Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[F:9][C:10]1[CH:18]=[C:17]([C@H:19]2[CH2:24][CH2:23][C@H:22]([CH2:25][CH3:26])[CH2:21][CH2:20]2)[CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].O>N1C=CC=CC=1.C1(C)C=CC=CC=1>[F:9][C:10]1[CH:18]=[C:17]([C@H:19]2[CH2:24][CH2:23][C@H:22]([CH2:25][CH3:26])[CH2:21][CH2:20]2)[CH:16]=[CH:15][C:11]=1[C:12]([O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)=[O:13]
Reactant: Oc1ccc(F)cc1
Reactant: CC[C@H]1CC[C@H](c2ccc(C(=O)Cl)c(F)c2)CC1
Solvent: c1ccncc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC[C@H]1CC[C@H](c2ccc(C(=O)Oc3ccc(F)cc3)c(F)c2)CC1
Temperature: 60 °C

Procedure:
4-Fluorophenol (5.6 g, 0.05 mol) was dissolved in pyridine (10 ml), followed by adding to the solution, a solution of 2-fluoro-4-(trans-4-ethylcyclohexyl)benzoyl chloride (13.4 g, 0.05 mol) dissolved in toluene (50 ml), with stirring, thereafter heating the reaction mixture at 60° C. for 3 hours, adding water (100 ml) to the reaction material, washing the separated toluene layer with 6N HCl, then with 2N NaOH aqueous solution and further with water, thereafter drying it with anhydrous sodium sulfate, distilling off toluene and recrystallizing the residual solids from ethyl acetate to obtain the objective 4-fluorophenyl 2-fluoro-4-(trans-4-ethylcyclohexyl)benzoate (12.2 g, yield 65%). This compound exhibited following phase transition points:
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([CH3:6])([CH3:5])[CH3:4].[N:19]([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:20]=[O:21].C(N(CC)CC)C.O1CCCC1>O>[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][N:16]([C:20]([NH:19][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:21])[CH2:15][CH2:14]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CCOC(=O)CCN=C=O
Reactant: CC(C)(C)c1ccccc1N1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CCNC(=O)N1CCN(c2ccccc2C(C)(C)C)CC1
Temperature: 25 °C
Yield: 95 %

Procedure:
A mixture of 1-(2-tert-butylphenyl)piperazine dihydrochloride obtained in Reference Example 1 (400 mg), ethyl 3-isocyanatopropionate (286 mg), triethylamine (0.418 mL), and tetrahydrofuran (20 mL) was stirred at room temperature for over-night. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to provide the title compound (470 mg, 95%) as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([F:12])[CH:3]=1.[NH2:13][CH:14]1[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)C>[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([NH:13][CH:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)=[O:8])=[C:4]([F:12])[CH:3]=1
Reactant: Nc1cc(F)c(C(=O)O)cc1Cl
Reactant: CN1CCC(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: CN1CCC(NC(=O)c2cc(Cl)c(N)cc2F)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.8 %

