Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([Cl:11])=[C:8]([OH:10])[CH:9]=1)([O-:3])=[O:2].[CH3:12][O:13][CH2:14][CH2:15]Cl.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:11][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][C:8]=1[O:10][CH2:15][CH2:14][O:13][CH3:12]
Reactant: O=[N+]([O-])c1ccc(Cl)c(O)c1
Reactant: COCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1cc([N+](=O)[O-])ccc1Cl
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a solution of 5-nitro-2-chlorophenol (1.0 g, 5.8 mmol) and 2-methyloxychloroethane (2.6 mL, 28.8 mmol) in DMF (20 mL) was added K2CO3 (2.4 g, 17.4 mmol). The suspension was stirred at 80° C. for 18 h. After cooling, the mixture was filtered, the salts washed with EtOAc and the solvents removed under vacuum. The residue was dissolved in EtOAc and washed twice with NaOH (1 N) and once with H2O. The EtOAc layer was dried over MgSO4 and concentrated under vacuum. The crude was purified on silica gel using a Hexanes/EtOAc gradient (100/0 to 50/50) to give 1-chloro-2-(2-methoxy-ethoxy)-4-nitro-benzene.
Reaction SMILES: [O-:1]O.[OH:3][CH2:4]/[CH:5]=[C:6](/[CH3:13])\[CH2:7][CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11]>>[OH:3][CH2:4][CH:5]1[O:1][C:6]1([CH3:13])[CH2:7][CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11]
Reactant: [O-]O
Reactant: CC(C)=CCC/C(C)=C\CO
Product: CC(C)=CCCC1(C)OC1CO

Procedure:
The hydroperoxide resulting from nerol can be reduced to the corresponding hydroxyl compound and this can then be cyclized with acid catalysis to give nerol oxide.
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][C@@H:8]([N:11]([CH3:21])[C:12](=[O:20])[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C@H:7]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=2)[CH2:6]1)(=[O:4])[CH:2]=[CH2:3].C(=O)([O-])[O-].[K+].[K+].[NH:36]1[CH2:40][CH2:39][CH2:38][C:37]1=[O:41].O>CN(C=O)C>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([C:12]([N:11]([C@@H:8]2[CH2:9][CH2:10][N:5]([C:1](=[O:4])[CH2:2][CH2:3][N:36]3[CH2:40][CH2:39][CH2:38][C:37]3=[O:41])[CH2:6][C@H:7]2[C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=2)[CH3:21])=[O:20])=[CH:18][CH:17]=1
Reactant: C=CC(=O)N1CC[C@@H](N(C)C(=O)c2ccc(Cl)cc2)[C@H](c2ccc(Cl)c(Cl)c2)C1
Reactant: O=C1CCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C(=O)c1ccc(Cl)cc1)[C@@H]1CCN(C(=O)CCN2CCCC2=O)C[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 110 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
To a solution of the compound obtained in Example 588 (0.050 mg) in DMF (1 mL) were added potassium carbonate (0.0166 mg) and 2-pyrrolidinone (0.0093 mL), and the mixture was stirred at 110° C. for 1 hr. To the reaction mixture was added water, and the resultant product was extracted with ethyl acetate. The organic layer was washed with brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH Chromatorex) (solvent gradient; 30→100% ethyl acetate/hexane) to give the title compound (37 mg, 63%) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[C:9](Cl)=[CH:8][C:7]([CH3:11])=[N:6][C:5]=1[O:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=1[CH3:21].[S:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[CH2:28][NH:29][CH2:30][CH2:31][OH:32]>CN1CCCC1=O>[CH3:1][O:2][C:3](=[O:22])[C:4]1[C:9]([N:29]([CH2:30][CH2:31][OH:32])[CH2:28][C:24]2[S:23][CH:27]=[CH:26][CH:25]=2)=[CH:8][C:7]([CH3:11])=[N:6][C:5]=1[O:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=1[CH3:21]
Reactant: COC(=O)c1c(Cl)cc(C)nc1Oc1c(C)cc(C)cc1C
Reactant: OCCNCc1cccs1
Solvent: CN1CCCC1=O
Product: COC(=O)c1c(N(CCO)Cc2cccs2)cc(C)nc1Oc1c(C)cc(C)cc1C
Temperature: 130 °C

Procedure:
A mixture of 4-chloro-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotinic acid methyl ester and 2-[(thiophen-2-ylmethyl)-amino]-ethanol in 1-methyl-2-pyrrolidinone was heated at 130° C. overnight. The mixture was quenched with water, brine and extracted with ethyl acetate. The organic layer was dried and concentrated to dryness. The residue was purified through silica gel column chromatography to give the title compound. 1H NMR (CDCl3) d 7.22(m,1H), 6.94m,2H), 6.84(s,2H), 6.44(s,1H), 4.52(s,2H), 3.91(s,3H), 3.679t,2H), 3.369t,2H), 2.279s,3H), 2.20(s,3H), 2.07(s,6H) ppm.
