Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH2:11][C:12]3[C:20]([O:21][CH3:22])=[CH:19][C:18]([CH3:23])=[C:17]4[C:13]=3[CH:14]=[CH:15][N:16]4[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[N:8][C:7]=2[CH:31]=1)#[N:2].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Cl[C:43]([O:45][CH2:46][CH3:47])=[O:44]>C1COCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11]([C:12]3[C:20]([O:21][CH3:22])=[CH:19][C:18]([CH3:23])=[C:17]4[C:13]=3[CH:14]=[CH:15][N:16]4[C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[C:43]([O:45][CH2:46][CH3:47])=[O:44])=[N:8][C:7]=2[CH:31]=1)#[N:2]
Reactant: CCOC(=O)Cl
Reactant: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1Cc1nc2cc(C#N)ccc2o1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(c1nc2cc(C#N)ccc2o1)c1c(OC)cc(C)c2c1ccn2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of tert-butyl 4-((5-cyanobenzo[d]oxazol-2-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (Example 144-A) (60 mg, 0.144 mmol) in THF (2.1 mL) under nitrogen at −78° C. was added LiHMDS (0.359 ml, 0.359 mmol) in THF. After 10 mins, ethyl chloroformate (0.276 mL, 2.87 mmol) was added and the reaction was warmed to room temperature. After 5 mins the reaction was quenched with sat. aq. NH4Cl, the layers were separated and the aqueous layer extracted with EtOAc. The EtOAc layer was concentrated, purified via FCC with Hep/EtOAc to obtain the title compound. MS (ESI+) m/z 490.0 (M+H).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].C(N(CC)CC)C.[Br:12][C:13]1[C:18]([O:19][CH2:20][CH3:21])=[CH:17][C:16]([OH:22])=[C:15]([CH2:23][CH3:24])[CH:14]=1>C(Cl)Cl>[Br:12][C:13]1[C:18]([O:19][CH2:20][CH3:21])=[CH:17][C:16]([O:22][C:1](=[O:3])[CH3:2])=[C:15]([CH2:23][CH3:24])[CH:14]=1
Reactant: CCOc1cc(O)c(CC)cc1Br
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOc1cc(OC(C)=O)c(CC)cc1Br
Reaction time: 0.75 h
Yield: 53.4 %

Procedure:
Acetyl chloride (0.91 mL, 12.8 mmol) followed by triethylamine (1.8 mL, 12.8 mmol) were added to a stirred solution of 4-bromo-5-ethoxy-2-ethyl-phenol (2.6 g, 10.7 mmol) dissolved in CH2Cl2 (20 mL). The reaction was stirred for 45 mins and then partitioned between 1N HCl and EtOAc. The organic layer was washed with saturated NaHCO3, brine dried over Na2SO4 and concentrated. Purification by flash column chromatography (0% to 20% EtOAc in hexanes) gave the product as a clear oil (1.64 g, 53%). 1H NMR (400 MHz, CDCl3): δ 1.16 (t, J=7.6 Hz, 3 H), 1.45 (t, J=7.1 Hz, 3 H), 2.31 (s, 3 H), 2.45 (q, J=7.6 Hz, 2 H), 4.05 (q, J=7.1 Hz, 2 H), 6.58 (s, 1 H), 7.41 (s, 1 H).
Reaction SMILES: [N+:1]([C:4]([CH2:9][CH3:10])([CH2:7][OH:8])[CH2:5][OH:6])([O-:3])=[O:2].[C:11]([O:18][CH2:19][CH2:20][CH2:21][CH3:22])(=[O:17])[CH2:12][CH2:13][C:14]([CH3:16])=O.O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:11]([CH2:12][CH2:13][C:14]1([CH3:16])[O:8][CH2:7][C:4]([N+:1]([O-:3])=[O:2])([CH2:9][CH3:10])[CH2:5][O:6]1)([O:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:17]
Reactant: CCCCOC(=O)CCC(C)=O
Reactant: CCC(CO)(CO)[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCOC(=O)CCC1(C)OCC(CC)([N+](=O)[O-])CO1
Yield: 90 %

