Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([CH2:14][CH2:15]Cl)=[C:11]([CH3:13])[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2].[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)=[C:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:20][CH:19]=1>>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([CH2:14][CH2:15][N:28]3[CH2:27][CH2:26][C:25](=[C:24]([C:31]4[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=4)[C:21]4[CH:20]=[CH:19][C:18]([F:17])=[CH:23][CH:22]=4)[CH2:30][CH2:29]3)=[C:11]([CH3:13])[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: Fc1ccc(C(=C2CCNCC2)c2ccc(F)cc2)cc1
Reactant: CC(=O)N1CCc2c(sc(C)c2CCCl)C1
Product: CC(=O)N1CCc2c(sc(C)c2CCN2CCC(=C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)C1
Yield: 46.9 %

Procedure:
The reaction and procedure were conducted in a similar manner as in Example 24 using 0.7 g of 6-acetyl-3-(2-chloroethyl)-4,5,6,7-tetrahydro-2-methylthieno[2,3-c]pyridine and 0.6 g of 4-(bis(4-fluorophenyl)-methylene)piperidine to give 0.5 g of 6-acetyl-3-(2-(4-(bis(4-fluorophenyl)methylene)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydro-2-methylthieno[2,3-c]pyridine as an oil, m.p. 209°-211° C. as axalate thereof.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[Cl:10][C:11]1[CH:33]=[CH:32][C:14]([CH2:15][NH:16][C:17]([C:19]2[C:20](=[O:31])[C:21]3[CH:28]=[C:27]([CH2:29]Cl)[O:26][C:22]=3[N:23]([CH3:25])[CH:24]=2)=[O:18])=[CH:13][CH:12]=1.[OH:34][CH:35]([C:39]1[S:43][C:42]([C:44]#[N:45])=[CH:41][CH:40]=1)[CH2:36][NH:37][CH3:38].O>CN(C=O)C>[Cl:10][C:11]1[CH:33]=[CH:32][C:14]([CH2:15][NH:16][C:17]([C:19]2[C:20](=[O:31])[C:21]3[CH:28]=[C:27]([CH2:29][N:37]([CH2:36][CH:35]([C:39]4[S:43][C:42]([C:44]#[N:45])=[CH:41][CH:40]=4)[OH:34])[CH3:38])[O:26][C:22]=3[N:23]([CH3:25])[CH:24]=2)=[O:18])=[CH:13][CH:12]=1
Reactant: CNCC(O)c1ccc(C#N)s1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CCl)oc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CN(Cc1cc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c2o1)CC(O)c1ccc(C#N)s1
Temperature: 90 °C
Yield: 31.7 %

Procedure:
N,N-Diisopropylethylamine (0.18 mL) and N-(4-chlorobenzyl)-2-(chloromethyl)-7-methyl-4-oxo-4,7-dihydrofuro[2,3-b]pyridine-5-carboxamide (Example 2, 0.250 g) were added to a solution of rac-5-(1-hydroxy-2-(methylamino)ethyl)thiophene-2-carbonitrile (Preparation 51, 0.188 g) in DMF (15 mL). The reaction mixture was heated to 90° C. for 2 h. The mixture was allowed to cool to room temperature and was poured into water (30 mL). The suspension was filtered and the resulting solid was purified by column chromatography (CH2Cl2/methanol; 98/2) followed by recrystallization from ethyl acetate/methanol to yield 0.111 g of the title compound as a pale yellow solid. Physical characteristics. M.p. 190-195° C. (dec); 1H NMR (400 MHz, DMSO-d6) δ 10.63, 8.56, 7.80, 7.41-7.32, 7.14, 6.88, 6.06, 5.01-4.97, 4.55, 3.92, 3.76, 2.69-2.64, 2.34; 13C NMR (100 MHz, CDCl3) δ 173.7, 164.6, 154.3, 153.2, 150.0, 141.2, 137.4, 137.2, 132.8, 128.9, 128.7, 123.3, 116.9, 114.7, 114.3, 108.5, 106.9, 66.3, 63.9, 54.1, 42.6, 41.8, 37.8; MS (ESI+) m/z 511 (M+H)+.
Reaction SMILES: C([O:3][C:4](=O)[C:5]([CH3:22])([CH3:21])[CH2:6][N:7]([C:13]1[C:18]([NH2:19])=[CH:17][N:16]=[C:15]([Cl:20])[N:14]=1)[CH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)C>CN(C=O)C>[Cl:20][C:15]1[N:16]=[CH:17][C:18]2[NH:19][C:4](=[O:3])[C:5]([CH3:22])([CH3:21])[CH2:6][N:7]([CH:8]3[CH2:12][CH2:11][CH2:10][CH2:9]3)[C:13]=2[N:14]=1
Reactant: CCOC(=O)C(C)(C)CN(c1nc(Cl)ncc1N)C1CCCC1
Solvent: CN(C)C=O
Product: CC1(C)CN(C2CCCC2)c2nc(Cl)ncc2NC1=O