Reaction SMILES: Cl.[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:27])([F:26])[F:25])(=[O:17])=[O:16])[CH2:12][NH:11]2)=[O:9])[CH2:6][CH2:5]1)#[N:3].[CH3:28][O:29][CH2:30][CH:31]=O>>[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:27])([F:25])[F:26])(=[O:17])=[O:16])[CH2:12][N:11]2[CH2:31][CH2:30][O:29][CH3:28])=[O:9])[CH2:5][CH2:6]1)#[N:3]
Reactant: COCC=O
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3C(F)(F)F)CN2)CC1
Agent: Cl
Product: COCCN1C[C@H](S(=O)(=O)c2ccccc2C(F)(F)F)C[C@H]1C(=O)NC1(C#N)CC1

Procedure:
(2S,4R)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide hydrochloride from experiment K5 was reductively aminated with methoxy acetaldehyde in analogy to experiment L3 to give (2S,4R)-1-(2-methoxy-ethyl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide as a colorless oil. MS: 446.3 [M+H]+.
Reaction SMILES: N1C=CC=CC=1.C(N(CC)CC)C.[CH3:14][CH:15]([CH3:38])[CH2:16][CH2:17][NH:18][C:19]([N:21]1[C:29]2[C:24](=[CH:25][C:26]([O:30][C:31]3[CH:36]=[CH:35][N:34]=[C:33]([NH2:37])[CH:32]=3)=[CH:27][CH:28]=2)[CH:23]=[CH:22]1)=[O:20].Cl[C:40]([O:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:41]>CN(C)C=O>[CH3:14][CH:15]([CH3:38])[CH2:16][CH2:17][NH:18][C:19]([N:21]1[C:29]2[C:24](=[CH:25][C:26]([O:30][C:31]3[CH:36]=[CH:35][N:34]=[C:33]([NH:37][C:40](=[O:41])[O:42][C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[CH:32]=3)=[CH:27][CH:28]=2)[CH:23]=[CH:22]1)=[O:20]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(C)CCNC(=O)n1ccc2cc(Oc3ccnc(N)c3)ccc21
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)CCNC(=O)n1ccc2cc(Oc3ccnc(NC(=O)Oc4ccccc4)c3)ccc21
Yield: 101.7 %

Procedure:
N,N-dimethylformamide (30 ml), pyridine (0.52 ml, 6.4 mmol) and triethylamine (1.35 ml, 9.69 mmol) were added to N1-(3-methylbutyl)-5-((2-amino-4-pyridyl)oxy)-1H-1-indolecarboxamide (1.45 g, 4.29 mmol); phenyl chloroformate (0.81 ml, 6.4 mmol) was added at 0° C. while stirring; and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was partitioned between ethyl acetate and water; and the organic layer was concentrated and subjected to silica gel column chromatography to yield a mixture (2.0 g) of phenyl N-(4-(1-((3-methylbutyl)amino)carbonyl-1H-5-indolyl)oxy-2-pyridyl)carbamate and phenyl N-(4-(1-((3-methylbutyl)amino)carbonyl-1H-5-indolyl)oxy-2-pyridyl)-N-(phenoxycarbonyl)carbamate. A portion of 0.4 g of the mixture was dissolved in N,N-dimethylformamide (4 ml); 4-(1-pyrrolidinyl)piperidine (0.43 g, 2.8 mmol) was added thereto; and the reaction mixture was stirred for 2 hours. The reaction mixture was partitioned between ethyl acetate and water; the organic layer was concentrated; and the residue was purified by silica gel column chromatography (Fuji Silysia NH, ethyl acetate:methanol=10:1) to yield the title compound as white crystals (275 mg, 0.53 mmol).