Procedure:
7.46 g of 2-nitro-2-ethyl-1,3-propanediol, 8.61 g of butyl levulinate, 50 mg of p-toluenesulfonic acid in 50 ml of toluene was refluxed until no more water separated. The reaction mixture was cooled, washed with 2% sodium bicarbonate and water, dried and concentrated to give 13.65 g of 2-carbobutoxyethyl-2-methyl-5-nitro-5-ethyl-1,3-dioxane as a light yellow oil. This was dissolved in 50 ml of ethanol and hydrogenated over 1 g Raney Nickel catalyst at 60 under pressure. Distillation of the crude material at 160° C./3mm gave 11 g of the product.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH2:10][N:11]2[C:15]3=[N:16][C:17](Br)=[CH:18][N:19]=[C:14]3[N:13]=[N:12]2)=[CH:2]1.[CH3:21][N:22]1[CH:26]=[C:25](B2OC(C)(C)C(C)(C)O2)[CH:24]=[N:23]1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH2:10][N:11]2[C:15]3=[N:16][C:17]([C:25]4[CH:24]=[N:23][N:22]([CH3:21])[CH:26]=4)=[CH:18][N:19]=[C:14]3[N:13]=[N:12]2)=[CH:2]1
Reactant: Brc1cnc2nnn(Cc3c[nH]c4ncccc34)c2n1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Cn1cc(-c2cnc3nnn(Cc4c[nH]c5ncccc45)c3n2)cn1
Temperature: 80 °C
Reaction time: 8 h
Yield: 38.8 %

Procedure:
The mixture of 1-((1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)-6-bromo-1H-[1,2,3]triazolo-[4,5-b]pyrazine (46 mg, 0.14 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (77 mg, 0.35 mmol), PdCl2(dppf) (12 mg, 0.014 mmol) and Cs2CO3 (137 mg, 0.42 mmol) in dioxane/H2O (10:1, 8 mL) was stirred at 80° C. overnight. After being cooled to room temperature, the mixture was concentrated and purified by chromatography to afford the title compound (18 mg) MS (m/z): 332 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[O:12]1[CH2:17][CH2:16][CH:15](O)[CH2:14][CH2:13]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=CC=1>C1COCC1>[O:12]1[CH2:17][CH2:16][CH:15]([O:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[C:7](=[O:11])[CH2:6][CH2:5]3)[CH2:14][CH2:13]1
Reactant: O=C1CCc2cc(O)ccc21
Reactant: OC1CCOCC1
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1CCc2cc(OC3CCOCC3)ccc21
Reaction time: 8 h
Yield: 85.1 %

Procedure:
5-Hydroxy-1-indanone (0.636 g, 4.30 mmol), tetrahydro-pyran-4ol (1.22 mL, 12.80 mmol), PPh3-polymer supported (2.864 g, 8.59 mmol), DBAD (1.978 g, 8.59 mmol) and THF (40 mL) were mixed, and shaken overnight. The mixture was filtered, and washed with THF (10 mL×3). The filtrate was concentrated. The residue was purified by flash chromatography to give the above intermediate (0.85 g, 85%). MS (APCI) m/z 233 (M+H)+; 1H NMR (300 MHz, CD3OD) δ ppm 1.79-1.89 (m, 2H) 2.01-2.12 (m, 2H) 2.62-2.69 (m, 2H) 3.07-3.15 (m, 2H) 3.85-4.00 (m, 4H) 4.75 (m, 1H) 6.97 (dd, J=8.65, 2.20 Hz, 1H) 7.08 (s, 1H) 7.63 (d, J=8.48 Hz, 1H).
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][CH2:21][C@H:22]1[O:26][C:25](=[O:27])[C@H:24](S(C2C=CC=CC=2)=O)[C@H:23]1[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1(C)C=CC=CC=1>[Si:1]([O:18][CH2:19][CH2:20][CH2:21][CH:22]1[O:26][C:25](=[O:27])[CH:24]=[C:23]1[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)[Si](OCCC[C@H]1OC(=O)[C@H](S(=O)c2ccccc2)[C@H]1c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](OCCCC1OC(=O)C=C1c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 61.5 %