Procedure:
3-[(5-Amino-2-chloro-pyrimidin-4-yl)-cyclopentyl-amino]-2,2-dimethyl-propionic acid ethyl ester in DMF was heated to 140° C. for 2 hours. Solvent was evaporated in vacuo, ethyl acetate added, and the resulting solid filtered and dried under vacuum to give 2-Chloro-9-cyclopentyl-7,7-dimethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:31][C:32]2[CH:41]=[CH:40][CH:39]=[CH:38][C:33]=2[C:34]([O:36]C)=[O:35])[C:4](=[O:30])[C:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[NH:28][C:27](=[O:29])[O:26][N:25]=3)=[CH:14][CH:13]=2)=[C:6]([CH2:8][CH2:9][CH3:10])[N:7]=1.[OH-].[Na+].CO.Cl>O>[CH3:1][C:2]1[N:3]([CH2:31][C:32]2[CH:41]=[CH:40][CH:39]=[CH:38][C:33]=2[C:34]([OH:36])=[O:35])[C:4](=[O:30])[C:5]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[NH:28][C:27](=[O:29])[O:26][N:25]=3)=[CH:16][CH:17]=2)=[C:6]([CH2:8][CH2:9][CH3:10])[N:7]=1
Reactant: CCCc1nc(C)n(Cc2ccccc2C(=O)OC)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCc1nc(C)n(Cc2ccccc2C(=O)O)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 80.6 %

Procedure:
A mixture of methyl 2-{[2-methyl-6-oxo-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-propylpyrimidin-1(6H)-yl]methyl}benzoate (0.28 g), 2 N aqueous sodium hydroxide solution (5 mL) and methanol (5 mL) was stirred at 50° C. for 3 hr. The reaction mixture was adjusted to pH 4 with water (20 mL) and 1 M hydrochloric acid, and the obtained crystallized product was collected by filtration to give the title compound as colorless crystals (0.22 g, 80%).
Reaction SMILES: [Br:1][C:2]1[C:3](Br)=[C:4]([Br:8])[CH:5]=[CH:6][CH:7]=1.[Li]CCCC.[CH3:15][Si:16](Cl)([CH3:18])[CH3:17].Cl>CCOCC>[Br:1][C:2]1[CH:7]=[C:6]([Si:16]([CH3:18])([CH3:17])[CH3:15])[CH:5]=[C:4]([Br:8])[CH:3]=1
Reactant: C[Si](C)(C)Cl
Reactant: Brc1cccc(Br)c1Br
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: C[Si](C)(C)c1cc(Br)cc(Br)c1
Temperature: -55 °C
Reaction time: 0.58 h