Reaction SMILES: N1C=CC=CC=1.[C:7](OC(=O)C)(=[O:9])[CH3:8].[F:14][C:15]([F:34])([F:33])[C:16]1[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:20]([OH:27])[C:19]([CH3:28])=[C:18]([C:29]([F:32])([F:31])[F:30])[N:17]=1>CCOCC>[F:34][C:15]([F:33])([F:14])[C:16]1[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:20]([O:27][C:7](=[O:9])[CH3:8])[C:19]([CH3:28])=[C:18]([C:29]([F:32])([F:31])[F:30])[N:17]=1
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)F)c(C)c1O
Reactant: CC(=O)OC(C)=O
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)F)c(C)c1OC(C)=O
Reaction time: 3 h
Yield: 93.6 %

Procedure:
A mixture of 1.26 g (0.016 mol) of pyridine, 1.61 g (0.016 mol) of acetic anhydride and 5.0 g (0.016 mol) of product of Example 35 in 50 ml of ether was stirred for 3 hours and filtered. The filtrate was concentrated in vacuo to give 5.38 g (95%) of product as a solid; mp 49°-51° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH:4](Br)[CH2:5][CH:6]([CH3:8])[CH3:7].[O-:11][C:12]#[N:13].[K+].[CH3:15][OH:16]>>[CH3:1][O:2][C:3](=[O:10])[CH:4]([NH:13][C:12]([O:16][CH3:15])=[O:11])[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: N#C[O-]
Reactant: COC(=O)C(Br)CC(C)C
Reactant: CO
Agent: [K+]
Product: COC(=O)NC(CC(C)C)C(=O)OC
Yield: 66 %

Procedure:
14.64 grams of 2-bromo-4-methyl valeric acid methyl ester were brought to reaction with potassium cyanate and methanol in the manner described in Example 1 (using the same amounts of potassium cyanate and methanol as in Example 1 ), reaction time 1 hour and then worked up. There were obtained 9.39 grams (66%) of 2-methoxycarbonylamino-4-methyl valeric acid methyl ester with a boiling point of 100° C./0.0013 mbar.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:16](=[O:19])(=[O:18])[NH2:17])[C:10]=1[NH:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:5]([OH:7])=[O:6].[OH-].[Na+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O>[CH2:22]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:16](=[O:19])(=[O:18])[NH2:17])[C:10]=1[NH:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:5]([OH:7])=[O:6])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCc1ccccc1
Reactant: CCCCNc1c(N)cc(C(=O)O)cc1S(N)(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCNc1c(NCc2ccccc2)cc(C(=O)O)cc1S(N)(=O)=O

Procedure:
A suspension of 3-amino-4-butylamino-5-sulphamyl-benzoic acid (6.5 g) in water (30 ml) was adjusted to pH 7.5 H by addition of 1N sodium hydroxide. Benzyl bromide (3.87 g) was added and, under stirring, the pH was kept at pH 7.5 by automatic titration with 1N sodium hydroxide. After the base consumption had become negligible, the pH was adjusted to 3 by addition of diluted hydrochloric acid. The precipitated 3-benzylamino-4-butylamino-5-sulphamyl-benzoic acid was collected and recrystallized several times from aqueous methanol, after which the compound was obtained with a melting point of 198.5-199°C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:19]=[CH:18][C:17](=[O:20])[N:16]([CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:10]=2[N:11]=[C:12](SC)[N:13]=1.[NH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>>[CH2:31]([O:30][C:28](=[O:29])[CH2:27][NH:26][C:12]1[N:13]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:9]2[CH:19]=[CH:18][C:17](=[O:20])[N:16]([CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:10]=2[N:11]=1)[CH3:32]
Reactant: CCOC(=O)CN
Reactant: CCC(CC)n1c(=O)ccc2c(-c3ccccc3Cl)nc(SC)nc21
Product: CCOC(=O)CNc1nc(-c2ccccc2Cl)c2ccc(=O)n(C(CC)CC)c2n1

Procedure:
The product of Example 44, and ethyl glycinate were reacted by the procedure of Example 60 to afford the title compound [4-(2-chloro-phenyl)-8-(1-ethyl-propyl)-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino]-acetic acid ethyl ester. LC MS (m/e)=429 (MH+). Rt=2.49 min.
