Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([OH:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N+](=[CH:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N-]>ClCCl.CCOCC.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[CH2:16]([O:15][C:13](=[O:14])[CH2:12][O:9][CH:1]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH3:17]
Reactant: OC1CCCCCCC1
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh]
Solvent: CCOCC
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)COC1CCCCCCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 37.8 %

Procedure:
To a solution of cyclooctanol (640 mg, 4.9 mmol) in dichloromethane (15 mL) is added rhodium (II) acetate dimer (21 mg) followed by ethyl diazoacetate (0.60 g, 5.7 mmol). The reaction mixture is stirred at RT for 10 min. The reaction mixture is rotary evaporated, and the residue dissolved in Et2O, filtered through celite, and the filtrate is evaporated and the residue is vacuum distilled at 150° C. to give 397 mg of the product 413. 1H NMR (CDCl3) δ 4.21 (q, 2H), 4.06 (s, 2H), 3.50 (m, 1H), 1.93 (m, 2H), 1.7-1.4 (m, 8H), 1.4-1.3 (m, 2H), 1.28 (t, 3H); MS: m/z 215 (M++1).
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:12][C@H:13]2[CH2:17][CH2:16][CH2:15][C@@H:14]2[NH:18][C:19]([C:21]2[C:26](N3N=CC=N3)=[CH:25][CH:24]=[CH:23]N=2)=[O:20])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:7]=1.Cl.C[N:34]([C:41]1[CH:46]=N[C:44]([C:47](F)(F)F)=[CH:43][N:42]=1)[C@H]1CCC[C@@H]1N.N1C=CC=NC=1C1C=CC=CC=1C(O)=O>>[CH3:1][C:2]1[C:3]([NH:12][C@H:13]2[CH2:17][CH2:16][CH2:15][C@@H:14]2[NH:18][C:19](=[O:20])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:46]=2[C:41]2[N:34]=[CH:47][CH:44]=[CH:43][N:42]=2)=[N:4][CH:5]=[C:6]([C:8]([F:10])([F:11])[F:9])[N:7]=1
Reactant: Cc1nc(C(F)(F)F)cnc1N[C@H]1CCC[C@@H]1NC(=O)c1ncccc1-n1nccn1
Reactant: CN(c1cnc(C(F)(F)F)cn1)[C@H]1CCC[C@@H]1N
Agent: Cl
Agent: O=C(O)c1ccccc1-c1ncccn1
Product: Cc1nc(C(F)(F)F)cnc1N[C@H]1CCC[C@@H]1NC(=O)c1ccccc1-c1ncccn1

Procedure:
Prepared according to the procedure for N-[(1S,2S)-2-{ [3-methyl-5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]-3-(2H-1,2,3-triazol-2-yl)pyridine-2-carboxamide (Example 76) from (1S,2S)-1-N-methyl-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 23; 60 mg, 0.20 mmol) and 2-(pyrimidin-2-yl)benzoic acid (CAS number 400892-62-8; 41 mg, 0.20 mmol) except this was purified only by column chromatography (silica, 0 to 100% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: C[O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2([OH:17])[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.[NH:19]1[CH2:22][CH:21]([NH:23][C:24]([CH2:26][NH:27][C:28](=[O:39])[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=2)=[O:25])[CH2:20]1>>[OH:17][C:10]1([C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:2])=[O:18])=[CH:5][CH:6]=2)[CH2:15][CH2:14][CH:13]([N:19]2[CH2:22][CH:21]([NH:23][C:24](=[O:25])[CH2:26][NH:27][C:28](=[O:39])[C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:37])([F:38])[F:36])[CH:30]=3)[CH2:20]2)[CH2:12][CH2:11]1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: COC(=O)c1ccc(C2(O)CCC(=O)CC2)cc1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(O)(c3ccc(C(=O)O)cc3)CC2)C1

