Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[N:14]1[CH:18]=[CH:17][CH:16]=[N:15]1)([O-])=O.N#N>CCO.[Pd]>[N:14]1([C:5]2[CH:6]=[CH:7][C:8]([C:10]([F:12])([F:13])[F:11])=[CH:9][C:4]=2[NH2:1])[CH:18]=[CH:17][CH:16]=[N:15]1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1-n1cccn1
Agent: [Pd]
Agent: N#N
Solvent: CCO
Product: Nc1cc(C(F)(F)F)ccc1-n1cccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.7 %

Procedure:
Compound 73 (206 mg, 0.8 mmol) was dissolved in EtOH (25 mL) in a 50 mL flask. 2 spatulas of 5% Pd on Activated Carbon and a stirrbar was added followed by evacuation and N2(g) purging of the flask. H2(g) was then introduced into the flask by a balloon and the reaction stirred at room temperature under H2-atmosphere for 2 h. The H2(g) inlet was closed and the flask evacuated and N2(g) purged 3 times. LC/MS analysis showed complete hydrogenation and the mixture was filtered through a plug of Celite before removal of the solvent in vacuo to afford the crude aniline (163 mg, 90%). LC/MS, >95%, m/z (ESI+)=228 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([CH:11]2[CH2:13][CH2:12]2)[CH2:9][OH:10])=[CH:4][CH:3]=1.[S:14](Cl)([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15].C(N(CC)CC)C>ClCCl>[CH3:21][C:20]1[CH:22]=[CH:23][C:17]([S:14]([O:10][CH2:9][C@@H:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH:11]2[CH2:13][CH2:12]2)(=[O:16])=[O:15])=[CH:18][CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC[C@@H](c1ccc(Cl)cc1)C1CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OC[C@@H](c2ccc(Cl)cc2)C2CC2)cc1
Reaction time: 72 h
Yield: 95.9 %

Procedure:
(2R)-2-(4-Chlorophenyl)-2-cyclopropylethanol (6.50 g, 33.0 mmol), tosyl chloride (7.86 g, 41.0 mmol) and 6.0 ml of triethylamine (6.0 ml) are dissolved in dichloromethane (150 ml) and allowed to stir for 3 days. The reaction mixture is washed successively with 1 N HCl (100 ml), water (100 ml) and saturated brine solution (100 ml). The organic layer is dried over anhydrous sodium sulfate and concentrated in vacuo. The residue is chromatographed on silica gel eluting with ether:hexane (10:90 to 25:75) to afford the title compound as a colorless oil (11.1 g, 96%) which is characterized by 1HNMR, 13CNMR and mass spectral analysis.
Reaction SMILES: [C-:1]#[N:2].[Na+].S(=O)(=O)(O)O.Br[CH2:10][C:11]1[CH:27]=[C:26]([Cl:28])[C:14]([CH2:15][C:16]2[CH:17]=[C:18]([CH:23]([CH3:25])[CH3:24])[C:19](=[O:22])[NH:20][N:21]=2)=[C:13]([Cl:29])[CH:12]=1.C(=O)(O)[O-].[Na+]>CS(C)=O.O>[Cl:29][C:13]1[CH:12]=[C:11]([CH2:10][C:1]#[N:2])[CH:27]=[C:26]([Cl:28])[C:14]=1[CH2:15][C:16]1[CH:17]=[C:18]([CH:23]([CH3:25])[CH3:24])[C:19](=[O:22])[NH:20][N:21]=1
Reactant: [C-]#N
Reactant: CC(C)c1cc(Cc2c(Cl)cc(CBr)cc2Cl)n[nH]c1=O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)c1cc(Cc2c(Cl)cc(CC#N)cc2Cl)n[nH]c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of sodium cyanide (270 mg, 5.51 mmol) in dimethyl sulfoxide (2 mL) at room temperature was treated with concentrated sulfuric acid (0.1 mL, 1.88 mmol) and a solution of 6-(4-bromomethyl-2,6-dichloro-benzyl)-4-isopropyl-pyridazin-3-one (54) (70 mg, 0.180 mmol) in dimethyl sulfoxide (2 mL). The reaction mixture was stirred at room temperature for 30 min and then at 50° C. for 1 h. The reaction was cooled to room temperature, poured into a saturated aqueous sodium bicarbonate solution (50 mL), was diluted with water (20 mL) and then extracted with ethyl acetate (3×75 mL). The organic layers were combined and washed with a saturated aqueous sodium chloride solution (50 mL), dried over magnesium sulfate, filtered, and concentrated under vacuum. The resulting oil was dried under high vacuum to afford [3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-ylmethyl)-phenyl]-acetonitrile (55) as an orange oil (assume 0.180 mmol) which was used without further purification.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:6]=2[N:7]=1.[NH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([S:12][C:8]2[C:6]3[N:7]=[C:2]([N:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[N:3]=[C:4]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[C:5]=3[N:11]=[CH:10][N:9]=2)=[CH:14][CH:15]=1
Reactant: C1CNCCN1
Reactant: COc1ccc(Sc2ncnc3c(N4CCOCC4)nc(Cl)nc23)cc1
Product: COc1ccc(Sc2ncnc3c(N4CCOCC4)nc(N4CCNCC4)nc23)cc1

