Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([OH:10])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[NH2:12][CH:13]1[C:24](=[O:25])[N:15]2[CH:16]([C:21]([OH:23])=[O:22])[C:17]([CH3:20])([CH3:19])[S:18][C@H:14]12.F[C:27]1[NH:28][C:29]2[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=2[N:31]=1>CN(C=O)C>[C:1]1([CH3:11])[CH:2]=[CH:3][C:4]([S:7]([OH:10])(=[O:8])=[O:9])=[CH:5][CH:6]=1.[N:28]1[C:29]2[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=2[NH:31][C:27]=1[NH:12][CH:13]1[C:24](=[O:25])[N:15]2[CH:16]([C:21]([OH:23])=[O:22])[C:17]([CH3:20])([CH3:19])[S:18][C@H:14]12
Reactant: Fc1nc2ccccc2[nH]1
Reactant: CC1(C)S[C@@H]2C(N)C(=O)N2C1C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Product: CC1(C)S[C@@H]2C(Nc3nc4ccccc4[nH]3)C(=O)N2C1C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 83.3 %

Procedure:
To a solution of anhydrous 6-amino-2,2-dimethylpenam-3-carboxylic acid toluene-p-sulphonate (171 mg.) in dry DMF was added 2-fluorobenzimidazole (150 mg.) in one portion and the mixture stirred at ambient temperature for 1.5 hours. The mixture was evaporated to dryness under reduced pressure at room temperature and the resulting residue, a mobile oil, was triturated with EtOAc (2×10 ml.) and then dry acetonitrile (2 ml.) whereupon the product crystallised. The solid was filtered and washed with acetonitrile and ether to give 6-(benzimidazol-2-yl)amino-2,2-dimethylpenam-3-carboxylic acid toluene-p-sulphonate (185 mg.), m.p. 181°-183°, having the following n.m.r. spectrum in d6DMSO: 1.49 (s, 3H); 1.62 (s, 3H); 2.29 (s, 3H); 4.39 (s, 1H); 5.54 (br, 1H); 5.68 (d, 1H); 7.0-7.56 (m, 8H); 9.93 (br, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)=[N:10][C:9]([Br:21])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].N([O-])=O.[Na+].[N-:26]=[N+:27]=[N-].[Na+].CCOCC>C(O)(C(F)(F)F)=O.C(Cl)Cl.C1COCC1>[N:1]([C:2]1[C:11]([C:12]2[CH:13]=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=2)=[N:10][C:9]([Br:21])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])=[N+:26]=[N-:27]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1cc(Br)nc(-c2ccc([N+](=O)[O-])cc2)c1N
Agent: O=N[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)c1cc(Br)nc(-c2ccc([N+](=O)[O-])cc2)c1N=[N+]=[N-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 330 %

Procedure:
Methyl 3-amino-6-bromo-2-(4-nitrophenyl)isonicotinate (7.2 g, 20 5 mmol) was dissolved in TFA (70 mL) and the yellow solution was cooled in an ice bath. Sodium nitrite (2.82 g, 40.9 mmol) was added in small portions with stirring to give a dark yellow mixture. After 30 min, sodium azide (13.29 g, 204 mmol) was added in small portions followed by Et2O (20 mL). The light yellow mixture was stirred in the ice-bath for 30 min and then partitioned between DCM and water. The organic phase washed with water (3×250 mL), sat. aq. Na2CO3 solution (3×250 mL), brine, dried with sodium sulfate, and the solvent removed. Silica gel chromatography (30% THF in DCM) afforded methyl 3-azido-6-bromo-2-(4-nitrophenyl)isonicotinate (6.8 g, 16.5 mmol, 81% yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 8.37 (2H, d, J=8.85 Hz), 8.06 (1H, s), 8.02 (2H, d, J=9.16 Hz), 3.97 (3H, s).
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:23])[N:5](C2C=CC(OC)=CC=2)[CH2:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)[CH3:2].S([O-])([O-])=O.[Na+].[Na+].C(=O)(O)[O-].[Na+]>O.C(#N)C>[CH2:1]([C:3]1[C:4](=[O:23])[NH:5][CH2:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)[CH3:2]
Reactant: CCC1=C(c2ccc(F)cc2)CN(c2ccc(OC)cc2)C1=O
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCC1=C(c2ccc(F)cc2)CNC1=O
Reaction time: 0.5 h