Procedure:
A solution of (3R*,4S*,5R*)-5-[3-(t-butyldiphenylsilyloxy)propyl]-2-oxo-4-phenyl-3- phenylsulfinyltetrahydrofuran (650 mg) in toluene (6.5 ml) was refluxed for 30 minutes. The reaction mixture was chromatographed on silica gel (20 g) eluting with a mixture of benzene and acetone (100:1 to 25:1) to give 5-[3-(t-butyldiphenylsilyloxy)propyl]-4-phenyl-2(5H)furanone (313 mg) as an oil.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:18]([OH:20])=O)=[N:8][C:9]=2[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH2:3][CH2:2]1.Cl.[F:22][C:23]([F:33])([F:32])[C@H:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)[NH2:25]>>[F:33][C:23]([F:22])([F:32])[C@@H:24]([NH:25][C:18]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)[N:8]=1)=[O:20])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1
Reactant: N[C@@H](c1ccccn1)C(F)(F)F
Reactant: O=C(O)c1ccc(C2CC2)c(Cc2ccc(F)cc2)n1
Agent: Cl
Product: O=C(N[C@@H](c1ccccn1)C(F)(F)F)c1ccc(C2CC2)c(Cc2ccc(F)cc2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carboxylic acid (Example 155 g) and (S)-2,2,2-trifluoro-1-(pyridin-2-yl)ethanamine hydrochloride (CAN 336105-45-4) as starting materials. MS (EI): m/e=430.3 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-])=O)[C:5]([Cl:8])=[N:6][CH:7]=1.[Cl-].[NH4+]>CO.ClCCl.[Zn]>[Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: ClCCl
Product: Nc1cc(Br)cnc1Cl
Reaction time: 24 h

Procedure:
To a solution of 5-bromo-2-chloro-3-nitropyridine (5.0 g, 21.1 mmol) in methanol (50 mL) and dichloromethane (5 mL) was added zinc (7.6 g, 115.8 mmol) and ammonium chloride (5.6 g, 105.3 mmol). The reaction mixture was stirred for 24 hours. The solids were removed by filtration and washed with dichloromethane. The filtrate was washed with water (50 mL), brine (50 mL), dried over sodium sulfate, filtered and concentrated to dryness under reduced pressure. The crude 5-bromo-2-chloropyridin-3-amine (4.2 g) was used without further purification. LCMS [M+H]: 207.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[NH:3]1.[CH3:17][C:18]1[CH:31]=[CH:30][CH:29]=[CH:28][C:19]=1[CH2:20][N:21]1[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]1>CO.[Cl-].[Cl-].[Zn+2].[BH3-]C#N.[Na+]>[CH3:17][C:18]1[CH:31]=[CH:30][CH:29]=[CH:28][C:19]=1[CH2:20][N:21]1[CH2:22][CH2:23][CH:24]([N:10]2[CH2:9][CH2:8][CH:7]([N:6]3[C:5]4[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=4[NH:3][C:2]3=[O:1])[CH2:12][CH2:11]2)[CH2:25][CH2:26]1
Reactant: Cc1ccccc1CN1CCC(=O)CC1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: Cc1ccccc1CN1CCC(N2CCC(n3c(=O)[nH]c4ccccc43)CC2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 58.1 %

Procedure:
To a solution of 1.73 g of 4-(2-keto-1-benzimidazolyl)piperidine and 1.54 g of N-(2-methylbenzyl)4-piperidone in 20 ml of MeOH was added 51 ml of 0.3M methanolic solution of ZnCl2—NaBH3CN at room temperature. The reaction mixture was stirred at room temperature for 4 h and quenched with saturated aqueous NaHCO3. The mixture was extracted with EtOAc, and the organic layer was washed with the 1:1 solution of saturated aqueous NaHCO3 and brine, and dried over anhydrous Na2SO4. The organic solvent was evaporated and recrystallization of the residue from EtOAc gave 1.78 g of the target compound as a colorless powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:9]([C:13]3[N:23]([S:24]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)(=[O:26])=[O:25])[C:16]4[N:17]=[CH:18][CH:19]=[C:20]([CH:21]=O)[C:15]=4[CH:14]=3)=[CH:10][N:11]([CH3:12])[C:6]2=[CH:5][C:4]=1[O:34][CH3:35].[O:36]1[CH2:41][CH2:40][N:39]([C:42]2[CH:49]=[CH:48][C:45]([CH2:46][NH2:47])=[CH:44][CH:43]=2)[CH2:38][CH2:37]1>>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:9]([C:13]3[N:23]([S:24]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)(=[O:26])=[O:25])[C:16]4=[N:17][CH:18]=[CH:19][C:20]([CH2:21][NH:47][CH2:46][C:45]5[CH:44]=[CH:43][C:42]([N:39]6[CH2:40][CH2:41][O:36][CH2:37][CH2:38]6)=[CH:49][CH:48]=5)=[C:15]4[CH:14]=3)=[CH:10][N:11]([CH3:12])[C:6]2=[CH:5][C:4]=1[O:34][CH3:35]
Reactant: COc1cc2c(nc1OC)c(-c1cc3c(C=O)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Reactant: NCc1ccc(N2CCOCC2)cc1
Product: COc1cc2c(nc1OC)c(-c1cc3c(CNCc4ccc(N5CCOCC5)cc4)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C

