Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:22])[C:7]=1[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[C:12](=O)[NH:11][N:10]=1.O=P(Cl)(Cl)[Cl:25]>C(#N)C>[Cl:25][C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)[C:9]([CH2:8][C:7]2[C:2]([Cl:1])=[CH:3][N:4]=[CH:5][C:6]=2[Cl:22])=[N:10][N:11]=1
Reactant: COc1ccc2c(Cc3c(Cl)cncc3Cl)n[nH]c(=O)c2c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: COc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(Cl)c2c1
Reaction time: 3 h
Yield: 110.6 %

Procedure:
A suspension of 4-(3,5-dichloro-pyridin-4-ylmethyl)-7-methoxy-2H-phthalazin-1-one (10 g, 25.5 mmoles), prepared as described in example 38, in acetonitrile (300 ml), was added with POCl3 (22.2 ml, 230 mmoles) and the mixture was refluxed. After 3 hours, the solution was concentrated, taken up in CH2Cl2, in water, and the pH was brought to 7-8 by Na2CO3. The organic phases were discoloured with charcoal, anhydrified and concentrated to give 10 g of the title compound (stoichiometric yield). m.p.: 156-166° C.
Reaction SMILES: [NH:1]([C:3]1[CH:4]=[C:5]([C:12]([OH:14])=[O:13])[CH:6]=[C:7]([C:9]([OH:11])=[O:10])[CH:8]=1)N.[CH:15]([C:18]([CH3:20])=O)([CH3:17])[CH3:16]>C(O)(=O)C>[CH3:20][C:18]1[C:15]([CH3:17])([CH3:16])[C:4]2[C:3](=[CH:8][C:7]([C:9]([OH:11])=[O:10])=[CH:6][C:5]=2[C:12]([OH:14])=[O:13])[N:1]=1
Reactant: CC(=O)C(C)C
Reactant: NNc1cc(C(=O)O)cc(C(=O)O)c1
Solvent: CC(=O)O
Product: CC1=Nc2cc(C(=O)O)cc(C(=O)O)c2C1(C)C
Temperature: 25 °C
Yield: 95.4 %

Procedure:
A solution of 5-hydrazinylbenzene-1.3-dicarboxylic acid (30.0 g, 129 mmol), isopropylmethylketone (22.0 mL, 205 mmol) in acetic acid (300 mL) and was heated under reflux in an oil bath for 18 h. After cooling to ambient temperature the solvent was evaporated off under reduced pressure to a small volume of ˜100 mL. To the crude mixture was added iPrOH (200 mL) and the solid was collected with a filter funnel, washed with EtOAc (3×200 mL) and ethyl ether (2×200 mL) and dried. Further drying of the solid in an oven at 50° C. under high vacuum for 18 h provided 30.44 g (95.5%) of the product.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[OH:13].[H-].[Na+].[Cl:16][C:17]1[CH:22]=[C:21]([N+]([O-])=O)[CH:20]=[CH:19][N:18]=1>>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[O:13][C:21]1[CH:20]=[CH:19][N:18]=[C:17]([Cl:16])[CH:22]=1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Reactant: CCOC(=O)c1ccc(Cl)c(O)c1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1ccc(Cl)c(Oc2ccnc(Cl)c2)c1
Yield: 53 %

Procedure:
Following the method of Example 3, Step A, ethyl 4-chloro-3-hydroxybenzoate (5.75 g, 28.7 mmol), sodium hydride (0.724 g, 28.7 mmol), DM (30 mL), and 2-chloro-4-nitropyridine (4.54 g, 28.7 mmol) were combined to give the desired product (4.75 g, 47.8% yield) as a yellow oil.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[C:14]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([CH2:30][S:31][CH2:32][CH3:33])[CH:24]=2)=[N:15][N:16]([CH3:22])[C:17]=1[O:18][CH:19]([F:21])[F:20]>ClCCl>[Cl:12][C:13]1[C:14]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([CH2:30][S:31]([CH2:32][CH3:33])=[O:9])[CH:24]=2)=[N:15][N:16]([CH3:22])[C:17]=1[O:18][CH:19]([F:21])[F:20]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCSCc1cc(-c2nn(C)c(OC(F)F)c2Cl)ccc1Cl
Solvent: ClCCl
Product: CCS(=O)Cc1cc(-c2nn(C)c(OC(F)F)c2Cl)ccc1Cl
Reaction time: 0.5 h

