Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([O:9][C:10](=[O:11])[C:5]=12)=O)([O-:3])=[O:2].[NH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21]>>[N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([N:15]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[C:10](=[O:11])[C:5]=12)=[O:9])([O-:3])=[O:2]
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Reactant: NCCCCC(=O)O
Product: O=C(O)CCCCN1C(=O)c2cccc([N+](=O)[O-])c2C1=O
Yield: 72.4 %

Procedure:
3-nitrophthalic anhydride (0.5 g, 0.0026 mol) and 5-aminopentanoic acid (0.30 g, 0.0026 mol) were refluxed as above overnight. The clear solution was purified as per 120 to yield 0.55 g (73%) 123 as pale yellow flat crystals: mp=158-160° C.; Rf0.69 (A): Rf0.90 (C): Rf0.73 (D): 1H NMR (DMSO-d6) δ1.53 (m, 2H), 1.58 (m, 2H), 2.24 (t, J=7.1 Hz, 2H), 3.57 (t, J=6.7 Hz, 2H), 8.04 (dd, J=8.0, 7.5 Hz, 1H), 8.16 (d, J=7.5 Hz, 1H), 8.27 (d, J=8.0 Hz, 1H); IR (cm−1): 2800-3130 (OH), 3096 (C═CH), 2691 (C—H), 1774 (C═O), 1723 (bs, C═O), 1616 (C═C), 1543 (N═O), 1466 (C═C), 1443 (C═C), 1396 (C—O), 1358 (N═O), 1209 (C—O), 1050 (C—O), 722 (C═CH); MS m/z (rel intensity) 291 (92), 247 (31), 191 (100).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([O:5]CC)=O.C(N(CC)CC)C.[Cl:17][C:18]1[CH:37]=[CH:36][C:21]2[O:22][C:23]3[CH:35]=[CH:34][CH:33]=[CH:32][C:24]=3[C@@H:25]3[C@H:30]([NH2:31])[CH2:29][CH2:28][CH2:27][N:26]3[C:20]=2[CH:19]=1>CO>[Cl:17][C:18]1[CH:37]=[CH:36][C:21]2[O:22][C:23]3[CH:35]=[CH:34][CH:33]=[CH:32][C:24]=3[C@@H:25]3[C@H:30]([NH:31][C:3](=[O:5])[C:2]([F:1])([F:8])[F:9])[CH2:29][CH2:28][CH2:27][N:26]3[C:20]=2[CH:19]=1
Reactant: CCOC(=O)C(F)(F)F
Reactant: N[C@@H]1CCCN2c3cc(Cl)ccc3Oc3ccccc3[C@H]12
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(N[C@@H]1CCCN2c3cc(Cl)ccc3Oc3ccccc3[C@H]12)C(F)(F)F
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 85.7 %

Procedure:
Successively, ethyl trifluoroacetate (1.41 mL, 11.8 mmol) and triethylamine (628 μL, 4.5 mmol) were added to trans-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-amine (291 mg, 0.97 mmol) in 11.8 mL of methanol. The resulting mixture was heated to 50° C. for 18 h. A precipitate was formed. The mixture was evaporated under reduced pressure to remove volatile reagents and 5 mL of methanol was added. After 30 min. stirring the precipitate was filtered off, washed with diethyl ether and dried to give trans-N-(7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide as an off-white solid (330 mg, 86%). Data: 1H-NMR (400 MHz, CDCl3) 1.85 (m, 2H), 2.26 (m, 1H), 3.12 (m, 1H), 3.20 (m, 1H), 3.62 (dt, J=12.0, 4.0, 1H), 4.38 (d, J=8.0, 1H), 4.68 (m, 1H), 6.76 (dd, J=8.0, 3.0, 1H), 6.93 (d, J=3.0, 1H), 7.04 (d, J=8.0, 1H), 7.08 (dt, J=8.0, 2.0, 1H), 7.17 (dd, J=8.0, 2.0, 2H), 7.29 (dt, J=8.0, 2.0, 1H). (m/z)=397 (M+H)+.
Reaction SMILES: [C:1]1([C:11]([OH:13])=O)[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:16])=O>>[C:1]1([C:11]([Cl:16])=[O:13])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cccc2c1CCCC2
Product: O=C(Cl)c1cccc2c1CCCC2

