Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=O)[CH2:6][CH2:5]2.[CH3:12][C:13]1([CH3:20])[CH2:18][CH2:17][CH:16]([NH2:19])[CH2:15][CH2:14]1.[BH3-]C#N.[Na+].O>CCO.CO.C1COCC1.CC(O)=O.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([NH:19][CH:16]1[CH2:17][CH2:18][C:13]([CH3:20])([CH3:12])[CH2:14][CH2:15]1)[CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(Br)ccc21
Reactant: CC1(C)CCC(N)CC1
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC1(C)CCC(NC2CCc3cc(Br)ccc32)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a slurry of 5-bromo-1-indanone (0.449 g; 2.13 mmol) and 4,4-dimethylcyclohexanamine (2.24 mmol; Note 1) under N2 was added Ti(OiPr)4 (0.94 mL; 3.2 mmol) via syringe. The mixture was stirred 16 h at room temperature, a solution of NaBH3CN (0.134 g; 2.13 mmol) in EtOH (5 mL) was added and stirring continued an additional 4 h. Water was added and the whole was filtered through a pad of Celite (washed 2×EtOH, 2×THF). Combine filtrate and washings were concentrated in vacuo, the residue was taken up in CH2Cl2 and stirred under 1N NaOH for 1 h. Layers were separated, the aqueous layer was extracted with CH2Cl2 (×2), combined organics were washed (water, brine), dried over Na2SO4 and concentrated in vacuo. The residue was dissolved in MeOH/THF/HOAc (15/3/0.3 mL respectively), NaBH3CN (0.134 g; 2.13 mmol) was added and the mixture was stirred at room temperature overnight. After 17 h the mixture was concentrated in vacuo, partitioned between CH2Cl2/1N NaOH and the layers were separated. The aqueous layer was extracted with CH2Cl2 (×2), combined organics were washed (water, brine), dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography (EtOAc/hexanes; Note 2), affording the title compound as a pale yellow syrup. LC/MS (method A) tR 1.79 min; m/z 322, 324 (M+H, Br isotopes).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:18][C:19](=[O:21])[CH3:20])[C:13]=1[O:14][C:15](=[O:17])[CH3:16])[C:8]([NH2:10])=[O:9])(=[O:3])[CH3:2].C(Cl)(=O)[C:23](Cl)=[O:24].C(OC1C=C(C=CC=1OC(=O)C)C(N)=O)(=O)C>ClCCl>[C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:18][C:19](=[O:21])[CH3:20])[C:13]=1[O:14][C:15](=[O:17])[CH3:16])[C:8]([N:10]=[C:23]=[O:24])=[O:9])(=[O:3])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(=O)Oc1cc(C(N)=O)cc(OC(C)=O)c1OC(C)=O
Agent: CC(=O)Oc1ccc(C(N)=O)cc1OC(C)=O
Solvent: ClCCl
Product: CC(=O)Oc1cc(C(=O)N=C=O)cc(OC(C)=O)c1OC(C)=O

Procedure:
The procedure used in Example 1 (1) was repeated except that 3,4,5-triacetoxybenzamide (8.0 g) and oxalyl chloride (8.6 g) were used instead of 3,4-diacetoxybenzamide (7.5 g) and oxalyl chloride (10.1 g) to give a solution of 3,4,5-triacetoxybenzoyl isocyanate in anhydrous dichloromethane (40 ml).
Reaction SMILES: [CH2:1]([C:3]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[C:7]([CH2:13][CH3:14])[C:4]=1[CH:5]=O)[CH3:2].[C:15](Br)(Br)([Br:17])[Br:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[Br:16][C:15]([Br:17])=[CH:5][C:4]1[C:3]([CH2:1][CH3:2])=[C:10]([O:11][CH3:12])[CH:9]=[CH:8][C:7]=1[CH2:13][CH3:14]
Reactant: BrC(Br)(Br)Br
Reactant: CCc1ccc(OC)c(CC)c1C=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCc1ccc(OC)c(CC)c1C=C(Br)Br

