Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4](OCC)(OCC)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[N:17]#[C:18][NH2:19].C(OC(=O)C)(=O)C>C(OCC)(=O)C>[CH2:2]([O:3][C:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[N:19][C:18]#[N:17])[CH3:1]
Reactant: N#CN
Reactant: CCOC(OCC)(OCC)c1ccccc1
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=NC#N)c1ccccc1
Yield: 93 %

Procedure:
Following the method of Huffmann and Schaefer (J. Org. Chem. 1963, 28, 1816), a stirred mixture of 50 ml (221 mmol) triethylorthobenzoate, 9.3 g (221 mmol) cyanamide and 42 ml (442 mmol) acetic anhydride was heated at 130-150° C. for 1.5 hours with concomitant removal of the ensuing ethyl acetate and acetic anhydride by distillation from the reaction flask. The reaction mixture was then concentrated in vacuo using a rotary evaporater. Kugelrohr distillation (120° C., 3 mbar) afforded 35.8 g (93%) N-cyano-benzenecarboximidic acid ethyl ester as a colourless oil. ES-MS m/e (%): 175 (M+H+, 100).
Reaction SMILES: [CH:1]1([N:4]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[C:5]([C:7]2[O:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][C:13]=3[F:20])[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.[F:27][C:28]([F:39])([F:38])[C:29]1([CH2:32]OS(C)(=O)=O)[CH2:31][CH2:30]1>>[CH:1]1([N:4]([CH:21]2[CH2:26][CH2:25][N:24]([CH2:32][C:29]3([C:28]([F:39])([F:38])[F:27])[CH2:31][CH2:30]3)[CH2:23][CH2:22]2)[C:5]([C:7]2[O:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][C:13]=3[F:20])[CH:8]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: CS(=O)(=O)OCC1(C(F)(F)F)CC1
Reactant: N#Cc1ccc(-c2cc(C(=O)N(C3CCNCC3)C3CC3)on2)c(F)c1
Product: N#Cc1ccc(-c2cc(C(=O)N(C3CC3)C3CCN(CC4(C(F)(F)F)CC4)CC3)on2)c(F)c1

Procedure:
The title compound is prepared from 3-(4-cyano-2-fluoro-phenyl)-isoxazole-5-carboxylic acid cyclopropyl-piperidin-4-yl-amide and methanesulfonic acid (1-trifluoromethyl-cyclopropyl)methyl ester following a procedure analogous to that described for Example 3. LC (method 4): tR=1.35 min; Mass spectrum (ESI+): m/z=477 [M+H]+.
Reaction SMILES: [OH-].[Na+].[CH:3]1[CH2:7][CH:6]=[CH:5][CH:4]=1.[CH3:8][CH:9](Br)[CH2:10][CH2:11][CH3:12]>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].O>[CH3:8][CH:9]([C:4]1[C:3]([CH:4]([CH2:3][CH2:7][CH3:6])[CH3:5])=[C:7]([CH:9]([CH2:10][CH2:11][CH3:12])[CH3:8])[CH2:6][CH:5]=1)[CH2:10][CH2:11][CH3:12]
Reactant: C1=CCC=C1
Reactant: CCCC(C)Br
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CCCC(C)C1=CCC(C(C)CCC)=C1C(C)CCC
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A double-walled reactor having a volume of 1 L, provided with baffles, condenser, top stirrer, thermometer and dropping funnel was charged with 900 g (11.25 mol) of clear 50% strength NaOH. Then 31 g of Aliquat 336 (77 mmol) and 26.8 g (0.41 mol) of freshly cracked cyclopentadiene were added. The reaction mixture was stirred turbulently for a few minutes. Then 155 g of 2-pentyl bromide (1.03 mol) were added over a period of 1 hour, cooling with water taking place at the same time. After 3 hours' stirring at room temperature the reaction mixture was warmed to 70° C., followed by a further 2 hours' stirring. Stirring was stopped and phase separation was awaited. The water layer was drawn off and 900 g (11.25 mol) of fresh 50% strength NaOH were added, followed by a further two hours' stirring at 70° C. GC was used to show that at that instant the mixture consisted of di- and tri(2-pentyl)cyclopentadiene (approximately 1:1). The products were distilled at 2 mbar, 79-81° C. and 0.5 mbar, 102° C., respectively. After distillation, 28 g of di- and 40 g of tri(2-pentyl)cyclopentadiene were obtained. Characterization took place with the aid of GC, GC-MS, 13C- and 1H-NMR.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:20][CH:19]=1)=[C:12]2[CH3:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[I:35][C:36]1[CH:43]=[CH:42][C:39]([CH2:40]Br)=[CH:38][CH:37]=1>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:40][C:39]1[CH:42]=[CH:43][C:36]([I:35])=[CH:37][CH:38]=1)[C:13]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:20][CH:19]=1)=[C:12]2[CH3:32])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCc1ccc(I)cc1
Reactant: Cc1c(-c2ccc(OCc3ccccc3)cc2)[nH]c2ccc(OCc3ccccc3)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(-c2ccc(OCc3ccccc3)cc2)n(Cc2ccc(I)cc2)c2ccc(OCc3ccccc3)cc12
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 31.3 %

