Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]([O:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[C:3](=[O:11])[C:4]([CH2:9][CH3:10])([CH3:8])[CH2:5][CH2:6]Cl.[NH:20]1[CH:24]=[CH:23][N:22]=[CH:21]1.C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:2]([N:20]2[CH:24]=[CH:23][N:22]=[CH:21]2)=[C:3]2[C:4]([CH2:9][CH3:10])([CH3:8])[CH2:5][CH2:6][O:11]2)=[CH:14][CH:15]=1
Reactant: CCC(C)(CCCl)C(=O)C(Br)Oc1ccc(Cl)cc1
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCC1(C)CCOC1=C(Oc1ccc(Cl)cc1)n1ccnc1
Yield: 14 %

Procedure:
69.9 g (0.19 mole) of 1-bromo-1-(4-chlorophenoxy)-5-chloro-3-ethyl-3-methyl-2-pentanone, 26.2 g (0.38 mole) of imidazole and 52.4 g (0.38 mole) of potassium carbonate in 500 ml of toluene are heated at 90° C. for 10 hours. The reaction mixture is then allowed to cool and is poured onto 500 ml of water. The organic phase is separated off, washed with water, dried over sodium sulphate and concentrated. The residue is purified by column chromatography (ethyl acetate/cyclohexane=3:1). 8.5 g (14% of theory) of (4-chlorophenoxy)-(imidazol-1-yl)-(3-ethyl-3-methyltetrahydrofuran-2-ylidene)-methane of refractive index nD20 1.5552 are obtained.
Reaction SMILES: [CH2:1]([C:13]1([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[OH:36])[CH2:26][O:25][CH2:24][CH2:23][O:22][CH2:21][C:20]([CH3:28])([CH3:27])[CH2:19][O:18][CH2:17][CH2:16][O:15][CH2:14]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].F[P-](F)(F)(F)(F)F.[CH3:44][S:45]([C:48]1[CH:53]=[C:52]([N+:54]([O-:56])=[O:55])[CH:51]=[CH:50][C:49]=1[N+:57]#[N:58])(=[O:47])=[O:46]>C(O)(=O)C.O.O1CCCC1>[CH2:1]([C:13]1([CH2:29][C:30]2[CH:35]=[C:34]([N:58]=[N:57][C:49]3[CH:50]=[CH:51][C:52]([N+:54]([O-:56])=[O:55])=[CH:53][C:48]=3[S:45]([CH3:44])(=[O:47])=[O:46])[CH:33]=[CH:32][C:31]=2[OH:36])[CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][C:20]([CH3:27])([CH3:28])[CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CS(=O)(=O)c1cc([N+](=O)[O-])ccc1[N+]#N
Reactant: CCCCCCCCCCCCC1(Cc2ccccc2O)COCCOCC(C)(C)COCCOC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCCCCCC1(Cc2cc(N=Nc3ccc([N+](=O)[O-])cc3S(C)(=O)=O)ccc2O)COCCOCC(C)(C)COCCOC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 4.9 %

Procedure:
To a solution of 3.1 g (6.1 mmol) of Compound 15 in 50 cc acetic acid at 5° C. was added a solution of 3.0 g (8.0 mmol) of 2-methylsulfonyl-4-nitrophenyldiazonium hexafluorophosphate in 25 cc water and 75 cc tetrahydrofuran. The suspension was stirred at room temperature for 16 hours. The product was extracted into ethyl acetate and isolated by silica gel chromatography yielding 0.22 g (4.7%) of Compound 16. The 1H NMR spectrum is consistent with the assigned structure.
Reaction SMILES: C[N:2]([CH3:17])/[CH:3]=[CH:4]/[C:5]([C:7]1[CH:8]=[C:9]([NH:13][C:14](=[O:16])[CH3:15])[CH:10]=[CH:11][CH:12]=1)=O.[NH2:18][C:19]1[NH:23][N:22]=[C:21]([C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:26][CH:25]=2)[C:20]=1C#N>CC(O)=O>[C:19]([C:20]1[C:21]([C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:26][CH:25]=2)=[N:22][N:23]2[C:5]([C:7]3[CH:8]=[C:9]([NH:13][C:14](=[O:16])[CH3:15])[CH:10]=[CH:11][CH:12]=3)=[CH:4][CH:3]=[N:2][C:17]=12)#[N:18]
Reactant: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)n[nH]c1N
Reactant: CC(=O)Nc1cccc(C(=O)/C=C/N(C)C)c1
Solvent: CC(=O)O
Product: CC(=O)Nc1cccc(-c2ccnc3c(C#N)c(-c4ccc(Oc5ccccc5)cc4)nn23)c1
Temperature: 118 °C
Reaction time: 4 h
Yield: 89.8 %