Procedure:
2-(2,2-Dibromo-vinyl)-1,3-diethyl-4-methoxy-benzene was prepared from 2,6-diethyl-3-methoxy-benzaldehyde, carbon tetrabromide and triphenylphosphine in analogy to Example 1d): colourless oil; 1H-NMR (CDCl3): 1.08 (3H, t, CH3), 1.17 (3H, t, CH3), 2.55 (4H, m, 2×CH2), 3.81 (3H, s, OMe), 6.82 (1H, d, ArH), 7.05 (1H, d, ArH), 7.44 (1H, s, CH═CBr2).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]#[C:9][CH2:10][C@H:11]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:12]([O:14][CH3:15])=[O:13])=[N:6][CH:7]=1.C([O-])=O.[NH4+]>CO.C(OCC)(=O)C.[Pd]>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][C@H:11]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:12]([O:14][CH3:15])=[O:13])=[N:6][CH:7]=1
Reactant: COC(=O)[C@H](CC#Cc1cnc(N)cn1)NC(=O)OC(C)(C)C
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)[C@H](CCCc1cnc(N)cn1)NC(=O)OC(C)(C)C
Yield: 78.1 %

Procedure:
A mixture of methyl (S)-5-(5-amino-2-pyrazinyl)-2-[[(1,1-dimethylethoxy)carbonyl]amino]-pent-4-ynoate (10.0 g; 31.2 mmol), ammonium formate (29.7 g; 468.0 mmol) and active 10% palladium-on-charcoal (1.2 g) in methanol (100 ml) is refluxed for 3 hours. The reaction mixture is filtered and concentrated under reduced pressure. The residue obtained is taken up in ethyl acetate (300 ml), washed with brine (2×200 ml), dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue obtained is purified on a column of silica eluted under pressure with a dichloromethane/methanol mixture (96/4). 7.9 g of methyl (S)-5-(5-amino-2-pyrazinyl)-2-[[(1,1-dimethylethoxy)carbonyl]amino]pentanoate are isolated in the form of a viscous oil.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([NH:16][CH2:17][CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)=[C:6]2[CH:5]=[N:4]1)=[CH:13][C:12]([OH:24])=[CH:11][CH:10]=3)[CH3:2].CS(C)=O.[OH-].[K+].Br[CH:32]([CH3:38])[C:33]([O:35]CC)=[O:34]>O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([NH:16][CH2:17][CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)=[C:6]2[CH:5]=[N:4]1)=[CH:13][C:12]([O:24][CH:32]([C:33]([OH:35])=[O:34])[CH3:38])=[CH:11][CH:10]=3)[CH3:2]
Reactant: CCOC(=O)C(C)Br
Reactant: CCn1ncc2c(NCC3CCCCC3)c3cc(O)ccc3nc21
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCn1ncc2c(NCC3CCCCC3)c3cc(OC(C)C(=O)O)ccc3nc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of 1-ethyl-6-hydroxy-N-(cyclohexylmethyl)-1H-pyrazolo[3,4-b]quinolin-4-amine (0.5 g, 1.5 mmol), DMSO (5 ml) and KOH (0.5 g) is stirred at room temperature for 20 minutes, then ethyl 2-bromopropionate (0.2 ml) is added, and the mixture is stirred overnight. The reaction mixture is poured into 10 volumes of water, extracted with CH2Cl2 (2×10 ml), and the aqueous layer is acidified with acetic acid. A precipitate forms which is collected by filtration, dissolved in methanol and filtered. The filtrate is allowed to stand, and the product that precipitates is collected by filtration and dried to afford 180 mg of 1-ethyl-6-(1-carboxyethoxy)-N-(cyclohexylmethyl)-1H-pyrazolo[3,4-b]quinolin-4-amine. 1/4 Hydrate, m.p. 280° C. (dec.).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:6][CH2:5][CH2:4][C:3]1([C:8]1[N:12]([CH3:13])[N:11]=[CH:10][CH:9]=1)O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:14])[C:3]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][CH:9]=2)=[CH:4][CH2:5][CH2:6]1
Reactant: Cn1nccc1C1(O)CCCC1(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cn1nccc1C1=CCCC1(C)C
Yield: 89.7 %