Procedure:
A solution of 5-(benzyloxy)-2-(4-(benzyloxy)phenyl)-3-methyl-1H-indole (4.2 g, 10 mmol; see PCT/US98/21609 for synthesis) in DMF (40 mL) was cooled to 0° C. under nitrogen atmosphere. Sodium hydride (60% dispersion in mineral oil; 420 mg, 10.5 mmol) was added in one portion. The reaction mixture was stirred at 0° C. for 5 min, and then ice bath was removed and allowed to warm to room temperature. After 1 h, the reaction was cooled back to 0° C. and 4-iodobenzyl bromide (3.7 g, 12.5 mmol) was added slowly. After 5 minutes, the ice bath was removed and the reaction mixture was stirred at room temperature for 6 h. The reaction was diluted with water (200 mL), and ethyl acetate. The precipitate was sonicated, filtered off and dried to give 1.99 g of the desired product. The filtrate was extracted with ethyl acetate (50 mL), the organic layer was washed with water, washed with brine and dried (MgSO4), filtered, concentrated and purified by silica gel chromatography (20%-70% DCM in hexanes) to afford 2.62 g. The reaction resulted in total 4.6 g of 5-(benzyloxy)-2-(4-(benzyloxy)phenyl)-1-(4-iodobenzyl)-3-methyl-1H-indole as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 7.56 (d, 2H), 7.51-7.46 (m, 4H), 7.44-7.38 (m, 4H), 7.38-7.32 (m, 2H), 7.29 (d, 2H), 7.16 (d, 1H), 7.16-7.10 (m, 3H), 6.82 (dd, 1H), 6.62 (d, 2H), 5.20 (s, 2H), 5.14 (d, 4H), 2.17 (s, 3H).
Reaction SMILES: C([Li])CCC.[Br:6][C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([F:14])=[CH:9][C:8]=1I.CN(C)[CH:18]=[O:19].C(OC)(C)(C)C>O1CCCC1.O>[Br:6][C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([F:14])=[CH:9][C:8]=1[CH:18]=[O:19]
Reactant: Fc1cc(I)c(Br)cc1Cl
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1cc(F)c(Cl)cc1Br
Temperature: -78 °C

Procedure:
A solution of 1 mmol of n-butyllithium (1N in hexane) is added dropwise to a solution of 1 mmol of 1-bromo-5-chloro-4-fluoro-2-iodo-benzene in 20 ml of tetrahydrofuran cooled to −78° C. After the addition, 1.1 mmol of N,N-dimethylformamide is added and the mixture is allowed to warm to room temperature. 100 ml of tert-butylmethyl ether then 20 ml of water are added. The organic phase is separated, washed with 20 ml of brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue is purified by flash chromatography (SiO2 60 F) to afford the title compound which is identified based on the Rf value.
Reaction SMILES: Br[C:2]1[O:3][C:4]2[C:24]([O:25]C(=O)C)=[C:23]([O:29][CH3:30])[CH:22]=[CH:21][C:5]=2[C:6]=1[C:7](=[O:20])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=1.[NH2:31][CH2:32][C:33]([OH:35])=[O:34].C(=O)([O-])[O-].[K+].[K+]>CC#N.O>[OH:25][C:24]1[C:4]2[O:3][C:2]([NH:31][CH2:32][C:33]([OH:35])=[O:34])=[C:6]([C:7](=[O:20])[C:8]3[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=3)[C:5]=2[CH:21]=[CH:22][C:23]=1[O:29][CH3:30]
Reactant: NCC(=O)O
Reactant: COc1cc(C(=O)c2c(Br)oc3c(OC(C)=O)c(OC)ccc23)cc(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1cc(C(=O)c2c(NCC(=O)O)oc3c(O)c(OC)ccc23)cc(OC)c1OC
Reaction time: 0.33 h
Yield: 53.3 %