Procedure:
The product is prepared by following the procedure described in example 34, stage (j) starting with 0.1 g of 2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-carbaldehyde and 0.196 cm3 of 4-morpholinobenzylamine instead of the cyclopropylamine used in example 34, stage (j). After purification by flash-pack chromatography (SiO2, dichloromethane/methanol 98/2 by volume as eluents), 0.031 g of [2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-ylmethyl]-(4-morpholin-4-yl-benzyl)amine is obtained with the following characteristics:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:7](=[O:14])[NH:6][C:5]2=[O:15].[C:16]([O:20][C:21](=[O:27])[N:22]([CH2:24][CH2:25]N)[CH3:23])([CH3:19])([CH3:18])[CH3:17].N1C=CN=C1>O1CCOCC1>[C:16]([O:20][C:21](=[O:27])[N:22]([CH2:24][CH2:25][N:6]1[C:5](=[O:15])[C:4]2[C:8](=[CH:9][C:10]([N+:11]([O-:13])=[O:12])=[C:2]([NH2:1])[CH:3]=2)[C:7]1=[O:14])[CH3:23])([CH3:19])([CH3:18])[CH3:17]
Reactant: CN(CCN)C(=O)OC(C)(C)C
Reactant: Nc1cc2c(cc1[N+](=O)[O-])C(=O)NC2=O
Agent: c1c[nH]cn1
Solvent: C1COCCO1
Product: CN(CCN1C(=O)c2cc(N)c([N+](=O)[O-])cc2C1=O)C(=O)OC(C)(C)C
Temperature: 140 °C
Yield: 93 %

Procedure:
A mixture of 5-amino-6-nitro-isoindole-1,3-dione (2.07 g, 10 mmol), (2-Amino-ethyl)-methyl-carbamic acid tert-butyl ester (3.485 g, 20 mmol), imidazole (1.36 g, 20 mmol) in dioxane (30 mL) was sealed in a ChemGlass heavy wall pressure flask. After it was heated at 140° C. for 38 h, the reaction mixture was evaporated to dryness at 95° C. (the bath temperature) under reduced pressure. The chromatography of the residue with CH2Cl2/MeOH/28% aqueous NH4OH (500:10:1) afforded the title compound (3.39 g, 93%). 1H NMR (CDCl3) δ 1.08 (s, 9H), 2.78 (s, 3H), 3.42 (m, 2H), 3.68 (m, 2H), 7.48 (s, 1H), 8.34 (s, 1H), 8.42 (br s, 2H, NH).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:29])[CH2:21][CH2:22][CH2:23][CH2:24][S:25][CH2:26][CH2:27][OH:28])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:30](OC(=O)C)(=[O:32])[CH3:31]>>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:29])[CH2:21][CH2:22][CH2:23][CH2:24][S:25][CH2:26][CH2:27][O:28][C:30](=[O:32])[CH3:31])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)OC(C)=O
Reactant: O=C(CCCCSCCO)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Product: CC(=O)OCCSCCCCC(=O)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Yield: 92 %

Procedure:
Following a procedure similar to that described in Example 67(c), but using N-[4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-5-(2-hydroxyethylthio)pentanamide [prepared as described in step (c) above] and acetic anhydride as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as an oil in a 92% yield.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C[Al](C)C.[Cl:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[CH2:16][C:17]#[N:18]>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl.CO>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:17](=[NH:18])[CH2:16][C:15]2[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=2[Cl:13])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Br)cc1
Reactant: N#CCc1ccccc1Cl
Agent: C[Al](C)C
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: Cc1ccccc1
Product: N=C(Cc1ccccc1Cl)Nc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 48.3 %

Procedure:
4-Bromoaniline (6.4 g, 37 mmol) was placed into a three-neck reactor, and the reactor was flushed with argon for 20 min. 60 mL anhydrous toluene was added. After cooling to 0° C., trimethylaluminum (28 mL, 2.0M solution in toluene, 56 mmol) was added slowly to keep the inner temperature below 20° C. Over 0.5 h, the addition was completed. Ice bath was removed, and the reaction mixture was warmed to room temperature and then stirred for additional 2.5 hrs. A solution of 2-chlorobenzyl cyanide (8.4 g, 55 mmol) in 35 mL anhydrous toluene was added, and the reaction mixture was heated to 80° C. After 18 hrs, the reaction mixture was cooled to room temperature and poured over a slurry of silica gel in CHCl3/MeOH (4/1, 400 mL). After stirring for 30 min, the mixture was filtered and the residue was washed with a mixture of CHCl3/MeOH (4/1). The combined filtrates were concentrated in vacuo, and the resulting solid was washed with hexane to give a light pink solid (5.78 g, 48% yield).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[OH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+:15].C1(C)C=CC=CC=1>O>[CH:4]1[CH:3]=[CH:2][C:1]([C:7]2[C:8]([O-:13])=[CH:9][CH:10]=[CH:11][CH:12]=2)=[CH:6][CH:5]=1.[K+:15]
Reactant: Oc1ccccc1-c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: [O-]c1ccccc1-c1ccccc1