Procedure:
A solution of the 2,2-dimethyl-1-(1-methyl-1H-pyrazol-5-yl)cyclopentanol (630 mg, 3.24 mmol) prepared in Example 99a and p-toluenesulfonic acid hydrate (2.00 g, 10.5 mmol) in toluene (20 mL) was stirred for 8 hours under reflux, and the solvent was subjected to azeotropic distillation with water. After allowing to cool, water (50 mL) was added to the reaction solution, and an organic layer was extracted. The thus obtained organic layer was dried over anhydrous sodium sulfate. After vacuum concentration, the residue was purified with silica gel chromatography (hexane/ethyl acetate=3:1) to yield the title compound (512 mg, 90%) as a brown oil.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]1[CH:4]=[CH:5][C:6]([N+:12]([O-:14])=[O:13])=[C:7]([CH:11]=1)[C:8](O)=[O:9].[BH4-].[Na+].B(F)(F)F.CCOCC>COCCOC>[CH3:1][N:2]([CH3:15])[C:3]1[CH:4]=[CH:5][C:6]([N+:12]([O-:14])=[O:13])=[C:7]([CH:11]=1)[CH2:8][OH:9]
Reactant: CN(C)c1ccc([N+](=O)[O-])c(C(=O)O)c1
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: COCCOC
Product: CN(C)c1ccc([N+](=O)[O-])c(CO)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 189 g of 5-dimethylamino-2-nitrobenzoic acid in 1.5 l of 1,2-dimethoxyethane was treated with 52 g of sodium borohydride and then dropwise at 10° with a solution of 225 ml of boron trifluoride etherate in 500 ml of 1,2-dimethoxyethane. The mixture was then stirred at room temperature for 1 hour, cautiously poured into ice/water and the crude product was filtered. Recrystallization from ethyl acetate/hexane gave pure 5-dimethylamino-2-nitrobenzyl alcohol, m.p. 138°-139°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH:9]([SH:13])[C:10](O)=[O:11].S(Cl)([Cl:16])=O>CN1CCCC1=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH:9]([SH:13])[C:10]([Cl:16])=[O:11]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C(S)c1cc(Cl)ccc1Cl
Solvent: CN1CCCC1=O
Product: O=C(Cl)C(S)c1cc(Cl)ccc1Cl
Temperature: 50 °C

Procedure:
94.8 g of 2,5-dichlorophenylthioglycolic acid are added to 103.2 g of thionyl chloride. 0.24 g of N-methylpyrrolidone is added, and the mixture is heated at 50° C. for 2 hours and is then cooled down to 0° C. At this temperature the 2,5-dichlorophenylthioglycoloyl chloride formed is then added dropwise in the course of 1 hour to a suspension of 160 g of thionyl chloride and 77.2 g of anhydrous aluminum chloride. The suspension is stirred at 0°-5° C. for 1 hour and is then poured onto a mixture of 1,200 g of ice and 800 ml of water, the resulting mixture is stirred at 80° C. for 1 hour and is then filtered with suction, and the filter cake is washed until neutral and dried in vacuo at 50° C. This gives 88.4 g of 94.5% pure 4,7-dichloro-3-oxythionaphthene.
Reaction SMILES: [C:1]([OH:13])(=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].[CH2:14]1[O:16][CH:15]1[CH2:17][OH:18]>[Cr]>[OH:16][CH:15]([CH2:17][OH:18])[CH2:14][O:10][C:9](=[O:11])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([O:13][CH2:14][CH:15]([OH:16])[CH2:17][OH:18])=[O:12]
Reactant: OCC1CO1
Reactant: O=C(O)CCCCCCCC(=O)O
Agent: [Cr]
Product: O=C(CCCCCCCC(=O)OCC(O)CO)OCC(O)CO
Temperature: 120 °C
Reaction time: 1 h