Reaction SMILES: [C:1]([OH:8])(=O)[CH2:2][CH2:3][CH:4]=[CH:5][CH3:6].C(N(CC)CC)C.[C:16](Cl)(=O)[C:17](C)(C)[CH3:18].[C:23]1([CH2:29][C@@H:30]2[O:34][C-:33]=[N:32][C:31]2=[O:35])C=CC=[CH:25][CH:24]=1.C1(C(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([Li])CCC>C1COCC1>[C:31]([N:32]1[C@@H:2]([CH2:3][C:4]2[CH:5]=[CH:6][CH:18]=[CH:17][CH:16]=2)[CH2:1][O:8][C:33]1=[O:34])(=[O:35])[CH2:30][CH2:29][CH:23]=[CH:24][CH3:25]
Reactant: CC(C)(C)C(=O)Cl
Reactant: O=C1N=[C-]O[C@H]1Cc1ccccc1
Reactant: CC=CCCC(=O)O
Agent: [Li]CCCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: c1ccc(C(c2ccccc2)c2ccccc2)cc1
Product: CC=CCCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a mechanically stirred solution of 9.50 g (83.2 mmol, 1.10 equiv.) of 4-hexenoic acid (commericially available from Lancaster, Catalog #252-427-6) and 13.9 mL (10.1 g, 99.7 mmol, 1.33 equiv.) of triethylamine in 150 mL of dry THF, cooled to −78° C. under dry N2, was added 10.71 mL (10.49 g, 87.0 mmol, 1.15 equiv.) of pivaloyl chloride (Aldrich). The mixture was warmed to 0° C. for 60 min, and then recooled to −78° C. A solution of 13.4 g (75.6 mmol, 1.00 equiv) of (S)-(−)-(phenylmethyl)-2-oxazolidone (Aldrich) and 22 mg of triphenylmethane (indicator) in 150 mL of dry THF, stirred at −30° C. to −45° C. under N2, was treated dropwise with n-butyllithium (−2.5 M in hexanes) (Aldrich) until an orange color persisted (−30 mL required). The resulting solution was cooled to −78° C. and then added, via rapid cannulation, to the above stirred mixture containing the mixed anhydride. The residual lithiated oxazolidone was rinsed in with two 10-mL portions of dry THF and the resulting mixture was stirred at −78° C. for 1.5 h, and then at 0° C. for 1 h. The mixture was partitioned between CH2Cl2 and pH 7 phosphate buffer. The CH2Cl2 phase was washed with saturated aqueous NaHCO3 followed by half-saturated aqueous NaCl, dried (MgSO4), and evaporated in vacuo. The residual cream-colored solid (22.4 g) was chromatographed (Waters Prep 2000, 5.0 cm×25 cm 10μ Kromasil KR60-1OSIL-5025 column) in two batches eluting with 85:15 hexanes/EtOAc. The chromatographed product was recrystallized from hexane to yield 14.34 g (first crop, 69%) of the title compound as fine white needles. 