Procedure:
The title compound was prepared as a white solid by reductive amination of 4-(1-hydroxy-4-oxo-cyclohexyl)-benzoic acid methyl ester (as prepared in Example 9, Step B) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in step B of Example 4) using the procedure described in Step C of Example 4 followed by base catalyzed hydrolysis of the ester using the procedure described in Example 10.
Reaction SMILES: [C:1]([CH2:3][CH:4]([OH:16])[CH2:5][C:6](=[O:15])[CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])#[N:2].C(B(CC)OC)C.O1CCCC1.[BH4-].[Na+]>CO.COCCOCCOCCOC>[C:1]([CH2:3][CH:4]([OH:16])[CH2:5][CH:6]([OH:15])[CH2:7][C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9])#[N:2]
Reactant: CC(C)(C)OC(=O)CC(=O)CC(O)CC#N
Agent: CCB(CC)OC
Agent: [BH4-]
Agent: [Na+]
Solvent: COCCOCCOCCOC
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC(O)CC(O)CC#N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Crude 5R 1,1-dimethylethyl 6-cyano-5-hydroxy-3-oxohexanoate (about 150 mmoles) is dissolved by adding 22 mL diethylmethoxyborane and 200 mL tetrahydrofuran. The solution is stirred for about 2 hours at room temperature, then cooled to −70° C. to −75° C., and further diluted with 25 mL methanol. Sodium borohydride (6 g) as a solution in triglyme (75 mL) is added slowly at between −65° C. to −75° C. After the addition, the reaction mixture is warmed to 15° C. to 25° C., quenched by the addition of acetic acid and concentrated by vacuum distillation—keeping this distillate. The residue is diluted with methanol and concentrated by vacuum distillation—keeping this distillate and all subsequent ones separate from the first one. The residue is dissolved in a mixture of water and ethyl acetate, the layers separated, and the organic layer is concentrated by vacuum distillation. The residue is dissolved in methanol and acetic acid and concentrated by vacuum distillation. The residue is dissolved in ethyl acetate and concentrated by vacuum distillation resulting in crude [R(R*,R*)]-1,1-dimethylethyl 6-cyano-3,5-dihydroxyhexanoate.
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([NH:26][C:27]([CH:29]3[CH2:34][CH2:33][C:32]([F:36])([F:35])[CH2:31][CH2:30]3)=[O:28])[CH:24]=2)[N:19](C2CCCCO2)[N:18]=1>C(Cl)Cl>[NH:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:8]=[C:9]1[C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([NH:26][C:27]([CH:29]3[CH2:30][CH2:31][C:32]([F:36])([F:35])[CH2:33][CH2:34]3)=[O:28])[CH:24]=2)[NH:19][N:18]=1
Reactant: O=C(Nc1ccc2c(c1)c(-c1nc3ccccc3[nH]1)nn2C1CCCCO1)C1CCC(F)(F)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc2[nH]nc(-c3nc4ccccc4[nH]3)c2c1)C1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 72.8 %

Procedure:
TFA (0.5 mL, 6.490 mmol) was added to a solution of N-(3-(1H-benzo[d]imidazol-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-4,4-difluorocyclo hexane carboxamide (10 mg) in CH2Cl2 (4 mL). The reaction mixture was stirred at room temperature for 24 h, and then the solvent was removed in vacuo. Purification by flash chromatography (6% CH3OH/CH2Cl2) afforded the title compound (6 mg) as an off-white solid. 1H NMR (400 MHz, CD3OD): δ 8.67 (s, 1H), 7.80 (m, 2H), 7.69 (d, 1H, J=9.2 Hz), 7.52 (m, 3H), 2.57 (m, 1H), 2.18 (m, 2H), 2.01 (m, 2H), 1.97-1.87 (m, 3H); ESI-MS [M+H]+: 396.3.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][CH:3]=1.[OH-:18].[K+]>O1CCOCC1>[CH:9]1([NH:8][C:6]2[N:7]=[C:2]([OH:18])[CH:3]=[CH:4][C:5]=2[N+:15]([O-:17])=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1NC1CCCCC1
Reactant: [OH-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc(O)nc1NC1CCCCC1
Temperature: 100 °C