Procedure:
4-amino-5-chloro-2-fluorobenzoic acid (Intermediate 176; 500 mg, 2.64 mmol), 4-amino-1-methylpiperidine (452 mg, 3.96 mmol) and diisopropylethylamine (1.38 ml, 7.91 mmol) were stirred in DMF (5 mL) and HATU (1.50 g, 3.96 mmol) added. The reaction mixture was stirred for 3 hours at room temperature. The mixture was absorbed on to an SCX column, which was washed with methanol and eluted with ammonia in methanol. Product containing fractions were concentrated to give a crystalline solid that was suspended in diethyl ether and filtered to yield the title compound as a pale brown solid (572 mg, 76%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[CH:10]2[N:18]3[CH:13]([CH2:14][CH2:15][CH2:16][CH2:17]3)[CH:12]3[C:19](=[O:24])[N:20]([CH3:23])[C:21](=[O:22])[CH:11]23)=[N:6][CH:7]=1.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[CH3:23][N:20]1[C:21](=[O:22])[CH:11]2[CH:10](/[CH:9]=[CH:8]/[C:5]3[CH:4]=[CH:3][C:2]([C:31]4[CH:30]=[CH:29][CH:28]=[C:27]([C:26]([F:37])([F:36])[F:25])[CH:32]=4)=[CH:7][N:6]=3)[N:18]3[CH:13]([CH:12]2[C:19]1=[O:24])[CH2:14][CH2:15][CH2:16][CH2:17]3
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: CN1C(=O)C2C(C1=O)C1CCCCN1C2/C=C/c1ccc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CN1C(=O)C2C(C1=O)C1CCCCN1C2/C=C/c1ccc(-c2cccc(C(F)(F)F)c2)cn1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
A mixture consisting of 42 mg of 4-[(E)-2-(5-bromopyridin-2-yl)vinyl]-2-methyloctahydropyrrolo[3,4-a]indolizine-1,3-dione (from Example 6, racemic mixture 1), 2.5 mg of tetrakis(triphenylphosphine)palladium(0), 25 mg of 3-trifluoromethylphenylboronic acid, 37 mg of potassium carbonate, 1.5 ml of toluene, 0.3 ml of ethanol and 0.75 ml of water is stirred at 100° C. for 5 h. After cooling, the mixture is taken up in 20 ml of water and the product is extracted by shaking with 20 ml of ethyl acetate. After drying and concentration of the organic phase, an oil is obtained. The crude product is purified by column chromatography (silica gel, MeOH:DCM=1:99).
Reaction SMILES: [NH2:1][C:2]([CH3:7])=[CH:3][C:4](=O)[CH3:5].[C:8]1(=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](=O)[CH2:9]1.C([O-])(=O)C.[NH4+]>C(O)(=O)C>[CH3:7][C:2]1[N:1]=[C:10]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:8](=[O:18])[C:9]2=[C:4]([CH3:5])[CH:3]=1
Reactant: O=C1CC(=O)c2ccccc21
Reactant: CC(=O)C=C(C)N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: Cc1cc(C)c2c(n1)-c1ccccc1C2=O
Yield: 24.4 %

Procedure:
A solution of 23.6 g (0.24 mol) of 4-amino-3-penten-2-one, 29.2 g (0.2 mol) of indene-1,3-(2H)dione and 7.7 g (0.1 mol) of ammonium acetate in 500 ml of acetic acid was stirred at 115° C. for 3 hours and concentrated under reduced pressure, and the residue was treated with 500 ml of water and rendered alkaline with solid potassium carbonate. The mixture was extracted three times with methylene chloride, and the combined extracts were washed with 100 ml of water and concentrated under reduced pressure. The residue was crystallized at +5° C. using 20 ml of diethyl ether. 10.2 g of 2,4-dimethyl-5H-indeno[3,2-b]pyridin-5- one were obtained as slightly yellow crystals of m.p. 102°-104° C.
Reaction SMILES: C(O)(=O)C(O)=O.[N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]([CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[C:14]([C:16]1[CH:36]=[CH:35][C:19]2[N:20]([CH3:34])[C:21]([CH2:23][NH:24][C:25]3[CH:30]=[CH:29][C:28]([C:31](=[NH:33])[NH2:32])=[CH:27][CH:26]=3)=[N:22][C:18]=2[CH:17]=1)=[O:15].C(=O)([O-])[O-].[K+].[K+].[CH2:50]([O:56][C:57](Cl)=[O:58])[CH2:51][CH2:52][CH2:53][CH2:54][CH3:55]>C(C(C)=O)C.O>[CH3:55][CH2:54][CH2:53][CH2:52][CH2:51][CH2:50][O:56][C:57](/[N:33]=[C:31](\[NH2:32])/[C:28]1[CH:27]=[CH:26][C:25]([NH:24][CH2:23][C:21]2[N:20]([CH3:34])[C:19]3[CH:35]=[CH:36][C:16]([C:14]([N:13]([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][N:7]=4)[CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[O:15])=[CH:17][C:18]=3[N:22]=2)=[CH:30][CH:29]=1)=[O:58]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Reactant: CCCCCCOC(=O)Cl
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: CCCCCCOC(=O)/N=C(\N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OCC)c4ccccn4)ccc3n2C)cc1
Temperature: 15 °C

