Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH:3]([C:8]([O:10][CH3:11])=[O:9])[C:4]([O:6][CH3:7])=[O:5].[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1.O>ClCCl>[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([NH:2][CH:3]([C:8]([O:10][CH3:11])=[O:9])[C:4]([O:6][CH3:7])=[O:5])=[O:18])=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: COC(=O)C(N)C(=O)OC
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: COC(=O)C(NC(=O)c1ccc(Cl)cc1)C(=O)OC
Reaction time: 8 h
Yield: 78.5 %

Procedure:
Part A: To a stirred solution of dimethyl aminomalonate hydrochloride (25 gram, 0.136 mol) in dichloromethane (200 mL) triethylamine (41.4 mL, 2.2 molar equivalent) is added at 0° C. 4-Chlorobenzoyl chloride (23.8 gram, 0.136 mol) is slowly added and the resulting solution is allowed to stand at room temperature overnight. Water is added and the organic layer is separated. The water layer is extracted twice with dichloromethane. The collected organic layers are washed with water, dried over MgSO4, filtered and concentrated in vacuo. The residue is recrystallised from methanol (400 mL) to give dimethyl 2-(4-chlorobenzoylamino)malonate (30.5 gram, 79% yield). Melting point: 146-148° C. 1H-NMR (200 MHz, CDCl3): δ 3.86 (s, 6H), 5.38 (d, J=6 Hz, 1H), 7.15 (br d, J˜6 Hz, 1H), 7.43 (d, J=8 Hz, 2H), 7.79 (d, J=8 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[Br:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][NH2:22])=[CH:17][CH:16]=1>>[Br:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][NH:22][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=2)=[CH:17][CH:16]=1
Reactant: NNc1ccc(Br)cc1
Reactant: O=C(Cl)c1ccc(Cl)c([N+](=O)[O-])c1
Product: O=C(NNc1ccc(Br)cc1)c1ccc(Cl)c([N+](=O)[O-])c1

Procedure:
A mixture of 4-chloro-3-nitrobenzoyl chloride was reacted with (4-Bromo-phenyl)-hydrazine to produce 4-Chloro-3-nitro-benzoic acid N′-(4-bromo-phenyl)-hydrazide according to the procedure of Example 10A, which was treated sequentially using the procedures from Examples 100A, 100B and 100C to provide the title product.
Reaction SMILES: [CH2:1]1[CH2:6][C@H:5]([C:7]([OH:9])=[O:8])[CH2:4][CH2:3][C@H:2]1[CH2:10][NH2:11].[C:12]([O:20][CH:21]([O:24][C:25](ON1C(=O)CCC1=O)=[O:26])[CH2:22][CH3:23])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CC(OC)(C)C.CC(C)=O.O>[C:12]([O:20][CH:21]([O:24][C:25]([NH:11][CH2:10][C@H:2]1[CH2:3][CH2:4][C@H:5]([C:7]([OH:9])=[O:8])[CH2:6][CH2:1]1)=[O:26])[CH2:22][CH3:23])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: CCC(OC(=O)ON1C(=O)CCC1=O)OC(=O)c1ccccc1
Solvent: COC(C)(C)C
Solvent: O
Solvent: CC(C)=O
Product: CCC(OC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1)OC(=O)c1ccccc1