Procedure:
To a solution of 6-chloro-N-cyclohexyl-3-nitropyridin-2-amine (2.16 g, 8.45 mmol) dissolved in dioxane (845 mL) was added 3 M aqueous potassium hydroxide (8.5 mL). The reaction mixture was heated at 100° C. until LCMS showed the starting material was entirely consumed. The reaction mixture was cooled to room temperature and then diluted with water. 1 N HCl was added until the solution turned acidic and a solid was formed. The solid was filtered, washed with water, and dried under vacuum to afford the title compound as a yellow solid (1.58 g). LCMS m/z=238.30 [M+H]+.
Reaction SMILES: [C:1]1([C:7]([C:9]2[CH:10]=[N:11][C:12]3[C:17]([C:18]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:16][CH:15]=[CH:14][C:13]=3[C:25]([F:28])([F:27])[F:26])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:30][OH:31].O.O.O.C([O-])(=O)C.[Na+]>CCO.O>[C:1]1(/[C:7](/[C:9]2[CH:10]=[N:11][C:12]3[C:17]([C:18]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:16][CH:15]=[CH:14][C:13]=3[C:25]([F:28])([F:27])[F:26])=[N:30]\[OH:31])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1ccccc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O/N=C(\c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1ccccc1
Reaction time: 8 h
Yield: 75.2 %

Procedure:
Phenyl[4-phenyl-8-(trifluoromethyl)quinolin-3-yl]methanone (Example 1, 0.128 g, 0.339 mmol) was taken into EtOH/H2O (7 mL, 7:3 mixture) along with hydroxylamine hydrochloride (0.028 g, 0.407 mmol) and sodium acetate trihydrate (0.061 g, 0.447 mmol) and this mixture was refluxed for 1.5 hours. TLC and LC-MS showed no reaction. Therefore, excess quantities of hydroxylamine hydrochloride and sodium acetate trihydrate were added and refluxing was continued overnight. The reaction was concentrated and the resulting material was taken up into CH2Cl2/H2O. The layers were separated and the aqueous layer was extracted with CH2Cl2. The combined organics were dried over sodium sulfate and concentrated. The product was purified via column chromatography using 15% ethyl acetate in hexane as the eluent to afford 0.100 g of desired product as a white solid. MS (ESI) m/z 393 ([M+H]+);
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[C:5]([NH2:10])[CH:4]=1.[C:11](O)(=O)[CH3:12]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[NH:9][C:11]([CH3:12])=[N:10][C:5]=2[CH:4]=1
Reactant: COc1ccc(N)c(N)c1
Reactant: CC(=O)O
Product: COc1ccc2[nH]c(C)nc2c1

Procedure:
1.95 g (14.11 mmol) 4-methoxy-o-phenylenediamine were refluxed in 30.0 mL acetic acid for 2 h with stirring. The reaction mixture was evaporated down i.vac. The residue was taken up in an aqueous NaHCO3 solution and filtered. The filtrate was extracted with dichloromethane. The organic phase was separated off, dried and evaporated down i.vac.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][NH:7][CH2:8][CH2:9][NH2:10])=[N:2]1.CS[C:13](=[NH:18])[NH:14][N+:15]([O-:17])=[O:16]>>[S:1]1[CH:5]=[CH:4][C:3]([CH2:6][NH:7][CH2:8][CH2:9][NH:10][C:13]([NH:14][N+:15]([O-:17])=[O:16])=[NH:18])=[N:2]1
Reactant: NCCNCc1ccsn1
Reactant: CSC(=N)N[N+](=O)[O-]
Product: N=C(NCCNCc1ccsn1)N[N+](=O)[O-]