Procedure:
Azelaic acid 94 parts, 0.5 mol.) was heated to 120° C. A catalyst, AMC-2 (commercial chromium salt, 0.8 g) was added. Glycidol (81.5 g, 1.1 mol.) was added dropwise with stirring during 1 hour while keeping the temperature within 115° and 125° C. To complete the reaction, heating at 120° C. was continued for another hour. The product was a viscous liquid which crystallized very slowly to a waxy solid. It had residual acid and epoxy contents of 0.03 and 0.07 meq./g, respectively, and a purity of about 95%; 2,3-dihydroxypropyl groups per molecule: 2; molecular weight; 336.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][C@@H:9]2[CH3:14])[CH:5]=[C:4]([C:15]([S:18]([CH:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])([CH3:17])[CH3:16])[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].C[N:31]([CH:33]=O)C>COCCOC.O.C(O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:14][C@H:9]1[CH2:10][O:11][CH2:12][CH2:13][N:8]1[C:6]1[CH:5]=[C:4]([C:15]([S:18]([CH:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])([CH3:17])[CH3:16])[N:3]=[C:2]([C:4]2[CH:15]=[CH:16][C:33]([NH2:31])=[CH:6][CH:5]=2)[N:7]=1
Reactant: CC(C)S(=O)(=O)C(C)(C)c1cc(N2CCOC[C@@H]2C)nc(Cl)n1
Reactant: CN(C)C=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Solvent: O
Product: CC(C)S(=O)(=O)C(C)(C)c1cc(N2CCOC[C@@H]2C)nc(-c2ccc(N)cc2)n1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
Dichlorobis(triphenylphosphine)palladium(II) (116 mg, 0.17 mmol) was added to 2-chloro-4-[(3S)-3-methylmorpholin-4-yl]-6-(2-propan-2-ylsulfonylpropan-2-yl)pyrimidine (1.2 g, 3.32 mmol), and sodium carbonate (5 mL, 10.00 mmol) in 18% DMF in a mixture of DME:water:ethanol (7:3:2) (20 mL). The resulting solution was stirred at 90° C. for 4 hours.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:18]([O:19]C(=O)C)[C@H:17]([O:23][C@@H:24]2[O:41][C@H:40]([CH2:42][O:43]C(=O)C)[C@@H:35]([O:36]C(=O)C)[C@H:30]([O:31]C(=O)C)[C@H:25]2[O:26]C(=O)C)[C@@H:16]([CH2:47][O:48]C(=O)C)[O:15][C@H:6]1[S:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=1)(=O)C>O>[C@@H:24]1([O:23][C@@H:17]2[C@@H:16]([CH2:47][OH:48])[O:15][C@@H:6]([S:7][C:8]3[CH:9]=[CH:10][C:11]([NH2:14])=[CH:12][CH:13]=3)[C@H:5]([OH:4])[C@H:18]2[OH:19])[O:41][C@H:40]([CH2:42][OH:43])[C@@H:35]([OH:36])[C@H:30]([OH:31])[C@H:25]1[OH:26]
Reactant: CC(=O)OC[C@H]1O[C@@H](Sc2ccc(N)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1O[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Solvent: O
Product: Nc1ccc(S[C@@H]2O[C@H](CO)[C@@H](O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)[C@H](O)[C@H]2O)cc1

Procedure:
A 3.0 g portion of 4-aminophenyl 2,3,6-tri-O-acetyl-4-O-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-1-thio-β-D-glucopyranoside was reacted as described in Example 29, giving 1.49 g of the desired intermediate as a solid, [α]D26 =-47°±4° (0.34%, water).
Reaction SMILES: C(#N)C.[OH:4][CH:5]1[CH:9]2[O:10][C:11](=[O:21])[CH:12]3[CH:13]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:6]1[CH2:7][CH:8]23.C(N(CC)CC)C.[C:29](Cl)(=[O:33])[C:30]([CH3:32])=[CH2:31]>O>[C:29]([O:4][CH:5]1[CH:9]2[O:10][C:11](=[O:21])[CH:12]3[CH:13]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH:6]1[CH2:7][CH:8]23)(=[O:33])[C:30]([CH3:32])=[CH2:31]
Reactant: C=C(C)C(=O)Cl
Reactant: CC(C)(C)OC(=O)C1C2CC3C(OC(=O)C31)C2O
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OC1C2CC3C1OC(=O)C3C2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.3 %