Procedure:
Following the general nucleophilic carbamoylation procedure, tranexamic acid (472 mg, 3.0 mmol) and 1-[(2,5-dioxopyrrolidinyl)oxycarbonyloxy]propyl benzoate (602 mg, 2.0 nmol) were reacted in the MTBE/acetone/water mixture (16 mL) to yield the title compound 32 (679 mg, 93% yield) as a white powder after work-up and mass-guided preparative HPLC purification. 1H NMR (400 MHz, DMSO-d6): δ=0.80-0.95 (br. m, 2H), 0.96 (t, J=7.6 Hz, 3H), 1.15-1.38 (br. m., 3H), 1.60-1.74 (m, 2H), 1.82-1.91 (m, 4H), 2.08 (tt, J=12.0, 3.2 Hz, 1H), 2.76-2.87 (br. m, 2H), 6.78 (t, J=5.6 Hz, 1H), 7.48-7.56 (br. m, 3H), 7.67 (tt, J=7.6, 1.2 Hz, 1H), 7.90-7.95 (m, 2H), 11.96 (br. s, 1H). MS (ESI) m/z 386.12 (M+Na)+; 362.14 (M−H)−.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:52])[NH:10][C@@H:11]1[CH2:15][CH2:14][N:13]([C:16]2[N:24]=[C:23]3[C:19]([N:20]=[CH:21][N:22]3[C@@H:25]3[CH2:29][C@H:28]([NH:30][C:31](=[O:34])[CH2:32][CH3:33])[C@@H:27]([OH:35])[C@H:26]3[OH:36])=[C:18]([NH:37][CH2:38][CH:39]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[N:17]=2)[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:53]1(C)[C:54](S(O)(=O)=O)=CC=C[CH:58]=1.[OH-].[NH4+]>CC(C)=O.COC(OC)(C)C>[CH2:1]([O:8][C:9](=[O:52])[NH:10][C@@H:11]1[CH2:15][CH2:14][N:13]([C:16]2[N:24]=[C:23]3[C:19]([N:20]=[CH:21][N:22]3[C@H:25]3[C@H:26]4[C@H:27]([O:35][C:53]([CH3:54])([CH3:58])[O:36]4)[C@@H:28]([NH:30][C:31](=[O:34])[CH2:32][CH3:33])[CH2:29]3)=[C:18]([NH:37][CH2:38][CH:39]([C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=3)[C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[N:17]=2)[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)OCc5ccccc5)C4)nc32)[C@H](O)[C@@H]1O
Reactant: Cc1ccccc1S(=O)(=O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: COC(C)(C)OC
Solvent: CC(C)=O
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)OCc5ccccc5)C4)nc32)[C@@H]2OC(C)(C)O[C@@H]21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of {(R)-1-[9-((1R,2S,3R,4S)-2,3-dihydroxy-4-propionylamino-cyclopentyl)-6-(2,2-diphenyl-ethylamino)-9H-purin-2-yl]-pyrrolidin-3-yl}-carbamic acid benzyl ester (0.63 g, 0.89 mmol) in acetone (10 ml) and 2,2-dimethyloxypropane (5 ml) is treated with toluenesulfonic acid (ca.60 mg) and then stirred at room temperature overnight. The mixture is basified using ammonium hydroxide and the solvent is removed in vacuo. The crude product is partitioned between DCM and water and the organic portion is washed with brine, dried over MgSO4, filtered and the solvent is removed in vacuo to give the titled compound. [MH+ 745].
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:25]([O:27][C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=1)=[O:26]>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([O:17][C:25]([O:27][C:28]2[CH:29]=[CH:30][C:31]([N+:34]([O-:36])=[O:35])=[CH:32][CH:33]=2)=[O:26])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: O=C(OCc1ccccc1)N1CCC(O)CC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)OC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of the alcohol (72.3 g, 0.31 moles) produced in Example 20 and pyridine (37.3 ml, 0.46 moles) in 300 ml of methylene chloride was added dropwise under nitrogen over two hours to a solution of 4-nitrophenyl chloroformate (92.8 g, 0.46 moles) in 600 ml of methylene chloride at room temperature. After the addition the reaction was stirred for two days at room temperature. The reaction was then extracted two times with 1N HCl, multiple times with saturated Na2CO3, dried (MgSO4) and the solvent removed under reduced pressure. Recrystallization of the crude product from methylene chloride-diisopropyl ether gave the tide compound as a crystalline solid, mp 118-120° C.
Reaction SMILES: [ClH:1].O1CCOCC1.OC(C(F)(F)F)=O.[O:15]1[CH2:20][CH2:19][N:18]([C:21]2[O:22][CH:23]=[C:24]([C:26]([N:28]3[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH:29]3[CH2:41][O:42][C:43]3[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=3)=[O:27])[N:25]=2)[CH2:17][CH2:16]1>CO>[ClH:1].[ClH:1].[O:15]1[CH2:20][CH2:19][N:18]([C:21]2[O:22][CH:23]=[C:24]([C:26]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH:29]3[CH2:41][O:42][C:43]3[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=3)=[O:27])[N:25]=2)[CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2coc(N3CCOCC3)n2)C(COc2cccnc2)C1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Solvent: CO
Product: O=C(c1coc(N2CCOCC2)n1)N1CCNCC1COc1cccnc1
Reaction time: 8 h
Yield: 85 %