Procedure:
Reaction of N-(3-isothiazolylmethyl)ethylenediamine with S-methyl-N-nitroisothiourea by the procedure of Example 2(ii) gives N-[2-(3-isothiazolylmethylamino)ethyl]-N'-nitroguanidine.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=[O:7].[C:9](Br)([CH3:12])([CH3:11])[CH3:10]>C(Cl)Cl>[CH3:10][C:9]([C:5]1[S:1][C:2]([C:6]([OH:8])=[O:7])=[CH:3][CH:4]=1)([CH3:12])[CH3:11]
Reactant: CC(C)(C)Br
Reactant: O=C(O)c1cccs1
Solvent: ClCCl
Product: CC(C)(C)c1ccc(C(=O)O)s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 46.3 %

Procedure:
To a solution of 5.0 g (39.02 mmol) of thiophene-2-carboxylic acid (Aldrich Chemical Co.) in 100 mL of methylene chloride stirred at 0° C. was added 11 g (82.5 mmol) of AICl3 and 5.8 g (43.0 mmol) of t-butyl bromide. The solution was stirred at room temperature for 18 hours then poured into 100 mL of ice water, and the mixture was extracted with ether. The extracts were washed with brine and dried over MgSO4, then concentrated to give 3.33 g of the title product. MS (M+H)+ : 202. NMR (CDCl3) δ:1.42 (s, 9H), 6.89 (d, 1H, J=4 Hz), 7.72 (d, 1H, J=4 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([O:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[CH:8]=[C:9]2[O:13][CH:12](C)[CH2:11][C:10]=12)=[O:4].[CH3:26]S(C1C=CC(F)=CC=1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+].C(OC(C1C=C(O)C2C=COC=2C=1)=O)C>>[CH2:1]([O:2][C:3]([C:5]1[CH:6]=[C:7]([O:15][C:16]2[CH:17]=[CH:18][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][CH:21]=2)[C:8]2[CH:11]=[CH:12][O:13][C:9]=2[CH:10]=1)=[O:4])[CH3:26]
Reactant: COC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2c1CC(C)O2
Reactant: CS(=O)(=O)c1ccc(F)cc1
Agent: CCOC(=O)c1cc(O)c2ccoc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCOC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)c2ccoc2c1

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 1f, from 4-fluorophenyl methyl sulfone (180 mg, 1.03 mmol), Cs2CO3 (630 mg, 1.93 mmol), and 4-hydroxy-benzofuran-6-carboxylic acid ethyl ester (8a) (199 mg, 0.97 mmol). Purification by flash column chromatography eluting with 15% EtOAc in hexanes gave a pale yellow oil (261 mg, 75% yield). 1H NMR (400 MHz, CDCl3) δ 8.13 (s, 1 H) 7.91 (s, 2 H) 7.74 (s, 1 H) 7.65 (s, 1 H) 7.13 (s, 2 H) 6.66 (s, 1 H) 4.41 (s, 2 H) 3.08 (s, 3 H) 1.42 (s, 3 H); LCMS for C18H1606S m/z 383.00 (M+Na)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[C:10]([OH:16])(=[O:15])[CH2:11]C(O)=O.C(O)(=O)C.[CH3:21][NH2:22]>C(O)C>[OH:1][C:2]1[CH:3]=[C:4]([CH:5]([NH:22][CH3:21])[CH2:11][C:10]([OH:16])=[O:15])[CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1cccc(O)c1
Reactant: CN
Reactant: O=C(O)CC(=O)O
Solvent: CC(=O)O
Solvent: CCO
Product: CNC(CC(=O)O)c1cccc(O)c1
Yield: 58.8 %