Procedure:
A solution of 5,6,7,8-tetrahydro-1-naphthalenecarboxylic acid (J. W, Burnham, W. P. Duncan, E. J. Eisenbaum, G. W. Keen, M. C. Hamming, Org. Prep. Proc. Int. 285-290 (1973))(0.205 g, 1.16 mmol) in thionyl chloride (3.26 g, 27.42 minol) was heated at 80 ° C. for 3 h under a stream of nitrogen. Excess thionyl chloride was removed in vacuo, and the residue concentrated a second time from toluene to afford 5,6,7,8 tetrahydo-1-naphthalenecarbonyl chloride as a brown oil. The residue was dissolved in dry CH2Cl2 and used without further purification.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[C:4]#[N:5].[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]=1[CH3:19].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:2]2[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=2[C:4]#[N:5])=[CH:14][C:13]=1[CH3:19]
Reactant: Cc1cc(O)ccc1N
Reactant: N#Cc1cc(F)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(Oc2ccc(F)cc2C#N)ccc1N
Temperature: 25 °C
Yield: 98.6 %

Procedure:
In a 3 L, 4-necked flask that had been evacuated and back-filled with argon, 2,5-difluorobenzonitrile (295.3 ml, 812.0 mmol) and 4-amino-3-methylphenol (100.0 g, 812.0 mmol) were dissolved in dry DMSO (2.75 M) with rapid stirring at room temperature. The solution was evacuated/backfilled with argon (3×). Potassium carbonate (185.2 g, 1340 mmol) (−325 mesh) was added. The reaction mixture was evacuated/backfilled with argon (3×) and warmed to 80° C. (internal probe) for 16 hours. TLC indicated complete conversion. The reaction mixture was cooled to room temperature and poured slowly into 2 L of ice water with rapid stirring. The residue in the round bottom flask was taken up in water repeatedly and poured into the ice water until a total volume of 3 L was achieved and all solids were in the ice water. The suspension was stirred rapidly for 2 hours as it came to room temperature. The brown solids were collected by filtration, washed with water (3 L), air dried, dried with latex dam, and dried under high vacuum at 40° C. for 44 hours to provide 194 g (99%) of the desired product as a tan solid. MS (APCI+) m/z 243 (M+1) was detected. 1H NMR (400 MHz, CDCl3) δ 7.38 (m, 1H), 7.18 (m, 1H), 6.65-6.85 (m, 5H), 3.60 (br, 2H), 2.17 (s, 3H).
Reaction SMILES: C[N:2]([CH:4]=[C:5]1[CH2:11][CH2:10][N:9]([C:12](=[O:22])[C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)[C:8]2[CH:23]=[CH:24][CH:25]=[N:26][C:7]=2[C:6]1=O)C.O.[NH2:29]N>>[N+:19]([C:16]1[CH:17]=[CH:18][C:13]([C:12]([N:9]2[CH2:10][CH2:11][C:5]3[CH:4]=[N:2][NH:29][C:6]=3[C:7]3[N:26]=[CH:25][CH:24]=[CH:23][C:8]2=3)=[O:22])=[CH:14][CH:15]=1)([O-:21])=[O:20]
Reactant: CN(C)C=C1CCN(C(=O)c2ccc([N+](=O)[O-])cc2)c2cccnc2C1=O
Reactant: NN
Solvent: O
Product: O=C(c1ccc([N+](=O)[O-])cc1)N1CCc2cn[nH]c2-c2ncccc21