Procedure:
4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution of tert-butyl 4-(2-morpholinooxazole-4-carbonyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate TFA salt (165 mg, 0.277 mmol) in MeOH (1 mL). After stirring overnight, the reaction mixture was concentrated under reduced pressure to give 105.5 mg (85%) of the title compound as a white solid. LC-MS: RT=2.70 min, [M+H]+=374.0.
Reaction SMILES: Cl[C:2]([F:11])([C:7]([F:10])([F:9])[F:8])[C:3]([F:6])([F:5])[F:4].[F:12]C(F)(F)C(F)=C(F)F.FC(F)(F)C(F)C(F)(F)F>>[F:4][C:3]([F:6])([F:5])[C:2]([F:11])([F:12])[C:7]([F:10])([F:9])[F:8]
Reactant: FC(F)=C(F)C(F)(F)F
Reactant: FC(F)(F)C(F)(Cl)C(F)(F)F
Agent: FC(C(F)(F)F)C(F)(F)F
Product: FC(F)(F)C(F)(F)C(F)(F)F

Procedure:
The product of this invention, 2-chloro-1,1,1,2,3,3,3-heptafluoropropane (CFC-217ba), is useful as an intermediate for commercially valuable fluorocarbons. For example, hydrodechlorination of CFC-217ba gives either hexafluoropropene, a useful polymer intermediate, or 1,1,1,2,3,3,3-heptafluoropropane (HFC-227ea), which finds application as a propellant and fire extinguishant. Fluorination of CFC-217ba gives octafluoropropane (FC-218) which is useful as an etchant in the electronics industry.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH2:25][CH3:26])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.Cl[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=1)=[O:30]>>[CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][C:14]=2[CH2:23][N:24]([C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=2)=[O:30])[CH2:25][CH3:26])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC
Reactant: O=C(Cl)OCc1cccc(Cl)c1
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC)C(=O)OCc1cccc(Cl)c1

Procedure:
Prepared according to the procedure described in Example 56, Step 2, using the following starting materials: (2′-ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and 3-chlorobenzyl chloroformate.
Reaction SMILES: C(O[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13](O)=[C:12](F)[C:11]=2F)=[C:6](F)[C:5]=1F)C.C(=O)([O-])[O-].[Na+].[Na+].CN(C=O)C.O>C1(C)C=CC=CC=1>[C:7]1([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:8]=[CH:9][CH:4]=[CH:5][CH:6]=1
Reactant: CCOc1ccc(-c2ccc(O)c(F)c2F)c(F)c1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(-c2ccccc2)cc1
Temperature: 80 °C