Procedure:
3-Hydroxybenzaldehyde (25.7 g, 210 mmol) was dissolved in ethanol (70 ml), and malonic acid (25.7 g) and the acetic acid salt of methylamine (38.6 g) were added to the solution. The resulting mixture was heated under reflux for 3 hours. Crystals which precipitated in the reaction mixture were collected by filtration to afford the desired compound (24.1 g).
Reaction SMILES: Br[CH:2]([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[C:3]([C:5]1[CH:16]=[CH:15][C:8]2[N:9]=[N:10][N:11]([CH:12]([CH3:14])[CH3:13])[C:7]=2[CH:6]=1)=O.C(=O)([O-])[O-].[Cs+].[Cs+].Cl.[C:31]([C:34]1[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=1)(=[NH:33])[NH2:32].O>CN(C)C=O>[F:23][C:20]1[CH:21]=[CH:22][C:17]([C:2]2[N:33]=[C:31]([C:34]3[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=3)[NH:32][C:3]=2[C:5]2[CH:16]=[CH:15][C:8]3[N:9]=[N:10][N:11]([CH:12]([CH3:14])[CH3:13])[C:7]=3[CH:6]=2)=[CH:18][CH:19]=1
Reactant: N=C(N)c1cccnc1
Reactant: CC(C)n1nnc2ccc(C(=O)C(Br)c3ccc(F)cc3)cc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)n1nnc2ccc(-c3[nH]c(-c4cccnc4)nc3-c3ccc(F)cc3)cc21
Temperature: 50 °C
Yield: 39.1 %

Procedure:
To a stirred solution of 29 mg of 2-bromo-2-(4-fluoro-phenyl)-1-(3-isopropyl-3H-benzotriazol-5-yl)-ethanone in 0.38 mL of N,N-dimethylformamide was added 75 mg of cesium carbonate and 24 mg of 3-amidinopyridine hydrochloride. The mixture was heated at 50° C. for 30 min. The orange-brown mixture was cooled to 22° C., transferred to a separatory funnel with water, and extracted with ethyl acetate (3×). The combined organic layers were washed with brine, dried (sodium sulfate), filtered, and the filtrate was concentrated to an orange oil. This oil was purified by flash chromatography (eluting with ethyl acetate) to give 12 mg of 6-[5-(4-fluoro-phenyl)-2-pyridin-3-yl-3H-imidazol-4-yl]-1-isopropyl-1H-benzotriazole as a white solid. LCMS m/z 399 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:32])=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][CH:16]3[CH2:18][CH2:17]3)[N:12]3[N:19]=[CH:20][C:21](/[CH:22]=[C:23]4/[C:24](=[O:31])[N:25]([CH2:29][OH:30])[C:26](=[O:28])[NH:27]/4)=[C:11]3[N:10]=2)[CH:7]=1.[CH3:33][N:34]1[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][C:42](O)=[O:43])[CH2:36][CH2:35]1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C=O)C.CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[CH3:33][N:34]1[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][C:42]([O:30][CH2:29][N:25]2[C:24](=[O:31])/[C:23](=[CH:22]/[C:21]3[CH:20]=[N:19][N:12]4[C:13]([NH:15][CH:16]5[CH2:17][CH2:18]5)=[CH:14][C:9]([NH:8][C:6]5[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=5[F:32])=[N:10][C:11]=34)/[NH:27][C:26]2=[O:28])=[O:43])[CH2:36][CH2:35]1
Reactant: O=C1N/C(=C\c2cnn3c(NC4CC4)cc(Nc4cc(Cl)ccc4F)nc23)C(=O)N1CO
Reactant: CN1CCN(CCC(=O)O)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1CCN(CCC(=O)OCN2C(=O)N/C(=C\c3cnn4c(NC5CC5)cc(Nc5cc(Cl)ccc5F)nc34)C2=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.2 %