Procedure:
A solution of 1-methyl-2-[N-[4-amidinophenyl]aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide oxalate compound of formula-3a (100 g) in a mixture of methyl ethyl ketone (1200 ml) and water (800 ml) was cooled to 12-18° C. Potassium carbonate (66.24 g) was added to the above reaction mixture and stirred for 15 minutes at 12-18° C. n-hexylchloroformate (28.95 g) was added to the reaction mixture and stirred for 4½ hours at 12-18° C. After completion of the reaction, the reaction mixture was quenched with water. Filtered the obtained solid, washed with methyl ethyl ketone and water. Dried the solid to get the title compound. Dichloromethane was added to the obtained compound and stirred for 15 minutes. Water was added to the reaction mixture and stirred for 20 minutes at 25-35° C. Both the organic and aqueous layers were separated, and the dichloromethane layer was washed with water followed by sodium chloride and then distilled off completely under reduced pressure. Acetone (600 ml) was added to the obtained residue and stirred for 45 minutes at 25-35° C. to obtain a clear solution. Water (500 ml) was added to the obtained solution and stirred for 45 minutes at 25-35° C. to get the solid. Filtered the solid, washed with water and finally with methyl tertiary butyl ether and then dried to get the pure title compound. Yield: 98 g; Purity by HPLC: 99.58%
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4](Cl)=[O:5].N1C=CC=CC=1.[C:15]1([NH:21][OH:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCCCCC>C(Cl)Cl>[Cl:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4]([N:21]([OH:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:5]
Reactant: ONc1ccccc1
Reactant: CC(C)(CCl)C(=O)Cl
Solvent: CCCCCC
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(CCl)C(=O)N(O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25 %

Procedure:
Under an argon atmosphere a stirred solution of 10.0 grams (0.065 mole) of 3-chloro-2,2-dimethylpropionyl chloride (prepared in the manner of Example 1, Step B) in 70 ml of methylene chloride was cooled to -70° and 6.1 grams (0.075 mole) of pyridine was added dropwise. A solution of 7.0 grams (0.065 mole) of N-phenylhydroxylamine in 30 ml of methylene chloride was then added dropwise over a 20-minute period. During the addition the reaction mixture temperature rose to -55°. Upon completion of addition the reaction mixture was stirred at -70° to -55° for 30 minutes, then was allowed to warm to ambient temperature where it was stirred for two hours. The reaction mixture was diluted with 100 ml of methylene chloride and washed with 100 ml of water, 100 ml of an aqueous 10% hydrochloric acid solution, and finally with 100 ml of water. The organic layer was dried by standing over magnesium sulfate for 16 hours. The darkened mixture was filtered and the filtrate concentrated under reduced pressure to give a black residue. The residue was slurried with 15 ml of hexane and the insolubles collected by filtration. The insoluble material was recrystallized from hexane/ethyl acetate to give 3.7 grams of 3-chloro-N-hydroxy-N-phenyl-2,2-dimethylpropanamide; mp 120°-121°.
Reaction SMILES: ClCCl.C([O:11][C:12]1[CH:13]=[C:14]([C:18]2[C:23]([CH3:24])=[C:22]([C:25]#[N:26])[C:21]([NH:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])=[C:20]([O:34]C)[C:19]=2[Br:36])[CH:15]=[CH:16][CH:17]=1)C1C=CC=CC=1.BrB(Br)Br.O>[Cl-].[Na+].O>[Br:36][C:19]1[C:20]([OH:34])=[C:21]([NH:27][C:28](=[O:33])[C:29]([CH3:31])([CH3:32])[CH3:30])[C:22]([C:25]#[N:26])=[C:23]([CH3:24])[C:18]=1[C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([OH:11])[CH:13]=1
Reactant: COc1c(Br)c(-c2cccc(OCc3ccccc3)c2)c(C)c(C#N)c1NC(=O)C(C)(C)C
Agent: BrB(Br)Br
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1c(C#N)c(NC(=O)C(C)(C)C)c(O)c(Br)c1-c1cccc(O)c1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 92.9 %

