Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].[CH2:9](O)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[NH2:1][CH:2]([CH:3]([CH3:5])[CH3:4])[C:6]([O:8][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH3:9])=[O:7]
Reactant: CC(C)C(N)C(=O)O
Reactant: CCCCCCCCCCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCOC(=O)C(N)C(C)C

Procedure:
To a stirred solution of DL-valine 34 (20 g, 170.7 mmol) in toluene (200 mL) was added 1-dodecanol 2 (28.6 g, 153 mmol) in one lot, followed by pTSA (35.7 g, 187.7 mmol). After addition, the temperature of the reaction mixture was slowly raised to reflux temperature and the water was separated azeotropically. The reaction mixture was monitored by TLC. The reaction mixture was concentrated under vacuum. The obtained residue was taken in ethyl acetate (200 mL) and washed with aqueous 5% Na2CO3 (3×50 mL) followed by brine solution. The organic layer was dried over Na2SO4 and concentrated under vacuum to afford crude 35 (40 g, yield, 82%) as a liquid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].[C:10](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: Oc1ccc(Cl)cc1Br
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: COc1ccc(Cl)cc1Br
Yield: 99.5 %

Procedure:
A rapidly stirred solution of 15.5 grams (0.074 mole) of 2-bromo-4-chlorophenol, 20.0 grams (0.145 mole) of anhydrous powdered potassium carbonate, and 10 mL (0.106 mole) of dimethyl sulfate in 150 mL of acetone was heated at reflux for about 18 hours. After this time, the reaction mixture was concentrated under reduced pressure to a residue. The residue was partitioned between 100 mL each of water and methylene chloride. The organic layer was removed and washed with an aqueous solution saturated with sodium chloride. The organic layer was then dried with magnesium sulfate and filtered. The filtrate was passed through a short column of silica gel. Elution was accomplished with 500 mL of methylene chloride. The eluate was concentrated under reduced pressure, yielding 16.3 grams of 3-bromo-4-methoxychlorobenzene. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[S:6][CH:5]([C:7]2[O:8][C:9]([N+:12]([O-:14])=[O:13])=[CH:10][CH:11]=2)[NH:4][C@H:3]1[C:15]([OH:17])=[O:16].[C:19](OC(=O)C)(=[O:21])[CH3:20]>O>[C:19]([N:4]1[C@@H:3]([C:15]([OH:17])=[O:16])[C:2]([CH3:18])([CH3:1])[S:6][C@H:5]1[C:7]1[O:8][C:9]([N+:12]([O-:14])=[O:13])=[CH:10][CH:11]=1)(=[O:21])[CH3:20]
Reactant: CC1(C)SC(c2ccc([N+](=O)[O-])o2)N[C@H]1C(=O)O
Reactant: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)N1[C@@H](C(=O)O)C(C)(C)S[C@H]1c1ccc([N+](=O)[O-])o1
Temperature: 100 °C
Yield: 84.3 %

Procedure:
A solution containing 2.72 g (10 mmoles) of 5,5-dimethyl-2-(5-nitro-2-furyl)-thiazolidine-4(S)-carboxylic acid in 5.6 ml of water is heated to 100° C. on the steam bath. After adding 5.6 ml of acetic anhydride, the mixture is heated for additional 3 minutes. On the addition of water, 2.6 g (84.3%) of the title compound are precipitated, m.p.: 191°14 194° C., [α]D25 =-315.8° (c=0.938, dimethylsulphoxide).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C@H:7]2[O:9][C@@H:8]2[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:5][CH:6]=1.[CH3:16][O:17][CH2:18][CH2:19][NH2:20]>>[CH3:16][O:17][CH2:18][CH2:19][NH:20][CH:7]([C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)[CH:8]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[OH:9]
Reactant: c1ccc([C@H]2O[C@@H]2c2ccccc2)cc1
Reactant: COCCN
Product: COCCNC(c1ccccc1)C(O)c1ccccc1
Temperature: 125 °C