Procedure:
A mixture of 526.36 grams (3.092 moles) of 2-phenylphenol, a 45% aqueous solution containing 171.79 grams (3.062 moles) of potassium hydroxide and 2000 ml. of toluene was heated to reflux under nitrogen, with stirring, and the water which passed over was collected in a Dean-Stark trap. When all water had been removed by azeotropic distillation, the mixture was cooled and anhydrous potassium 2-phenylphenate was isolated in nearly quantitative yield by filtration and dried under vacuum at 120° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[CH3:14][CH2:15][O:16][C:17]([CH:19]([C:23]([CH3:25])=O)[C:20]([CH3:22])=O)=[O:18]>>[CH2:15]([O:16][C:17]([C:19]1[C:20]([CH3:22])=[N:9][N:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([C:10]([F:11])([F:12])[F:13])[CH:4]=2)[C:23]=1[CH3:25])=[O:18])[CH3:14]
Reactant: Cc1ccc(NN)cc1C(F)(F)F
Reactant: CCOC(=O)C(C(C)=O)C(C)=O
Product: CCOC(=O)c1c(C)nn(-c2ccc(C)c(C(F)(F)F)c2)c1C
Yield: 96 %

Procedure:
In analogy to the procedure described in Example 38A], (4-methyl-3-trifluoromethyl-phenyl)-hydrazine and ethyl diacetoacetate gave the title compound after crystallisation (EtOAc) in 96% yield as red oil. MS: 327.3 (MH+).
Reaction SMILES: C[O-].[Na+].CO.C1(S([CH2:15][CH2:16][CH2:17][CH:18]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][C:19]2=O)(=O)=O)C=CC=CC=1.CS(C)=O>C1(C)C=CC=CC=1>[C:18]12[CH2:17][CH2:16][CH:15]=[C:19]1[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=2
Reactant: O=C1CCCCCCCCCCC1CCCS(=O)(=O)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: CS(C)=O
Product: C1=C2CCC=C2CCCCCCCCC1
Yield: 75.8 %

Procedure:
2.37 ml of a 30% solution of sodium methoxide in methyl alcohol (10.2 mmole) were added dropwise to a solution of 0.728 g (2.0 mmole) of 2-(3-phenylsulfonyl-prop-1-yl)-cyclododecanone in 10 ml of toluene as indicated sub letter b). After 90 min. of heating, 0.57 ml (8.0 mmole) of dimethylsulfoxide (DMSO) were added to the reaction mixture which was then heated to reflux for 4 further hours. After extraction and distillation, there were isolated 0.310 g (76% yield) of the desired compound.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:12][CH2:13][CH2:14][C:15]1([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]1>C(Cl)(Cl)Cl.FC(F)(F)C(O)=O>[O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:12][CH2:13][CH2:14][C:15]1([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]1
Reactant: CCOC(=O)C1(CCCn2c(=O)ccc3cccnc32)CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1(CCCn2c(=O)ccc3cccnc32)CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 114.5 %