Procedure:
42.4 g of Tribromobenzene (134.6 mmol) was dissolved in 600 mL Et2O. The solution was chilled to −55° C., at which temperature starting material precipitated. 54 mL of n-BuLi (2.5 M in hexanes, 135 mmol) were added within 20 minutes. After stirring for 35 minutes at −52° C., 20 ml TMSCl (158 mmol) and 20 mL Et2O were added within 7 minutes. The suspension turned into a solution at −42° C., and a fine precipitate appeared at −30° C. The suspension was stirred overnight at room temperature. 100 mL 2M HCl were used to hydrolyze the mixture. After stirring for 30 minutes, the Et2O-phase was dried with MgSO4, filtered, and solvent evaporated until compound crystallized out of solution. The flask was stored overnight at +4° C. The crystalline compound was filtered, washed with a small amount cold pentane, and dried under vacuo. A second fraction of crystalline compound was obtained from the filtrate. Yield: 31.9 g (103.5 mmol, 77%). 1H-NMR (CHCl3=7.24 ppm): δ 7.62 (t, 1H), 7.49 (d, 2H), 0.25 (s, 3×3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH2:11][C:12]([NH:14][C:15]1[C:16](=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:17]([OH:19])=O)=O.[CH3:24][N:25]([CH3:29])[CH2:26][CH2:27][NH2:28]>C1(C)C(C)=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH2:11][C:12]1[N:28]([CH2:27][CH2:26][N:25]([CH3:29])[CH3:24])[C:17](=[O:19])[C:16]2[C:15](=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:14]=1
Reactant: COc1ccc(OC)c(CC(=O)Nc2ccccc2C(=O)O)c1
Reactant: CN(C)CCN
Solvent: Cc1ccccc1C
Product: COc1ccc(OC)c(Cc2nc3ccccc3c(=O)n2CCN(C)C)c1
Yield: 13.6 %

Procedure:
A mixture of 0.62 g (2 mmol) of N-(2,5-dimethoxyphenylacetyl) anthranilic acid and 0.36 g (3 mmol) of 2-dimethylaminoethylamine in xylene (5 ml) were heated under reflux for 24 hours. After cooling, the resulting reaction mixture was purified by silica gel column chromatography (eluent; chloroform: ethanol=98:2) to obtain 0.10 g (yield 14%) of 2-(2,5-dimethoxyphenylmethyl)-3-(2-dimethylaminoethyl)-4(3H) quinazolinone as an oily substance. 0.10 g of the oily substance thus obtained was dissolved in ethanol (1 ml) and then a 7% HCl-ethanol solution (0.2 mol) was added thereto and the resulting reaction mixture was cooled overnight. The resulting colorless precipitates were collected by filtration to obtain 0.1 g of the hydrochloride which is the desired compound. This hydrochloride coincides with the compound obtained in Example 16 in melting point and infrared absorption spectrum.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[CH2:14][CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH2:20]([N:22]([CH2:25][CH2:26][O:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=1)[CH2:23][CH3:24])[CH3:21]>[OH-].[K+].[Cl-].[Na+].O>[CH2:23]([N:22]([CH2:20][CH3:21])[CH2:25][CH2:26][O:27][C:28]1[CH:29]=[CH:30][C:31]([CH:32]=[C:14]2[CH2:13][CH2:12][C:11]3[C:16](=[CH:17][CH:18]=[C:9]([O:8][CH2:7][CH2:6][N:1]4[CH:5]=[CH:4][N:3]=[CH:2]4)[CH:10]=3)[C:15]2=[O:19])=[CH:34][CH:35]=1)[CH3:24]
Reactant: O=C1CCCc2cc(OCCn3ccnc3)ccc21
Reactant: CCN(CC)CCOc1ccc(C=O)cc1
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: CCN(CC)CCOc1ccc(C=C2CCc3cc(OCCn4ccnc4)ccc3C2=O)cc1
Yield: 30.3 %

Procedure:
6-(2-Imidazole-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one (0.505 g, 1.97 mmol) was reacted with 4-(diethylamino)ethoxy benzaldehyde (0.662 g, 3.0 mmol) in 2.5 mL of 4% KOH for 20 hours at room temperature. The reaction was diluted with brine, and the resulting mixture was extracted into DCM. The combined extracts were dried, filtered, and evaporated to dryness. The resulting oil was purified twice by flash chromatography (silica gel, 150 g, 10% MeOH in DCM) to afford 0.274 g (30%) of the title compound as a yellow oil: CI-MS m/e 459 (M+), 460 (M+ +1);
Reaction SMILES: [CH:1]([CH:3]=O)=[O:2].[CH2:5]([NH:7][N:8]=[CH:9][C:10](=[O:12])[CH3:11])[CH3:6]>O>[CH2:5]([N:7]1[CH:11]=[C:10]([OH:12])[C:9]([C:1](=[O:2])[CH3:3])=[N:8]1)[CH3:6]
Reactant: O=CC=O
Reactant: CCNN=CC(C)=O
Solvent: O
Product: CCn1cc(O)c(C(C)=O)n1
Temperature: 25 °C
Yield: 87.6 %