Procedure:
A solution of ceric ammonium nitrate (542 g, 0.99 mol) in water (1L) is added dropwise over 45 minutes to a suspension of 3-ethyl-4-(4-fluorophenyl)-1,5-dihydro-1-(4-methoxyphenyl)-2H-pyrrol-2-one (103 g, 0.33 mol) in acetonitrile (2 L), while the temperature of the reaction mixture is maintained at 0°-10° C. After stirring 30 minutes sodium sulfite (125 g) is added. The mixture is stirred 30 minutes more and sodium bicarbonate (83 g) is added. After stirring an additional 30 minutes the mixture is concentrated to 1L and extracted with methylene chloride and ethyl acetate. The extracts are dried with magnesium sulfate, evaporated, and recrystallized from ethanol. Chromatography of this material on silica gel followed by drying under vacuum at 60° C. for 18 hr affords the title compound.
Reaction SMILES: CC(C)=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.[N+:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[CH:27]=[CH:26][S:25][C:24]=1[CH:28]=[O:29])([O-:16])=[O:15].C(O)(C)C>CC(C)=O>[N+:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[CH:27]=[CH:26][S:25][C:24]=1[C:28]([OH:3])=[O:29])([O-:16])=[O:15]
Reactant: O=Cc1sccc1-c1ccccc1[N+](=O)[O-]
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Product: O=C(O)c1sccc1-c1ccccc1[N+](=O)[O-]
Reaction time: 18 h
Yield: 66 %

Procedure:
8N Jones' reagent (ca. 30 ml) was added dropwise to a solution of 3-(2-nitrophenyl)-thiophen-2-aldehyde (8) (4.4 g, 3.1 mmol) in 32 ml of acetone, until an orange colour persisted. The mixture was left at room temperature for 18 hrs with stirring. Isopropanol (20 ml) was added to remove the excess Jones' reagent and the mixture was then filtered, the organic solvents were removed under vacuum and extracted with ethyl acetate (4×100 ml). The combined organic layer was washed with a saturated solution of NaCl, dried (Na2SO4), and evaporated under reduced pressure. The mixture was then chromatographed using 95/5 chloroform/methanol, thus giving the compound (9) (3.6 g, 66% yield).
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].Br[CH:6]([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[CH:7]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[C:8]([F:11])([F:10])[F:9].Cl>C1(OC)C=CC=CC=1>[F:26][C:23]1[CH:24]=[CH:25][C:20]([CH:6]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH:7]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:8]([F:11])([F:10])[F:9])=[CH:21][CH:22]=1
Reactant: COc1ccc(C(C(Br)c2ccc(F)cc2)C(F)(F)F)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: COc1ccccc1
Product: COc1ccc(C(c2ccc(F)cc2)C(c2ccc(OC)cc2)C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 114.1 %

Procedure:
20 g (0.15 moles) of anhydrous aluminium trichloride are added to a solution of 56.6 g (0.15 moles) of 1-bromo-3,3,3-trifluoro-1-(4-fluorophenyl)-2-(4-methoxyphenyl)-propane, prepared as described in Example 19, in 570 ml of anisol at 6° C. under stirring. The reaction mixture is allowed to stand at room temperature overnight, then it is poured into a mixture of 600 g of crushed ice and 100 ml of a 36% aqueous hydrochloric acid, and the resulting mixture is extracted with 500 ml of chloroform. The organic solution is washed with aqueous sodium hydrocarbonate solution and water, dried, and the solvent is evaporated. The dry residue is crystallized from 240 ml of isopropanol to obtain 34.6 g (57%) of 1-(4-fluorophenyl)-3,3,3-trifluoro-1,2-bis (4-methoxyphenyl)-propane; m.p.: 132°-135° C.
Reaction SMILES: [Br:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=1[CH3:12].Br[CH2:14][CH:15](OCC)OCC>C(#N)C>[Br:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([C:6]2[O:7][CH:14]=[CH:15][N:8]=2)=[CH:9][C:10]=1[CH3:11]
Reactant: CCOC(CBr)OCC
Reactant: Cc1cc(C(N)=O)cc(C)c1Br
Solvent: CC#N
Product: Cc1cc(-c2ncco2)cc(C)c1Br
Temperature: 150 °C