Procedure:
As described for Reference Example 223, 8-[(dimethylamino)methylene]-5,6,7,8-tetrahydro-5-(4-nitrobenzoyl)-9H-pyrido[3,2-b]azepin-9-one is reacted with hydrazine hydrate to give the product as a solid, m.p. 255°-256° C.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:9]2[N:10]=[CH:11][NH:12][C:8]=2[CH:7]=[CH:6][N:5]=1.[CH2:13]([O:20][C@H:21]1[C@H:25]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C@@H:24]([CH2:34][O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[O:23][C@@H:22]1Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C)C=O>[Cl:3][C:4]1[C:9]2[N:10]=[CH:11][N:12]([C@@H:22]3[O:23][C@H:24]([CH2:34][O:35][CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C@@H:25]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C@@H:21]3[O:20][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:8]=2[CH:7]=[CH:6][N:5]=1
Reactant: Clc1nccc2[nH]cnc12
Reactant: Cl[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1nccc2c1ncn2[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Reaction time: 2 h
Yield: 89.2 %

Procedure:
A solution of 2.4 g of sodium hydride, 15.4 g of 4-chloro-1H-imidazo[4,5-c]pyridine, and 200 ml of dry dimethylformamide (DMF) is stirred at 50° C. for 5 minutes, cooled, and added to 43.9 g of 2,3,5-tri-O-benzyl-α-D-arabinofuranosyl chloride. The solution is kept at ambient temperature for two hours, concentrated in vacuo, and distributed between a mixture of ethyl acetate-water. Chromatography of the dried ethyl acetate layer over silica gel with 4:1 benzene-ethyl acetate provides 49.6 g of syrupy 4-chloro-1-(2,3,5-tri-O-benzyl-β-D-arabinofuranosyl)imidazo[4,5-c]-pyridine.
Reaction SMILES: [C:1]1([N:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][N:23]=[C:22]([NH2:26])[N:21]=4)=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[CH2:35](Br)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.O>CS(C)=O>[C:27]1([N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:9]=[CH:10][C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][N:23]=[C:22]([N:26]([CH2:14][C:11]5[CH:12]=[CH:13][CH:8]=[CH:9][CH:10]=5)[CH2:35][C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)[N:21]=4)=[CH:16][CH:15]=3)=[CH:12][CH:13]=2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: Nc1nccc(-c2ccc(-c3ccc(N(c4ccccc4)c4ccccc4)cc3)cc2)n1
Reactant: BrCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: c1ccc(CN(Cc2ccccc2)c2nccc(-c3ccc(-c4ccc(N(c5ccccc5)c5ccccc5)cc4)cc3)n2)cc1
Reaction time: 5 h
Yield: 81 %

Procedure:
4-(4′-Diphenylaminobiphenyl-4-yl)pyrimidine-2-amine (100 mg, 0.24 mmol) and sodium hydroxide (38 mg, 0.96 mmol) were added in dimethylsulfoxide (1 mL), and mixed at 100° C. for 30 minutes. This solution was added with a solution of benzyl bromide (63.1 μL, 0.53 mmol) in dimethylsulfoxide (1 mL) at 100° C. for 30 minutes, followed by stirring for 5 hours. This solution was cooled and added with water (100 mL) and a saturated saline solution, and then allowed to stand for 24 hours. The precipitated crystalline material was purified by column chromatogram (silica gel, hexane: EtOAc=8:1) to give the title compound.
Reaction SMILES: Br[C:2]1[O:3][C:4]([C:8]2[N:12]3[N:13]=[C:14]([CH3:22])[CH:15]=[C:16]([CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])[C:11]3=[N:10][C:9]=2[CH3:23])=[C:5]([CH3:7])[N:6]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:30][NH:31][CH3:32]>C1COCC1>[CH2:18]([CH:17]([C:16]1[C:11]2[N:12]([C:8]([C:4]3[O:3][C:2]([N:31]([CH3:32])[CH3:30])=[N:6][C:5]=3[CH3:7])=[C:9]([CH3:23])[N:10]=2)[N:13]=[C:14]([CH3:22])[CH:15]=1)[CH2:20][CH3:21])[CH3:19]
Reactant: CCC(CC)c1cc(C)nn2c(-c3oc(Br)nc3C)c(C)nc12
Reactant: CNC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: CCC(CC)c1cc(C)nn2c(-c3oc(N(C)C)nc3C)c(C)nc12
Temperature: 110 °C
Yield: 89 %