Procedure:
A dichloromethane (18 ml) solution of N-(3′-benzyloxy-2-bromo-5-cyano-3-methoxy-6-methylbiphenyl-4-yl)-2,2-dimethylpropionamide (I-13) (620 mg, 1.22 mmol) was cooled at −78° C., a dichloromethane solution of 1 N tribromoborane (3.67 ml, 3.67 mmol) was dropwise added, followed by stirring at −78° C. for 20 minutes. Afterwards, this was heated up to −12° C. and stirred for 1 hour, then heated up to 0° C. and stirred for 30 minutes. The reaction liquid was put into cold water (50 ml), saturated brine (50 ml) was added, the intended product was extracted with ethyl acetate (70 ml×2). The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1) to obtain the entitled compound (457 mg, 96%) as a yellow white semi-solid.
Reaction SMILES: C(O[CH:4]=[C:5]([C:11](=[O:27])[C:12]1[CH:17]=[C:16]([F:18])[C:15]([CH:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)=[CH:14][C:13]=1[F:26])[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[CH:28]1([NH2:31])[CH2:30][CH2:29]1>CCOCC>[CH:28]1([NH:31][CH:4]=[C:5]([C:11](=[O:27])[C:12]2[CH:17]=[C:16]([F:18])[C:15]([CH:19]3[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]3)=[CH:14][C:13]=2[F:26])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:30][CH2:29]1
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(C2CCN(C)CC2)cc1F
Reactant: NC1CC1
Solvent: CCOCC
Product: CCOC(=O)C(=CNC1CC1)C(=O)c1cc(F)c(C2CCN(C)CC2)cc1F
Reaction time: 8 h

Procedure:
A solution of 3.81 g (10 mmoles) of ethyl α-(ethoxymethylene)-2,5-difluoro-4-(1-methyl-4-piperidinyl)-β-oxobenzenepropanoate in 50 ml of ether was treated with 0.60 g (10 mmoles) of cyclopropylamine. After standing overnight the mixture was evaporated to dryness to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][CH:12]=[CH2:13])[C:6]=1[OH:14].S(OC)(O[CH3:23])(=O)=O>[OH-].[K+]>[CH3:23][O:14][C:6]1[C:7]([CH2:11][CH:12]=[CH2:13])=[CH:8][CH:9]=[CH:10][C:5]=1[O:4][C:3]1[CH:15]=[CH:16][CH:17]=[CH:18][C:2]=1[Cl:1]
Reactant: COS(=O)(=O)OC
Reactant: C=CCc1cccc(Oc2ccccc2Cl)c1O
Agent: [K+]
Agent: [OH-]
Product: C=CCc1cccc(Oc2ccccc2Cl)c1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.9 %

Procedure:
An aqueous solution (100 ml) of potassium hydroxide (17.0 g) was added all at once to a mixture of 2-(2-chlorophenoxy)-6-allylphenol (22.0 g) and dimethyl sulfate (23.0 g) under cooling. The mixture was stirred at room temperature for 30 minutes and extracted with diethyl ether. The extract was washed with water 3 times, dried over magnesium sulfate and then evaporated. The oily residue was subjected to distillation under reduced pressure to give colorless oil of 2-chlorophenyl 2-methoxy-3-allylphenyl ether (22.0 g). bp 149° C./0.8 mmHg.
Reaction SMILES: [CH2:1]=[C:2]([CH:4]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:11])[CH3:3].[CH2:12]([O:14][N:15]=[CH:16][CH3:17])[CH3:13].Cl[Sn](Cl)(Cl)Cl>ClCCCl>[CH2:12]([O:14][N:15]1[CH:16]([CH3:17])[CH2:3][C:2]([CH3:1])=[CH:4][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:11])[CH3:13]
Reactant: CC=NOCC
Reactant: C=C(C)C1CCCCCC1=O
Agent: CCON1C(=O)CCCCC/C=C(\C)CC1C
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCCl
Product: CCON1C(=O)CCCCCC=C(C)CC1C

Procedure:
Following the general procedure as described in Example 17, 2-(prop-1-en-2-yl)cycloheptanone (0.97 g, 6.38 mmol), acetaldehyde O-ethyl oxime (0.66 g, 7.65 mmol), and SnCl4 (1.66 g, 6.38 mmol) in 1,2-dichloroethane (65 ml) were reacted to give the title product as a colorless liquid (1.11 g, 73% yield).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([O:11][CH3:12])=[O:10])=[N:4][C:5](Br)=[CH:6][CH:7]=1.CC1(C)C(C)(C)OB([C:21]2[CH:22]=[C:23]3[CH:29]=[CH:28][N:27]([Si:30]([CH:37]([CH3:39])[CH3:38])([CH:34]([CH3:36])[CH3:35])[CH:31]([CH3:33])[CH3:32])[C:24]3=[N:25][CH:26]=2)O1.C(=O)([O-])O.[Na+]>O1CCOCC1.O.CC(=O)OCC.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>[NH2:1][C:2]1[C:3]([C:9]([O:11][CH3:12])=[O:10])=[N:4][C:5]([C:21]2[CH:22]=[C:23]3[CH:29]=[CH:28][N:27]([Si:30]([CH:34]([CH3:36])[CH3:35])([CH:37]([CH3:39])[CH3:38])[CH:31]([CH3:32])[CH3:33])[C:24]3=[N:25][CH:26]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1nc(Br)ccc1N
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(B3OC(C)(C)C(C)(C)O3)cnc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)c1nc(-c2cnc3c(ccn3[Si](C(C)C)(C(C)C)C(C)C)c2)ccc1N
Yield: 65.5 %