Procedure:
In a microwave vial 4-bromo-3,5-dimethylbenzamide (200 mg) is mixed with 2-bromo-1,1-diethoxyethane (1 mL), the vial is sealed and the mixture is heated to 150° C. for 30 minutes. The mixture is diluted with acetonitrile (2 mL) and purified by HPLC on reversed phase to give the title compound. Yield: 125 mg; LC (method 7): tR=1.13 min; Mass spectrum (ESI+): m/z=252 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[N:12]1([CH2:17][CH2:18][CH2:19][NH:20][C:21]([C:23]2[NH:24][C:25]([CH:29]=O)=[C:26]([CH3:28])[CH:27]=2)=[O:22])[CH2:16][CH2:15][CH2:14][CH2:13]1>>[N:12]1([CH2:17][CH2:18][CH2:19][NH:20][C:21]([C:23]2[NH:24][C:25]([CH:29]=[C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=4)[NH:7][C:6]3=[O:11])=[C:26]([CH3:28])[CH:27]=2)=[O:22])[CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: Cc1cc(C(=O)NCCCN2CCCC2)[nH]c1C=O
Reactant: O=C1Cc2cc(Br)ccc2N1
Product: Cc1cc(C(=O)NCCCN2CCCC2)[nH]c1C=C1C(=O)Nc2ccc(Br)cc21
Yield: 17.3 %

Procedure:
5-Bromo-1,3-dihydroindol-2-one (0.16 g, 0.76 mmol) was condensed with 5-formyl-4-methyl-1H-pyrrole-2-carboxylic acid (3-pyrrolidin-1-ylpropyl)amide (0.2 g, prepared by method C) to give 60 mg (17%) of the title compound as an orange solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14]([O:19]C)[CH:13]=[C:12]([O:21]C)[C:11]=2[C@@H:23]1[CH2:27][CH2:26][N:25]([CH3:28])[C@H:24]1[C:29]([OH:31])=[O:30].Cl.N1C=CC=CC=1>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14]([OH:19])[CH:13]=[C:12]([OH:21])[C:11]=2[C@@H:23]1[CH2:27][CH2:26][N:25]([CH3:28])[C@H:24]1[C:29]([OH:31])=[O:30]
Reactant: COc1cc(OC)c2c(=O)cc(-c3ccccc3Cl)oc2c1[C@@H]1CCN(C)[C@H]1C(=O)O
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CN1CC[C@@H](c2c(O)cc(O)c3c(=O)cc(-c4ccccc4Cl)oc23)[C@@H]1C(=O)O
Temperature: 180 °C

Procedure:
Compound of example 143 (0.25 g, 0.563 mmol) was treated with pyridine hydrochloride (2.5 g, 21 mmol) and the reaction mixture was further heated at 180° C. for 2 h. Water (1 mL) was added after completion of the reaction and reaction mixture was purified on HP-20 column using water as eluant, followed by methanol and water in the ratio 70:30 to obtain the title compound.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([NH:5][CH2:6][CH2:7][NH:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)=[O:4].[C:20](OC(=O)C)(=[O:22])[CH3:21]>C(O)(=O)C>[C:20]([N:8]([C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)[CH2:7][CH2:6][NH:5][C:3](=[O:4])[C:2]([F:18])([F:19])[F:1])(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(NCCNc1ccc([N+](=O)[O-])cc1)C(F)(F)F
Solvent: CC(=O)O
Product: CC(=O)N(CCNC(=O)C(F)(F)F)c1ccc([N+](=O)[O-])cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
0.6 g (2.1 mmol) of 4-(2-trifluoroacetylamino-ethylamino)-nitrobenzene are dissolved in 10 ml of glacial acetic acid and after the addition of 2 ml (21.2 mmol) of acetic acid anhydride stirred for 5 hours at 80° C. and overnight at ambient temperature. The solvent is distilled off, the residue is made alkaline with sodium hydrogen carbonate and extracted with ethyl acetate. The combined organic extracts are dried and evaporated down.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.[BH4-].[Li+].[Cl-].[NH4+].Cl>C1COCC1.CO>[OH:12][CH2:8][CH2:7][CH2:6][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:11][C:10]=1[OH:9]
Reactant: O=c1ccc2ccc(O)cc2o1
Agent: Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: CO
Solvent: C1CCOC1
Product: OCCCc1ccc(O)cc1O
Temperature: 65 °C
Yield: 42 %