Procedure:
The compound was prepared analogous to Example 1 from 2-chloro-8-(4-methoxyphenyl-thio)-4-morpholino-pyrimido-[5,4-d]-pyrimidine (m.p.: 196°-199° C.) and piperazine.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9]([C:12]1[CH:33]=[CH:32][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[N:24]=[CH:25][C:18]=23)=[CH:14][CH:13]=1)(=[O:11])=[O:10].[CH3:34][C:35]1[O:39][N:38]=[C:37]([C:40](O)=[O:41])[CH:36]=1.[B-](F)(F)(F)F.CN(C(ON1C(=O)CCC1=O)=[N+](C)C)C.C(N(C(C)C)CC)(C)C>>[CH3:8][S:9]([C:12]1[CH:13]=[CH:14][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:27][CH2:28][N:29]([C:40]([C:37]5[CH:36]=[C:35]([CH3:34])[O:39][N:38]=5)=[O:41])[CH2:30][CH2:31]4)[N:24]=[CH:25][C:18]=23)=[CH:32][CH:33]=1)(=[O:11])=[O:10]
Reactant: Cc1cc(C(=O)O)no1
Reactant: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCNCC2)cc1
Agent: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C(=O)N2CCC(n3ncc4c(Oc5ccc(S(C)(=O)=O)cc5)ncnc43)CC2)no1
Yield: 22.3 %

Procedure:
{4-[4-(4-Methanesulfonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidin-1-yl}-(5-methyl-isoxazol-3-yl)-methanone (14 mg, 22%) was prepared as a white solid using the conditions described in Example 152, by the reaction of 4-(4-methanesulfonyl-phenoxy)-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine trifluoroacetate salt (Intermediate 27, 63 mg, 0.13 mmol) with 5-methylisoxazole-3-carboxylic acid (available from Alfa Aesar, Ward Hill, Mass., USA; 20 mg, 0.16 mmol) in the presence of TSTU (O—(N-succinimidyl)-1,1,3,3-tetramethyluronium tetrafluoroborate; 78 mg, 0.26 mmol) and diisopropylethylamine (0.14 mL, 0.8 mmol).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[Cl:34][C:35]1[C:40]([F:41])=[CH:39][CH:38]=[C:37]([Cl:42])[C:36]=1[CH:43]([OH:45])[CH3:44].O[C:47]1[C:48]([N+:53]([O-:55])=[O:54])=[N:49][CH:50]=[CH:51][CH:52]=1.[NH4+].[Cl-]>C1COCC1>[Cl:34][C:35]1[C:40]([F:41])=[CH:39][CH:38]=[C:37]([Cl:42])[C:36]=1[CH:43]([O:45][C:47]1[C:48]([N+:53]([O-:55])=[O:54])=[N:49][CH:50]=[CH:51][CH:52]=1)[CH3:44]
Reactant: CC(O)c1c(Cl)ccc(F)c1Cl
Reactant: O=[N+]([O-])c1ncccc1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(Oc1cccnc1[N+](=O)[O-])c1c(Cl)ccc(F)c1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.8 %