Procedure:
7.50 g of methyl 3-amino-6-bromopyridine-2-carboxylate, 12.10 g of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-triisopropylsilanyl-1H-pyrrolo-[2,3-b]pyridine, 8.18 g of sodium hydrogencarbonate and 2.27 g of PdCl2(PPh3)2 in 90 ml of dioxane and 15 ml of water are heated at 90° C. under nitrogen in a flask until the reaction is complete (HPLC check, about 7 hours). The cooled reaction solution is diluted with EA and washed 3 times with water. The organic phase is dried over sodium sulfate and purified by means of column chromatography (gradient heptane: EA 5-100% in 25 min), giving 8.40 g of methyl 3-amino-6-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridine-2-carboxylate as white solid (yield 56%, content 92%); MS-FAB (M+H+)=425.2; Rf (Esi1rod method): 3.10 min.
Reaction SMILES: Cl[CH2:2][C:3]([O:5][CH3:6])=[O:4].[CH3:7][N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1>C(OCC)(=O)C>[CH3:7][N:8]1[CH2:13][CH2:12][N:11]([CH2:2][C:3]([O:5][CH3:6])=[O:4])[CH2:10][CH2:9]1
Reactant: CN1CCNCC1
Reactant: COC(=O)CCl
Solvent: CCOC(C)=O
Product: COC(=O)CN1CCN(C)CC1
Reaction time: 17 h
Yield: 94.6 %

Procedure:
Methyl chloroacetate (8.8 ml., 0.10 mole) was added to a solution of N-methylpiperazine (24.4. ml., 0.22 mole) in ethyl acetate (140 ml.) and the mixture was stirred for 17 hours. The reaction mixture was filtered and the solvent was removed under vacuum. The resulting oil was dissolved in methylene chloride-methanol (9:1) and purified by flash chromatography (silica) to give 2-(4-methyl-1-piperazinyl)acetic acid, methyl ester as an oil (16.3 g, 95%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]#[N:12])[CH:7]=[CH:8][CH:9]=1)([O-])=O.O.O.[Sn](Cl)Cl>C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[NH2:1][C:4]1[CH:5]=[C:6]([CH2:10][C:11]#[N:12])[CH:7]=[CH:8][CH:9]=1
Reactant: N#CCc1cccc([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: N#CCc1cccc(N)c1

Procedure:
3-Nitrophenylacetonitrile (6.87 g, 42 mmol) and tin(II)chloride dihydrate (50 g, 220 mmol) in ethyl acetate (125 ml) were stirred at room temperature for 72 hours. The reaction was diluted with ethyl acetate and saturated aqueous sodium bicarbonate solution was added. The resulting precipitate was filtered off and the filtrate extracted with ethyl acetate (3×). The combined organic solutions were dried (MgSO4), filtered and evaporated under reduced pressure to afford the title compound as a pale yellow oil, 5.33 g.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](/[C:10](=[CH:18]\[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)/C(OC(C)(C)C)=O)=[O:9]>NC(N)=S.C1(C)C=CC=CC=1>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([C@H:18]2[CH2:10][C:8](=[O:9])[C:3]3[C:2](=[CH:7][CH:6]=[CH:5][CH:4]=3)[O:1]2)=[CH:20][CH:21]=1
Reactant: COc1ccc(/C=C(/C(=O)OC(C)(C)C)C(=O)c2ccccc2O)cc1
Agent: NC(N)=S
Solvent: Cc1ccccc1
Product: COc1ccc([C@H]2CC(=O)c3ccccc3O2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Prepared according to general procedure using (E)-tert-butyl 2-(2-hydroxyphenylcarbonyl)-3-(4-methoxyphenyl)prop-2-enoate (35.0 mg, 0.10 mmol), thiourea catalyst III (7 mg, 0.01 mmol) in 1.0 mL toluene for 3 d at −25° C. After completion of reaction, 100 mL sample was withdrawn to determine ee of 3-tert-butylcarboxy-(4-methoxyphenyl)chromanone 12 (90% ee). Anhydrous MgBr2.OEt2 (170 mg) was added to the remaining solution and stirred at RT for 48 h. Purification via column chromatography with 10% EtOAc/hexanes afforded 11 mg (49%) as a yellow solid in 78% ee. Analytical data match those reported in the literature.6
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.C1CCN2C(=NCCC2)CC1.[C:45](Cl)(=[O:48])[CH2:46][CH3:47].CO>ClCCl>[C:45]([N:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:32][CH2:33]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)(=[O:48])[CH2:46][CH3:47]
Reactant: O=C(NC1CCNCC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Reactant: CCC(=O)Cl
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Solvent: CO
Product: CCC(=O)N1CCC(NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1
Reaction time: 2 h