Procedure:
A 40% aqueous solution of glyoxal (2.3 g, 1.8 mL, 16 mmol) was added to a solution of 2-oxopropanal ethylhydrazone (1.83 g, 16 mmol) in water (90 mL). The mixture was heated at reflux for 1 hour. The reaction was cooled to room temperature and extracted with CH2Cl2 (4×). The combined organic extracts were dried over Na2SO4, filtered and concentrated to afford 1-(1-ethyl-4-hydroxy-1H-pyrazol-3-yl)ethanone as a yellow oil (2.16 g, 87%).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH2:31][C:32]2[S:33][CH:34]=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2].[Br:37]Br.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH2:31][C:32]2[S:33][C:34]([Br:37])=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2]
Reactant: BrBr
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(C)c(Cc3cccs3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(=O)OC[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(Br)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 55.9 %

Procedure:
1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-methyl-3-(2-thienylmethyl)benzene (11.08 g) obtained in Example 158-(1) was dissolved in chloroform (100 ml), and added dropwise thereto at 0° C. was a solution of bromine (3.71 g) in chloroform (13 ml). The mixture was stirred at 0° C. for 1.5 hours, and then, at room temperature for 1 hour, and the mixture was poured into a 10% aqueous sodium thiosulfate solution and a saturated aqueous sodium hydrogen carbonate solution. The mixture was extracted twice with chloroform, washed with brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=80:20-67:33) to give 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-methylbenzene (7.13 g) as a colorless solid. APCI-Mass m/Z 614/616 (M+NH4). (2) The above 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-methylbenzene was treated in a manner similar to Example 106-(3) to give the desired 1-(β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-methylbenzene as colorless powder. APCI-Mass m/Z 446/448 (M+NH4).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:25]1[O:26][C:27]([C:30]2[C:31]([O:40][CH3:41])=[N:32][C:33]3[C:38]([CH:39]=2)=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:28][N:29]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]C(C)(C)C)=[O:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.C1(C)C=CC=CC=1.CCOCC>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:25]1[O:26][C:27]([C:30]2[C:31]([O:40][CH3:41])=[N:32][C:33]3[C:38]([CH:39]=2)=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:28][N:29]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1nc2ccccc2cc1-c1cnc([C@H](CCCCCC(=O)OC(C)(C)C)NC(=O)OCc2ccccc2)o1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: COc1nc2ccccc2cc1-c1cnc([C@H](CCCCCC(=O)O)NC(=O)OCc2ccccc2)o1
Temperature: 0 °C
Reaction time: 72 h

Procedure:
To a stirred solution of F4 in DCM (0.11 M) cooled to 0° C. TFA (15 eq.) was slowly added. The reaction mixture was stirred at 0° C. for 3 days. The solvent was evaporated to afford an oily residue that was co-evaporated first with toluene then with Et2O to give the title compound as a pale yellow solid which was used directly in the next step. MS (ES+) C28H29N3O6: 504 (M+H)+.
Reaction SMILES: SC1C(=O)C=CC=CC=1.SC1C2C=CC=CC=2C=CC(=O)C=1.[NH2:23][C:24]1[C:30]2[CH:31]=[N:32][CH:33]=[CH:34][C:29]=2[CH:28]=[CH:27][C:26](=[O:35])[CH:25]=1.[CH2:36]([O:38][C:39](=[O:42])[CH:40]=[O:41])[CH3:37]>>[CH2:36]([O:38][C:39](=[O:42])[C:40]([NH:23][C:24]1[C:30]2[CH:31]=[N:32][CH:33]=[CH:34][C:29]=2[CH:28]=[CH:27][C:26](=[O:35])[CH:25]=1)=[O:41])[CH3:37]
Reactant: Nc1cc(=O)ccc2ccncc12
Reactant: CCOC(=O)C=O
Agent: O=c1ccc2ccccc2c(S)c1
Agent: O=c1cccccc1S
Product: CCOC(=O)C(=O)Nc1cc(=O)ccc2ccncc12