1H NMR (300 MHz, CDCl3) δ7.37-7.20 (m, 5H, —C6H5), 5.60-5.43(m, 2H, CH═CHCH3), 4.71-4.63 (m, 1H, NCH(Ph) CH2O), 4.23-4.14 (m, 2H, NCH(Ph)CH2O), 3.295 (dd, J=13.3, 3.3 Hz, 1H, CHHC6H5), 3.11-2.90 (m, 2H, CH2C═O), 2.758 (dd, J=13.3, 9.6 Hz, 1H, CHHC6H5), 2.42-2.34 (m, 2H, CH═CHCH2), 1.67-1.65 (m, 2H, CH═CHCH3).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][OH:5].CC(C)([O-])C.[K+].Cl[C:14]1[C:23]2[CH2:22][CH2:21][CH2:20][C:19]3([CH2:27][CH2:26][CH2:25][CH2:24]3)[C:18]=2[N:17]=[C:16]([NH2:28])[N:15]=1>C1COCC1.C(Cl)Cl.O>[CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][O:5][C:14]1[C:23]2[CH2:22][CH2:21][CH2:20][C:19]3([CH2:27][CH2:26][CH2:25][CH2:24]3)[C:18]=2[N:17]=[C:16]([NH2:28])[N:15]=1
Reactant: CN(C)CCO
Reactant: Nc1nc(Cl)c2c(n1)C1(CCCC1)CCC2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: CN(C)CCOc1nc(N)nc2c1CCCC21CCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-(dimethylamino)ethanol (63.9 μL, 0.631 mmol) in THF (5 mL) was treated with potassium tert-butoxide (78 mg, 0.694 mmol) at 0° C., and the reaction mixture was stirred for 30 minutes at ambient temperature. It was then treated with a solution of the product from Example 14A (30 mg, 0.126 mmol) in THF (2 mL) at ambient temperature, and the whole was stirred for 2 hours. The mixture was diluted with CH2Cl2 (20 mL) and H2O (10 mL), then the organic layer was separated, dried with MgSO4, and concentrated under reduced pressure. The resulting residue was chromatographed on silica gel, eluting with NH4OH/MeOH/CH2Cl2 (0.8/7.2/92), to afford the title product. 1H NMR (300 MHz, CDCl3) δ 4.56 (s, 2 H), 4.37 (t, 2 H), 2.68 (t, J=5.93 Hz, 2 H), 2.43 (t, J=6.10 Hz, 2 H), 2.32 (s, 6 H), 2.01-2.13 (m, 2 H), 1.79-1.90 (m, 2 H), 1.59-1.74 (m, 6 H), 1.47-1.57 (m, 2 H). MS (DCI+) m/z 291 (M+H).