Procedure:
To (Z)-5-((5-(5-chloro-2-fluorophenylamino)-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)-3-(hydroxymethyl)imidazolidine-2,4-dione (100 mg, 0.218 mmol) in DMF (3 mL) was added 3-(4-methylpiperazin-1-yl)propanoic acid (75 mg, 0.436 mmol), dicyclohexylcarbodiimide (90 mg, 0.436 mmol), and DMAP (4.0 mg, 0.33 mmol). The reaction mixture was stirred at room temperature overnight and then diluted with ethyl acetate and washed 1× water, 3× brine. The organic layer was dried with MgSO4, filtered and adsorbed onto silica gel. The crude material was purified by column chromatography eluting with 0-10% MeOH/CH2Cl2 gradient. Pure fractions were combined and the solvent was removed. This material was crystallized from ethyl acetate and hexane to provide 35 mg (26%) of (Z)-(4-((5-(5-chloro-2-fluorophenylamino)-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)methyl 3-(4-methylpiperazin-1-yl)propanoate as a yellow solid. LCMS (ES): >95% pure, m/z 612 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([OH:7])=O.CN(C(ON1N=NC2[CH:23]=[CH:24][CH:25]=[N:26]C1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.C1(N)CC1.CCN(C(C)C)C(C)C>CN(C=O)C.CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([NH:26][CH:25]1[CH2:23][CH2:24]1)=[O:7]
Reactant: O=C(O)c1ccc(Cl)c(Br)c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CC1
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CC1)c1ccc(Cl)c(Br)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3-bromo-4-chlorobenzoic acid (120 mg) in DMF (1 ml) was added a solution of HATU (192 mg) in DMF (1 ml) and a solution of HOBT (69 mg) in DMF (1 ml). To this mixture was added cyclopropylamine (0.04 ml) and DIPEA (0.27 ml). The reaction was stirred at room temperature for 18 hours, before diluting with methanol (5 ml) and filtration through a SPE cartridge (SCX, 2 g). The filtrate was applied to a SPE cartridge (Aminopropyl, 10 g) and washed through with methanol (10 ml). The combined filtrate and washings were reduced to dryness under vacuum to give 3-bromo-4-chloro-N-cyclopropylbenzamide.
Reaction SMILES: Cl[C:2]1[C:3]([C:10]([OH:12])=[O:11])=[CH:4][N:5]([CH3:9])[C:6](=[O:8])[CH:7]=1.C([N-]C(C)C)(C)C.[Li+].[Cl:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[Cl:29])[NH2:25]>O1CCCC1.C(OCC)C>[Cl:21][C:22]1[CH:23]=[C:24]([NH:25][C:2]2[C:3]([C:10]([OH:12])=[O:11])=[CH:4][N:5]([CH3:9])[C:6](=[O:8])[CH:7]=2)[CH:26]=[CH:27][C:28]=1[Cl:29]
Reactant: Cn1cc(C(=O)O)c(Cl)cc1=O
Reactant: Nc1ccc(Cl)c(Cl)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cn1cc(C(=O)O)c(Nc2ccc(Cl)c(Cl)c2)cc1=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 86.9 %

Procedure:
A suspension of 4-chloro-1-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid (161 mg, 0.86 mmol) was treated with lithium diisopropylamide (2.0 M solution in tetrahydrofuran-ethylbenzene-heptane, 0.45 mL, 0.9 mmol). The resultant solution was stirred for 30 min at ambient temperature under nitrogen and was then cooled to −78° C. This is solution A. In a separate flask, a solution of 3,4-dichloroaniline (147 mg, 1.21 mmol) in tetrahydrofuran (3.0 mL) was cooled to −78° C. and treated with lithium diisopropylamide (2.0 M solution in tetrahydrofuran-ethylbenzene-heptane, 1.2 mL, 2.4 mmol). The resultant solution was stirred for 30 min at −78° C. and was transferred to solution A (also at −78° C.) via cannula. The resultant reaction mixture was stirred for 30 min at −78° C. and was then warmed to ambient temperature for 2.5 h. The reaction was diluted with ethyl ether (10 mL) and filtered. The solid was washed with ether (10 mL). The filtrate and washings were discarded. The solid was partitioned between ethyl acetate (60 mL) and 1 N hydrochloric acid (20 mL). The organics were washed with water (2×20 mL) and brine (20 mL). The combined aqueous portion was further extracted with ethyl acetate (20 mL). All organics were combined and dried over magnesium sulfate and concentrated in vacuo to afford a brown-colored solid (234 mg), used in step B without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:11])=[C:4]([Cl:10])[C:5]([Cl:9])=[C:6]([Cl:8])[CH:7]=1.[N+:12]([O-])([OH:14])=[O:13].S(=O)(=O)(O)O.Cl>>[Cl:1][C:2]1[C:7]([N+:12]([O-:14])=[O:13])=[C:6]([Cl:8])[C:5]([Cl:9])=[C:4]([Cl:10])[C:3]=1[Cl:11]
Reactant: Clc1cc(Cl)c(Cl)c(Cl)c1Cl
Reactant: O=[N+]([O-])O
Agent: Cl
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Temperature: 125 °C