Procedure:
To a stirred solution of 7-hydroxycoumarin (7.0 g, 43.2 mmol ) in anhydrous THF (200 mL ) at rt under argon was added Lithium borohydride (2M, 65.8 mL, 129.6 mmol, 3.0 eq) solution in THF dropwise. Anhydrous methanol (1.0 mL) was added as catalyst to the reaction mixture. The mixture was heated at 65° C. for 17 h. The reaction mixture was then cooled to ambient temperature. Saturated ammonium chloride solution (40 mL) was added dropwise to the solution, followed by 1N HCl solution (40 mL). The mixture was extracted with ethyl acetate (2×100 mL). The combined organic extracts were dried (Na2SO4), filtered, and evaporated in vacuo. The residue was purified on silica gel (flash column chromatography) eluting with 30% ethyl acetate-hexane to provide the desired product as white solid (3.05 g, 42%). 1H-NMR (CD3CN) δ 6.91 (d, 1H), 6.29 (s, 1H), 6.28 (d, 1H), 3.51 (t, 2H), 2.56 (t, 2H), 1.73 (m, 2H). MS GC-MS (M+=168).
Reaction SMILES: [NH2:1][C:2]1[C:15]([O:16][CH3:17])=[CH:14][C:5]2[N:6]([CH2:12][CH3:13])[C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:19]1[N:24]=[C:23]([NH:25][C@@H:26]2[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]2[NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[C:22]([Cl:37])=[CH:21][N:20]=1.Cl.CC[NH+](CC)CC.CC[NH+](CC)CC.C([O-])([O-])=O>O1CCOCC1>[Cl:37][C:22]1[C:23]([NH:25][C@@H:26]2[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]2[NH:32][S:33]([CH3:36])(=[O:35])=[O:34])=[N:24][C:19]([NH:1][C:2]2[C:15]([O:16][CH3:17])=[CH:14][C:5]3[N:6]([CH2:12][CH3:13])[C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:20][CH:21]=1
Reactant: CCN1C(=O)CCCc2cc(N)c(OC)cc21
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Agent: CC[NH+](CC)CC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CCN1C(=O)CCCc2cc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NS(C)(=O)=O)n3)c(OC)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Combined 7-Amino-1-ethyl-8-methoxy-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (124.8 mg, 0.0005327 mol), N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (180 mg, 0.00053 mol), 4 M of Hydrogen chloride in 1,4-Dioxane (200 uL) and heat in a Radley tube for 4.5 h at 110° C. Cool to RT and then treated with xs solid MP-carbonate resin and stirred for 30 min. Filtration, followed by concentration afforded a gummy solid that was put on high-vac overnight. The mixture was purified by ISCO chromatography (40 g SiO2, 30% EA/hexane to 100% EA) afforded N-{(1R,2R)-2-[5-Chloro-2-(1-ethyl-8-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino)-pyrimidin-4-ylamino]-cyclohexyl}-methanesulfonamide as an off-white foam that was dried under high vac and broken into a powder (112.41 mg, 39%). MP: 120-128° C. 1H-NMR (DMSO, 400 MHz) δ 8.10 (s, 1H), 7.96 (d, J=1.1 Hz, 1H), 7.69 (s, 1H), 7.18 (d, J=8.3 Hz, 1H), 7.00 (s, 1H), 6.85 (d, J=7.9 Hz, 1H), 3.88-3.83 (m, 1H), 3.35-3.31 (m, 1H), 2.90 (s, 3H), 2.60 (broad s, 2H), 2.11-2.00 (m, 8H), 1.70-1.67 (m, 2H), 1.40-1.15 (m, 5H), 1.00 (t, J=6.9 Hz, 3H); LC/MS: 537.34 (M+H).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([CH3:11])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:12][O:13][CH2:14][CH:15]1[CH:20]([NH:21][C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:19][CH2:18][NH:17][CH2:16]1.C(N(CC)C(C)C)(C)C.C(OCC)(=O)C>CN1C(=O)CCC1>[CH3:12][O:13][CH2:14][CH:15]1[CH:20]([NH:21][C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:19][CH2:18][N:17]([C:2]2[C:3]3[C:10]([CH3:11])=[CH:9][NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:16]1
Reactant: Cc1c[nH]c2ncnc(Cl)c12
Reactant: COCC1CNCCC1NC(=O)c1ccccc1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COCC1CN(c2ncnc3[nH]cc(C)c23)CCC1NC(=O)c1ccccc1
Temperature: 150 °C
Reaction time: 0.11 h