Procedure:
1.4 g (4 mmol) of m-chloroperbenzoic acid were added a little at a time at 0° C. to a solution of 1.5 g (4 mmol) of 4-chloro-3-[4-chloro-3-(ethylthiomethyl)phenyl]-5-difluoromethoxy-1-methyl-1H-pyrazole in 40 ml of dichloromethane. The mixture was stirred at 0° for 30 minutes was subsequently stirred at room temperature for 4 hours and then the solids were removed by filtration. The filtrate was concentrated, and the crude product thus obtained was purified by chromatography on silica gel (eluent: hexane/ethyl acetate=1:1). Yield: 0.2 g.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][CH:13]=[C:14]([CH2:16][CH3:17])[N:15]=2)=[CH:7][C:6]=1[CH2:18][CH2:19][CH3:20].[CH2:21]([O:23][C:24](=[O:36])[CH2:25][C@H:26]1[C:34]2[C:29](=[CH:30][C:31]([OH:35])=[CH:32][CH:33]=2)[CH2:28][CH2:27]1)[CH3:22].O.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH2:21]([O:23][C:24](=[O:36])[CH2:25][C@H:26]1[C:34]2[C:29](=[CH:30][C:31]([O:35][CH2:2][CH2:3][O:4][C:5]3[CH:10]=[CH:9][C:8]([C:11]4[S:12][CH:13]=[C:14]([CH2:16][CH3:17])[N:15]=4)=[CH:7][C:6]=3[CH2:18][CH2:19][CH3:20])=[CH:32][CH:33]=2)[CH2:28][CH2:27]1)[CH3:22]
Reactant: CCOC(=O)C[C@@H]1CCc2cc(O)ccc21
Reactant: CCCc1cc(-c2nc(CC)cs2)ccc1OCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1cc(-c2nc(CC)cs2)ccc1OCCOc1ccc2c(c1)CC[C@H]2CC(=O)OCC
Temperature: 25 °C
Reaction time: 24 h
Yield: 44.6 %

Procedure:
To a mixture of 2-[4-(2-bromoethoxy)-3-propylphenyl]-4-ethyl-1,3-thiazole (105 mg 0.30 mmol) (Example 34) and ethyl[(1S)-5-hydroxy-2,3-dihydro-1H-inden-1-yl]acetate (65 mg, 0.30 mmol) (Example 6) in DMF (4 mL, containing 1% v/v of water), was added Cs2CO3 (145 mg, 0.44 mmol), and the mixture was stirred for 24 h at rt. The reaction mixture was concentrated under reduced pressure, and the residue was suspended in EtOAc and filtered. The filtrate was concentrated and purified by silica gel chromatography (gradient: 100% hexane to 1:9 (v/v) EtOAc/hexane) to give 66 mg (41%) of the title compound as an oil. 1H NMR (400 MHz, CDCl3): δ 7.72-7.58 (m, 3H), 6.98 (d, 1H), 6.86-6.60 (m, 3H), 4.33-4.28 (br, 2H), 4.28-4.20 (br, 1H), 4.10 (q, 2H), 3.52-3.40 (m, 1H), 2.84 (m, 4H), 2.64 (dd, 1H), 2.58-2.50 (m, 3H), 2.40-2.24 (m, 2H), 1.72-1.50 (m, 3H), 1.26 (t, 3H), 1.20 (t, 3H), 0.84 (t, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1)#[N:2].O[N:15]1[C:19](=[O:20])[CH2:18][CH2:17][C:16]1=[O:21].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:1]([C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([O:11][N:15]2[C:19](=[O:20])[CH2:18][CH2:17][C:16]2=[O:21])=[O:10])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C=CC(=O)O)cc1
Reactant: O=C1CCC(=O)N1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: N#Cc1ccc(C=CC(=O)ON2C(=O)CCC2=O)cc1
Yield: 79.5 %