Procedure:
A mixture of trans-stilbene oxide (3.93 g, 0.020 mole) and 2-methoxyethylamine (4.51 g, 0.060 mole) was heated at 125° C. for 2 hours with an oil bath. A mass spectra analysis showed no title compound was present. The mixture was heated for another 2 hours at 150° C. The mixture was poured into water (using methanol rinse) to obtain an off-white solid. NMR analysis showed the solid contained approximately 60% unreacted stilbene oxide. The mixture was added to another 4.51 g (0.060 mole) of 2-methoxy ethylamine and the mixture heated at 135° C. for 4 hours in a stainless-steel bomb. After cooling, the reaction mixture was shown by NMR analysis to contain 20% stilbene oxide and 80% of the title compound. The solid was recrystallized from toluene to give 2.92 g (54%) of a white solid, m.p. 137°-139° C.
Reaction SMILES: [CH2:1](Cl)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH2:7][C@@H:8]([CH2:10][CH2:11][CH2:12][C@@H:13]([CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH3:14])[CH3:9])\[CH3:4].[CH3:22][O-:23].[Na+]>CO.C(OCC)(=O)C>[CH2:1]([O:23][CH3:22])/[CH:2]=[C:3](/[CH2:5][CH2:6][CH2:7][C@@H:8]([CH2:10][CH2:11][CH2:12][C@@H:13]([CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH3:14])[CH3:9])\[CH3:4]
Reactant: C/C(=C\CCl)CCC[C@H](C)CCC[C@H](C)CCCC(C)C
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC/C=C(\C)CCC[C@H](C)CCC[C@H](C)CCCC(C)C
Temperature: 60 °C
Reaction time: 4 h
Yield: 95.3 %

Procedure:
10.0 g of phytyl chloride was dropped into a solution of 2.0 g of sodium methoxide dissolved in 70 ml of methanol. The resulting mixture was stirred for 4 hours at 60° C. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue obtained was dissolved in 30 ml of ethyl acetate, and the resulting solution was washed with water. The solution was dried over anhydrous magnesium sulfate and the solvent was removed by distillation under reduced pressure. The residue thus obtained was subjected to distillation (b.p.: 148°-150° C., 1.5 mmHg) to obtain 9.4 g (yield: 95%) of oily methyl phytyl ether.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1.C(=O)([O-])O.[Na+]>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([O:17][CH3:16])[CH:19]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: COc1cccc(O)c1
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1cccc(Oc2ccnc3cc(OC)c(OC)cc23)c1
Temperature: 160 °C
Reaction time: 9 h
Yield: 20.2 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (103 mg) and commercially available 3-methoxyphenol (158 mg) were mixed and stirred at 160° C. for 9 hours. The reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate and then partitioned between water and ethyl acetate, and the ethyl acetate layer was washed with brine and then dried with sodium sulfate. After removing the solvent by reduced-pressure distillation, the resulting residue was purified by chromatography on silica gel eluting with hexane/ethyl acetate to obtain 29 mg of the title compound (yield: 52%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[CH2:21]Br)[CH:7]=1)[CH3:2].[CH3:24][C@@H:25]1[C@H:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:28][C:27](=[O:36])[NH:26]1>>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[CH2:21][N:26]2[C@H:25]([CH3:24])[C@H:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[O:28][C:27]2=[O:36])[CH:7]=1)[CH3:2]
Reactant: C[C@H]1NC(=O)O[C@H]1c1ccccc1
Reactant: CCOC(=O)Cc1cc(Cl)cc(Oc2ccc(Br)cc2CBr)c1
Product: CCOC(=O)Cc1cc(Cl)cc(Oc2ccc(Br)cc2CN2C(=O)O[C@@H](c3ccccc3)[C@H]2C)c1

Procedure:
Prepared according to the procedure described in Example 24, Step 7, using the following starting materials: [3-(4-bromo-2-bromomethyl-phenoxy)-5-chloro-phenyl]-acetic acid ethyl ester and (4R,5S)-4-methyl-5-phenyl-2-oxazolidinone.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)=[C:4]2[C:18]3[CH2:19][CH2:20][CH:21]([C:23](O)=[O:24])[CH2:22][C:17]=3[S:16][C:5]2=[N:6][C:7]=1[CH2:8][N:9]1[C:13](=[O:14])[CH2:12][CH2:11][C:10]1=[O:15].[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.Cl.CN(C)CCCN=C=NCC.CN(C=O)C>O>[Cl:1][C:2]1[C:3]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)=[C:4]2[C:18]3[CH2:19][CH2:20][CH:21]([C:23]([N:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)=[O:24])[CH2:22][C:17]=3[S:16][C:5]2=[N:6][C:7]=1[CH2:8][N:9]1[C:13](=[O:14])[CH2:12][CH2:11][C:10]1=[O:15]
Reactant: C1COCCN1
Reactant: COc1ccc(-c2c(Cl)c(CN3C(=O)CCC3=O)nc3sc4c(c23)CCC(C(=O)O)C4)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2c(Cl)c(CN3C(=O)CCC3=O)nc3sc4c(c23)CCC(C(=O)N2CCOCC2)C4)cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 455.1 %