Procedure:
In a reactor under nitrogen atmosphere, 4.4 g of compound (a4) and 3.2 g of sodium carbonate were added into 20 ml of DMF, followed by stirring at 80° C. 3.8 g of compound (a9) was added thereto, followed by stirring at 80° C. for an hour. The resulting reaction mixture was cooled to 30° C., to which 30 ml of water and 30 ml of toluene were added. The mixture was separated into organic layer and aqueous layer and the organic layer was extracted. The resulting organic layer was separated and washed with salt water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to provide the residue. The resulting residue was purified by column chromatography (volume ratio heptane: toluene=4:1), further by recrystallization from the solvent mixture of Solmix A-11 and heptane (volume ratio Solmix A-11: heptane=1:2), dried to provide 1.8 g of 4′-ethoxy-2,3,2′,3′-tetrafluoro-4-(trans-4-vinylcyclohexylmethoxy)-biphenylmethoxy)-biphenyl (a10).
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[CH:8][C:9]([C:17]([OH:19])=O)=[N:10][C:11]=2[O:12][CH2:13][CH:14]2[CH2:16][CH2:15]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:20][C@@H:21]([CH2:25][CH:26]1[CH2:28][CH2:27]1)[C:22]([NH2:24])=[O:23]>>[C:22]([C@@H:21]([NH:20][C:17]([C:9]1[CH:8]=[CH:7][C:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[C:11]([O:12][CH2:13][CH:14]2[CH2:15][CH2:16]2)[N:10]=1)=[O:19])[CH2:25][CH:26]1[CH2:28][CH2:27]1)(=[O:23])[NH2:24]
Reactant: NC(=O)[C@@H](N)CC1CC1
Reactant: O=C(O)c1ccc(C2CCCC2)c(OCC2CC2)n1
Product: NC(=O)[C@H](CC1CC1)NC(=O)c1ccc(C2CCCC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopentyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 39 b) and (S)-2-amino-3-cyclopropyl-propionamide (CAN 156077-93-9) as starting materials, MS (EI): m/e=372.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C@H:7]([N:11]1[C:19]3[C:14](=[CH:15][C:16]([CH:20]=O)=[CH:17][CH:18]=3)[CH:13]=[N:12]1)[CH2:6][CH2:5]2.[N:22]1([CH2:27][CH2:28][N:29]2[C:33](=[O:34])[CH2:32][S:31][C:30]2=[O:35])[CH2:26][CH2:25][CH2:24][CH2:23]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C@H:7]([N:11]1[C:19]3[C:14](=[CH:15][C:16](/[CH:20]=[C:32]4/[C:33](=[O:34])[N:29]([CH2:28][CH2:27][N:22]5[CH2:26][CH2:25][CH2:24][CH2:23]5)[C:30](=[O:35])[S:31]/4)=[CH:17][CH:18]=3)[CH:13]=[N:12]1)[CH2:6][CH2:5]2
Reactant: O=C1CSC(=O)N1CCN1CCCC1
Reactant: O=Cc1ccc2c(cnn2[C@@H]2CCc3cc(Cl)ccc32)c1
Product: O=C1S/C(=C\c2ccc3c(cnn3[C@@H]3CCc4cc(Cl)ccc43)c2)C(=O)N1CCN1CCCC1

Procedure:
(5Z)-5-({1-[(1R)-5-Chloro-2,3-dihydro-1H-inden-1-yl]-1H-indazol-5-yl}methylidene)-3-(2-pyrrolidin-1-ylethyl)-1,3-thiazolidine-2,4-dione was prepared by the method described for Example 172, using the isomeric (1R)-(5-chloroindan-1-yl)-1H-indazole-5-carbaldehyde and 3-(2-pyrrolidin-1-ylethyl)-1,3-thiazolidine-2,4-dione following General Procedure F.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([N-][C@@H:15]1[CH2:20][O:19][CH2:18][C:17](=O)[N:16]1[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)C1C=CC=CC=1.[OH-].[Na+]>O1CCCC1>[CH2:22]([NH:16][CH2:15][CH:17]1[CH2:18][O:19][CH2:20][CH2:15][N:16]1[CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C1COC[C@@H]([N-]Cc2ccccc2)N1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: c1ccc(CNCC2COCCN2Cc2ccccc2)cc1
Temperature: 70 °C
Reaction time: 15 h
Yield: 59.8 %

Procedure:
Lithium aluminum hydride (4.7 g) was added by small portions to a solution of N-benzyl((3S)-4-benzyl-5-oxomorpholin-3-yl)amide (8.0 g) in tetrahydrofuran (50 ml) under nitrogen atmosphere, and the whole was stirred at 70° C. for 15 hours. After being cooled with ice, 2N sodium hydroxide (2 ml) was added to the mixture under nitrogen atmosphere. The resulting precipitates were filtered off and washed with tetrahydrofuran, and the filtrate and the washings were combined and evaporated under reduced pressure to give a crude oil. The oil was purified by column chromatography on silica gel using a mixed solvent of dichloromethane and methanol (9:1). The fractions containing the objective compound were collected, evaporated under reduced pressure to give an oil of N-benzyl[(4-benzylmorpholin-3-yl)methyl]amine (2.4 g).
Reaction SMILES: C([O-])(=O)C.[Na+].[NH2:6]O.[CH2:8]([O:15][C:16]1[C:23]([O:24][CH3:25])=[C:22]([O:26][CH3:27])[CH:21]=[CH:20][C:17]=1[CH:18]=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O>C(O)(=O)C>[CH2:8]([O:15][C:16]1[C:23]([O:24][CH3:25])=[C:22]([O:26][CH3:27])[CH:21]=[CH:20][C:17]=1[C:18]#[N:6])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NO
Reactant: COc1ccc(C=O)c(OCc2ccccc2)c1OC
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(C#N)c(OCc2ccccc2)c1OC