Procedure:
The same procedures as in Example 117 were carried out from 4-cyanocinnamic acid (5.0 g), N-hydroxysuccinic acid imide (5.0 g), WSC.HCl (8.3 g), and methylene chloride (150 mL), to give the captioned compound (6.2 g, 79%) as crystals.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([NH:9][CH2:10][CH3:11])[CH3:8].[Br:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Br)=[CH:15][CH:14]=1.Cl>O.C1COCC1>[Br:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][N:9]([CH2:10][CH3:11])[CH2:7][CH3:8])=[CH:15][CH:14]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: CCNCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCN(CC)Cc1ccc(Br)cc1
Yield: 74 %

Procedure:
Into a 500 ml round-bottomed flask were added 150 ml THF, 5 ml water, 2.2 g potassium carbonate, 6 ml diethyl amine, and 5 g p-bromobenzyl bromide. The resultant mixture was refluxed for 12 h. The mixture was then cooled to room temperature, into which 6 ml concentrated HCl was added, followed by the addition of 150 ml water. The mixture was extracted with 100 ml diethyl ether for three times. The diethyl ether solution was dried with anhydrous magnesium sulfate over night and then the magnesium sulfate was removed by filtration. Diethyl ether was evaporated and the raw product was purified by a silica gel column using hexane/chloroform mixture (1:1 by volume) as the eluent. (p-bromobenzyl)diethyl amine (BBDA) was obtained in 74% yield (3.6 g).
Reaction SMILES: [CH3:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].CO[CH:20](OC)[N:21]([CH3:23])[CH3:22]>C1(C)C=CC=CC=1>[CH3:20][N:21]([CH3:23])/[CH:22]=[CH:1]/[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(C)c([N+](=O)[O-])c1
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Product: COC(=O)c1cc([N+](=O)[O-])c(/C=C/N(C)C)c([N+](=O)[O-])c1
Temperature: 110 °C
Yield: 99.5 %

Procedure:
To a mixture of methyl 4-methyl-3,5-dinitrobenzoate (5.6 g) in toluene (20 mL) was added dimethylformamide dimethyl acetal (4.17 g) and 5-sulfo salycylic acid hydrate (0.1 g). The mixture was heated to 110° C. for 19 h, removed from heat and cooled to room temperature. The solvents were removed under reduced pressure at which time hexanes was added to the residue and the residue was filtered to give 6.85 g of the title compound: 1H NMR (CDCl3) δ 2.97, 3.96, 5.54, 6.74, 8.33.
Reaction SMILES: [NH2:1][C@@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5]([OH:7])=[O:6].[OH-].[Na+].[C:13](Cl)(=[O:20])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>CC(C)=O>[C:13]([NH:1][C@@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5]([OH:7])=[O:6])(=[O:20])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: N[C@H](CCC(=O)O)C(=O)O
Reactant: CCCCCCC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CCCCCCC(=O)N[C@H](CCC(=O)O)C(=O)O
Temperature: 10 °C
Yield: 83 %

Procedure:
A solution of 75.0 g (510 mmol) of D-glutamic acid in one liter of aqueous acetone (50:50) was adjusted to pH 9.0 with 2N sodium hydroxide. The resulting solution was cooled to 10° C. and treated over 45 minutes with 114.2 g (770 mmol) of heptanoyl chloride, maintaining the pH at 9.0 with 2N sodium hydroxide. The reaction was allowed to warm to room temperature for three hours. The acetone was removed under vacuum, and the resulting aqueous solution was acidified with dilute hydrochloric acid and extracted three times with 700 ml portions of ethyl acetate. The extracts were combined, dried over magnesium sulfate, filtered and concentrated. The resulting oil was triturated with hexane to give 109.8 g (83%) of desired product: mp 92°-96° C. IR (Nujol) 3300, 2700-3250, 1720, 1625 cm-1 ; NMR (D6 -DMSO) delta 4.20 (m, 1H), 2.28 (t, 2H), 2.20 (t, 2 H), 1.85-2.05 (m, 1H), 1.65-1.85 (m, 1H), 1.40-1.60 (m, 2H), 1.15-1.30 (m, 6H), 0.75 (t, 3H); [alpha]D =+9.6 (C=1.0, MeOH).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:25]([OH:27])=[O:26])[CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[F:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1>>[F:28][C:29]1[CH:34]=[CH:33][C:32]([S:35]([NH:24][CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]([C:25]([OH:27])=[O:26])[NH:18][C:16]([O:15][CH2:14][CH:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)=[O:17])(=[O:37])=[O:36])=[CH:31][CH:30]=1
Reactant: NCCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Product: O=C(N[C@@H](CCCCNS(=O)(=O)c1ccc(F)cc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Yield: 51 %