Procedure:
To a solution of 0.53 g of 1-tert-butyl 4-ethyl 4-(3-(2-oxo-1,8-naphthyridin-1(2H)-yl)propyl)piperidine-1,4-dicarboxylate in 6 mL of chloroform, 25 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added to the resultant residue and the mixture was neutralized, and chloroform was then added thereto. The organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resultant solution was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 0.47 g of ethyl 4-(3-(2-oxo-1,8-naphthyridin-1(2H)-yl)propyl)piperidine-4-carboxylate as a colorless oily substance.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13](/[CH:14]=[C:15]4/[C:16](=[O:21])[NH:17][C:18](=[O:20])[NH:19]/4)=[C:9]3[N:8]=[C:7](S(C)=O)[N:6]=2)[CH2:3][CH2:2]1.C1(NC2N3N=CC(/C=[C:39]4/[C:40](=O)[NH:41][C:42](=O)[NH:43]/4)=C3N=C(S(C)(=O)=O)N=2)CC1.N1C=CN=C1>C(O)(C)C>[CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13](/[CH:14]=[C:15]4/[C:16](=[O:21])[NH:17][C:18](=[O:20])[NH:19]/4)=[C:9]3[N:8]=[C:7]([N:41]3[CH:40]=[CH:39][N:43]=[CH:42]3)[N:6]=2)[CH2:3][CH2:2]1
Reactant: CS(=O)c1nc(NC2CC2)n2ncc(/C=C3\NC(=O)NC3=O)c2n1
Reactant: CS(=O)(=O)c1nc(NC2CC2)n2ncc(/C=C3\NC(=O)NC3=O)c2n1
Agent: c1c[nH]cn1
Solvent: CC(C)O
Product: O=C1NC(=O)/C(=C/c2cnn3c(NC4CC4)nc(-n4ccnc4)nc23)N1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A mixture of (Z)-5-((4-(cyclopropylamino)-2-(methylsulfinyl)pyrazolo[1,5-a][1,3,5]triazin-8-yl)methylene)imidazolidine-2,4-dione and (Z)-5-((4-(cyclopropylamino)-2-(methylsulfonyl)pyrazolo[1,5-a][1,3,5]triazin-8-yl)methylene)imidazolidine-2,4-dione (10 mg, 0.028 mmol) was mixed with imidazole (6 mg, 0.084 mmol) in isopropanol (1 mL). The mixture was stirred at 80° C. for 16 h. The reaction mixture was cooled to room temperature and the resulting solid was filtered off and washed with isopropanol. The solid was dried under vacuum to provide (Z)-5-((4-(cyclopropylamino)-2-(1H-imidazol-1-yl)pyrazolo[1,5-a][1,3,5]triazin-8-yl)methylene)imidazolidine-2,4-dione as a yellow solid. LCMS (ES): >95% pure, m/z 352 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:37])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[C:18]([CH2:33][CH2:34][CH2:35][CH3:36])=[N:19][C:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)=[N:21][CH:22]=2)=[CH:11][CH:10]=1)([CH3:7])[CH3:6])C.[Li+].[OH-]>O1CCCC1.CCOCC>[CH2:33]([C:18]1[C:17]([CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][C:5]([CH3:6])([CH3:7])[C:4]([OH:37])=[O:3])=[CH:10][CH:11]=2)=[CH:22][N:21]=[C:20]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:31])([F:32])[F:30])=[CH:25][CH:24]=2)[N:19]=1)[CH2:34][CH2:35][CH3:36]
Reactant: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)ncc1COc1ccc(OC(C)(C)C(=O)OCC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)ncc1COc1ccc(OC(C)(C)C(=O)O)cc1
Yield: 91.9 %

Procedure:
297 mg (0.575 mmol) 2-{4-[4-butyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-phenoxy}-2-methyl-propionic acid ethyl ester and 2 ml 1N LiOH in 3 ml terahydrofurane were stirred over night at RT. The reaction mixture was taken up in ether and washed with 1N HCl and water. The crude product was suspended in AcOEt/heptane 1:19. The resulting crystals were filtered off providing 258 mg pure 2-{4-[4-butyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-phenoxy}-2-methyl-propionic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][C:4]=1[CH2:15][NH:16][CH:17]1[CH2:22][CH2:21][CH:20]([N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:19][CH2:18]1.[Cl:32][C:33]1[C:34]2[CH:44]=[CH:43][CH:42]=[CH:41][C:35]=2[S:36][C:37]=1[C:38](Cl)=[O:39]>>[Cl:32][C:33]1[C:34]2[CH:44]=[CH:43][CH:42]=[CH:41][C:35]=2[S:36][C:37]=1[C:38]([N:16]([CH2:15][C:4]1[CH:5]=[C:6]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[CH:17]1[CH2:18][CH2:19][CH:20]([N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[CH2:21][CH2:22]1)=[O:39]
Reactant: O=C(Cl)c1sc2ccccc2c1Cl
Reactant: COc1ccc(-c2ccccc2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Product: COc1ccc(-c2ccccc2)cc1CN(C(=O)c1sc2ccccc2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Biaryl amine 46 (423 mg, 1.00 mmol) is treated with 3-chloro-benzo[b]thiophene-2-carbonyl chloride (507 mg, 2.20 mmol) using Method D to give the title compound.