Procedure:
A mixture of 2-bromo-7-acetoxy-3-(3,4,5-trimethoxybenzoyl)-6-methoxy-benzofuran (50 mg, 0.10 mmol), glycine (18 mg, 0.29 mmol) and potassium carbonate (29 mg, 0.21 mmol) in a mixture of MeCN/water 80:20 (5 mL) was refluxed for six hours. Solvent was distilled and the residue was taken in water:dichloromethane 1:2 (30 mL) and stirred for 20 minutes. Aqueous layer was separated, washed with dichloromethane (20 mL) and acidified with 2 drops of concentrated HCl and was diluted with dichloromethane (50 mL) and was stirred for 30 minutes. The organic layer was separated and dried over magnesium sulfate and solvent was distilled to afford the title compound as yellow powder (23 mg, 51%); 1H NMR (300 MHz, Acetone d6) δ 9.09 (b, 1H, NH), 6.97 (s, 2H, benzoyl Hs), 6.74 (d, 1H, J=8.53 Hz), 6.45 (d, 1H, J=8.48 Hz), 4.48 (d, 2H, J=4.28 Hz), 3.82 (s, 6H, 2×OMe), 3.79 (s, 3H, OMe), 3.78 (s, 3H, OMe).
Reaction SMILES: [C:1]([O:20][CH2:21][C@H:22]([CH2:35][CH2:36][O:37][C:38](=[O:51])[C@H:39]([CH:48]([CH3:50])[CH3:49])[NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:23][N:24]1[CH:32]=[N:31][C:30]2[C:29](=O)[NH:28][C:27]([NH2:34])=[N:26][C:25]1=2)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(N(CC)C1C=CC=CC=1)C.P(Cl)(Cl)([Cl:65])=O>C(#N)C.[Cl-].C[N+](C)(C)C>[NH2:34][C:27]1[N:26]=[C:25]2[C:30]([N:31]=[CH:32][N:24]2[CH2:23][C@H:22]([CH2:21][O:20][C:1](=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:35][CH2:36][O:37][C:38](=[O:51])[C@H:39]([CH:48]([CH3:50])[CH3:49])[NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])=[C:29]([Cl:65])[N:28]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCCCCCCCCCCCCCCCC(=O)OC[C@H](CCOC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)Cn1cnc2c(=O)[nH]c(N)nc21
Agent: C[N+](C)(C)C
Agent: [Cl-]
Solvent: CCN(CC)c1ccccc1
Solvent: CC#N
Product: CCCCCCCCCCCCCCCCCC(=O)OC[C@H](CCOC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)Cn1cnc2c(Cl)nc(N)nc21

Procedure:
To a solution of (R)-9-(2-stearoyloxymethyl-4-(N-tert-butoxycarbonyl-L-valyloxy)butyl)guanine from step b) of Example 1 (646 mg, 0.9 mmole) in acetonitrile were added tetramethylammonium chloride (427 mg, 2.7 mmole), N,N-diethylaniline (0.716 ml, 4.5 mmole) and phosphorous oxychloride (0.417 ml, 4.5 mmole). The reaction was kept under reflux and the progression monitored by TLC. After 3 hours the reaction mixture was evaporated in vacuo and the residue was dissolved in dichloromethane, then poured into cold sodium hydrogen carbonate aqueous solution. The organic phase was evaporated and purified by silica gel column chromatography. Yield: 251 mg.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:9][OH:10])([CH2:7][OH:8])[N+:4]([O-:6])=[O:5].[CH2:11](OC=C)[CH3:12]>Cl.C(#N)C>[CH3:11][CH:12]1[O:8][CH2:7][C:3]([CH2:9][OH:10])([N+:4]([O-:6])=[O:5])[CH2:2][O:1]1
Reactant: O=[N+]([O-])C(CO)(CO)CO
Reactant: C=COCC
Agent: Cl
Solvent: CC#N
Product: CC1OCC(CO)([N+](=O)[O-])CO1
Temperature: 25 °C
Yield: 86 %