Reaction SMILES: [CH3:1][CH:2]1[CH:7]=[C:6]([CH3:8])[CH2:5][CH2:4][C:3]1([C:11]([CH3:13])=[CH2:12])C=O.CC(C1C=CC(C[CH:24]([CH:26]=[O:27])C)=CC=1)C.B(F)(F)F.C[CH2:33][O:34]CC>ClCCCl>[CH:33]([O:27][CH:26]([CH2:13][C:11](=[C:3]1[CH2:4][CH2:5][C:6]([CH3:8])=[CH:7][CH:2]1[CH3:1])[CH3:12])[CH3:24])=[O:34]
Reactant: CC(C=O)Cc1ccc(C(C)C)cc1
Reactant: C=C(C)C1(C=O)CCC(C)=CC1C
Reactant: CCOCC
Agent: FB(F)F
Solvent: ClCCCl
Product: CC1=CC(C)C(=C(C)CC(C)OC=O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
An argon flushed three-necked flask which was cooled by an ice-water bath was charged with β,γ-unsaturated carbonyl compound A (2,4-dimethyl-1-(prop-1-en-2-yl)cyclohex-3-enecarbaldehyde, mixture of syn and anti in a ratio of 4:1; 1.78 g, 10 mmol), aldehyde B (acetaldehyde, 0.53 g, 12 mmol) and 1,2-dichloroethane (20 mL). Boron trifluoride etherate (0.14 g, 1.0 mmol) were added dropwise under argon. After completion of the addition the ice-water bath was removed and the mixture was stirred for 2 hours at room temperature. The completion of reaction was checked by GC analysis of reaction aliquots quenched with a solution of saturated NaHCO3 in water. After complete conversion (>95%), the reaction mixture was quenched with sat. aqueous NaHCO3 solution (10 mL). The organic phase was separated and the aqueous layer was extracted with MTBE three times. The combined organic layers were washed with brine (20 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by column chromatography on silica gel (MTBE/hexane=1:20) to yield the title product (1.55 g, 70%) as colorless liquid. Mixture of four isomers in a ratio of 1 :2:3:16.
Reaction SMILES: ClC1N=C(N2CCOCC2)C2SC(C3C=C([C:17](O)=[O:18])C=NC=3)=CC=2N=1.[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH3:26][N:27]1[CH2:32][CH2:31][N:30]([CH:17]=[O:18])[CH2:29][CH2:28]1
Reactant: CN1CCNCC1
Reactant: O=C(O)c1cncc(-c2cc3nc(Cl)nc(N4CCOCC4)c3s2)c1
Product: CN1CCN(C=O)CC1

Procedure:
5-(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)pyridine-3-carboxylic acid (40 mg) was reacted with 1-methylpiperizine via General Procedure B to yield 5-(2-chloro-4-morpholinothieno[3,2-d]-pyrimidin-6-yl)pyridine-3-yl)(4-methylpiperazin-1-yl)methanone. Crude 5-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)pyridine-3-yl)(4-methylpiperazin-1-yl)methanone (48 mg) was coupled to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 via General Procedure A to yield 14.6 mg of 348. MS (Q1) 541.1 (M)+
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.C1(C)C(C)=CC=CC=1.Cl[C:27]1[C:36]2[C:31](=[CH:32][C:33]([O:39][CH3:40])=[C:34]([O:37][CH3:38])[CH:35]=2)[N:30]=[CH:29][CH:28]=1>CN(C)C1C=CN=CC=1.CCCCCC.C(OCC)(=O)C>[CH3:38][O:37][C:34]1[CH:35]=[C:36]2[C:31](=[CH:32][C:33]=1[O:39][CH3:40])[N:30]=[CH:29][CH:28]=[C:27]2[O:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: N#Cc1ccc(C(=O)c2ccc(O)cc2)cc1
Agent: CN(C)c1ccncc1
Solvent: CCCCCC
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Product: COc1cc2nccc(Oc3ccc(C(=O)c4ccc(C#N)cc4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.1 %

Procedure:
Under argon, 4-(4-hydroxybenzoyl)benzonitrile (230 mg) obtained in Example 123 and 4-dimethylaminopyridine (138 mg) were added to xylene (5 ml), and the admixture was stirred at room temperature for 1 hour. 4-Chloro-6,7-dimethoxyquinoline (230 mg) was added, and the admixture was refluxed with heat for 20 hours. The reaction mixture was partitioned between saturated aqueous sodium hydrogen carbonate and chloroform, and the chloroform layer was then dried with anhydrous magnesium sulfate. After removing the solvent by reduced-pressure distillation, the resulting residue was purified by chromatography on silica gel eluting with hexane/ethyl acetate and then by thin layer chromatography on silica gel eluting with chloroform/ethyl acetate (5/1) to obtain 199 mg of the title compound (yield: 47%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=2)=[N:2]1.F[C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[C:16]#[N:17].