Procedure:
32 mg of 3-(2-Bromo-4-methyl-oxazol-5-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.08 mmol) and 78 mg of cesium carbonate (0.24 mmol) are placed into vial with 3 ml of dimethylamine 2.0 M in THF. The vial is capped with a Teflon cap and heated at 110° C. for 3 days. The reaction mixture is cooled to room temperature, concentrated, and applied onto a silica-gel chromatography column (Hexane:AcOEt:2M NH3 in MeOH=10:2:1) to give 24 mg of the title product. Yield 89%. mass spectrum (m/e): 342 (M+1). 1H-NMR (CDCl3): 6.71 (s, 1H), 3.34 (m, 1H), 3.13 (s, 6H), 2.56 (s, 3H), 2.49 (s, 3H), 2.14 (s, 3H), 1.84 (m, 4H), 0.89 (t, J=7.5 Hz, 6H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].[C:12](=O)([O-])[O-].[K+].[K+].CI>CC(=O)CC>[CH3:12][O:11][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[NH2:1]
Reactant: O=C([O-])[O-]
Reactant: Nc1c(O)cccc1[N+](=O)[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CI
Product: COc1cccc([N+](=O)[O-])c1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.6 %

Procedure:
2-Amino-3-nitrophenol (0.5 g, 3.2 mmol) was dissolved in 10 mL 2-butanone, and potassium carbonate (0.54 g, 3.9 mmol) and methyl iodide (0.4 mL) were added. The suspension was stirred overnight at room temperature. The reaction mixture was filtered through a plug of Celite, and the solid residue was washed with ethyl acetate. The resulting filtrate was washed with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 0.52 g of 2-methoxy-6-nitroaniline, which was used without further purification. 1H-NMR (400 MHz, CDCl3): δ 7.74 (d, 1H), 6.87 (d, 1H), 6.61 (dd, 1H), 6.42 (b, 2H), 3.92 (s, 3H). MS (EI): 169 (MH+).
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=O)[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[S:32]1[CH:36]=[CH:35][CH:34]=[C:33]1[CH:37]1[CH2:41][CH2:40][CH2:39][NH:38]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][N:38]5[CH2:39][CH2:40][CH2:41][CH:37]5[C:33]5[S:32][CH:36]=[CH:35][CH:34]=5)[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2]
Reactant: c1csc(C2CCCN2)c1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(C=O)c4)cc23)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CN5CCCC5c5cccs5)c4)cc23)CC1
Yield: 31 %

Procedure:
Following the general procedure of example 1, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1H-indole-7-carboxamide (50.0 mg, 0.112 mmol), 2-(2-thienyl)pyrrolidine (132.4 mg, 0.86 mmol) and NaBH(OAc)3 (58.0 mg, 0.303 mmol) were reacted to give the title compound (20.0 mg, 30.4%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:24]=[C:25]([F:27])[CH:26]=1)[O:5][CH2:6][CH2:7][N:8]([CH3:23])[CH2:9][CH2:10][CH2:11][N:12]1C(=O)C2C(=CC=CC=2)C1=O.O.NN>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:24]=[C:25]([F:27])[CH:26]=1)[O:5][CH2:6][CH2:7][N:8]([CH3:23])[CH2:9][CH2:10][CH2:11][NH2:12]
Reactant: CN(CCCN1C(=O)c2ccccc2C1=O)CCOc1cc(F)cc(F)c1
Agent: NN
Solvent: CCO
Solvent: O
Product: CN(CCCN)CCOc1cc(F)cc(F)c1
Yield: 99.7 %