Procedure:
Dissolved into 900 mL of acetonitrile were 226.8 g of tert-butyl 6-hydroxy-2-oxohexahydro-3,5-methano-2H-cyclopenta[b]furane-7-carboxylate (24) and 135.2 g of triethylamine. Into this mixture was gradually added 121.1 g of methacryloyl chloride at 20° C. or lower. After the resulting mixture was stirred at room temperature for 3 hours, 300 g of water was added into it and usual work-up was carried out. Recrystallization was made from ethyl acetate to give 202.2 g of the intended product (Yield 70%).
Reaction SMILES: C1([O:6][C:7](=[O:47])[C@@H:8]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][NH:25][CH2:26][C:27]3[CH:28]=[CH:29][C:30]4[CH:34]=[C:33]([C:35](=[O:45])[NH:36][O:37][CH:38]([O:40][CH2:41][CH:42]([CH3:44])[CH3:43])[CH3:39])[S:32][C:31]=4[CH:46]=3)=[CH:20][CH:19]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)CCCC1.[Li+].[OH-].Cl>C1COCC1.O>[CH2:41]([O:40][CH:38]([O:37][NH:36][C:35]([C:33]1[S:32][C:31]2[CH:46]=[C:27]([CH2:26][NH:25][CH2:24][C:21]3[CH:20]=[CH:19][C:18]([CH2:17][NH:16][C@@H:8]([CH2:9][C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:7]([OH:47])=[O:6])=[CH:23][CH:22]=3)[CH:28]=[CH:29][C:30]=2[CH:34]=1)=[O:45])[CH3:39])[CH:42]([CH3:44])[CH3:43]
Reactant: CC(C)COC(C)ONC(=O)c1cc2ccc(CNCc3ccc(CN[C@@H](Cc4ccccc4)C(=O)OC4CCCC4)cc3)cc2s1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)COC(C)ONC(=O)c1cc2ccc(CNCc3ccc(CN[C@@H](Cc4ccccc4)C(=O)O)cc3)cc2s1
Temperature: 50 °C

Procedure:
(S)-2-[4-({[2-(1-Isobutoxy-ethoxycarbamoyl)-benzo[b]thiophen-6-ylmethyl]-amino}-methyl)-benzylamino]-3-phenyl-propionic acid cyclopentyl ester (40 mg, 0.06 mmol) was dissolved in THF (2 mL) and water (2 mL). LiOH (8 mg, 0.30 mmol) was added and the reaction mixture heated to 50° C. for 36 h. THF was removed by evaporation and the residue partitioned between water (10 mL) and EtOAc (10 mL). The aqueous layer was isolated and the pH adjusted to 3 by addition of 1M HCl. This was extracted with EtOAc (3×20 mL), the organic layers combined and evaporated to dryness.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12](=[O:17])[CH2:13][C:14](=O)[CH3:15])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.OS(O)(=O)=O.CCCCCC.C(OCC)(=O)C>O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]2[C:4]=1[C:14]([CH3:15])=[CH:13][C:12](=[O:17])[NH:11]2
Reactant: COc1cc(NC(=O)CC(C)=O)cc(OC)c1
Agent: O=S(=O)(O)O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(OC)c2c(C)cc(=O)[nH]c2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97.3 %