Procedure:
A slurry of sodium acetate (17.06 g, 0.208 mol) and hydroxylamine (14.45 g, 0.208 mol) in glacial acetic acid (120 ml) was added to 2-benzyloxy-3,4-dimethoxybenzaldehyde (28.3 g, 0.104 mol) and the resulting suspension stirred at reflux for 18 hours. On cooling, water (250 ml) was added and the mixture extracted with dichloromethane (500 ml). The combined organic extracts were dried (MgSO4), filtered and evaporated under reduced pressure. The crude product was purified on silica gel eluting with hexane:ethyl acetate (80:20 v/v) to give the subtitle compound as an oil that crystallised on standing (21.06 g, 75%). Rf 0.52 (ethyl acetate:hexane, 1:1, v/v). MS m/z 270 (MH)+.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:7]=1[NH:15][C:16]1[N:21]=[C:20]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[CH:19]=[CH:18][N:17]=1)C=C.[Cl-].[Na+]>C1COCC1.[Cl-].[Zn+2].[Cl-]>[OH:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:7]=1[NH:15][C:16]1[N:21]=[C:20]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[CH:19]=[CH:18][N:17]=1
Reactant: C=CCOCc1ccc([N+](=O)[O-])cc1Nc1nccc(-c2cccnc2)n1
Agent: [Cl-]
Agent: [Na+]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(CO)c(Nc2nccc(-c3cccnc3)n2)c1
Temperature: 30 °C
Reaction time: 30 h

Procedure:
Polymethylhydrosiloxane (860 mg), tetrakis(triphenylphoshine)palladium (70 mg) and zinc chloride (2.66 mL of 0.5 M in THF, 1.33 mmol) is added to a stirred solution of N-{2-[(2-propenyloxy)-methyl]-5-nitro-phenyl}-4-(3-pyridinyl)-2-pyrmidinamine (2.60 g, 7.2 mmol) in dry THF (60 mL). The mixture is then stirred under an argon atmosphere at 30° C. for 30 h. The solvent is then evaporated off under reduced pressure to give a residue which is treated with saturated aqueous sodium chloride solution (50 mL) and extracted with ethyl acetate (3×50 mL). The combined extracts are dried (Na2SO4), filtered and the solvent is evaporated off under reduced pressure to yield the crude product which is recrystallised from THF to give the title compound as a pale-yellow crystalline solid, m.p. 247-250° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([NH:17][C@H:18]([C:20]4[N:25]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[C:24](=[O:32])[C:23]5=[C:33]([CH3:36])[CH:34]=[CH:35][N:22]5[N:21]=4)[CH3:19])=[N:14][CH:13]=[N:12][C:11]=3[N:10](COCC[Si](C)(C)C)[CH:9]=2)=[C:4]([O:45][CH3:46])[CH:3]=1.FC(F)(F)C(O)=O.N>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([NH:17][C@H:18]([C:20]4[N:25]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[C:24](=[O:32])[C:23]5=[C:33]([CH3:36])[CH:34]=[CH:35][N:22]5[N:21]=4)[CH3:19])=[N:14][CH:13]=[N:12][C:11]=3[NH:10][CH:9]=2)=[C:4]([O:45][CH3:46])[CH:3]=1
Reactant: COc1cc(F)ccc1-c1cn(COCC[Si](C)(C)C)c2ncnc(N[C@@H](C)c3nn4ccc(C)c4c(=O)n3-c3ccccc3)c12
Agent: N
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(F)ccc1-c1c[nH]c2ncnc(N[C@@H](C)c3nn4ccc(C)c4c(=O)n3-c3ccccc3)c12
Yield: 65.4 %