Procedure:
A mixture of 2-(3-([2-(3,5-difluoro-phenoxy)-ethyl]-methyl-amino)-propyl)-isoindole-1,3-dione (1 g, 2.67 mmol), hydrazine hydrate (0.8 ml) and ethanol (20 ml) was heated under reflux for 2 hours. The solvent was concentrated and the residue was suspended in diethyl ether. The solid formed was filetered off and washed with ether. The filtrated was concentrated to dryness to give N1-[2-(3,5-difluoro-phenoxy)-ethyl]-N1-methyl-propane-1,3-diamine (0.65 g, 99%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([F:10])[C:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[N:13]([CH3:22])[C:12]2=[O:23])=[CH:6][C:5]=1[OH:24].[I-].[Na+].Cl[CH:28]([S:32][CH3:33])[C:29]([NH2:31])=[O:30]>O.C(COC)OC>[Cl:3][C:4]1[CH:9]=[C:8]([F:10])[C:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:20])([F:21])[F:19])[N:13]([CH3:22])[C:12]2=[O:23])=[CH:6][C:5]=1[O:24][CH:28]([S:32][CH3:33])[C:29]([NH2:31])=[O:30]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(O)c(Cl)cc2F)c1=O
Reactant: CSC(Cl)C(N)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CSC(Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl)C(N)=O
Reaction time: 0.5 h
Yield: 78.2 %

Procedure:
To a mixture of 1.3 g of sodium hydride and 100 ml of dimethoxyethane, 10 g of 2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-1,2,3,6-tetrahydropyrimidin-1-yl)phenol were added at room temperature and stirred for 30 minutes. Then, 2.2 g of sodium iodide and 6.7 g of crude 2-chloro-2-(methylthio)acetamide were added thereto and stirred at room temperature for 3 hours, and water was poured into the reaction mixture. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography (eluent: ethyl acetate) to give 10.2 g of 2-[2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-1,2,3,6-tetrahydropyrimidin-1-yl)phenoxy]-2-(methylthio)acetamide.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[N:6][C:5]([CH3:8])=[CH:4][N:3]=1.C[N:10](C)C1C=CC=CC=1>>[CH3:8][C:5]1[C:4]([NH2:10])=[N:3][C:2]([CH3:1])=[CH:7][N:6]=1
Reactant: Cc1cnc(C)cn1
Reactant: CN(C)c1ccccc1
Product: Cc1cnc(C)c(N)n1
Temperature: 170 °C
Reaction time: 1 h

Procedure:
A mixture of 2,5-dimethylpyrazine (14 g, 0.13 mol) in N,N-dimethylaniline (50 mL) was heated to 170° C. and NaNH2 (22 g, 0.56 mol) was added in portions. The reaction mixture was stirred at 170° C. for 1 h, and the solvent was removed. The product was purified by column chromatography to give 3,6-dimethylpyrazin-2-amine as a brown solid (1.6 g). MS (ESI): m/z 124 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:33])([C:27]2[N:28]([CH3:32])[CH:29]=[N:30][CH:31]=2)[C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[CH2:12][CH:11]3[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25]C)[CH:20]=2)=[CH:4][CH:3]=1.B(Br)(Br)Br.[CH2:38](Cl)Cl>>[Cl:1][C:2]1[S:6][C:5]([C:7]([OH:33])([C:27]2[N:28]([CH3:32])[CH:29]=[N:30][CH:31]=2)[C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH3:38])[C:13](=[O:18])[CH:12]=[C:11]3[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([OH:25])[CH:20]=2)=[CH:4][CH:3]=1
Reactant: ClCCl
Reactant: COc1cccc(C2CC(=O)Nc3ccc(C(O)(c4ccc(Cl)s4)c4cncn4C)cc32)c1
Agent: BrB(Br)Br
Product: Cn1cncc1C(O)(c1ccc2c(c1)c(-c1cccc(O)c1)cc(=O)n2C)c1ccc(Cl)s1
Yield: 66 %