Procedure:
Following the procedure 2(A) described in this application, to a 100 ml round bottom flask equipped with a stir bar and reflux condenser topped with a nitrogen inlet was added 5 g (0.03 mol) tris(hydroxymethyl)nitromethane, 2.86 g (0.04 mol) ethylvinyl ether, 50 ml acetonitrile and 5 drops concentrated HCl. The reaction was heated to 35°-40° C. for 4 hours. After cooling to room temperature the volatiles were removed to give the product, 2-methyl-5-hydroxymethyl-5-nitro-1,3-dioxane, in 86% yield. 1H NMR in CD3OD confirmed the structure.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:8]([N:10]2[CH:14]([C:15](O)=[O:16])[CH2:13][CH:12]=[N:11]2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.CN1CCOCC1.[NH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>C(#N)C>[CH:1]1([CH2:6][C@@H:7]([C:8](=[O:9])[N:10]2[CH:14]([C:15]([NH:50][C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)=[O:16])[CH2:13][CH:12]=[N:11]2)[CH2:18][C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ccccc1
Reactant: CC(C)(C)OC(=O)C[C@@H](CC1CCCC1)C(=O)N1N=CCC1C(=O)O
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Solvent: CN1CCOCC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)C[C@@H](CC1CCCC1)C(=O)N1N=CCC1C(=O)Nc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
To a solution of 1-{(2R)-2-(cyclopentylmethyl)-4-[(1,1-dimethylethyl)oxy]-4-oxobutanoyl}-4,5-dihydro-1H-pyrazole-5-carboxylic acid (352 mg, 1.0 mmol) in acetonitrile (10 mL) at 0° C. was added 4-[4,6-bis(methyloxy)-1,3,5-triazin-2-yl]-4-methylmorpholin-4-ium (656 mg, 2.0 mmol) and N-methylmorpholine (0.29 mL, 2.6 mmol). The reaction was stirred for 2 hours at 0° C. Aniline (93 mg, 1.0 mmol) was added to the reaction, which was allowed to warm to room temperature and stirred for 3 hours. The solvent was then removed under reduced pressure, and water (5 mL) and DCM (15 mL) were added to the residue. The phases were separated. The aqueous phase was extracted twice with DCM (15 mL), and the combined organics were dried over sodium sulfate and concentrated. The resulting residue was purified by Combiflash silica gel chromatography (0-60% EtOAc in hex) to give 1,1-dimethylethyl (3R)-3-(cyclopentylmethyl)-4-oxo-4-{5-[(phenylamino)carbonyl]-4,5-dihydro-1H-pyrazol-1-yl}butanoate (386 mg, 0.90 mmol, 90% yield) as a yellow oil. MS: 428 ([M+H]).
Reaction SMILES: I.[CH3:2][CH:3]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([F:16])([F:15])[F:14])=[CH:10][CH:11]=2)[N:6]=[C:5](SC)[NH:4]1.[O:19]([CH2:26][CH2:27][NH2:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[OH-].[Na+].C(Cl)Cl>C(#N)C.OO.O>[CH3:2][CH:3]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([F:16])([F:15])[F:14])=[CH:10][CH:11]=2)[N:6]=[C:5]([NH:28][CH2:27][CH2:26][O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[NH:4]1
Reactant: NCCOc1ccccc1
Reactant: CSC1=Nc2cc(C(F)(F)F)ccc2C(C)N1
Agent: I
Agent: OO
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Solvent: O
Product: CC1NC(NCCOc2ccccc2)=Nc2cc(C(F)(F)F)ccc21
Temperature: 170 °C
Yield: 99.2 %

Procedure:
4-Methyl-2-methylsulfanyl-7-trifluoromethyl-3,4-dihydro-quinazoline hydroiodide (116 mg, 0.30 mmol) and 2-phenoxyethyl amine (126 mg, 0.9 mmol) were dissolved in acetonitrile (0.9 ml) and heated to 170° C. in a sealed tube in a microwave oven for 30 minutes. After cooling the reaction was treated with 1N aqueous sodium hydroxide solution, methylene chloride and 5 to 7 drops of 30% aqueous hydrogen peroxide solution. After the reaction has ceased the reaction was diluted with little water and the precipitated product was filtered off, washed with water, dried in vacuo to yield the title compound as a white solid (104 mg, 94%).
Reaction SMILES: Br[CH:2]([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].II.[C:11](#[N:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Cl-].[NH4+]>O1CCCC1.[Zn].CCOCC.O>[NH2:18][C:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[C:2]([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(C)Br
Reactant: N#Cc1ccccc1
Agent: II
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(C)=C(N)c1ccccc1