Procedure:
4-(5-Cyclopropylmethoxy-1,3-benzodioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide hydrochloride from example A138 (472 mg; 1.0 mmol) and DBU (2.5 mmol) is dissolved in dry dichloromethane (5 mL). Propionyl chloride (1.1 mmol) is syringed into the reaction mixture at ice bath temperature. After complete addition stirring is continued at ambient temperature over night. Methanol (1 mL) is added and stirring is continued for two hours. The volatiles are evaporated. The residue is purified by reversed phase preparative HPLC. The collected product fraction is freeze-dried to yield 375 mg of the title compound as colorless solid.
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:26]1[CH:27]=[CH:28][C:29]2[N:30]([CH:32]=[C:33]([C:35]([CH3:39])([CH3:38])[CH2:36][OH:37])[N:34]=2)[N:31]=1.C(=O)(O)[O-].[Na+]>>[C:19]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:26]3[CH:27]=[CH:28][C:29]4[N:30]([CH:32]=[C:33]([C:35]([CH3:39])([CH3:38])[CH2:36][OH:37])[N:34]=4)[N:31]=3)[CH2:11][CH2:10]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(CO)c1cn2nc(Cl)ccc2n1
Reactant: NCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(C)(CO)c1cn2nc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)ccc2n1
Yield: 45.3 %

Procedure:
1.29 g of 4-(diphenylmethoxy)-1-piperidinepropanamine and 0.451 g of 2-(6-chloroimidazo[1,2-b]pyridazin-2-yl]-2-methylpropanol were stirred at 190-200° C. for 90 minutes. After cooling, aqueous sodium bicarbonate was added, followed by extraction with ethyl acetate. The extract was washed with saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate:methanol:triethylamine (90:10:1). The desired fraction was collected; the residue was recrystallized from ethyl ether to yield 0.465 g of the title compound.
Reaction SMILES: [C:1]([C:3]1[C:4]2[C:5]([CH3:18])=[N:6][N:7]([CH3:17])[C:8]=2[CH2:9][CH2:10][C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])#[N:2].C1(Cl)C(Cl)=C(Cl)C(=O)C(=O)C=1Cl>C1C=CC=CC=1>[C:1]([C:3]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=[C:8]2[C:4]=1[C:5]([CH3:18])=[N:6][N:7]2[CH3:17])#[N:2]
Reactant: CCOC(=O)C1=C(C#N)c2c(C)nn(C)c2CC1
Agent: O=C1C(=O)C(Cl)=C(Cl)C(Cl)=C1Cl
Solvent: c1ccccc1
Product: CCOC(=O)c1ccc2c(c(C)nn2C)c1C#N
Reaction time: 1.5 h
Yield: 47.3 %

Procedure:
A mixture of ethyl 4-cyano-6,7-dihydro-1,3-dimethyl-1H-indazole-5-carboxylate (13.5 g, 55.0 mmol), o-chloranil (16.3 g, 66.0 mmol) and dry benzene is stirred for 1.5 hours at reflux temperature, cooled and filtered. The filtrate is concentrated in vacuo, filtered through two pads of neutral alumina and evaporated to dryness to afford a yellow solid. Recrystallization from ethyl acetate affords the title product (6.33 g, 47.2%), mp 170°-175.5° C.