Procedure:
A mixture of the compound obtained in Example 37 (500 mg), morpholine (99 mg), N,N-dimethylaminopyridine (13 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (197 mg), and DMF (10 ml) was stirred at room temperature for 10 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and then evaporated under reduced pressure to remove the solvent. The residue was subjected to column chromatography on silica gel to obtain 1-{[3-chloro-4-(4-methoxyphenyl)-7-[(4-morpholinyl)carbonyl]-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-2-yl]methyl}-2,5-pyrrolidinedione (2.6 g, 92%) from the eluates with ethyl acetate. It was recrystallized from chloroform-hexane. Colorless prisms. Melting point 170–171° C.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([C:22]#[C:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]([NH2:21])=[N:19][CH:20]=2)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si:30]([O:37][C:38]1[CH:43]=[CH:42][C:41]([CH2:44][C:45](Cl)=[O:46])=[CH:40][CH:39]=1)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31].O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[Si:30]([O:37][C:38]1[CH:39]=[CH:40][C:41]([CH2:44][C:45]([NH:21][C:18]2[C:17]([C:22]#[C:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:16][C:15]([C:12]3[CH:11]=[CH:10][C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3])=[CH:14][CH:13]=3)=[CH:20][N:19]=2)=[O:46])=[CH:42][CH:43]=1)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Cl)cc1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2cnc(N)c(C#Cc3ccccc3)n2)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Nc2ncc(-c3ccc(O[Si](C)(C)C(C)(C)C)cc3)nc2C#Cc2ccccc2)cc1
Temperature: 50 °C
Reaction time: 20 h
Yield: 60 %

Procedure:
Under an argon atmosphere, to a mixture of 5-[4-(tert-butyldimethylsilyloxy)phenyl]-3-(phenylethynyl)pyrazin-2-amine (7p) (300 mg, 747 μmol) and 4-(dimethylamino)pyridine (13.8 mg, 113 μmol) dissolved in anhydrous pyridine (15 mL) was added 2-[4-(tert-butyldimethylsilyl oxy)phenyl]acetyl chloride (10) prepared above at 0° C. and the mixture was heated with stirring at 50° C. for 20 hours. After cooling to room temperature, to this was added water and the product was extracted with ethyl acetate (100 mL×3). The combined organic extract was washed successively with water (200 mL) and brine (200 mL), followed by drying over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by column chromatography (silica gel 50 g, n-hexane/ethyl acetate=3/1) to give Compound 11p (291 mg, 448 μmol, 60.0%) as a brown solid. Rf=0.19 (n-hexane/ethyl acetate=3/1); 1H NMR (400 MHz, DMSO-d6) δ 0.10 (s, 6H), 0.20 (s, 6H), 0.90 (s, 9H), 0.93 (s, 9H), 3.65 (s, 2H), 6.63-6.73 (AA′BB′, 2H), 6.92-7.02 (AA′BB′, 2H), 7.17-7.27 (AA′BB′, 2H), 7.33-7.48 (m, 5H), 7.96-8.05 (AA′BB′, 2H), 8.99 (s, 1H), 10.69 (s, 1H); 13C NMR (67.8 MHz, DMSO-d6) 8-4.60 (2C), −4.61 (2C), 17.8, 17.9, 25.5 (6C), 41.7, 85.8, 94.5, 119.5 (2C), 120.4 (2C), 121.2, 128.2, 128.28 (2C), 128.34, 128.6 (2C), 129.5, 130.3 (2C), 131.8 (2C), 133.1, 138.5, 146.6, 148.0, 153.8, 156.9, 169.4; IR (KBr, cm−1) 530, 689, 756, 781, 839, 914, 1007, 1125, 1169, 1258, 1379, 1433, 1510, 1605, 1672, 2214, 2857, 2930, 2955, 3235.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([CH3:13])[CH:9]=[CH:10][CH:11]=2)[C:6]([C:14]([OH:16])=O)=[CH:5][CH:4]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([CH3:13])[CH:9]=[CH:10][CH:11]=2)[C:6]([C:14]([N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)=[O:16])=[CH:5][CH:4]=1
Reactant: C1COCCN1
Reactant: COc1ccc(C(=O)O)c2c(C)cccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)N2CCOCC2)c2c(C)cccc12
Reaction time: 8 h