Procedure:
Under vigorous agitation, 73.2 g of powdered electrolytic zinc were refluxed in 1.2 liter of anhydrous tetrahydrofuran and 10 ml of ethyl 2-bromopropionate were added together with a crystal of sublimed iodine. The reaction started and then, away from reflux, 40.8 ml of benzonitrile were added and the mixture was refluxed which was maintained by the slow addition of 58 ml of ethyl 2-bromopropionate. After cooling, the mixture was poured into 1.5 liters of water containing 200 g of ammonium chloride and extraction was done with ether. The extracts were washed with water, dried, and concentrated under reduced pressure. The residue was taken up with ether and the insoluble matter was filtered off. The filtrate was concentrated under reduced pressure to obtain 76 g of an unstable product which was used rapidly for the next step.
Reaction SMILES: [NH2:1][C:2]1[N:34]=[C:5]2[C:6]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)=[C:7]([CH3:23])[C:8]([C:10]3[N:14]([C:15]4[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=4)[N:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1.CCN(C(C)C)C(C)C.[Cl:44][CH2:45][C:46](Cl)=[O:47]>C1COCC1>[Cl:44][CH2:45][C:46]([NH:1][C:2]1[N:34]=[C:5]2[C:6]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:32])([F:33])[F:31])[CH:25]=3)=[C:7]([CH3:23])[C:8]([C:10]3[N:14]([C:15]4[CH:16]=[CH:17][C:18]([C:19]#[N:20])=[CH:21][CH:22]=4)[N:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1)=[O:47]
Reactant: O=C(Cl)CCl
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(N)nc2c1-c1cccc(C(F)(F)F)c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(NC(=O)CCl)nc2c1-c1cccc(C(F)(F)F)c1
Reaction time: 0.75 h
Yield: 71.6 %

Procedure:
4-{5-[2-Amino-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl]-pyrazol-1-yl}-benzonitrile (Ex. 1, 400 mg, 0.87 mmol) was stirred in dry THF (5 mL) and DIPEA (0.3 mL, 1.765 mmol) was added followed by the dropwise addition of chloroacetyl chloride (104 μL, 1.258 mmol). After 45 mins, a further quantity (69 μL) of chloroacetyl chloride was added and stirring was continued for 18 hrs. The reaction mixture was partitioned between EtOAc and water, the organic layer washed with saturated brine and then dried (Na2SO4) and concentrated in vacuo. The resultant residue was purified by flash chromatography eluting with 65% EtOAc in cyclohexane to give title compound (334 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[N+:11]([O-])=O.C(O)(=O)C.C(N)=N.[H][H]>[Ni].CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[NH2:11]
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Ni]
Agent: N=CN
Solvent: CC(=O)O
Solvent: CO
Product: Nc1ccc(Cl)c(N)c1

Procedure:
40.8 g of 1-chloro-2,4-dinitrobenzene, 2 g of Raney nickel (60%, aqueous), 1.5 g of formamidine acetate and 120 ml of methanol are introduced in an autoclave equipped with gas introduction stirrer. The air in the autoclave is then displaced by nitrogen and then by hydrogen. The hydrogenation is carried out at a pressure of 10 bar and a temperature of 60° C. The hydrogenation time is 11/4 hours. 1-Chloro-2,4-diaminobenzene, 99% pure (analysed as 1-Chloro-2,4-acetamidobenzene by liquid chromatography), is obtained in quantitative yield.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12]C)=[CH:4][CH:3]=1.C(O)(=O)C.Br>O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][CH:3]=1
Reactant: COc1ccc(Cl)c2ccccc12
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: Oc1ccc(Cl)c2ccccc12

Procedure:
The known compound 1-chloro-4-methoxynaphthalene is dissolved in 150 ml. of acetic acid and 150 ml. of 48 percent hydrobromic acid, and the mixture is heated at its reflux temperature for 2 hours. The mixture is diluted with 200 ml. of water and cooled to provide 1-chloro-4-hydroxynaphthalene as a crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1F.[OH:10][CH:11]([CH2:23][CH2:24][CH3:25])[CH2:12][CH2:13][N:14]([CH3:22])[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18]>>[CH3:19][C:17]([O:16][C:15](=[O:21])[N:14]([CH2:13][CH2:12][CH:11]([O:10][C:3]1[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=1[Cl:1])[CH2:23][CH2:24][CH3:25])[CH3:22])([CH3:18])[CH3:20]
Reactant: Fc1cc(Cl)ccc1Cl
Reactant: CCCC(O)CCN(C)C(=O)OC(C)(C)C
Product: CCCC(CCN(C)C(=O)OC(C)(C)C)Oc1cc(Cl)ccc1Cl