Procedure:
To a solution of (E)-N-(3-(3-(dimethylamino)acryloyl)phenyl)acetamide (46 mg, 0.2 mmol) in HOAc (5 mL) was added 5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile (55 mg, 0.2 mmol). The mixture was stirred at 118° C. for 4 hr. Then the reaction mixture was concentrated to a residue and partitioned between ethyl acetate (100 mL) and brine (100 mL). Organic layer was separated, washed with brine (2×100 mL), dried over sodium sulfate and concentrated to afford 80 mg (90%) of N-(3-(3-cyano-2-(4-phenoxyphenyl)pyrazolo[1,5-a]pyrimidin-7-yl)phenyl)acetamide as a colorless oil. MS (ESI) m/e [M+1]+ 446.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C([O-])([O-])=O.[K+].[K+].[Cl:20][C:21]1[C:25](Cl)=[N:24][S:23][N:22]=1>CC#N.CCOC(C)=O.O>[Cl:20][C:21]1[C:25]([N:11]2[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:13][CH2:12]2)=[N:24][S:23][N:22]=1
Reactant: Clc1nsnc1Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2nsnc2Cl)CC1
Temperature: 100 °C
Reaction time: 96 h

Procedure:
A mixture of N-Boc-piperazine (2.97 g, 15.9 mmol), K2CO3 (2.20 g, 15.9 mmol) and 3,4-dichloro-1,2,5-thiadiazole (1.5 mL, 15.9 mmol) in CH3CN (30 mL) was stirred at 100° C. for 19 h and at room temperature for 4 days. The reaction mixture was then diluted with EtOAc and water. The organic phase was dried (K2CO3) and the solvent was removed under reduced pressure. The residue was purified by chromatography on two successive silica gel columns eluting with hexane/EtOAc (1:1) and (7:3), respectively. This gave 1.54 g (31%) of the title product as a yellow solid.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C)C=O.[Br:25]N1C(=O)CCC1=O.C1(C)C=CC=CC=1>O>[Br:25][C:4]1[CH:3]=[CH:2][C:1]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:6][CH:5]=1
Reactant: c1ccc(Nc2ccccc2-c2ccccc2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccc(Nc2ccccc2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.8 %

Procedure:
In a stream of nitrogen, a 100 mL three-necked flask was charged with 15.0 g (61.1 mmol) of N-phenyl-N-biphenylylamine. 100 mL of dimethylformamide and 10.8 g (61.1 mmol) of N-bromosuccinimide were added to the content, and the mixture was stirred at room temperature for 2 hours. To the thus-obtained reaction mixture, 10 mL of toluene and then 10 mL of pure water were added, and the reaction mixture was separated into an organic phase and an aqueous phase. The organic phase was washed with pure water and then with an aqueous saturated sodium chloride solution. The washed organic phase was dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The thus-obtained solid was recrystallized from toluene to give 13.4 g (41.4 mmol) of N-(4-bromophenyl)-N-biphenylylamine as a grey powder (yield: 67%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.C(=O)=O.O/[N:33]=[C:34](\[NH2:44])/[CH2:35][C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=1>CN(C=O)C.CCOC(C)=O>[CH3:43][O:42][C:39]1[CH:40]=[CH:41][C:36]([CH2:35][C:34]2[N:33]=[C:14]([CH:11]3[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]3)[O:16][N:44]=2)=[CH:37][CH:38]=1
Reactant: COc1ccc(C/C(N)=N/O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=C=O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(Cc2noc(C3CCN(C(=O)OC(C)(C)C)CC3)n2)cc1
Temperature: 70 °C
Reaction time: 6 h