Procedure:
4-chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidine D4 (218 mg), N-{3-[(methyloxy)methyl]-4-piperidinyl}benzamide D35 (500 mg) and N,N-diisopropylethylamine (504 mg, 3.9 mmol) were dissolved in NMP (10 ml). The tube was sealed and the reaction carried out in the microwave. The reaction was heated at 150° C. for 3 hours. The reaction mixture was poured into ethyl acetate (120 ml), washed with water (3×30 ml), brine (2×30 ml). Organic layer collected and dried with MgSO4, filtered and solvent removed. Purification of the crude product by chromatography on silica gel eluting with DCM/MeOH 30/1 to give product. Repurified by prep-HPLC (column: x-bridge C18sun, 30×, 50 mm; mobile phase: A 10 mmol/L NH3.H2O B ACN; gradient: 35-40% ACN in 6-7 min. Rt 6.3 min to give the product E42 as a yellow solid in 86 mg. LCMS [M+H] 380.2@1.57 min (mixture of 2 isomers) (5 min run)
Reaction SMILES: [NH2:1][C:2]1[C:7](Cl)=[C:6]([Cl:9])[CH:5]=[C:4]([NH2:10])[C:3]=1[CH3:11].[H][H].C([O-])(=O)C.[NH4+].C>[Pt].CO>[NH2:1][C:2]1[CH:7]=[C:6]([Cl:9])[CH:5]=[C:4]([NH2:10])[C:3]=1[CH3:11]
Reactant: Cc1c(N)cc(Cl)c(Cl)c1N
Reactant: [H][H]
Agent: [Pt]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CO
Product: Cc1c(N)cc(Cl)cc1N
Yield: 97.1 %

Procedure:
19.1 g (0.1 mol) of 2,6-diamino-3,4-dichlorotoluene are hydrogenated with hydrogen under a total pressure of 180 bar in an autoclave, in the presence of 500 ml of methanol, 15.4 g (0.2 mol) of ammonium acetate and 2 g of 1% strength platinum on medicinal charcoal, at 150° C. After separating off the catalyst by filtration and removing the solvent, the residue if taken up in water and the mixture is rendered neutral with sodium hydroxide solution and extracted with methylene chloride. 2,6-Diamino-4-chlorotoluene is obtained in a yield of 97.1% of theory; the purity is 95.3%.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][NH2:4].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[CH2:16]Br>CS(C)=O>[F:1][C:2]([F:6])([F:5])[CH2:3][NH:4][CH2:16][C:9]1[CH:10]=[C:11]([O:14][CH3:15])[CH:12]=[CH:13][C:8]=1[Br:7]
Reactant: COc1ccc(Br)c(CBr)c1
Reactant: NCC(F)(F)F
Solvent: CS(C)=O
Product: COc1ccc(Br)c(CNCC(F)(F)F)c1
Temperature: 32.5 °C
Reaction time: 18 h
Yield: 115.6 %