Procedure:
By following serially the procedures of Examples 1 and 2 but replacing 2-mercapto-2,4,6-cycloheptatrien-1-one with an equivalent amount of 5-mercapto-7H-benzocyclohepten-7-one, 9-amino-7H-cyclohepta[c]pyridin-7-one, 5-mercapto-3H-6,7-dihydrocyclobutacyclohepten-3-one, 1-ethylamino-3H-6,7,8,9,10,11-hexahydrocycloheptacycloocten-3-one and 5-mercapto-3H-6,7,8,9,10,11,12,13-octahydrocycloheptacyclodecen-3-one, the following compounds are obtained respectively: ](7-oxo-7H-benzocyclohepten-5-yl)thio]oxoacetic acid ethyl ester (I; R1, R5, and R6 =H; R2 =S--CO--COOC2H5 ; and R3 and R4 together form a --CH=CH--CH=CH-- chain), [(7-oxo-7H-cyclohepta[c]pyridin-9-yl)-amino]oxo-acetic acid ethyl ester (I; R1, R5 and R6 =H; R2 =NC2H5 --CO--COOC2H5 ; and R3 and R4 together form a --CH=CH--N=CH-- chain). [(3-oxo-3H-6,7-dihydrocyclobutacyclohepten-5-yl)thio]oxo-acetic acid ethyl ester (I; R1, R5 and R6 =H; R2 =S--CO--COOC2H5 ; and R3 and R4 together form a --CH2CH2 -- chain), [N-(3-oxo-3H-6,7,8,9,10,11-hexahydrocycloheptacycloocten-1-yl)ethylamino]oxo-acetic acid ethyl ester (I; R1, R2 and R6 =H; R3 and R4 together form a --(CH2)6 chain; and R5 =NC2H5 --CO--COOC2H5) and [(3-oxo-3H-6,7,8,9,10,11,12,13-octahydrocycloheptacyclodecen-5 -yl)thio]oxoacetic acid ethyl ester (I; R1, R5 and R6 =H; R2 =S--CO--COOC2H5 ; and R3 and R4 together form a --(CH2)8 -- chain).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:15])[C:10]([O:12]CC)=[O:11])=[CH:5][CH:4]=1)#[N:2].O1CCCC1.O.[OH-].[Na+]>C(OC(=O)C)C.C(O)(=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]([CH3:15])[C:10]([OH:12])=[O:11])=[CH:7][CH:8]=1)#[N:2]
Reactant: CCOC(=O)C(C)c1ccc(C#N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C(=O)O)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 122.4 %