Procedure:
1-(tert-Butoxycarbonyl)piperidine-4-carboxylic acid (2.29 g, 10.0 mmoles) in 10 mL DMF was treated with 1,1′-carbonyldiimidazole (1.62 g, 10 mmoles, 1 eq.) at ambient temperature for 30 min until CO2 evolution ceased. (1Z)-N′-hydroxy-2-(4-methoxyphenyl)ethanimidamide [J. Med. Chem., 36(11), 1529 (1993)] (10.0 mmoles, 1 eq.) was dissolved in 5 mL DMF and added to the reaction mixture. The reaction mixture was heated at 70° C. for 6 h then at 120° C. for an additional 6 h. The reaction mixture was diluted with EtOAc and washed successively with water, 1N citric acid, saturated aqueous NaHCO3, and brine. The organic phase was isolated, dried over MgSO4, filtered and concentrated to give the title compound as an amber oil. 1H NMR (300 MHz, CDCl3) δ 7.26 (d, 2H, J=8.5 Hz), 6.88 (d, 2H, J=8.5 Hz), 4.10 (m, 2H), 4.00 (s, 2H), 3.80 (s, 3H), 3.08 (m, 1H), 2.97-2.90 (m, 2H), 2.04 (m, 2H), 1.87-1.73 (m, 2H), 1.47 (s, 9H). ES-LCMS m/z 395.99 (M+Na).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26].C(N(CC)CC)C>ClCCl>[O:11]=[CH:12][CH2:13][CH2:14][CH2:15][N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26]
Reactant: O=C1c2ccccc2C(=O)N1CCCCO
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=CCCCN1C(=O)c2ccccc2C1=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 82.8 %

Procedure:
Oxalyl Chloride (4.01 ml; 46 mmol) in 90 ml dichloromethane was cooled at -78° C. in a dry ice-acetone bath. Dimethylsulfoxide (4.26 ml; 60 mmol) in 22 ml dichloromethane was then added dropwise and the mixture stirred at -78° C. for 30 minutes. N-(4-Hydroxybutyl)phthalimide (9.108 g; 41.5 mmol) in 45 ml dichloromethane was then added and the mixture stirred in the -78° C. bath for 45 minutes. The mixture was then warmed in a 0° C. ice bath and stirred for one hour. Triethylamine (23 g; 230 mmol) in 23 ml dichloromethane was then added and the stirred for an additional 30 minutes. The mixture was worked up by washing with water. The organic layer was separated, dried (MgSO4), filtered, concentrated and the residue purified by flash chromatography; 200 g silica gel column using 1:3 ethyl acetate:Hexane to provide N-(4-oxobutyl)phthalimide as a white solid (7.469 g; 82.8% yield). 1 H NMR (300 MHz, CDCl3): 2.023 (m, 2H); 2.546 (dt, 2H, J1 =7.324 Hz, J2 =1.098 Hz); 3.749 (t, 2H, J=6.958 Hz); 7.734 (m, 2H); 7.845 (m, 2H); 9.777 (t, 1H, J=1.099 Hz).
Reaction SMILES: Cl.Cl.[N:3]1([CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[C:17]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[N:18][C:19]4[C:24]([C:25]=3[C:26](O)=[O:27])=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:11][CH2:10]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[CH3:35][C@H:36]([NH2:41])[C:37]([CH3:40])([CH3:39])[CH3:38].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>C1COCC1.C(Cl)Cl>[CH3:35][C@H:36]([NH:41][C:26]([C:25]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=[C:17]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:16]=1[CH2:15][N:12]1[CH2:11][CH2:10][CH:9]([N:3]2[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:14][CH2:13]1)=[O:27])[C:37]([CH3:40])([CH3:39])[CH3:38]
Reactant: C[C@H](N)C(C)(C)C
Reactant: O=C(O)c1c(CN2CCC(N3CCCCC3)CC2)c(-c2ccccc2)nc2ccccc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: C[C@H](NC(=O)c1c(CN2CCC(N3CCCCC3)CC2)c(-c2ccccc2)nc2ccccc12)C(C)(C)C
Yield: 60.2 %