Procedure:
(S)-2-(1-((5-(4-Fluoro-2-methoxyphenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (21 mg, 0.03 mmol) was treated with trifluoroacetic acid (420 μl, 5.45 mmol) and a solution of ammonia (7N in methanol, 420 μl, 2.94 mmol) according to the method described in Example 27 to give 10 mg (59% yield) of the title compound as a white solid. Purity 98%.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([CH3:14])([CH3:13])[S:10][C:9]=2[CH:15]=1)=[O:4].[N-:16]=[N+:17]=[N-:18].[Na+]>C(#N)C>[N:16]([CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([CH3:14])([CH3:13])[S:10][C:9]=2[CH:15]=1)=[O:4])=[N+:17]=[N-:18]
Reactant: CC1(C)Oc2ccc(C(=O)CCl)cc2S1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC#N
Product: CC1(C)Oc2ccc(C(=O)CN=[N+]=[N-])cc2S1

Procedure:
A solution of 20 g of 5-chloroacetyl-2,2-dimethyl-1,3-benzoxathiole (VII) in acetonitrile (100 ml) was stirred for two days with 7 g of finely powdered sodium azide. The reaction mixture was filtered, evaporated and the residue recrystallized from methanol to yield 12 g of 5-azidoacetyl-2,2-dimethyl-1,3-benzoxathiole (VIII), m.p. 52°-53° C.
Reaction SMILES: [OH:1]S(O)(=O)=O.[F:6][C:7]1[CH:8]=[C:9]([N+:17]([O-:19])=[O:18])[C:10]([OH:16])=[C:11](C(=O)C)[CH:12]=1>O1CCOCC1>[F:6][C:7]1[CH:12]=[C:11]([OH:1])[C:10]([OH:16])=[C:9]([N+:17]([O-:19])=[O:18])[CH:8]=1
Reactant: O=S(=O)(O)O
Reactant: CC(=O)c1cc(F)cc([N+](=O)[O-])c1O
Solvent: C1COCCO1
Product: O=[N+]([O-])c1cc(F)cc(O)c1O
Temperature: 28 °C
Reaction time: 1 h

Procedure:
H2SO4 (50 mL) was added to a solution of H3BO3 (89.3 g, 1.4 mol) in 1,4-Dioxane (300 mL) at 0° C. and stirred at 28° C. for 1 h. 1-(5-fluoro-2-hydroxy-3-nitrophenyl) ethanone (50 g, 289 mmol) was added portion wise to the above solution over 1 h, maintaining the temperature at 0° C., after addition was complete, the reaction mixture was warmed to 25° C. and stirred for 16 h. Reaction mixture was quenched with cold water, solid separated was collected by filtration. The solid was suspended in diethyl ether (500 mL) and filtered to remove insoluble inorganic mass, ether layer was washed with cold water (2 to 3 times) followed by brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the crude sticky solid. The crude solid was triturated over n-Hexane and filtered to afford 5-fluoro-3-nitrobenzene-1,2-diol (Int-50) as pale yellow solid. MS (ESI): m/z 171.9 (M−1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1[NH:10][CH2:11][CH2:12][OH:13].N[C:15](N)=[O:16]>O>[Cl:8][C:6]1[C:5]([Cl:9])=[CH:4][C:3]2[N:10]([CH2:11][CH2:12][OH:13])[C:15](=[O:16])[NH:1][C:2]=2[CH:7]=1
Reactant: Nc1cc(Cl)c(Cl)cc1NCCO
Reactant: NC(N)=O
Solvent: O
Product: O=c1[nH]c2cc(Cl)c(Cl)cc2n1CCO
Temperature: 190 °C
Yield: 99 %