Procedure:
To a solution of triphenylphosphine (24.29 g, 92.6 mmol) in THF (dry, 160 mL) was added DIAD (18.23 mL, 92.6 mmol) dropwise at 0° C. under N2. After addition of DIAD, a solution of 1-(2,6-dichloro-3-fluorophenyl)ethanol (13.35 g, 63.86 mmol) and 3-hydroxy-2-nitropyridine (10.29 g, 73.44 mmol) in THF (anhydrous, 160 mL) was added dropwise. The ice-bath was removed and the reaction mixture was allowed to warm to room temperature and stirred at room temperature for 4 hrs. The reaction mixture was concentrated by evaporator to give a yellow residue. A saturated solution of NH4Cl (200 mL) was added. The aqueous phase was extracted with EtOAc (3×150 mL). The combined organic phase was washed with brine (2×80 mL), dried over anhydrous Na2SO4, concentrated by evaporation in vacuo to give a yellow residue which was purified by CombiFlash (220 g silica gel column, Hexane/EtOAc) to afford (±)-3-(1-(2,6,-dichloro-3-fluorophenyl)ethoxy)-2-nitropyridine (21.1 g, 100%) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][NH:11][C:10]=1[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:23]([CH:27](OC)[OH:28])([F:26])([F:25])[F:24].ClCCl>O>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[C:13]([CH:27]([OH:28])[C:23]([F:26])([F:25])[F:24])=[CH:12][NH:11][C:10]=1[CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(O)C(F)(F)F
Reactant: Cc1[nH]ccc(=O)c1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: Cc1[nH]cc(C(O)C(F)(F)F)c(=O)c1OCc1ccccc1
Yield: 24 %

Procedure:
A mixture of 3-benzyloxy-2-methyl-1H-pyridin-4-one (10.0 g, 46.4 mmol), potassium carbonate (19 g, 138 mmol), and CF3CH(OH)OCH3 (35 mL, 0.35 mol) in a 500 mL 3-necked round bottom flask equipped with a mechanical stirrer was heated to reflux for 6 days. The progress of the reaction was monitored by HPLC Method 3 (Example 24). Analysis of the HPLC data indicated that there was about 42% conversion. The reaction was stopped, and dichloromethane and deionized water were added. The organic fraction was collected, washed with brine, dried over Na2SO4, filtered and concentrated to dryness. Purification of the residue by column chromatography on silica (methanol/dichloromethane 2/100 to 5/100 v:v) afforded 3-benzyloxy-2-methyl-5-(2,2,2-trifluoro-1-hydroxy-ethyl)-1H-pyridin-4-one as a solid product (3.5 g, 24% yield, HPLC Method 3 (Example 24), RT=14.3 min). 1H NMR (DMSO-d6) 8 ppm: 11.68 (br s, 1H), 7.58 (s, 1H), 7.35, (m, 5H), 5.34 (q, J=7.3 Hz, 1H), 5.06 (m, 2H), 2.08 (s, 3H); MS-ESI (m/z) 313.7 [M+1]+, 206.1, 91.1 (100%).
Reaction SMILES: [NH2:1][CH:2]([CH3:50])[CH:3]([N:5]1[C:9](=[O:10])[N:8]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH:31]5[CH2:35][O:34][C:33]([C:42]6[CH:47]=[CH:46][C:45]([F:48])=[CH:44][C:43]=6[F:49])([CH2:36][N:37]6[CH:41]=[N:40][CH:39]=[N:38]6)[O:32]5)=[CH:25][CH:24]=4)[CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[CH:7]=[N:6]1)[CH3:4].[C:51]1([C@H:57]2[CH2:59][O:58]2)[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>CC(O)C>[F:49][C:43]1[CH:44]=[C:45]([F:48])[CH:46]=[CH:47][C:42]=1[C:33]1([CH2:36][N:37]2[CH:41]=[N:40][CH:39]=[N:38]2)[O:32][CH:31]([CH2:30][O:29][C:26]2[CH:25]=[CH:24][C:23]([N:20]3[CH2:19][CH2:18][N:17]([C:14]4[CH:13]=[CH:12][C:11]([N:8]5[CH:7]=[N:6][N:5]([CH:3]([CH3:4])[CH:2]([NH:1][CH2:59][CH:57]([OH:58])[C:51]6[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=6)[CH3:50])[C:9]5=[O:10])=[CH:16][CH:15]=4)[CH2:22][CH2:21]3)=[CH:28][CH:27]=2)[CH2:35][O:34]1
Reactant: c1ccc([C@H]2CO2)cc1
Reactant: CC(N)C(C)n1ncn(-c2ccc(N3CCN(c4ccc(OCC5COC(Cn6cncn6)(c6ccc(F)cc6F)O5)cc4)CC3)cc2)c1=O
Solvent: CC(C)O
Product: CC(NCC(O)c1ccccc1)C(C)n1ncn(-c2ccc(N3CCN(c4ccc(OCC5COC(Cn6cncn6)(c6ccc(F)cc6F)O5)cc4)CC3)cc2)c1=O