Procedure:
539 mg (0.94 mmol) of 3-[1,4′]bipiperidinyl-1′-ylmethyl-2-phenyl-quinoline-4-carboxylic acid dihydrochloride (compound of Description 6), 202 microliters (1.5 mmol) of (S)-1,2,2-trimethyl-propylamine (Lancaster), 570 mg (1.5 mmol) of HBTU, 610 microliters (4.4 mmol) of triethylamine were dissolved in 12 ml THF and 8.5 ml of CH2Cl2 and the mixture was refluxed for 18 h. The solvent was concentrated, the residue was dissolved in methylene chloride, washed with water, then with 0.5 N aqueous NaOH, again with water, and the organic phase was dried over MgSO4. After concentration of the solvent, the residue was purified by flash chromatography over 40 g of silicagel (eluent EtOAc/MeOH/NH4OH:90/10/0.1), affording 290 mg (yield 56%) of the title compound as a beige amorphous solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:36])[CH2:35][O:34][C:5]2([CH2:33][CH2:32][C:8]3([O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]4[CH:22]=[CH:21][C:20](B5OC(C)(C)C(C)(C)O5)=[CH:19][CH:18]=4)[CH3:16])[CH2:10][CH2:9]3)[CH2:7][CH2:6]2)[O:4][CH2:3]1.[CH3:37][N:38]([CH3:48])[C:39]([C:41]1[CH:46]=[CH:45][C:44](Br)=[CH:43][N:42]=1)=[O:40]>>[CH3:37][N:38]([CH3:48])[C:39]([C:41]1[CH:46]=[CH:45][C:44]([C:20]2[CH:21]=[CH:22][C:17]([C@@H:15]([N:11]3[CH2:10][CH2:9][C:8]4([CH2:7][CH2:6][C:5]5([O:34][CH2:35][C:2]([CH3:36])([CH3:1])[CH2:3][O:4]5)[CH2:33][CH2:32]4)[O:13][C:12]3=[O:14])[CH3:16])=[CH:18][CH:19]=2)=[CH:43][N:42]=1)=[O:40]
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CCC2(CCC3(CC2)OCC(C)(C)CO3)OC1=O
Reactant: CN(C)C(=O)c1ccc(Br)cn1
Product: C[C@@H](c1ccc(-c2ccc(C(=O)N(C)C)nc2)cc1)N1CCC2(CCC3(CC2)OCC(C)(C)CO3)OC1=O
Yield: 76 %

Procedure:
The title compound is prepared from 12,12-dimethyl-3-{(S)-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-ethyl}-1,10,14-trioxa-3-aza-dispiro[5.2.5.2]hexadecan-2-one and 5-bromo-pyridine-2-carboxylic acid dimethylamide following a procedure analogous to that described in Example 7. Yield: 76% of theory; LC (method 3): tR=3.48 min; Mass spectrum (ESI+): m/z=522 [M+H]+.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[NH:13]C=3)=[CH:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[NH:20]1C2C(=CC=CN=2)C=C1>>[O:1]1[C:5]2([CH2:10][CH2:9][C:8]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[NH:13][N:20]=3)=[CH:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: C1=C(c2c[nH]c3ccccc23)CCC2(C1)OCCO2
Reactant: c1cnc2[nH]ccc2c1
Product: C1=C(c2n[nH]c3ccccc23)CCC2(C1)OCCO2
Yield: 68 %

Procedure:
This compound was prepared in the manner described above for intermediate 1a by replacing indole with 7-azaindole (3.65 g, 31 mmol) in 68% yield (5.42 g) as a white solid: mp 162-165° C.; MS EI m/e 256 (M+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:29][O:30][C:31]([C@H:33]1[CH2:37][C:36](=[O:38])[N:35]([C:39]2[CH:44]=[CH:43][C:42](O)=[CH:41][CH:40]=2)[CH2:34]1)=[O:32].N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH3:29][O:30][C:31]([C@H:33]1[CH2:37][C:36](=[O:38])[N:35]([C:39]2[CH:44]=[CH:43][C:42]([O:6][CH2:5][C:4]3[CH:7]=[CH:8][CH:9]=[C:2]([F:1])[CH:3]=3)=[CH:41][CH:40]=2)[CH2:34]1)=[O:32]
Reactant: COC(=O)[C@H]1CC(=O)N(c2ccc(O)cc2)C1
Reactant: OCc1cccc(F)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@H]1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 68.1 %

Procedure:
A solution 14.23 g (110.6 mmol) of 3-fluoro-benzylalcohol and 27.19 g (108.8 mmol) of triphenylphosphine in 150 ml of tetrahydrofurane is added dropwise within 50 min under a nitrogen atmosphere at 0° C. to a solution of 23.65 g (100.5 mmol) of (S)-1-(4-hydroxy-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester and 21.62 g (100.5 mmol) of diisopropyl azodicarboxylate in 200 ml of tetrahydrofurane. The mixture is left to warm to RT and stirring is continued for 18 hours. For the working-up, the mixture is evaporated under reduced pressure. The solid residue is triturated in 400 ml of ether to leave a white solid mainly consisting of the product and triphenylphosphinoxide. After filtration, the solid material is triturated in 100 ml of cold methanol to yield 23.5 g (68% of theory) of (S)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid methyl ester as a white solid [MS: m/e=344 (M+H)+] together with traces of triphenylphosphine and diisopropyl hydrazodicarboxylate.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]3[CH:19]=[C:20]([O:23][C:24]4[CH:29]=[C:28](Cl)[N:27]=[CH:26][N:25]=4)[CH:21]=[CH:22][C:13]2=3)=[O:11])[CH:6]=[CH:7][CH:8]=1.[N-:33]=[N+:34]=[N-:35].[Na+]>CN(C=O)C.CCOC(C)=O.O>[F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]3[CH:19]=[C:20]([O:23][C:24]4[CH:29]=[C:28]([N:33]=[N+:34]=[N-:35])[N:27]=[CH:26][N:25]=4)[CH:21]=[CH:22][C:13]2=3)=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)N1CCCCc2cc(Oc3cc(Cl)ncn3)ccc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: [N-]=[N+]=Nc1cc(Oc2ccc3c(c2)CCCCN3C(=O)Nc2cccc(C(F)(F)F)c2)ncn1