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C.CCOC(C)=O>[N:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:3]1[CH:4]=[CH:5][N:1]([C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=2)[C:16]#[N:17])[N:2]=1
Reactant: c1ccc(-c2cc[nH]n2)nc1
Reactant: N#Cc1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1cccc(-n2ccc(-c3ccccn3)n2)c1
Temperature: 145 °C

Procedure:
2-(1H-Pyrazol-3-yl)pyridine (435 mg, 3 mmol), 3-fluorobenzonitrile (0.32 mL, 3 mmol) and K2CO3 (830 mg, 6 mmol) were dissolved in DMF (10 mL) under Ar (g) and heated at 145° C. for 18 h. After cooling to ambient temperature, H2O (40 mL) and EtOAc (40 mL) were added and the reaction mixture shaken, the EtOAc layer was separated and the aqueous layer shaken with EtOAc (2×30 mL). The combined organic layers were washed with brine (3×40 mL), dried over Na2SO4 and concentrated onto silica gel. The crude material was purified by liquid chromatography on silica gel eluting with EtOAc:hexane (1:1) to afford a solid that was recrystallized from EtOAc-hexane to give 3-(3-pyridin-2-yl-1H-pyrazol-1-yl)benzonitrile as a solid. 1H NMR (CD3Cl, 300 MHz) δ 8.68-8.71 (1H, m), 8.18 (1H, m), 8.12-8.15 (1H, m), 8.02-8.06 (2H, m), 7.81 (1H, ddd), 7.60-7.62 (2H, m), 7.30 (1H, ddd), 7.20 (1H, d). MS (ESI) 247 (M+H)+
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[C:17]1([P:23]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(#N)C>[Br-:1].[CH2:2]([P+:23]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CCCCCCCCCCCCCCCBr
Solvent: CC#N
Product: CCCCCCCCCCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Temperature: 135 °C
Yield: 99.2 %

Procedure:
Under nitrogen atmosphere 1-bromopentadecane (6.5 g, 22.4 mmol) was treated with 5.87 g (22.4 mmol) of triphenylphosphine in 15 mL of acetonitrile and heated to 135° C. The reaction was monitored by TLC (salt formation, about 18 hours), and the mixture was dried under reduced pressure (24 hours) to ensure removal of traces of acetonitrile and provided 12.3 g of a colorless solid which was utilized in the next reaction without further purification.
Reaction SMILES: [C:1]([NH:8][C:9]1[S:10][C:11]([CH:26]=[CH2:27])=[C:12]([C:14]([O:16][CH2:17][P:18]([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])=[O:19])=[O:15])[N:13]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]>CO.[Pd]>[C:1]([NH:8][C:9]1[S:10][C:11]([CH2:26][CH3:27])=[C:12]([C:14]([O:16][CH2:17][P:18]([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])=[O:19])=[O:15])[N:13]=1)([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2]
Reactant: C=Cc1sc(NC(=O)OC(C)(C)C)nc1C(=O)OCP(=O)(OCC)OCC
Agent: [Pd]
Solvent: CO
Product: CCOP(=O)(COC(=O)c1nc(NC(=O)OC(C)(C)C)sc1CC)OCC
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A suspension of 2-[N-Boc(amino)]-5-vinyl-4-diethylphosphonomethoxycarbonyl thiazole (1 mmole) and 10% Pd/C (0.5 mmole) in MeOH (5 mL) was stirred under an atmosphere of H2 (balloon) at room temperature for 15 h. Filtration and evaporation gave 2-[N-Boc(amino)]-5-ethyl-4-diethylphosphonomethoxycarbonylthiazole as a yellow solid, which was subjected to Step D of Example 18 followed by Step C of Example 3 to give 2-amino-5-ethyl-4-phosphonomethoxycarbonylthiazole (18.3) as a solid. Mp>230° C. (decomp). Anal. Calcd. for C7H11N2O5PS: 31.58; H, 4.16; N, 10.52. Found: C, 31.80; H, 4.04; N, 10.18.