Procedure:
A mixture of compound (37) (0.0043 mol) and (S)-phenyl oxirane (0.005 mol) in 2-propanol (50 ml) was stirred and refluxed overnight. (S)-phenyl oxirane (0.005 mol) was added again. The mixture was stirred and refluxed for 3 hours. The solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 99/1). The pure fractions were collected and the solvent was evaporated. The residue was triturated in DIPE, filtered off and dried, yielding 1.6 g (47%) of [2S-[2α,4α[(S*,R*)(R*)]]]4-[4-[4-[4-[[2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-2,4-dihydro-2-[2[(2-hydroxy-2-phenylethyl)amino]-1-methylpropyl]-3H-1,2,4-triazol-3-one (compound 81).
Reaction SMILES: C(O[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]3[N:18]=[C:19]([O:24][CH2:25][C@@H:26]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH3:27])[N:20]=[CH:21][C:22]=3[N:23]=2)=[CH:11][C:10]=1[F:36])C1C=CC=CC=1.[N+](C1C=CC(S([O:49][CH2:50][C@H:51]2[CH2:53][C:52]2([F:55])[F:54])(=O)=O)=CC=1)([O-])=O>>[F:55][C:52]1([F:54])[CH2:53][C@@H:51]1[CH2:50][O:49][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]3[N:18]=[C:19]([O:24][CH2:25][C@@H:26]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])[CH3:27])[N:20]=[CH:21][C:22]=3[N:23]=2)=[CH:11][C:10]=1[F:36]
Reactant: C[C@@H](COc1ncc2nc(-c3ccc(OCc4ccccc4)c(F)c3)oc2n1)NC(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@H]2CC2(F)F)cc1
Product: C[C@@H](COc1ncc2nc(-c3ccc(OC[C@H]4CC4(F)F)c(F)c3)oc2n1)NC(=O)OC(C)(C)C

Procedure:
Using tert-butyl ((2S)-1-((2-(4-(benzyloxy)-3-fluorophenyl)[1,3]oxazolo[5,4-d]pyrimidin-5-yl)oxy)propan-2-yl)carbamate and ((1R)-2,2-difluorocyclopropyl)methyl 4-nitrobenzenesulfonate, and in the same manner as in Step A of Example 4 and Example 5, the title compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[NH2:4].[C:10]([NH:18][C:19]1[NH:23][N:22]=[C:21]([S:24](Cl)(=[O:26])=[O:25])[N:20]=1)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>N1C=CC=CC=1>[C:10]([NH:18][C:19]1[NH:23][N:22]=[C:21]([S:24]([NH:4][C:3]2[C:2]([Cl:1])=[CH:8][CH:7]=[CH:6][C:5]=2[Cl:9])(=[O:26])=[O:25])[N:20]=1)(=[O:17])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Nc1c(Cl)cccc1Cl
Reactant: O=C(Nc1nc(S(=O)(=O)Cl)n[nH]1)c1ccccc1
Solvent: c1ccncc1
Product: O=C(Nc1nc(S(=O)(=O)Nc2c(Cl)cccc2Cl)n[nH]1)c1ccccc1
Yield: 49.5 %