Procedure:
A solution of 300 mg (0.65 mMol) of 7-(6-chloro-pyrimidin-4-yloxy)-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide and 84 mg (1.3 mMol) NaN3 in 3.8 ml DMF is stirred at 60° C. for 90 min. Then the solution is diluted with EtOAc and water, the aqueous layer separated off and extracted twice with EtOAc. The organic phases are washed with water and brine, dried (Na2SO4) and concentrated, yielding the title compound: MS: [M+1]+=470; HPLC: AtRet=16.9.
Reaction SMILES: S(=O)(=O)(O)O.[C:6]1(=[O:11])[O:10][CH2:9][CH2:8][CH2:7]1.[CH:12](OCC)([O:16][CH2:17][CH3:18])OCC.[CH2:22](O)C>>[CH2:12]([O:16][CH2:17][CH2:18][CH2:7][C:6]([O:10][CH2:9][CH3:8])=[O:11])[CH3:22]
Reactant: O=C1CCCO1
Reactant: CCOC(OCC)OCC
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOCCCC(=O)OCC
Temperature: 50 °C
Yield: 95 %

Procedure:
Sulfuric acid 0.25 mL (0.0045 mmol, 0.035 eq) was added to an ice cooled solution of γ-butyrolactone (28) (11.2 g, 0.13009 mmol, 1.0 eq), triethyl orthoformate (29) (41.1 mL, 0.2497 mmol., 1.92 eq) in 100 mL of ethanol. The mixture was heated at 50° C. for 12 h while monitoring the reaction by TLC. The reaction mixture was cooled to room temperature and most of the solvent was evaporated under reduced pressure. The concentrated reaction mixture was quenched with cold saturated NaHCO3 solution and extracted with ethyl acetate twice. The combined organic extracts was dried over anhydrous Na2SO4 and concentrated under vacuum to yielded 20 g (95%) of ethyl 4-ethoxybutanoate (30) as light yellow oil. 1HNMR (400 MHz, CDCl3): δ 1.16-1.28 (m, 6H); 1.87-1.91 (m, 2H); 2.39 (t, J=9.6 Hz; 2H); 3.42-3.50 (m, 2H); 3.57-3.64 (m, 2H); 4.13 (q, J=6 Hz, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[CH2:5][C:6]#[N:7])[CH3:2].[Na].[NH2:10][C:11]1[N:16]=[C:15]([C:17](=[O:20])[CH2:18]Br)[CH:14]=[CH:13][N:12]=1.C(N(C(C)C)CC)(C)C>CCO.C1COCC1>[CH2:1]([O:3][C:4](=[O:8])[CH:5]([C:6]#[N:7])[CH2:18][C:17]([C:15]1[CH:14]=[CH:13][N:12]=[C:11]([NH2:10])[N:16]=1)=[O:20])[CH3:2]
Reactant: Nc1nccc(C(=O)CBr)n1
Reactant: CCOC(=O)CC#N
Agent: [Na]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)C(C#N)CC(=O)c1ccnc(N)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.3 %