Procedure:
2,2,2-Trifluoroethylamine (24 g, 242 mmol) was added rapidly to a stirred solution of 4-bromo-3-bromomethylanisole (33.6 g, 120 mmol) in anhydrous DMSO (125 mL) at RT. The reaction warmed to approximately 30-35° C. After stirring for 18 hr, the reaction was diluted with ice-cold 1 N NaOH (200 mL) and extracted with Et2O (2×300 mL). The combined organic layers were washed with brine (300 mL), dried (MgSO4), and concentrated to give the title compound (41.35 g, 96%) as a pale yellow oil: TLC (toluene) Rf 0.32; 1H NMR (400 MHz, CDCl3) δ 7.43 (d, J=9 Hz, 1H), 6.97 (d, J=3 Hz, 1H), 6.71 (dd, 1H), 3.93 (br s, 2H), 3.80 (s, 3H), 3.18 (m, 2H), 1.86 (br s, 1H).
Reaction SMILES: [Br:1][C:2]1[N:10]([CH2:11][O:12][CH2:13][CH3:14])[C:9]2[C:8](=[O:15])[NH:7][C:6](=[O:16])[N:5]([CH3:17])[C:4]=2[N:3]=1.[H-].[Na+].[C:20]([O:23][CH:24]([CH3:30])[CH2:25][CH2:26][CH2:27][CH2:28]Cl)(=[O:22])[CH3:21]>CS(C)=O>[C:20]([O:23][C@H:24]([CH3:30])[CH2:25][CH2:26][CH2:27][CH2:28][N:7]1[C:8](=[O:15])[C:9]2[N:10]([CH2:11][O:12][CH2:13][CH3:14])[C:2]([Br:1])=[N:3][C:4]=2[N:5]([CH3:17])[C:6]1=[O:16])(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)CCCCCl
Reactant: CCOCn1c(Br)nc2c1c(=O)[nH]c(=O)n2C
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOCn1c(Br)nc2c1c(=O)n(CCCC[C@@H](C)OC(C)=O)c(=O)n2C
Temperature: 75 °C
Reaction time: 0.5 h
Yield: 62.2 %

Procedure:
8-Bromo-7-ethoxymethyl-3-methylxanthine (prepared as described for CT12440) (3.03 g, 10 mmol) was added to a suspension of sodium hydride (264 mg, 11 mmol) in anhydrous dimethylsulfoxide (60 ml). After stirring for 30 minutes, (R) 5-acetoxy-1-chlorohexane (1.963 g, 11 mmol) was added and the mixture was heated at 70-80° C. for 12 hours. After cooling to room temperature, the reaction was quenched by the addition of water (150 ml) and extracted with 10% methanol-ethyl acetate (3×25 ml). The combined extracts were washed with water (2×50 ml), with saturated aqueous sodium chloride solution (50 ml), dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with 30% ethyl acetate-hexane to provide (R)-1-(5-acetoxyhexyl)-8-bromo-7-ethoxymethyl-3-methylxanthine (2.77 g).
Reaction SMILES: C1C2C(COC(=O)[NH:17][C@H:18]([C:26](=[O:44])[NH:27][C@H:28]([C:33](=[O:43])[NH:34][C:35]3[CH:40]=[CH:39][C:38]([CH2:41][OH:42])=[CH:37][CH:36]=3)[CH2:29][CH2:30][CH2:31][CH3:32])[CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)C3C(=CC=CC=3)C=2C=CC=1.C(NCC)C>C(Cl)Cl>[OH:42][CH2:41][C:38]1[CH:37]=[CH:36][C:35]([NH:34][C:33](=[O:43])[C@@H:28]([NH:27][C:26](=[O:44])[C@@H:18]([NH2:17])[CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:29][CH2:30][CH2:31][CH3:32])=[CH:40][CH:39]=1
Reactant: CCCC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)Nc1ccc(CO)cc1
Solvent: ClCCl
Solvent: CCNCC
Product: CCCC[C@H](NC(=O)[C@@H](N)Cc1ccccc1)C(=O)Nc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.5 %

Procedure:
In a round-bottomed flask, the above prepared {(S)-1-[(S)-1-(4-hydroxymethyl-phenylcarbamoyl)-pentylcarbamoyl]-2-phenyl-ethyl}-carbamic acid 9H-fluoren-9-ylmethyl ester (4.738 g, 7.822 mmol, Eq: 1.0) was dissolved in CH2Cl2 (28 ml). At 0°, diethylamine (28 ml, 19.80 g, 271 mmol, Eq: 35) was added and the reaction mixture stirred at ambient temperature overnight. All volatiles were evaporated i. V.; ensuing flash chromatography SiO2/CH2Cl2/10% MeOH, followed by crystallization from AcOEt, yielded 2.116 g of the title compound as light brown crystals. MS (ISP): (M+H) 384.2.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[OH-:11].[Na+].OO>C(O)(C)(C)C>[Cl:1][C:2]1[C:3]([F:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]([OH:11])=[O:6]
Reactant: O=Cc1cccc(Cl)c1F
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: CC(C)(C)O
Product: O=C(O)c1cccc(Cl)c1F
Temperature: 50 °C
Yield: 63.6 %