Procedure:
A small flask equipped with a magnetic stirrer and protected from the atmosphere by a drying tube was charged with 8.1 g (0.05 mole) of 2,6-dichloroaniline, 20 ml of dry pyridine and then 14.4 g (0.05 mole) of dry 5-benzoylamino-3-chlorosulfonyl-1,2,4-triazole was added over about 1 minute with vigorous stirring. After the exotherm had subsided somewhat, the mixture was heated with an oil bath maintained at 100°-106° C. for 3 hours with stirring. The mixture was next concentrated under reduced pressure on a rotary evaporator to remove the bulk of the pyridine (80° C./1 mm) and then taken up in a mixture of 25 ml of concentrated aqueous ammonia, 125 ml of water and 100 ml of methylene chloride. After cooling and filtration to remove the insoluble material, the methylene chloride phase was removed and the pH of the aqueous phase was adjusted to 2.5 with hydrochloric acid. The precipitate that formed was collected by filtration, washed with watery and dried to obtain 10.2 g (50 percent of theory) of the title sulfonamide. A sample purified by recrystallization from acetonitrile melted at 321°-322° (dec.). The carbon nmr spectrum was consistent with the assigned structure, having absorptions at 159.2, 149.7, 165.6, 135.9, 130.8, 128.9, 130.0, 132.8, 128.6, 128.1, and 131.7 ppm.
Reaction SMILES: [CH3:1][C@@H:2]([CH2:8][CH3:9])[C@H:3]([Cl:7])[C:4]([OH:6])=[O:5].O[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1>>[Cl:7][CH:3]([CH:2]([CH3:1])[CH2:8][CH3:9])[C:4]([O:6][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:4](=[O:5])[CH:3]([Cl:7])[CH:2]([CH3:1])[CH2:8][CH3:9])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)=[O:5]
Reactant: CC[C@H](C)[C@H](Cl)C(=O)O
Reactant: Oc1ccc(-c2ccc(O)cc2)cc1
Product: CCC(C)C(Cl)C(=O)Oc1ccc(-c2ccc(OC(=O)C(Cl)C(C)CC)cc2)cc1

Procedure:
An excess of (S,S)-3-methyl-2-chloropentanoic acid is reacted with 4,4'-bis-hydroxybiphenyl analogously to Example 1. Customary working up gives optically active 4,4'-bis-(2-chloro-3-methylpentanoyloxy)-biphenyl.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4](F)[C:3]=1[N+:10]([O-:12])=[O:11].[CH3:13][NH2:14].O>CCO>[F:1][C:2]1[C:3]([N+:10]([O-:12])=[O:11])=[C:4]([NH:14][CH3:13])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=[N+]([O-])c1c(F)cc(F)cc1F
Reactant: CN
Solvent: CCO
Solvent: O
Product: CNc1cc(F)cc(F)c1[N+](=O)[O-]
Reaction time: 4 h
Yield: 83 %

Procedure:
1,3,5-Trifluoro-2-nitrobenzene (3.0 g, 16.90 mmol) was dissolved in EtOH (29.7 mL) and Methylamine 40% in Water (1.44 mL, 17.80 mmol) was added dropwise at 0° C. The color went from bright yellow to an orange precipitate within 20 min. After 4 h at RT. 0.66 mL of Methylamine was added (9 mmol). To complete the reaction, an additional 0.26 ml (3.6 mmol) of Methylamine was added after 2 h at RT. The completion was achieved within 20 min. Water (75 mL) was added to the reaction mixture and the solid was isolated by filtration, washed with water (2*10 mL) and dried over high vacuum to afford 2.64 g of 3,5-difluoro-N-methyl-2-nitrobenzenamine (Yield: 83%) as an orange solid.
Reaction SMILES: [ClH:1].[F:2][CH:3]([F:16])[O:4][C:5]1[C:11]([F:12])=[CH:10][C:8]([NH2:9])=[C:7]([N+:13]([O-])=O)[CH:6]=1>CO>[ClH:1].[ClH:1].[F:16][CH:3]([F:2])[O:4][C:5]1[C:11]([F:12])=[CH:10][C:8]([NH2:9])=[C:7]([NH2:13])[CH:6]=1
Reactant: Nc1cc(F)c(OC(F)F)cc1[N+](=O)[O-]
Agent: Cl
Solvent: CO
Product: Nc1cc(F)c(OC(F)F)cc1N
Yield: 85 %