Procedure:
To a mixture of 4-methoxy-8-methyl-1-naphthoic acid (above Step-5 intermediate) (1 equiv) in dry DMF (8 mL) was added, EDC.HCl (1.4 equiv) and HOBt (1.4 equiv) and the mixture was stirred for 10 min. To this, morpholine (1.5 equiv) and DIPEA (3 equiv) were added and the reaction mixture was stirred overnight. It was quenched with water (20 mL) and the aqueous layer was extracted with EtOAc (4×20 mL). The combined organic layer was washed with water (20 mL), 5% NaHCO3 solution (20 mL), brine (25 mL), dried (Na2SO4) and filtered. The solvent was evaporated under reduced pressure and the crude product was purified by column chromatography to furnish the title compound.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:16])[CH2:11][C:12](=[O:15])[CH2:13][CH3:14])=[CH:5][CH:4]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.[H][H]>CO.O>[F:1][C:2]([F:17])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:16])[CH2:11][C@@H:12]([OH:15])[CH2:13][CH3:14])=[CH:5][CH:4]=1
Reactant: CCC(=O)CC(=O)Nc1ccc(C(F)(F)F)cc1
Reactant: [H][H]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: CO
Solvent: O
Product: CC[C@H](O)CC(=O)Nc1ccc(C(F)(F)F)cc1
Temperature: 60 °C
Yield: 95 %

Procedure:
N-[4-(trifluoromethyl)phenyl]-3-oxopentanoic acid amide 1.30 g (5.0 mmol) produced in Example 1 and ((S)-BINAP)RuBr2 50.0 mg (0.057 mmol) (BINAP denotes 2,2′-bisdiphenylphosphino-1,1′-binaphthyl. It was prepared according to the method described in Tetrahedron Asymmetry, 1994,5,675) were mixed with 20 mL of a methanol-water (10/1 in volume) solution. Hydrogen replacement was carried out three times and after the reaction solution was heated to 60° C., reaction was carried out under hydrogen pressure (3.0 kg/cm2) for 12 hours. After releasing hydrogen, the solution was concentrated under reduced pressure and purifying on silica gel chromatography was carried out to obtain (S)-N-[4-(trifluoromethyl)phenyl]-3-hydroxypentanoic acid amide as a white solid (1.23 g, isolated yield: 95%). The optical purity of the product was determined by HPLC analysis (column; Daicel Chiral Pack AD-H 4.6×250 mm: eluent; hexane/isopropanol=90/10: flow rate; 1.0 mL/min: column temperature; 30° C.: detector; UV 210 nm: retention time; (S) antipode=12.0 minutes, (R) antipode=9.3 minutes) to be 84.7% ee. 1H-NMR (CDCl3, 400 MHz/ppm): δ 1.00 (3H, t), 1.5-1.7 (2H, br), 2.50 (1H, dd), 2.59 (1H, dd), 2.75 (br, 1H), 4.06 (1H, m), 7.57 (2H, d), 7.64 (2H, d), 8.21 (1H, br)
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:13][CH2:12][CH2:11][C:10](=[N:14]O)[C:9]2[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:8]1=2)=[O:6])([CH3:3])[CH3:2].[BH4-].[Na+].[OH-].[Na+]>CO.CN(C=O)C>[CH:1]([O:4][C:5]([N:7]1[CH2:13][CH2:12][CH2:11][CH:10]([NH2:14])[C:9]2[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:8]1=2)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)N1CCCC(=NO)c2ccc(Cl)cc21
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C)OC(=O)N1CCCC(N)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 8-chloro-5-hydroxyimino-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid isopropyl ester (3.33 g, 11.2 mmole) and MoO3 (2.45 g, 17.0 μmmole) in MeOH (50.0 ml) was added a solution of sodium borohydride (2.13 g, 56.2 mmole) in DMF (50.0 ml). The reaction was stirred at room temperature overnight. To the reaction mixture was added 2.0N NaOH (aq) (100 ml). The precipitate was removed by filtration, and the filtrate was extracted with ethyl acetate (5×100 ml). The combined organics was washed with brine (3×500 ml). Dried over Na2SO4, filtered and concentrated to 100 ml, which was then treated with 4.0N HCl in dioxane (3.50 ml). Removal of solvents in vacuo gave a white solid, which washed with ethyl ether and dried under vacuum to provide the titled compound as hydrochloride salt (2.87 g, 80%). MS (ES+): 283 (M+H).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH2:12]([OH:21])[CH2:13][CH2:14][CH:15]=[CH:16][C:17]#[C:18][CH2:19][CH3:20]>N1C=CC=CC=1>[S:7]([O:21][CH2:12][CH2:13][CH2:14][CH:15]=[CH:16][C:17]#[C:18][CH2:19][CH3:20])([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCC#CC=CCCCO
Solvent: c1ccncc1
Product: CCC#CC=CCCCOS(=O)(=O)c1ccc(C)cc1
Reaction time: 1 h
Yield: 89.5 %