Procedure:
3-Chloro-2-fluorobenzaldehyde (15.9 g, 0.1 mol) was dissolved in tert-butanol (60 ml), stirred and heated under N2 at 50° C. 2M aqueous NaOH (100 ml, 0.2 mol) was warmed to 50° C. and added to the solution of the aldehyde. Aqueous hydrogen peroxide solution (H2O2, 30%, 70 ml, 0.6 mol) was added over 45 min, maintaining the temperature at 55-60° C. The mixture was stirred and heated under N2 for a further 1 h, cooled and concentrated in vacuo. The residual slurry was filtered. The filtrate was washed with toluene (2×xx ml) and acidified to pH 1 with 5N hydrochloric acid whilst stirring vigorously. The resulting solid was collected by filtration, washed with water and dried in vacuo at 50° C. to give 11.1 g of product, mp 179-181° C.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:15]=2)[N:10]1C(OCC(Cl)(Cl)Cl)=O)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]>CO.[Zn]>[CH2:6]([O:5][P:4]([CH:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:19]([F:20])([F:21])[F:22])[CH:15]=2)[NH:10]1)(=[O:8])[O:3][CH2:1][CH3:2])[CH3:7]
Reactant: CCOP(=O)(OCC)C1CCc2cc(C(F)(F)F)ccc2N1C(=O)OCC(Cl)(Cl)Cl
Agent: [Zn]
Solvent: CO
Product: CCOP(=O)(OCC)C1CCc2cc(C(F)(F)F)ccc2N1
Temperature: 90 °C
Reaction time: 1.5 h

Procedure:
15.4 g of 1-(2,2,2-trichloroethoxycarbonyl)-6-trifluoromethyl-1,2,3,4-tetrahydroquinoline-2-phosphonic acid diethyl ester is dissolved in 400 ml of methanol, mixed with 7.2 g of zinc powder and stirred under nitrogen for 1.5 hours at 90° C. It is filtered on diatomaceous earth and the filtrate is concentrated by evaporation. The crude product is purified by column chromatography and recrystallized from isopropyl ether.
Reaction SMILES: [CH:1]1([C:4]2[N:8]=[C:7]([C:9]3[N:10]=[CH:11][N:12]4[C:18]=3[CH2:17][NH:16][C:15](=O)[C:14]3[CH:20]=[C:21]([O:24][CH3:25])[CH:22]=[CH:23][C:13]4=3)[O:6][N:5]=2)[CH2:3][CH2:2]1.CN(C)C1C=CC(C)=CC=1.P(Br)(Br)(Br)=O.[NH2:41][NH2:42]>C1(C)C=CC=CC=1>[CH:1]1([C:4]2[N:8]=[C:7]([C:9]3[N:10]=[CH:11][N:12]4[C:18]=3[CH2:17][N:16]=[C:15]([NH:41][NH2:42])[C:14]3[CH:20]=[C:21]([O:24][CH3:25])[CH:22]=[CH:23][C:13]4=3)[O:6][N:5]=2)[CH2:3][CH2:2]1
Reactant: COc1ccc2c(c1)C(=O)NCc1c(-c3nc(C4CC4)no3)ncn1-2
Reactant: NN
Agent: O=P(Br)(Br)Br
Solvent: Cc1ccc(N(C)C)cc1
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)C(NN)=NCc1c(-c3nc(C4CC4)no3)ncn1-2
Yield: 38 %

Procedure:
3-(3-Cyclopropyl-[1,2,4]oxadiazol-5-yl)-8-methoxy-4,5-dihydro-2,5,10b-triaza-benzo[e]azulen-6-one (1 g, 3 mmol) and N,N-dimethyl-p-toluidine (0.856 mL, 5.9 mmol) were mixed in toluene (25 mL), treated with phosphoryl bromide (0.935 g, 3.3 mmol), and refluxed for 15 h. Toluene was evaporated and the residue extracted with CH2Cl2 (50 mL) and water (50 mL). The organic layer was dried, evaporated, redissolved in THF (50 mL), and treated with a 1 M solution of anhydrous hydrazine in TBF (10 mL, 10 mmol) at reflux overnight. The mixture was evaporated and directly chromatographed on silica gel in CH2Cl2/MeOH 10:1. One obtained a light brow solid (0.4 g, 38%). m/z 352 (MH+).