Procedure:
Compound 9 (13.9 g, 58.6 mmol) was taken in a 100 mL round bottom flask and cooled to 0° C. Conc. H2SO4 (35 mL, 657 mmol) was added dropwise for 10 min at 0° C. and allowed the reaction mixture to reach room temperature over a period of 30 min. After completion of the reaction (TLC hexane : ethyl acetate 1:1, Rf=0.3) it was poured into water (200 mL) and solid separated was filtered, the solid was washed with water till neutral to pH and dried under vacuum to give product 5,7-dimethoxy4-methyl-1,2-dihydro-2-quinolinone (11, 12.5 g) in 97.6% yield as a solid. M.P. 239-240° C.
Reaction SMILES: [CH2:1]([N:5]1[C:9]([NH:10][C:11](=[O:23])[C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=2[F:22])=[CH:8][C:7]([C:24]([CH3:27])([CH3:26])[CH3:25])=[N:6]1)[CH2:2][CH2:3][CH3:4].F[C:29](F)(F)S(OC)(=O)=O.[NH4+].[OH-]>C1(C)C=CC=CC=1.O.CC(C)=O>[CH2:1]([N:5]1[N:6]([CH3:29])[C:7]([C:24]([CH3:26])([CH3:25])[CH3:27])=[CH:8]/[C:9]/1=[N:10]\[C:11](=[O:23])[C:12]1[CH:17]=[C:16]([C:18]([F:19])([F:21])[F:20])[CH:15]=[CH:14][C:13]=1[F:22])[CH2:2][CH2:3][CH3:4]
Reactant: COS(=O)(=O)C(F)(F)F
Reactant: CCCCn1nc(C(C)(C)C)cc1NC(=O)c1cc(C(F)(F)F)ccc1F
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Product: CCCCn1/c(=N/C(=O)c2cc(C(F)(F)F)ccc2F)cc(C(C)(C)C)n1C
Temperature: 100 °C
Reaction time: 20 h
Yield: 89.2 %

Procedure:
To a solution of Example 81B (50.2 g, 130 mmol) in toluene (500 mL) was added methyl trifluoromethanesulfonate (21.4 mL, 195 mmol). The mixture was warmed to 100° C. and stirred for 20 hours. The mixture was cooled to ambient temperature then diluted with water (200 mL) and acetone (500 mL). This solution was stirred for 30 minutes then concentrated NH4OH (100 mL) was added. The mixture was stirred for 30 minutes then partially concentrated under reduced pressure. The residue was diluted with EtOAc (300 mL) and brine (100 mL), the layers were separated and the aqueous phase was extracted with EtOAc (3×30 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 80% hexanes/EtOAc to 100% EtOAc to 10% MeOH in EtOAc) and the fractions collected and concentrated. The material was then dissolved in EtOAc (150 mL) and was washed with 10% NaOH (100 mL). The layers were separated, the aqueous phase was extracted with EtOAc (3×50 mL) and the combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give (46.3 g, 116 mmol, 89% yield) the title compound. MS (ESI+) m/z 400 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](I)[C:5]([NH2:8])=[N:6][CH:7]=1.[CH2:10]([Si:12]([CH2:20][CH3:21])([CH2:18][CH3:19])[C:13]#[C:14][CH2:15][CH2:16][OH:17])[CH3:11].[Cl-].[Li+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.ClCCl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:14]([CH2:15][CH2:16][OH:17])=[C:13]([Si:12]([CH2:20][CH3:21])([CH2:10][CH3:11])[CH2:18][CH3:19])[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC[Si](C#CCCO)(CC)CC
Reactant: Nc1ncc(Cl)cc1I
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC[Si](CC)(CC)c1[nH]c2ncc(Cl)cc2c1CCO
Yield: 88 %