Procedure:
To a stirred solution of ethyl 2-(4-cyanophenyl)propanoate (453 mg, 1.968 mmol) in co-solvent with tetrahydrofuran and water (1:1) were added sodium hydroxide (197 mg, 4.919 mmol). The reaction mixture was stirred for overnight at room temperature, then acidified to pH 3-4 with acetic acid. The residue was diluted with ethylacetate and washed with water and brine. The organic layer was dried over magnesium sulfate and filtered. The filtrate removed in vacuo. The crude 2-(4-cyanophenyl)propanoic acid (422 mg) was obtained as 99% yield.
Reaction SMILES: [CH3:1][NH2:2].Cl[C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[C:11](=[O:13])[CH3:12].O.O.O.O.O.O.O.O.O.[S-2].[Na+].[Na+]>O.[Cu]>[F:10][C:8]1[CH:7]=[CH:6][C:5]([C:11](=[O:13])[CH3:12])=[C:4]([NH:2][CH3:1])[CH:9]=1
Reactant: CN
Reactant: CC(=O)c1ccc(F)cc1Cl
Agent: [Cu]
Agent: [Na+]
Agent: [S-2]
Solvent: O
Product: CNc1cc(F)ccc1C(C)=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of a solution of methylamine in industrial methylated spirit (33% w/w; 120 ml), industrial methylated spirit (60 ml), 2'-chloro-4'-fluoroacetophenone (51.6 g) and copper powder (0.75 g), was charged to a pressure vessel and heated to 90° for 2 hours. After cooling in an ice bath to 30° the mixture was transferred to a second vessel, heated at 50° and then a solution of sodium sulphide nonahydrate (2.88 g) in water (30 ml) added. The mixture was heated to reflux with stirring for 10 minutes and then filtered. Water (300 ml) was added to the filtrate and the solution heated to reflux. Hydrochloric acid (5M; 90 ml) was added to the hot solution and the mixture heated to reflux for a brief period. The reaction mixture was cooled to ambient temperature and aqueous sodium hydroxide solution (5M; 30 ml) added. The mixture was extracted with dichloromethane (600 ml) and then further extracted with dichloromethane (200 ml). The combined dichloromethane extracts were dried (magnesium sulphate) and evaporated in vacuo to give a crude brown oil. The oil was distilled in vacuo (b.p. 90°, 1 mmHg) to give 4'-fluoro-2'-(methylamino)acetophenone, m.p. 52°-53°.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])[C:3]=1[CH3:20].[O:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:29][C:28]=2[NH2:39])[CH2:23][CH2:22]1.Cl.O1CCOCC1>CO>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:39][C:28]3[CH:29]=[C:30]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)[CH:31]=[CH:32][C:27]=3[N:24]3[CH2:23][CH2:22][O:21][CH2:26][CH2:25]3)=[C:3]([CH3:20])[C:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])=[N:5]2)=[CH:10][CH:9]=1
Reactant: Nc1cc(N2CCOCC2)ccc1N1CCOCC1
Reactant: Cc1c(-c2ccccc2F)nc2cc(Cl)ccc2c1Cl
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1c(-c2ccccc2F)nc2cc(Cl)ccc2c1Nc1cc(N2CCOCC2)ccc1N1CCOCC1

Procedure:
Prepared according to Procedure K, Method 1 using 4,7-dichloro-2-(2-fluorophenyl)-3-methylquinoline (125 mg, 408 μmol), 2,5-dimorpholinobenzenamine (108 mg, 408 μmol) and 4N hydrochloric acid solution in dioxane (0.10 mL, 408 μmol) in MeOH (3.00 mL) to afford product as a colorless solid after purification by chromatography on silica gel, eluting with MeOH gradient in DCM. 1H NMR (400 MHz, chloroform-d) δ ppm 8.02 (1H, d, J=2.3 Hz), 7.72 (1H, d, J=9.0 Hz), 7.46 (1H, td, J=7.4, 2.0 Hz), 7.26-7.40 (2H, m), 7.17-7.25 (1H, m), 7.13 (1H, s), 7.02-7.10 (1H, m), 6.98 (1H, d, J=8.6 Hz), 6.31 (1H, dd, J=8.6, 2.7 Hz), 5.91 (1H, br. s.), 3.77 (4H, t, J=4.7 Hz), 3.59-3.68 (4H, m), 2.91 (4H, br. s.), 2.74-2.87 (4H, m), 2.06 (3H, d, J=2.0 Hz). Mass Spectrum (ESI) m/e=533.2 (M+1).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:7]=[C:6]([CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[NH:5][N:4]=1.[F:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[C:24]([F:26])[CH:25]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:19][C:20]1[CH:21]=[C:22]([N:5]2[C:6]([CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:14])([CH3:15])[CH3:13])=[CH:7][C:3]([C:2]([F:1])([F:17])[F:18])=[N:4]2)[CH:23]=[C:24]([F:26])[CH:25]=1
Reactant: CC(C)(C)OC(=O)NCc1cc(C(F)(F)F)n[nH]1
Reactant: OB(O)c1cc(F)cc(F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCc1cc(C(F)(F)F)nn1-c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 60 %