Procedure:
Nα-(9-fluorenylmethoxycarbonyl)-L-lysine was reacted with 4-fluorobenzenesulfonyl chloride under the conditions used in example 2 giving 51% of the title compound.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]([C:9]2[C:13]3[N:14]=[CH:15][N:16]=[C:17]([C:18]4[C:26]5[O:25][CH2:24][O:23][C:22]=5[CH:21]=[CH:20][C:19]=4[O:27][CH2:28][CH2:29][CH3:30])[C:12]=3[NH:11][CH:10]=2)=[O:8])[CH2:2]1.Cl[C:32]([O:34][CH2:35][CH3:36])=[O:33]>>[CH2:35]([O:34][C:32]([N:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]([C:9]2[C:13]3[N:14]=[CH:15][N:16]=[C:17]([C:18]4[C:26]5[O:25][CH2:24][O:23][C:22]=5[CH:21]=[CH:20][C:19]=4[O:27][CH2:28][CH2:29][CH3:30])[C:12]=3[NH:11][CH:10]=2)=[O:8])[CH2:2]1)=[O:33])[CH3:36]
Reactant: CCCOc1ccc2c(c1-c1ncnc3c(C(=O)N[C@@H]4CCNC4)c[nH]c13)OCO2
Reactant: CCOC(=O)Cl
Product: CCCOc1ccc2c(c1-c1ncnc3c(C(=O)N[C@@H]4CCN(C(=O)OCC)C4)c[nH]c13)OCO2

Procedure:
Starting from 4-(5-propoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (R)-pyrrolidin-3-ylamide (example A178) and ethyl chloroformate the title compound was obtained as colorless solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH3:12])=[O:10].Cl[Si:14]([CH3:17])([CH3:16])[CH3:15]>C(Cl)Cl.N1C=CC=CC=1>[CH3:15][Si:14]([CH3:17])([CH3:16])[O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH3:12])=[O:10]
Reactant: C[Si](C)(C)Cl
Reactant: COC(=O)Cc1ccccc1O
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)Cc1ccccc1O[Si](C)(C)C
Reaction time: 18 h

Procedure:
To a solution of methyl (2-hydroxyphenyl)acetate (1.5 g) in CH2Cl2 (10 mL) and pyridine (10 mL) was added slowly chlorotrimethylsilane (1.26 mL). The mixture was stirred for 18 hours, then most of the solvent was evaporated under reduced pressure and the residue was chromatographed on silica gel using 15% of EtOAc in hexane to afford 1.3 g of methyl (2-trimethylsilyloxyphenyl)acetate.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][NH:8][C:9]2[CH:18]=[CH:17][C:16]3[C:15]([NH2:19])=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=2)=[CH:4][CH:3]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH:26]=O>>[CH3:1][C:2]1[O:6][C:5]([CH2:7][NH:8][C:9]2[CH:18]=[CH:17][C:16]3[C:15]([NH:19][CH2:26][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=4)=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccccn1
Reactant: Cc1ccc(CNc2ccc3c(N)cccc3n2)o1
Product: Cc1ccc(CNc2ccc3c(NCc4ccccn4)cccc3n2)o1