Procedure:
A mixture of 5-chloro-3-iodopyridin-2-amine (2 g; 7.86 mmol), 4-(triethylsilyl)but-3-yn-1-ol (4.35 g; 23.58 mmol); (1,1′-bis(diphenylphosphino)ferrocene)-dichloromethane (0.321 g; 0.393 mmol), lithium chloride (0.333 g; 7.86 mmol) and sodium carbonate (1.67 g; 15.72 mmol) in DMF (15 mL) was heated at 100° C. for approximately 20 hours. After cooling, the mixture was concentrated under reduced pressure and the residue was partitioned between brine and ethyl acetate. After separation the organic layer was evaporated and the residue was purified by flash chromatography on silica gel (eluent 7 to 80% of ethyl acetate in heptane) to give 2.15 g (88%) of 2-(5-chloro-2-(triethylsilyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)ethanol as a white solid.
Reaction SMILES: [CH:1]([C:4]1[S:13][C:12]2[NH:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[N:8]=[C:7]([NH2:18])[C:6]=2[N:5]=1)([CH3:3])[CH3:2].[CH2:19]([C@H:26]1[CH2:31]N[CH2:29][CH2:28][NH:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([C@@H:26]1[NH:27][CH2:28][CH2:29][N:18]([C:7]2[C:6]3[N:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[S:13][C:12]=3[NH:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[N:8]=2)[CH2:31]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)c1nc2c(s1)Nc1ccccc1N=C2N
Reactant: c1ccc(C[C@H]2CNCCN2)cc1
Product: CC(C)c1nc2c(s1)Nc1ccccc1N=C2N1CCN[C@@H](Cc2ccccc2)C1
Yield: 25.3 %

Procedure:
By using a similar method of the method of Example 460, using 2-isopropyl-4H-3-thia-1,4,9-triaza-benzo[f]azulen-10-ylamine(1.44 g, 5.5 mmol) and (S)-2-benzyl-piperazine (0.983 g, 5.5 mmol) to give 0.580 g of the title compound as a yellow solid: mass spectrum (ion spray): m/z=418 (M+1); Analysis for C24H27N5S(0.2 H2O): calcd: C, 68.44; H, 6.56; N, 16.63; found: C, 68.63; H, 6.43; N, 16.74.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH:11]([CH3:22])[CH2:10]2)=[CH:5][CH:4]=1)#[N:2].C(O)(C(F)(F)F)=O>ClCCl>[CH3:22][CH:11]1[CH2:10][CH:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)[CH2:14][CH2:13][NH:12]1
Reactant: CC1CC(c2ccc(C#N)cc2)CCN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1CC(c2ccc(C#N)cc2)CCN1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 93.2 %

Procedure:
To a solution of tert-butyl 4-(4-cyanophenyl)-2-methylpiperidine-1-carboxylate (compound 176.2, 500 mg, 1.50 mmol, 1.00 equiv, 90%) in dichloromethane (3 mL) was added TFA dropwise (1 mL). The resulting mixture was stirred for 1.5 h at room temperature, then diluted with 30 mL of dichloromethane. The resulting mixture was washed with sodium bicarbonate (aq., 1 M. Note: significant gas evolution). The aqueous phase was extracted with 2×50 mL of dichloromethane and the combined organic layers were dried (Na2SO4), and concentrated in vacuo. The residue was purified using silica gel column chromatography with methanol/dichloromethane (1:50-1:20) as eluent to yield 280 mg (93%) of 4-(2-methylpiperidin-4-yl)benzonitrile as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10](O)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:15]([O-:17])=[O:16])[CH:8]=2)[N:3]=1.P(Cl)(Cl)([Cl:20])=O>>[NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10]([Cl:20])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:15]([O-:17])=[O:16])[CH:8]=2)[N:3]=1
Reactant: N#Cc1c(N)nc2ccc([N+](=O)[O-])cc2c1O
Reactant: O=P(Cl)(Cl)Cl
Product: N#Cc1c(N)nc2ccc([N+](=O)[O-])cc2c1Cl

Procedure:
The stirred mixture of 48.5 g of 2-amino-3-cyano-4-hydroxy-6-nitroquinoline and 550 mL of phosphoryl chloride was refluxed for 4 hours. The reaction mixture was concentrated to half of its volume and the residue was poured onto 1500 g of ice. The yellow precipitate was filtered off, washed with water to give 60.5 g of solid. 25 g of this solid was stirred at room temperature in 500 mL of 0.5 N HCl for 6 hours, then the precipitate was filtered off, washed with water to give 18.5 g of product, m.p.: >360° C. LC-MS: MH+ 249; Ret. time: 5.94 min.