MgSO4, filtered, and concentrated under reduced pressure. Purification by silica gel flash chromatography (EtOAc/Hexane (v/v) 1:20) gave 0.86 g (66%) of the title compound as a light yellow oil. LC-MS: RT=4.12 min; (M+H)+ 422.0.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][C:9]=2[O:15][CH3:16])=[O:5])C.Br[CH2:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1>>[CH3:16][O:15][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:8]=1[N:7]([CH2:18][C:19]1[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=1)[C:6]([C:4]([OH:3])=[O:5])=[CH:14]2
Reactant: CCOC(=O)c1cc2cccc(OC)c2[nH]1
Reactant: BrCc1cccc2ccccc12
Product: COc1cccc2cc(C(=O)O)n(Cc3cccc4ccccc34)c12

Procedure:
Using general procedure B, 7-methoxy-1H-indole-2-carboxylic acid ethyl ester (Lit. 6) was coupled with 1-bromomethyl-naphthalene and the product obtained was hydrolyzed to give the title compound as a white solid. MS: 330.3 ([M−H]−).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[Br:14][C:15]1[CH:19]=[CH:18][S:17][C:16]=1[C:20](=[N:22]O)[NH2:21]>>[Br:14][C:15]1[CH:19]=[CH:18][S:17][C:16]=1[C:20]1[N:22]=[C:7]([C:6]2[CH:10]=[CH:11][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=2)[O:8][N:21]=1
Reactant: NC(=NO)c1sccc1Br
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Product: FC(F)(F)c1ccc(-c2nc(-c3sccc3Br)no2)cc1

Procedure:
The title compound was prepared from 4-trifluoromethyl-benzoyl chloride (66 μL, 0.44 mmol) and 3-bromo-thiophene-2-amidoxime (98 mg, 0.44 mmol) similar to Example 16, and yielded 130 mg (78%) of white solid.