Procedure:
The title compound, MS: m/e=345.3 (M+H+), was prepared from N2-(5-methyl-furan-2-ylmethyl)-quinoline-2,5-diamine and 2-pyridinecarboxaldehyde as described in example 21 step C.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][C:27]1[CH:48]=[CH:47][C:30]([CH2:31][N:32]2[C:41]3[C:36](=[C:37]([CH2:44][CH3:45])[N:38]=[C:39]([CH2:42][CH3:43])[CH:40]=3)[CH:35]=[CH:34][C:33]2=[O:46])=[CH:29][C:28]=1[CH2:49][CH2:50][CH3:51])(C(C)(C)C)(C)C>O1CCCC1>[CH2:44]([C:37]1[N:38]=[C:39]([CH2:42][CH3:43])[CH:40]=[C:41]2[C:36]=1[CH:35]=[CH:34][C:33](=[O:46])[N:32]2[CH2:31][C:30]1[CH:47]=[CH:48][C:27]([OH:26])=[C:28]([CH2:49][CH2:50][CH3:51])[CH:29]=1)[CH3:45]
Reactant: CCCc1cc(Cn2c(=O)ccc3c(CC)nc(CC)cc32)ccc1O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCCc1cc(Cn2c(=O)ccc3c(CC)nc(CC)cc32)ccc1O
Reaction time: 2 h
Yield: 79.6 %

Procedure:
1.0M Tetrabutylammonium fluoride in tetrahydrofuran (2 ml) was added to a stirred solution of compound E (0.9 g) in tetrahydrofuran (8 ml) under an atmosphere of argon. The solution was left to stand for 2 hours and then volatile material was removed by evaporation. The residue was purified by flash chromatography, eluting with ethyl acetate, to give 5,7-diethyl-1-(4-hydroxy-3-propylbenzyl)-1,6-naphthyridin-2(1H)-one (F) (0.54 g) as a foam; NMR: 0.9(t, 3H), 1.2(t, 3H), 1.3(t, 3H), 1.55-1.65(m, 2H), 2.55(t, 2H), 2.8(q, 2H), 3.1(q, 2H), 5.4(s, 2H), 5.5(br s, 1H), 6.65(d, 1H), 6.75(d, 1H), 6.9(d, 1H), 6.95(s, 1H), 7.05(s, 1H), 7.95(d, 1H).
Reaction SMILES: CS[C:3]1[N:4]=[C:5]([CH2:12][C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[NH:6][C:7](=[O:11])[C:8]=1[C:9]#[N:10].[C:18]([CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)([CH3:21])([CH3:20])[CH3:19]>>[C:18]([CH:22]1[CH2:27][CH2:26][N:25]([C:3]2[N:4]=[C:5]([CH2:12][C:13]3[CH:17]=[CH:16][S:15][CH:14]=3)[NH:6][C:7](=[O:11])[C:8]=2[C:9]#[N:10])[CH2:24][CH2:23]1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)C1CCNCC1
Reactant: CSc1nc(Cc2ccsc2)[nH]c(=O)c1C#N
Product: CC(C)(C)C1CCN(c2nc(Cc3ccsc3)[nH]c(=O)c2C#N)CC1

Procedure:
In analogy to the preparation of Example 1, 100 mg (0.38 mmol) of 4-(methylsulphanyl)-6-oxo-2-(3-thienylmethyl)-1,6-dihydropyrimidine-5-carbonitrile are reacted with 536 mg (3.80 mmol) of 4-tert-butylpiperidine to give 57 mg (42% of theory) of the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][C:9]([O:11][CH2:12][C:13]1([CH2:18][O:19][C:20]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[O:21])[CH2:17][CH2:16][CH2:15][O:14]1)=[O:10].C(N(CC)CC)C.[C:48](OC(=O)C)(=[O:50])[CH3:49]>C(Cl)(Cl)Cl.CN(C)C1C=CN=CC=1>[C:48]([N:8]([CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[C:9]([O:11][CH2:12][C:13]1([CH2:18][O:19][C:20]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[O:21])[CH2:17][CH2:16][CH2:15][O:14]1)=[O:10])(=[O:50])[CH3:49]
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC1(COC(=O)NCc2ccccn2)CCCO1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC1(COC(=O)N(Cc2ccccn2)C(C)=O)CCCO1