Procedure:
Into a three-neck 300 ml flask equipped with a mechanical agitator, thermometer and condenser was charged 50 g of 99.7% pure powdered pentachlorobenzene which was heated to 105°-110° C. by means of an oil bath. The flask was then charged with 113 g of mixed nitric acid which contained 16.5% by weight nitric acid and 83.5% by weight sulfuric acid. This mixed nitric acid was gradually added over a period of three hours while the reaction mixture was stirred. Following this addition, the reaction mixture was heated to 125° C. for one hour, followed by further heating at 140° C. for one hour. Then, 7 g of HCl was gradually added over a time period of 15 minutes. After said HCl addition, the reaction mixture was heated again to raise the reaction temperature to 145° C. and to form a liquid melt of pentachloronitrobenzene. The reaction mixture was maintained at this temperature for 15 minutes. Next, the reaction mixture was cooled to 30°-70° C. by removal of the oil bath and by blowing cool air on the flask for about 15 minutes. The reaction mixture was then filtered by suction. The pentachloronitrobenzene product in the filter cake was pressed dry and washed twice with 100 ml water each time. After drying at reduced pressure (20 tor), the product was analyzed by Vapor Phase Chromatography (VPC). In this specific example, the product was of exceptional quality with an assay of 99.20% pentachloronitrobenzene, 0.05% pentachlorobenzene and 0.37% hexachlorobenzene.
Reaction SMILES: [CH2:1]([CH:4]([CH2:12][CH2:13][CH3:14])[C:5]([NH:7][CH2:8][C:9]([OH:11])=[O:10])=[O:6])[CH2:2][CH3:3].C1(N=C=NC2CCCCC2)CCCCC1.[C:30]([O:49][CH2:50][C@H:51]1[O:55][C@@H:54]([N:56]2[CH:63]=[C:62]([F:64])[C:60](=[O:61])[NH:59][C:57]2=[O:58])[CH2:53][C@@H:52]1O)([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(N(CC)CC)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:12]([CH:4]([CH2:1][CH2:2][CH3:3])[C:5]([NH:7][CH2:8][C:9]([O:11][C@@H:52]1[C@@H:51]([CH2:50][O:49][C:30]([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:55][C@@H:54]([N:56]2[CH:63]=[C:62]([F:64])[C:60](=[O:61])[NH:59][C:57]2=[O:58])[CH2:53]1)=[O:10])=[O:6])[CH2:13][CH3:14]
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)O2)cc1F
Reactant: CCCC(CCC)C(=O)NCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(CCC)C(=O)NCC(=O)O[C@H]1C[C@H](n2cc(F)c(=O)[nH]c2=O)O[C@@H]1COC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 70.8 %

Procedure:
To a suspension in which 0.11 g of N-(2-n-propyl-n-pentanoyl)glycine was suspended in 15 ml of methylene chloride was added 0.11 g of dicyclohexylcarbodiimide under ice-cooling and stirring, and then the mixture was stirred under ice-cooling for one hour. Then, 0.27 g of 2'-deoxy-5'-O-trityl-5-fluorouridine, 70 mg of triethylamine and 34 mg of 4-(N,N-dimethylamino)pyridine were added to the mixture, and the mixture was reacted at room temperature for two days under stirring. Thereafter, the reaction mixture was treated according to the same method as in Reference example 5 to give 0.26 g (Yield: 70%) of the title compound.