Procedure:
22.5 ml of 100% strength nitric acid are added dropwise to 20 g of the above compound in 200 ml of methylene chloride at 20° C. in the course of 30 min., and stirring is continued for 15 h at room temperature. Analogously to Examples 11c, N-(4-difluoroethoxy-5-fluoro-2-nitrophenyl)-acetamide of m.p. 72°-74° C. (89% yield, from cyclohexane), is obtained. Stirring this compound for several hours with 1M hydrogen chloride in methanol at 60° C. yields 4-difluoromethoxy-5-fluoro-2-nitroaniline of m.p. 95°-97,5° C. (95% yield), and further reaction analogously to Example 11e gives 4-difluoromethoxy-5-fluoro-1,2-phenylenediamine dihydrochloride (85% yield, decomposition at 210° C.)
Reaction SMILES: [NH2:1][C:2]1[C:3]([N+:17]([O-:19])=[O:18])=[C:4]([CH:8]=[C:9]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[N:10]=1)[C:5]([OH:7])=[O:6].[CH3:20]N(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CO.CCN(CC)CC>C1COCC1>[NH2:1][C:2]1[C:3]([N+:17]([O-:19])=[O:18])=[C:4]([CH:8]=[C:9]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[N:10]=1)[C:5]([O:7][CH3:20])=[O:6]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Nc1nc(N2CCOCC2)cc(C(=O)O)c1[N+](=O)[O-]
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(N2CCOCC2)nc(N)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 37.1 %

Procedure:
A mixture of 2-amino-6-morpholino-3-nitroisonicotinic acid (12.3 g, 45.9 mmol), HATU (19.2 g, 50.5 mmol), MeOH (14.7 g, 459 mmol) and Et3N (13.9 g, 137.7 mmol) in THF (300 mL) was stirred at room temperature for 16 h. The solvent was removed in vacuo and the residue was diluted with EA (500 mL). It was then washed with brine (500 mL×3). The organic layer was then concentrated in vacuo. The residue was then purified by chromatography on silica gel eluted with MeOH/DCM=1/100 to afford the crude product as a yellow solid (4.8 g, 37%); LC/MS: MS (ES+) m/e 283 (MH+).
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[N:12]=[C:11]([S:13][CH2:14][C:15]([O:17]C)=[O:16])[N:10]=[C:9]2[C:5]=1[N:6]=[C:7]([OH:26])[N:8]2[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl>CO>[NH2:3][C:4]1[N:12]=[C:11]([S:13][CH2:14][C:15]([OH:17])=[O:16])[N:10]=[C:9]2[C:5]=1[N:6]=[C:7]([OH:26])[N:8]2[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)CSc1nc(N)c2nc(O)n(Cc3ccccc3)c2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1nc(SCC(=O)O)nc2c1nc(O)n2Cc1ccccc1
Yield: 50.8 %

Procedure:
To a methanol solution (5 ml) containing 500 mg of sodium hydroxide was added 6-amino-9-benzyl-8-hydroxy-2-(methoxycarbonylmethyl)thiopurine (64 mg, 0.19 mmol). The solution was refluxed under heating, neutralized with 2N hydrochloric acid, filtered and washed with water to give the subject compound (32 mg, yield 52%).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:20]([OH:35])[CH2:21][NH:22][C:23]([CH3:34])([CH3:33])[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)C1C=CC=CC=1>CO.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH:20]([OH:35])[CH2:21][NH:22][C:23]([CH3:33])([CH3:34])[CH2:24][C:25]2[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2
Reactant: COc1ccc(CC(C)(C)NCC(O)c2ccc(OCc3ccccc3)c3[nH]c(=O)ccc23)cc1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(CC(C)(C)NCC(O)c2ccc(O)c3[nH]c(=O)ccc23)cc1