Procedure:
To a mixture of p-toluenesulfonyl chloride (22.4 g., 0.12 moles) and 50 ml. of anhydrous pyridine is added 14 g. of non-4-en-6-yn-1-ol (0.107 moles) with ice bath cooling. The mixture is stirred for 1 hour and then is stored at 0° overnight. Ice is added to the mixture which is extracted with several portions of 50:50 ether/hexane. The combined organic phase is washed with 5% HCl, water, saturated sodium bicarbonate and dried over sodium sulfate. Removal of solvent at reduced pressure and subsequent solvent removal at 0.1 mm. for 1 hour gives 1-tosyloxy-non-4-en-6yne (28 g.).
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[C:9]([N+:11]([O-])=O)[CH:10]=[C:5]2[CH:4]=[N:3]1.C(O)(=O)C>C(Cl)Cl.[Zn]>[CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[C:9]([NH2:11])[CH:10]=[C:5]2[CH:4]=[N:3]1
Reactant: Cn1ncc2cc([N+](=O)[O-])cnc21
Agent: [Zn]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cn1ncc2cc(N)cnc21
Temperature: 45 °C

Procedure:
To a solution of 1-methyl-5-nitro-1H-pyrazolo[3,4-b]pyridine (90 mg, 0.51 mmol) in CH2Cl2 (1 mL) is added zinc (200 mg, 3.06 mmol) and acetic acid (250 μL). The mixture is heated at 45° C. for 5 h. The zinc is removed by filtration and the filtrate was evaporated under reduced pressure. The residue is purified by flash column chromatography using a gradient of 0-10% methanol in CH2Cl2. 1N HCl in ether is added to the residue to afford the title compound as the hydrochloride salt (43 mg, 46%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[O:11][CH2:12][C:13]#[N:14])[C:5]([Cl:19])=[CH:4][N:3]=1.[NH2:20][C:21]1[CH:34]=[CH:33][C:24]2[CH2:25][CH2:26][CH2:27][C:28](=[O:32])[N:29]([CH2:30][CH3:31])[C:23]=2[CH:22]=1>>[Cl:19][C:5]1[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[O:11][CH2:12][C:13]#[N:14])=[N:7][C:2]([NH:20][C:21]2[CH:34]=[CH:33][C:24]3[CH2:25][CH2:26][CH2:27][C:28](=[O:32])[N:29]([CH2:30][CH3:31])[C:23]=3[CH:22]=2)=[N:3][CH:4]=1
Reactant: CCN1C(=O)CCCc2ccc(N)cc21
Reactant: N#CCOc1ccccc1Nc1nc(Cl)ncc1Cl
Product: CCN1C(=O)CCCc2ccc(Nc3ncc(Cl)c(Nc4ccccc4OCC#N)n3)cc21

Procedure:
{2-[5-Chloro-2-(1-ethyl-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-8-ylamino)-pyrimidin-4-ylamino]-phenoxy}-acetonitrile was prepared from [2-(2,5-Dichloro-pyrimidin-4-ylamino)-phenoxy]-acetonitrile and 8-Amino-1-ethyl-1,3,4,5-tetrahydro-1-benzazepin-2-one in an analogous manner to Example 12211d. (120° C., 20 min) Title compound was isolated as a white foam: 67 mg (61%) after silica gel chromatography (ISCO 12 g, 0-100% EtOAc in hexanes). HPLC purity 88%, LCMS 463.24 (M+H), 1H-NMR (CDCl3, 400 MHz) δ: 8.35 (d, J=8.0 Hz, 1H), 8.12 (s, 1H), 7.60 (s, 2H), 7.35 (s, 1H), 7.23 (d, J=6.5 Hz, 1H), 7.21-7.05 (m, 4H), 4.90 (s, 2H), 3.90-3.50 (bm, 2H), 2.71-2.60 (m, 2H), 2.34-2.23 (m, 2H), 2.05-2.12 (m, 2H), 1.08 (t, J=7.1 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Si:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[NH2:12].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Cl[C:24]1[N:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:25]=1[C:26]([OH:28])=[O:27]>C1COCC1>[Cl:33][C:31]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[C:24]([NH:12][C:3]2[CH:4]=[CH:5][C:6]([Si:8]([CH3:9])([CH3:11])[CH3:10])=[CH:7][C:2]=2[F:1])[N:32]=1
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Reactant: C[Si](C)(C)c1ccc(N)c(F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C[Si](C)(C)c1ccc(Nc2nc(Cl)ccc2C(=O)O)c(F)c1
Temperature: -78 °C
Reaction time: 2.5 h
Yield: 77.9 %