Procedure:
A mixture of 50 parts of 2-[(2-amino-4,5-dichlorophenyl)-amino]ethanol and 46 parts of urea is stirred and heated for 2 hours in an oil-bath at about 190° C. The reaction mixture is cooled and water is added. The water is decanted and the residue is boiled in 2-propanol. Upon stirring, the mixture is cooled to room temperature. The product is filtered off and dried, yielding 55 parts (99%) of 5,6-dichloro-1,3-dihydro-1-(2-hydroxyethyl)-2H-benzimidazol-2-one.
Reaction SMILES: C(OC([NH:8][C:9]([NH:25]C(OC(C)(C)C)=O)=[N:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][N:18]=2)[CH:12]=1)=O)(C)(C)C.[ClH:33]>ClCCl.O1CCOCC1>[ClH:33].[ClH:33].[CH3:24][O:23][C:21]1[CH:20]=[CH:19][N:18]=[C:17]([C:13]2[CH:12]=[C:11]([NH:10][C:9]([NH2:25])=[NH:8])[CH:16]=[CH:15][CH:14]=2)[CH:22]=1
Reactant: COc1ccnc(-c2cccc(N=C(NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c2)c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1ccnc(-c2cccc(NC(=N)N)c2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of N,N′-bis(tert-butoxycarbonyl)-N″-(3-(4-methoxypyridin-2-yl)phenyl)guanidine (200 mg) in dichloromethane (2 ml) was added a solution of hydrogen chloride in 1,4-dioxane (4N, 4 ml), and the mixture was stirred at room temperature for 24 hours. The solvent was evaporated under reduced pressure. To the residue was added 5% ethanol in ethyl acetate (100 ml), and the precipitate was collected by filtration and dried under reduced pressure to give 3-(4-methoxypyridin-2-yl)phenylguanidine dihydrochloride (120 mg).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]([CH3:15])[C@H:10]([C:12]([OH:14])=[O:13])[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([N:18]1[CH2:23][CH2:22][N:21]([C:24](Cl)=[O:25])[C:20](=[O:27])[C:19]1=[O:28])[CH3:17].CO.C(O)(=O)C>O.CC(C)=O.C(Cl)(Cl)Cl>[CH2:1]([O:8][C@@H:9]([CH3:15])[C@@H:10]([NH:11][C:24]([N:21]1[CH2:22][CH2:23][N:18]([CH2:16][CH3:17])[C:19](=[O:28])[C:20]1=[O:27])=[O:25])[C:12]([OH:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](OCc1ccccc1)[C@@H](N)C(=O)O
Reactant: CCN1CCN(C(=O)Cl)C(=O)C1=O
Solvent: CC(C)=O
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CCN1CCN(C(=O)N[C@@H](C(=O)O)[C@H](C)OCc2ccccc2)C(=O)C1=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
O-Benzyl-D-threonine (0.92 g, 4.4 mmole) (prepared by the method of T. Mizoguchi, G. Levin, D. W. Woolley, and J. M. Stewart, J. Org. Chem., 1968, 33, 903, who described the L-isomer) was suspended in water (20 ml) and the pH adjusted to 9.5 , giving a virtually complete solution. This was cooled to 0° C. and stirred while 4-ethyl-2,3-dioxopiperazine-1-carbonyl chloride (1.00 g, 4.9 m mole) in AR acetone (10 ml) was added dropwise. The pH was kept at 9.5 by the addition of further base while the solution was allowed to regain room temperature. After 2 h the solution was acidified to pH 2 and the bulk of the acetone removed by evaporation. The oily product was extracted into ethyl acetate (3×50 ml), then the total organic phase was washed once with brine and dried over sodium sulphate. Evaporation gave the title acid (1.36 g, 82%) as a colourless non-crystalline foam which retained solvent traces tenaciously; Rf 0.35 in chloroform:methanol:acetic acid, 17:2:1; δ(CDCl3) 0.75-1.35 (5H, m, CH3CH and NCH2CH3), 3.1-3.7 (4H, m, 2 NCH2), 3.9-4.25 (2H, m, NCH2), 4.50 (2H, m, CH--CH), 6.25 (1H, brs, D2O exch, OH), 7.25 (5H, s, aryl), 9.50 (1H, brd), J 7 Hz, D2O exch, NH), 9.70 (1H, brs, D2O exch, CO2H).