Procedure:
306 mg (0.6 mmol) 8-benzyloxy-5-{1-hydroxy-2-[2-(4-methoxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-1H-quinolin-2-one are dissolved in 10 mL methanol and hydrogenated with palladium on charcoal as catalyst at ambient temperature and normal pressure. Then the catalyst is separated off and the filtrate is freed from the solvent.
Reaction SMILES: [C:1]1([CH2:7][O:8][N:9]2[C:15](=[O:16])[N:14]3[CH2:17][C@H:10]2[CH2:11][CH2:12][C@H:13]3[C:18]([OH:20])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[I-].ClC1C=CC=C[N+]=1C.[NH2:37][C:38]1[CH:39]=[C:40]2[C:45](=[CH:46][CH:47]=1)[CH2:44][N:43]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:42][CH2:41]2>ClCCl>[C:51]([O:50][C:48]([N:43]1[CH2:42][CH2:41][C:40]2[C:45](=[CH:46][CH:47]=[C:38]([NH:37][C:18]([C@@H:13]3[CH2:12][CH2:11][C@@H:10]4[CH2:17][N:14]3[C:15](=[O:16])[N:9]4[O:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[O:20])[CH:39]=2)[CH2:44]1)=[O:49])([CH3:54])([CH3:52])[CH3:53]
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(N)ccc2C1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCc2cc(NC(=O)[C@@H]3CC[C@@H]4CN3C(=O)N4OCc3ccccc3)ccc2C1
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
To a solution of (2S,5R)-6-(phenylmethoxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (53.3 mg, 0.193 mmol) in dry dichloromethane (2 mL) was added triethylamine (0.067 mL, 0.482 mmol), 2-chloro-1-methylpyridinium iodide (58.7 mg, 0.230 mmol), and 6-amino-2-N-BOC-1,2,3,4-tetrahydro-isoquinoline (54.8 mg, 0.221 mmol) sequentially at room temperature under nitrogen. The reaction mixture was then heated to 50° C. for 45 minutes then the reaction product was concentrated in vacuo. Attempts to dissolve the reaction product in eluant (2:1:1 CH3CN/DMSO/water) for HPLC were unsuccessful, so it was partitioned between aqueous layer and dichloromethane. The organic layer was collected, dried over sodium sulfate, concentrated in vacuo and set aside for separate purification. The aqueous layer was also collected and purified by HPLC (30×100 mm Waters Sunfire column; 5 micron; 35 mL/min.; 210 nM; 15% to 100% CH3CN+0.05% TFA/water+0.05% TFA over 15 minutes; the title compound eluted at 80% CH3CN+0.05% TFA/water+0.05% TFA). Fractions containing the title compound were lyophilized overnight to afford the title compound as a white sticky solid. The organic layer from partitioning the crude product was purified by preparative TLC (1000 micron silica gel plate eluted with 50% ethyl acetate/hexane) to afford the title compound. Both batches of the title compound were combined and used without further purification in the next step.
Reaction SMILES: [CH2:1]([N:8]([C:10]([CH3:18])([CH3:17])[CH2:11][C:12](OCC)=[O:13])[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[CH2:1]([N:8]([C:10]([CH3:18])([CH3:17])[CH2:11][CH2:12][OH:13])[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(C)(C)N(C)Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CN(Cc1ccccc1)C(C)(C)CCO
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of ethyl 3-(N-benzyl-N-methylamino)-3-methylbutanoate (23.6 g--see Preparation 9) in anhydrous tetrahydrofuran (100 ml) was added, dropwise, over 20 minutes to a stirred suspension of lithium aluminium hydride (7.2 g) in anhydrous tetrahydrofuran (300 ml). When the addition was complete, the mixture was stirred at room temperature for 3 hours. Water (7 ml) was carefully added dropwise followed by 15% aqueous sodium hydroxide (7 ml) and finally more water (20 ml). The resulting solid precipitate was filtered off and washed with ethyl acetate (3×50 ml). The filtrate and washings were combined and concentrated in vacuo to give the title compound as a colourless, mobile oil, yield 19.00 g.