Procedure:
To a cold (−78° C.) solution of 2-fluoro-4-trimethylsilanyl-phenylamine (64.7 g, 353 mmol) in anhydrous THF (170 mL) was added a solution of LHMDS (555 mL, 1 M in hexanes, 555 mmol) dropwise over 45 minutes under a nitrogen atmosphere. After 2.5 hours at −78° C., a solution of 2,6-dichloro-nicotinic acid (33.8 g, 177 mmol) in anhydrous THF (100 mL) was added. The reaction mixture was stirred at −78° C. for 30 minutes then allowed to warm to room temperature. After 18 hours stirring at room temperature the reaction was quenched with crushed ice and the pH adjusted to pH 1 by the addition of concentrated HCl (ca. 90 mL). The resultant solution was extracted with ethyl acetate and the organic layer washed with water followed by brine, dried (Na2SO4), filtered and evaporated in vacuo. The resultant residue was triturated three times successively with methanol and filtered to afford the title compound as a yellow solid (46.7 g, 78%). LCMS (method B): RT=4.83 min, M+H+=339.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][N:11]([CH2:13][C:14]3([OH:27])[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]3)[CH:12]=2)=[CH:4][C:3]=1[O:28][CH:29]([C:31]1[C:36]([Cl:37])=[CH:35][CH:34]=[C:33]([F:38])[C:32]=1[Cl:39])[CH3:30].Cl.O1CCOCC1>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][N:11]([CH2:13][C:14]3([OH:27])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH:12]=2)=[CH:4][C:3]=1[O:28][CH:29]([C:31]1[C:36]([Cl:37])=[CH:35][CH:34]=[C:33]([F:38])[C:32]=1[Cl:39])[CH3:30]
Reactant: CC(Oc1cc(-c2cnn(CC3(O)CCN(C(=O)OC(C)(C)C)CC3)c2)cnc1N)c1c(Cl)ccc(F)c1Cl
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(Oc1cc(-c2cnn(CC3(O)CCNCC3)c2)cnc1N)c1c(Cl)ccc(F)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.3 %

Procedure:
A reaction mixture of compound (3-6) (145 mg; 0.25 mmol) with 4.0 M HCl in dioxane (2.0 mL; 8.1 mmol) in 5 mL of CH2Cl2 was stirred at room temperature for 2.0 hours. The reaction mixture was concentrated by vacuum. The residue was purified by Dionex system (5% to 95% MeCN:H2O w 0.1% HOAc buffer) to collect the desired fraction to afford 76 mg of (3-7) as a yellow grease (63% yield). 1H NMR (400 MHz, DMSO-D6) δ ppm 1.41-1.55 (m, 2H) 1.59-1.71 (m, 2H) 1.81 (d, J=6.57 Hz, 3H) 2.88-3.00 (m, 2H) 3.02-3.14 (m, 2H) 4.08 (s, 2H) 5.17 (s, 2H) 6.14-6.27 (m, J=6.57 Hz, 1H) 7.05 (s, 1H) 7.40-7.49 (m, J=8.72, 8.72 Hz, 1H) 7.51-7.60 (m, J=9.09, 4.80 Hz, 1H) 7.63 (s, 1H) 7.76 (s, 1H) 7.91 (s, 1H) 8.51 (s, 1H) 8.81 (s, 1H). LCMS calcd for C22H24Cl2FN5O2 (M+H) 481, found 481. HPLC purity 98%. Anal. (C22H24Cl2FN5O2×2.2HOAc×2.3H2O)C, H, N.