Procedure:
Following the same procedure as that described in Example 34A, the title compound of example 31 (100 mg, 0.203 mmol) was treated with BBr3 in CH2Cl2 (1M, 1.02 ml, 1.02 mmol) to give the title compound (64 mg, 67% yield).
Reaction SMILES: C([O:3][C:4]([CH:6]([O:8][C:9]1[N:13]=[CH:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:10]=1)[CH3:7])=[O:5])C.[OH-].[K+]>C(O)C>[C:4]([CH:6]([O:8][C:9]1[N:13]=[CH:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:21])[F:22])[CH:15]=2)[N:10]=1)[CH3:7])([OH:5])=[O:3]
Reactant: CCOC(=O)C(C)Oc1ncn(-c2cccc(C(F)(F)F)c2)n1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(Oc1ncn(-c2cccc(C(F)(F)F)c2)n1)C(=O)O

Procedure:
Fifteen g of the compound of Example 3 was refluxed for 3 hours with 5.1 g of potassium hydroxide in 150 ml of ethanol, and the product was collected as shown in Example 22 and recrystallized from ethanol to obtain 11.8 g of the desired product, m.p. 206°-208°.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6](N)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].S(=O)(=O)(O)[OH:13].N([O-])=O.[Na+]>O>[CH3:1][C:2]1[N:7]=[C:6]([OH:13])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: Cc1nc(N)ccc1[N+](=O)[O-]
Reactant: O=S(=O)(O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1nc(O)ccc1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
A 3-necked roundbottom flask was charged with a solution of 6-methyl-5-nitropyridin-2-amine (20 g, 130.72 mmol) in water (330 ml). To the mixture was added sulfuric acid (23.6 ml). The mixtir was cooled to 0° C. and a solution of sodium nitrite (12.0 g, 173.91 mmol) in water (30 ml) was added dropwise. The resulting solution was allowed to react, with stirring, for 20 at 0° C. and then allowed to warm to room temperature and stirred for an additional one hour. The resulting slurry was filtered and the solids collected to afford the title compound.
Reaction SMILES: C([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1Br)(C)(C)C.[Cl:18][C:19]1[CH:20]=[C:21]([C:25]#[CH:26])[CH:22]=[CH:23][CH:24]=1>>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:5])=[O:17])=[C:10]([C:26]#[C:25][C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([Cl:18])[CH:20]=2)[CH:11]=1
Reactant: CC(C)(C)OC(=O)COc1ccc(Cl)cc1Br
Reactant: C#Cc1cccc(Cl)c1
Product: O=C(O)COc1ccc(Cl)cc1C#Cc1cccc(Cl)c1

Procedure:
Following the general method as outlined in Example 1, starting from tert-butyl(2-bromo-4-chlorophenoxy)acetate (Intermediate 1) and 3-chloro-1-ethynylbenzene (Aldrich), the title compound was obtained as a brown solid after purification by preparative HPLC.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[CH:5][C:6]([CH:9]=O)=[N:7][CH:8]=1.[NH2:13][CH2:14][CH2:15][CH2:16][NH2:17]>C1C=CC=CC=1>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[CH:5][C:6]([CH2:9][NH:13][CH2:14][CH2:15][CH2:16][NH2:17])=[N:7][CH:8]=1
Reactant: NCCCN
Reactant: O=Cc1ccc(C(F)(F)F)cn1
Solvent: c1ccccc1
Product: NCCCNCc1ccc(C(F)(F)F)cn1
Yield: 75.1 %