Procedure:
Ethylcyanoacetate (5.3 mL, 0.05 mol) was added to a suspension of sodium metal (1.15 g, 0.05 mol) in 150 mL of anhydrous EtOH at 0° C. After sodium dissolution the reaction mixture was concentrated and the resultant solid was added to a solution of 1-(2-amino-pyrimidin-4-yl)-2-bromo-ethanone (15 g, 0.05 mol) in 300 mL of anhydrous THF and diisopropylethylamine (8.8 mL, 0.05 mol). The reaction mixture was stirred overnight at rt, concentrated and the residue was suspended in water and extracted with DCM. The organic extracts were dried (Na2SO4) and concentrated. The crude was purified by flash chromatography (DCM/MeOH 95:5) to give 4.5 g (37%) of the title compound as an oil.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.CCCC.[C:14](=[O:16])=[O:15].Cl>C(OCC)C.O>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:14]([OH:16])=[O:15])=[CH:2]1
Reactant: O=C=O
Reactant: C1=Cc2ccccc2C1
Agent: Cl
Solvent: CCCC
Solvent: CCOCC
Solvent: O
Product: O=C(O)C1=CCc2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.4 %

Procedure:
To a stirred solution of indene (21.9 mL, 188 mmol) in 150 mL of dry ethyl ether was added 129 mL (200 mmol) of η-BuLi dropwise at room temperature over 30 minutes with the evolution of butane. The rust colored mixture was refluxed for 2 h, and then poured in a thin stream onto 40 g of Dry Ice. The mixture was shaken at room temperature for 2 h, after which time 1 L of H2O was cautiously added. The aqueous layer was acidified with 10% HCl and then extracted with ethyl ether. Recrystallization from benzene gave 20 g (80%) of indene-3-carboxylic acid as yellowish crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH3:23])=[N:11][C:12]([N:16]2[C:20]([CH3:21])=[CH:19][CH:18]=[C:17]2[CH3:22])=[N:13][C:14]=1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:25][CH2:26][CH2:27][CH3:28].[Li]CCCC>C1COCC1.CCCCC>[CH2:1]([O:8][C:9]1[C:14]([CH3:15])=[N:13][C:12]([N:16]2[C:20]([CH3:21])=[CH:19][CH:18]=[C:17]2[CH3:22])=[N:11][C:10]=1[CH2:23][CH2:25][CH2:26][CH2:27][CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc(-n2c(C)ccc2C)nc(C)c1OCc1ccccc1
Reactant: CCCCBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCC
Product: CCCCCc1nc(-n2c(C)ccc2C)nc(C)c1OCc1ccccc1
Temperature: 23 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution at −78° C. containing 1.00 g (3.25 mmol) of 5-(Benzyloxy)-2-(2,5-dimethyl-1H-pyrrol-1-yl)-4,6-dimethylpyrimidine and 233 μL (2.16 mmol) of 4-bromobutane in 30 mL of anhydrous THF were added 2.70 mL (4.32 mmol) of a 1.6 M solution of n-BuLi in pentane. The reaction mixture was stirred at 23° C. for 30 min. The reaction was quenched with saturated aqueous ammonium chloride and then poured into 70 mL of water. The mixture was then extracted with two 70-mL portions of diethyl ether. The combined organic layer was then washed with a 100-mL portion of brine, dried (MgSO4) and then concentrated under diminished pressure. The residue was purified by chromatography on a silica gel column (15×5 cm). Elution with 4:1 hexanes-diethyl ether afforded the expected product as a colorless oil: yield 533 mg (69%); silica gel TLC Rf 0.50 (4:1 hexanes-diethyl ether); 1H NMR (CDCl3) δ 0.90 (t, 3H, J=7.2 Hz), 1.34 (m, 2H), 1.77 (m, 2H), 2.33 (s, 6H), 2.49 (s, 3H), 2.79 (dd, 2H, J=7.6, 7.6 Hz), 4.91 (s, 62), 5.88 (s, 2H) and 7.40-7.44 m, 5H); 13C NMR (CDCl3) δ 13.95, 14.34, 19.29, 22.47, 27.41, 31.59, 31.73, 75.72, 107.94, 107.94, 128.01, 128.01, 128.22, 128.72, 129.30, 136.22, 147.38, 147.38, 152.60, 161.62, 161.62 and 165.08; mass spectrum (APCI), m/z 364.2394 (M+H)+ (C23H30N3O requires 364.2389).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:18])[C:10]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=O.[Br-].[CH2:20]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:21][CH3:22]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:18])[C:10]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[CH:20][CH2:21][CH3:22]
Reactant: CC(C(=O)c1cccnc1)c1ccc(Cl)cc1Cl
Reactant: CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: CCC=C(c1cccnc1)C(C)c1ccc(Cl)cc1Cl

Procedure:
starting from 2-(2,4-dichlorophenyl)-1-(3-pyridyl)-1-propanone and propyltriphenylphosphonium bromide there is obtained 3-(2,4-dichloro-β-methyl-α-propylidenephenethyl)-pyridine