Procedure:
The title compound was prepared according to the method of Example 3 step (b) but using 2,5-dichlorofluorobenzene and (3-hydroxyhexyl)methylcarbamic acid, 1,1-dimethylethyl ester.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[N:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][OH:18])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(Cl)Cl.O=[Mn]=O>[C:1]([O:5][C:6]([NH:8][C:9]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[N:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]=[O:18])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC(=Nc1ccc(CO)cc1)NC(=O)OC(C)(C)C
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(=Nc1ccc(C=O)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.8 %

Procedure:
The alcohol (0.282 g, 0.771 mmol) from above was dissolved in CH2Cl2 (7 mL), treated with activated MnO2 (0.696 g, 8.01 mmol) and stirred at room temperature overnight. The mixture was filtered through celite© and the cake was washed with CH2Cl2. The solvent was removed from the filtrate under reduced pressure and provided N, N′-bis-(tert-butoxycarbonyl) -N″-(4-formyl-phenyl)-guanidine (0.260 g, 93%) as a white solid. 1H NMR (CDCl3) δ1.53 (s, 9H), 1.55 (s, 9H), 7.85 (s, 4H), 9.93 (s, 1H), 10.34 (br s, 1H).
Reaction SMILES: N[CH:2]([C:4](=[O:17])[CH2:5][C:6]([CH3:16])([CH3:15])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[CH3:3].[Br:18]Br>C(Cl)(Cl)(Cl)Cl>[Br:18][CH:2]([C:4](=[O:17])[CH2:5][C:6]([CH3:16])([CH3:15])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[CH3:3]
Reactant: CC(N)C(=O)CC(C)(C)Cc1ccc(Cl)cc1
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: CC(Br)C(=O)CC(C)(C)Cc1ccc(Cl)cc1
Reaction time: 2 h
Yield: 99.3 %

Procedure:
The ketone (20.0 g; 0.084 mole) was dissolved in carbontetrachloride (200 ml). The solution was cooled on ice and a 10% solution of bromine (0.084 mole) in CCl4 was added at such a rate that the drops were decolourized immediately. The total time of bromination was about 2 hours. After evaporation of the solvent in vacuo a pure oil of 2-bromo-5,5-dimethyl-6-(4-chlorophenyl)-3-hexanone (26.5 g; 99% yield) was obtained. To a solution of the bromoketone (5.0 g; 0.016 mole) in dimethylformamide (20 ml) was added potassium phtalimide (3.2 g; 0.017 mole) in portions under stirring during 5 minutes. The temperature was raised spontaneously to 40° C. Stirring was continued for 15 minutes. Chloroform (30 ml) was added and the mixture was poured into water (100 ml) under stirring. The organic layer was separated and the aqueous phase was washed with CHCl3. The combined chloroform phase was washed with 0.2 N sodium hydroxide solution and water. After drying over anhydrous sodium sulphate and evaporation of the solvent a yellow oil was obtained. The oil crystallized from ethanol-ether affording white crystals of 6-(4-chlorophenyl)-5,5-dimethyl-2-phtalimido-3-hexanone (2.6 g; 43% yield) melting at 96°-98° C.
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N[C:24]1C(C2C=CC=CC=2)=CS[C:25]=1C(OC)=O.C(OCC)(OCC)OCC.C(C1C=CC(N)=CC=1)=C>C(O)(=O)C>[C:17]1([C:16]2[C:10]3[N:9]=[CH:8][N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[C:3]([CH:24]=[CH2:25])[CH:2]=4)[C:12](=[O:13])[C:11]=3[S:14][CH:15]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)c1scc(-c2ccccc2)c1N
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Agent: C=Cc1ccc(N)cc1
Solvent: CC(=O)O
Solvent: CCOC(OCC)OCC
Product: C=Cc1cccc(-n2cnc3c(-c4ccccc4)csc3c2=O)c1
Yield: 11.5 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (50 mg, 0.21 mmol), triethyl orthoformate (0.47 ml), 4-vinylaniline (47.5 mg, 0.39 mmol), and acetic acid (0.06 ml) were used to give 8 mg (0.024 mmol, 11.5% yield) of the title compound.