Procedure:
To 3.2 g (5.7 mmol) of the compound prepared in (b) above dissolved in 25 ml of chloroform was added, with stirring and under a nitrogen atmosphere, 18.15 g (180 mmol) of triethylamine, 11.63 g (114 mmol) of acetic anhydride and 0.035 g (0.29 mmol) of 4-dimethylaminopyridine. The resultant mixture was then heated to reflux and maintained at the reflux temperature for 72 hours. The volatiles were then removed under high vacuum and the resultant residue was dissolved in methylene chloride and washed rapidly with a saturated aqueous sodium bicarbonate solution. The organic layer was then dried over sodium sulfate, filtered and concentrated. The resultant residue was then chromatographed on silica gel employing a mixture of petroleum ether and ethyl acetate in a ratio of 1:1 by volume initially, with the product being eluted when the eluent was pure ethyl acetate. The resultant solution was then concentrated to obtain a semi-solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH:9]([C:14]2[C:22]3[C:17](=[C:18]([CH2:23][S:24][CH3:25])[CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[CH2:10][CH2:11][C:12]#[N:13])=[C:4]([F:26])[CH:3]=1.ClCCl.ClC1C=CC=C(C(OO)=[O:38])C=1>CO>[Cl:1][C:2]1[CH:3]=[C:4]([F:26])[C:5]([CH:9]([C:14]2[C:22]3[C:17](=[C:18]([CH2:23][S:24]([CH3:25])=[O:38])[CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[CH2:10][CH2:11][C:12]#[N:13])=[C:6]([F:8])[CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSCc1cccc2c(C(CCC#N)c3c(F)cc(Cl)cc3F)c[nH]c12
Solvent: CO
Solvent: ClCCl
Product: CS(=O)Cc1cccc2c(C(CCC#N)c3c(F)cc(Cl)cc3F)c[nH]c12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
231 mg (0.59 mmol) of the compound from Example 153 were introduced into 40 ml of dichloromethane at 0° C., 198 mg (0.81 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was stirred at 0° C. for 2 h. 2 ml of methanol were added, and the solution was concentrated. The residue was taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, and the solvents were removed in a rotary evaporator. The crude product was purified by preparative HPLC (mobile phase: acetonitrile/water gradient) to result in 171 mg (71% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=O>FC(F)(F)C(OC(=O)C(F)(F)F)=O>[Br:1][C:2]1[CH:18]=[CH:17][C:16]2[C:9](=[O:11])[C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH2:6][O:5][C:4]=2[CH:3]=1
Reactant: O=C(O)c1ccccc1COc1cccc(Br)c1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: O=C1c2ccccc2COc2cc(Br)ccc21
Temperature: 0 °C
Yield: 44 %

Procedure:
A suspension of 2-(3-bromophenoxymethyl)benzoic acid (35 g, 0.11 mole) in 100 mL of trifluoracetic anhydride containing 20 drops of boron trifluoride-ether complex was refluxed for four hours. The mixture was poured into ice water and then extracted with diethyl ether. Concentration of ether solution under reduced pressure and chromatography of the residue on a silica gel column (Waters Associates, Prep 500) with hexane/methylene chloride (70:30) gave the pure product (14 g) , m.p. 110°-112° C. pmr (CDCL3) δ: 8.10 (d, J=9.1 Hz, 1H, H1), 7.90 (dd, J=l.4, 7.6 H, 1H, H10) 7.57 (dt, J=1.4, 7.4, 7.4 Hz, 1H, H8), 7.48 (dt, J=1.4, 7.6, 7.6 Hz, 1H, H9), 7.36 (dd, J=1.3, 7.3 Hz, H, H7), 7.27 (d, J=1.8 H, 1H, H4), 7.24 (dd, J=1.8, 9.1 Hz, 1H, H2), 5.18 (s, 2H, ARCH2O).
Reaction SMILES: [C@@H:1]12[CH2:8][C:7](=[O:9])[CH2:6][C@@H:5]1[CH2:4][C:3](=[O:10])[CH2:2]2.[N-:11]=[N+]=[N-].[Na+].[OH-].[Na+]>Cl>[CH2:4]1[C@H:5]2[CH2:6][C:7](=[O:9])[CH2:8][C@H:1]2[CH2:2][C:3](=[O:10])[NH:11]1
Reactant: O=C1C[C@H]2CC(=O)C[C@H]2C1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C1C[C@@H]2CNC(=O)C[C@@H]2C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 150.7 %