Procedure:
5-Trifluoromethylpicoline aldehyde (3.5 g) was added dropwise at room temperature to a solution of trimethylenediamine (7.4 g) in benzene (70 ml). After the addition, the mixture was gradually heated with stirring, and then while separating water as an azeotrope, refluxed for 2 hours. Benzene was distilled off under reduced pressure, and then the residue was dissolved in ethanol (100 ml). With stirring at 10° to 15° C., sodium borohydride (0.9 g) was added little by little. The mixture was then stirred at room temperature for 2 hours. Ethanol was distilled off at less than 30° C. Dichloromethane was added to the residue, and a portion of it soluble in dichloromethane was separated. Dichloromethane was distilled off under reduced pressure, and volatile materials were removed at 1 mmHg and less than 60 ° C. to give N-(5-trifluoromethyl-2-pyridylmethyl)trimethylenediamine (3.5 g)as a colorless oil. nD20 1.4651
Reaction SMILES: [F:1][C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[C:5](Br)=[CH:4][C:3]=1[F:12].[Mg].C[O:15][B:16](OC)[O:17]C.Cl>O1CCCC1.C(Br)CBr>[F:1][C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[C:5]([B:16]([OH:17])[OH:15])=[CH:4][C:3]=1[F:12]
Reactant: Fc1cc(Br)c2occc2c1F
Reactant: COB(OC)OC
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: OB(O)c1cc(F)c(F)c2ccoc12
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 97.6 %

Procedure:
Alternatively, a mixture of 0.484 gm (2.08 mMol) 4,5-difluoro-7-bromobenzofuran and 0.065 gm (2.67 mMol) magnesium in 5 mL tetrahydrofuran was heated at reflux. Two drops of 1,2-dibromomethane were added and the mixture heated at reflux for 45 minutes. To this mixture were added 260 μL (2.29 mMol) trimethylborate and heating was continued for an additional 45 minutes. After cooling to room temperature, 2.3 mL 1N hydrochloric acid were added and the mixture stirred for 45 minutes. The mixture was then extracted well with diethyl ether. The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure. The residue was slurried in 4 mL hexanes, the solvent removed by decantation, and the residual solid dried under reduced pressure to provide 0.402 gm (97.8%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[C:11]1([N:17]=C=O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>[O-]CC.[Na+].O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:17][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: O=C=Nc1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Product: O=C(Nc1ccccc1)c1ccc(O)cc1
Temperature: 23 °C
Reaction time: 1.57 h

Procedure:
p-Hydroxybenzoic acid (96.68 grams, 0.70 mole), sodium ethoxide catalyst (0.218 gram, 0.225% wt. of the p-hydroxybenzoic acid used) and N,N'-dimethylacetamide solvent (550 grams) are added to a reactor equipped with a reflux condenser and stirred under a nitrogen atmosphere at 23° C. to provide a solution. Phenyl isocyanate (87.55 grams, 0.735 mole) is added inducing a maximum exotherm of 46° C. four minutes later. Three minutes after the maximum exotherm temperature is achieved, heating of the reactor commences and a 160° C. reaction temperature is achieved 94 minutes later. After three hours at the 160° C. reaction temperature, the reactor is cooled to 50° C. then the contents poured into 4 liters of deionized water. A precipitated product is recovered via filtration of the aqueous slurry, washed with deionized water (500 milliliters) then dissolved into boiling methanol (850 milliliters) and refluxed therein (67° C.). After cooling the methanol solution to room temperature (23° C.) and maintaining therein for sixteen hours, a white crystalline product is filtered off, washed with methanol (100 milliliters) and dried in a vacuum oven at 80° C. and 1 mm Hg to a constant weight of 99.49 grams. Fourier transform infrared spectrophotometric analysis of a potassium bromide pellet of a portion of the product revealed the presence of the expected hydroxyl group O-H and secondary amide (solid state) N--H stretching at 3336 cm-1 (sharp) with a shoulder at 3409 cm-1 and the secondary amide carbonyl stretching (solid state) at 1656 cm-1 (sharp).