Procedure:
To a mixture tert-butyl (3-(trifluoromethyl)-1H-pyrazol-5-yl)methylcarbamate (251 mg, 0.946 mmol, 1 equiv.), 3,5-difluorophenylboronic acid (299 mg, 1.89 mmol, 2 equiv.) and copper acetate (258 mg, 1.49 mmol, 1.5 equiv.) in dichloromethane (14 mL) was added pyridine (151 mg, 0.151 mL, 1.89 mmol, 2 equiv) and the mixture was stirred in the presence of air for 2 d at room temperature. The reaction mixture was filtered over silica gel, the filter cake was washed with dichloromethane (250 mL) and the solvent of the filtrate was evaporated to give tert-butyl (1-(3,5-difluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methylcarbamate (214 mg, 60%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:46])[N:7]([C:37]1[CH:38]=[N:39][C:40]([O:43][CH2:44][CH3:45])=[CH:41][CH:42]=1)[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([OH:35])[C:15]2[C:23]3[C:18](=[N:19][CH:20]=[C:21]([CH3:24])[CH:22]=3)[N:17]([Si:25]([CH:32]([CH3:34])[CH3:33])([CH:29]([CH3:31])[CH3:30])[CH:26]([CH3:28])[CH3:27])[CH:16]=2)=[C:10]([F:36])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[C:1]([O:5][C:6](=[O:46])[N:7]([C:37]1[CH:38]=[N:39][C:40]([O:43][CH2:44][CH3:45])=[CH:41][CH:42]=1)[C:8]1[CH:13]=[CH:12][C:11]([C:14]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[C:21]([CH3:24])[CH:22]=3)[N:17]([Si:25]([CH:29]([CH3:30])[CH3:31])([CH:32]([CH3:33])[CH3:34])[CH:26]([CH3:28])[CH3:27])[CH:16]=2)=[O:35])=[C:10]([F:36])[N:9]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CCOc1ccc(N(C(=O)OC(C)(C)C)c2ccc(C(O)c3cn([Si](C(C)C)(C(C)C)C(C)C)c4ncc(C)cc34)c(F)n2)cn1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CCOc1ccc(N(C(=O)OC(C)(C)C)c2ccc(C(=O)c3cn([Si](C(C)C)(C(C)C)C(C)C)c4ncc(C)cc34)c(F)n2)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.1 %

Procedure:
(6-Ethoxy-pyridin-3-yl)-{6-fluoro-5-[hydroxy-(5-methyl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-pyridin-2-yl}-carbamic acid tert-butyl ester (70, 0.400 g, 0.616 mmol) is alternatively dissolved in 11.8 mL of dichloromethane, and Dess-Martin periodinane (0.100 g, 0.236 mmol) is added. The reaction is stirred at room temperature for 30 minutes, then concentrated under vacuum. The resulting material is purified by silica gel column chromatography, eluting with 20-100% ethyl acetate in hexane. Appropriate fraction are combined and concentrated under vacuum to provide the desired compound (71, 0.200 g).
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:12][C:13]([OH:15])=O.[S:16]1[CH:20]=[C:19]([C:21]2[S:22][CH:23]=[CH:24][C:25]=2[NH2:26])[N:18]=[CH:17]1>>[O:1]=[C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:12][C:13]([NH:26][C:25]1[CH:24]=[CH:23][S:22][C:21]=1[C:19]1[N:18]=[CH:17][S:16][CH:20]=1)=[O:15]
Reactant: O=C(O)CN1C(=O)CCc2ccccc21
Reactant: Nc1ccsc1-c1cscn1
Product: O=C(CN1C(=O)CCc2ccccc21)Nc1ccsc1-c1cscn1

Procedure:
The title compound was prepared from 2-(2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetic acid (88 mg, 0.43 mmol) and 2-(thiazol-4-yl)thiophen-3-amine (79 mg, 0.43 mmol) according to protocol A. Retention time (min)=5.703, method [7], MS(ESI) 370.0 (M+H); 1H NMR (300 MHz, CDCl3) δ 11.2 (s, 1H), 8.49 9d, J=2.7 Hz, 1H), 8.13 (d, J=5.4 Hz, 1H), 7.19-7.25 (m, 4H), 7.02-7.08 (m, 2H), 4.81 (s, 2H), 3.05-3.09 (m, 2H), 3.2.85-2.89 (m, 2H).