Procedure:
(cis)-Bicyclo[3.3.0]octane-3,7-dione 14c (1.80 g, 13 mmol) was dissolved in 25 mL of concentrated hydrochloric acid in an ice-water bath, added with sodium azide (1.10 g, 16.90 mmol) in batches, then heated to room temperature and stirred for 12 hours. The reaction solution was added dropwise with 20% sodium hydroxide solution to adjust pH to 10 to 11, extracted with dichloromethane (50 mL×3). The combined organic phase was washed with saturated sodium chloride solution (50 mL×3), then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to obtain the title compound (cis)-2,4,4a,5,7,7a-hexahydro-1H-cyclopenta[c]pyridine-3,6-dione 14d (3 g, yield: 100.0%) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:16]2[CH:17]=[C:18]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[N:19]3[C:24]=2[C:23]([NH2:25])=[N:22][CH:21]=[N:20]3)[CH:12]=[C:13]([F:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:33][C:34]([N:36]([CH3:38])[CH3:37])=[O:35]>>[NH2:25][C:23]1[C:24]2=[C:16]([C:11]3[CH:12]=[C:13]([F:15])[CH:14]=[C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:10]=3)[CH:17]=[C:18]([CH:26]3[CH2:31][CH2:30][N:29]([CH2:33][C:34]([N:36]([CH3:38])[CH3:37])=[O:35])[CH2:28][CH2:27]3)[N:19]2[N:20]=[CH:21][N:22]=1
Reactant: Nc1ncnn2c(C3CCNCC3)cc(-c3cc(F)cc(OCc4ccccc4)c3)c12
Reactant: CN(C)C(=O)CCl
Product: CN(C)C(=O)CN1CCC(c2cc(-c3cc(F)cc(OCc4ccccc4)c3)c3c(N)ncnn23)CC1
Yield: 17 %

Procedure:
In a manner similar to the procedure described for the preparation of Example 355 and using 5-[3-(benzyloxy)-5-fluorophenyl]-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine and 2-chloro-N,N-dimethylacetamide as starting material, 20 mg (17%) of the desired product was isolated. 1H NMR (400 MHz, CD2Cl2) δ 7.89 (s, 1H), 7.47-7.36 (m, 5H), 6.89 (s, 1H), 6.82 (d, 1H), 6.74 (d, 1H), 6.52 (s, 1H), 5.56 (s, 2H), 5.13 (s, 2H), 3.25-3.20 (m, 1H), 3.18 (s, 2H), 3.10 (s, 3H), 3.02-2.98 (m, 2H), 2.92 (s, 3H), 2.26 (t, 2H), 2.11-2.08 (m, 2H), 1.82-1.78 (m, 2H); LC-MS m/z [M+H]+ 503.9, RT 2.77 min.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.[CH3:22]/[C:23](/[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:24]\[CH2:25]O>C(#N)C>[Br:20][CH2:25]/[CH:24]=[C:23](\[CH3:22])/[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: CCCCCCCCC/C(C)=C/CO
Reactant: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CCCCCCCCC/C(C)=C/CBr
Temperature: 0 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
An acetonitrile solution (100 ml) of triphenylphosphine (18.6 g, 70.9 mmols) was stirred at 0° C. Bromine (11.4 g, 3.7 ml, 71.3 mmols) was slowly blended into the solution. To the mixture, an acetonitrile (30 ml) solution of (E)-3-methyl-2-dodecen-1-ol (3′) was added dropwise, followed by stirring for 2 hours at 0° C. The solvent was removed under vacuum, and the residue was dissolved in dichloromethane. The solution was washed with saturated sodium bicarbonate and a saturated aqueous solution of sodium chloride, then dried over sodium sulfate, and concentrated. Pentane was added to the residue, and a solid formed was removed by filtration. The filtrate was concentrated in a vacuum to obtain 17.9 g (97%) of (E)-1-bromo-3-methyl-2-dodecene (4′).